Assuntos
Boxe/lesões , Lesões Encefálicas/etiologia , Hematoma Epidural Craniano/etiologia , Hematoma Subdural/etiologia , Futebol/lesões , Adolescente , Adulto , Lesões Encefálicas/diagnóstico por imagem , Hematoma Epidural Craniano/diagnóstico por imagem , Hematoma Subdural/diagnóstico por imagem , Humanos , Masculino , Recuperação de Função Fisiológica , Remissão Espontânea , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: The validity of the Functional Capacity Index (FCI) is evaluated by examining its distributional characteristics, its correlation with other well-known measures of outcome and its ability to discriminate among persons with injuries of varying type and severity. METHODS: A telephone survey which included the FCI and the SF-36 was administered 1 year post-injury to 1240 blunt trauma patients discharged from 12 trauma centers. A subsample of 656 patients also completed the Sickness Impact Profile (SIP) by mail. RESULTS: FCI scores correlated well with the physical health subscores of the SIP and SF-36. They also correlated well with self-reported change in health status and return to work. The FCI, when compared to either the SF-36 or the SIP, however, appears to discriminate better among patients according to the presence and severity of head trauma. CONCLUSIONS: While further testing of the FCI is needed, it holds promise as a preference based measure for assessing the physical impact of trauma.
Assuntos
Avaliação da Deficiência , Avaliação de Resultados em Cuidados de Saúde/métodos , Perfil de Impacto da Doença , Ferimentos não Penetrantes/fisiopatologia , Atividades Cotidianas , Adolescente , Adulto , Idoso , Análise Discriminante , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pennsylvania , Inquéritos e Questionários , Centros de Traumatologia , Ferimentos não Penetrantes/psicologiaRESUMO
Conventional and functional proteomics have significant potential to expand our understanding of traumatic brain injury (TBI) but have not yet been used. The purpose of the present study was to examine global hippocampal protein changes in postnatal day (PND) 17 immature rats 24 h after moderate controlled cortical impact (CCI). Silver nitrate stains or protein kinase B (PKB) phosphoprotein substrate antibodies were used to evaluate high abundance or PKB pathway signal transduction proteins representing conventional and functional proteomic approaches, respectively. Isoelectric focusing was performed over a nonlinear pH range of 3-10 with immobilized pH gradients (IPG strips) using supernatant from the most soluble cellular protein fraction of hippocampal tissue protein lysates from six paired sham and injured PND 17 rats. Approximately 1,500 proteins were found in each silver stained gel with 40% matching of proteins. Of these 600 proteins, 52% showed a twofold, 20% a fivefold, and 10% a 10-fold decrease or increase. Spot matching with existing protein databases revealed changes in important cytoskeletal and cell signalling proteins. PKB substrate protein phosphorylation was best seen in large format two-dimensional blots and known substrates of PKB such as glucose transporter proteins 3 and 4 and forkhead transcription factors, identified based upon molecular mass and charge, showed altered phosphorylation 24 h after injury. These results suggest that combined conventional and functional proteomic approaches are powerful, complementary and synergistic tools revealing multiple protein changes and posttranslational protein modifications that allow for more specific and comprehensive functional assessments after pediatric TBI.
Assuntos
Lesões Encefálicas/metabolismo , Córtex Cerebral/química , Córtex Cerebral/lesões , Eletroforese em Gel Bidimensional/métodos , Proteínas Serina-Treonina Quinases , Proteoma/análise , Fatores Etários , Animais , Córtex Cerebral/enzimologia , Hipocampo/química , Hipocampo/enzimologia , Masculino , Fosforilação , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-akt , Ratos , Ratos Sprague-Dawley , Coloração pela PrataRESUMO
Despite considerable investigation in rodent models of traumatic brain injury (TBI), no novel therapy has been successfully translated from bench to bedside. Although well-described limitations of clinical trails may account for these failures, several modeling factors may also contribute to the lack of therapeutic translation from the laboratory to the clinic. Specifically, models of TBI may omit one or more critical, clinically relevant pathophysiologic features. In this invited review article, the impact of the limited incorporation of several important clinical pathophysiologic factors in TBI, namely secondary insults (i.e., hypotension and/or hypoxemia), coma, and aspects of standard neurointensive care monitoring and management strategies (i.e., intracranial pressure [ICP] monitoring and ICP-directed therapies, sedation, mechanical ventilation, and cardiovascular support) are discussed. Comparative studies in rodent and large animal models of TBI (which may, in some cases, represent super models) are also presented. We conclude that therapeutic breakthroughs will likely require a multidisciplinary approach, involving investigation in a range of models, including clinically relevant modifications of established animal models, along with development and application of new innovations in clinical trial design.
Assuntos
Lesões Encefálicas/patologia , Lesões Encefálicas/terapia , Animais , Lesões Encefálicas/complicações , Coma/etiologia , Modelos Animais de Doenças , Humanos , Camundongos , RatosRESUMO
OBJECT: In a recently conducted trial of hypothermia in patients with severe brain injury, differences were found in the effects of hypothermia treatment among various centers. This analysis explores the reasons for such differences. METHODS: The authors reviewed data obtained in 392 patients treated for severe brain injury. Prerandomization variables, critical physiological variables, treatment variables, and accrual methodologies were investigated among various centers. Hypothermia was found to be detrimental in patients older than the age of 45 years, beneficial in patients younger than 45 years of age in whom hypothermia was present on admission, and without effect in those in whom normothermia was documented on admission. Marginally significant differences (p < 0.054) in the intercenter outcomes of hypothermia-treated patients were likely the result of wide differences in the percentage of patients older than 45 years of age and in the percentage of patients in whom hypothermia was present on admission among centers. The trial sensitivity was likely diminished by significant differences in the incidence of mean arterial blood pressure (MABP) less than 70 mm Hg (p < 0.001) and cerebral perfusion pressure (CPP) less than 50 mm Hg (p < 0.05) but not intracranial pressure (ICP) greater than 25 mm Hg (not significant) among patients in the various centers. Hours of vasopressor usage (p < 0.03) and morphine dose (p < 0.001) and the percentage of dehydrated patients varied significantly among centers (p < 0.001). The participation of small centers increased intercenter variance and diminished the quality of data. CONCLUSIONS: For Phase III clinical trials we recommend: 1) a detailed protocol specifying fluid and MABP, ICP, and CPP management: 2) continuous monitoring of protocol compliance; 3) a run-in period for new centers to test accrual and protocol adherence; and 4) inclusion of only centers in which patients are regularly randomized.
Assuntos
Lesões Encefálicas/terapia , Hipotermia Induzida/normas , Estudos Multicêntricos como Assunto/normas , Ensaios Clínicos Controlados Aleatórios como Assunto/normas , Adulto , Humanos , Pessoa de Meia-Idade , Projetos de Pesquisa , Fatores de Tempo , Resultado do TratamentoRESUMO
The selective 5-HT(1A) receptor agonist Repinotan HCl (BAY x3702) has been reported to attenuate cortical damage and improve functional performance in experimental models of cerebral ischemia and acute subdural hematoma. Using a clinically relevant contusion model of traumatic brain injury, we tested the hypothesis that a 4-h continuous infusion of Repinotan HCl (10 microg/kg/h i.v.) commencing 5 min post-injury would ameliorate functional outcome and attenuate histopathology. Forty isoflurane-anesthetized male adult rats were randomly assigned to receive either a controlled cortical impact (2.7 mm tissue deformation, 4 m/s) or sham injury (Injury/Vehicle=10, Injury/MK-801=10, Injury/Repinotan HCl=10, Sham/Vehicle=10), then tested for vestibulomotor function on post-operative days 1-5 and for spatial learning on days 14-18. Neither Repinotan HCl nor the non-competitive N-methyl-D-aspartate receptor antagonist MK-801, which served as a positive control, improved vestibulomotor function on beam balance and beam walk tasks relative to the Injury/Vehicle group, but both did significantly attenuate spatial learning and memory deficits on a water maze task. Repinotan HCl also reduced hippocampal CA(1) and CA(3) neuronal loss, as well as cortical tissue damage, compared to the Injury/Vehicle group at 4 weeks post-trauma. No significant difference in histological outcome was revealed between the Repinotan HCl- and MK-801-treated groups.These findings extend the therapeutic efficacy of Repinotan HCl to a contusion model of experimental brain injury and demonstrate for the first time that 5-HT(1A) receptor agonists confer neuroprotection and attenuate spatial learning deficits following controlled cortical impact injury. This treatment strategy may be beneficial in a clinical context where memory impairments are common following human traumatic brain injury.
Assuntos
Benzopiranos/farmacologia , Lesões Encefálicas/tratamento farmacológico , Degeneração Neural/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Agonistas do Receptor de Serotonina/farmacologia , Tiazóis/farmacologia , Animais , Temperatura Corporal/efeitos dos fármacos , Temperatura Corporal/fisiologia , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/fisiopatologia , Lesões Encefálicas/patologia , Lesões Encefálicas/fisiopatologia , Cognição/efeitos dos fármacos , Cognição/fisiologia , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/fisiopatologia , Maleato de Dizocilpina/farmacologia , Esquema de Medicação , Antagonistas de Aminoácidos Excitatórios/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Hipocampo/fisiopatologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Degeneração Neural/patologia , Degeneração Neural/fisiopatologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Equilíbrio Postural/efeitos dos fármacos , Equilíbrio Postural/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores de Serotonina/metabolismo , Receptores 5-HT1 de Serotonina , Núcleos Vestibulares/efeitos dos fármacos , Núcleos Vestibulares/patologia , Núcleos Vestibulares/fisiopatologiaRESUMO
Adrenomedullin is a recently discovered 52-amino acid peptide that is a potent vasodilator and is produced in the brain in experimental models of cerebral ischemia. Infusion of adrenomedullin increases regional cerebral blood flow and reduces infarct volume after vascular occlusion in rats, and thus may represent an endogenous neuroprotectant. Disturbances in cerebral blood flow (CBF), including hypoperfusion and hyperemia, frequently occur after severe traumatic brain injury (TBI) in infants and children. We hypothesized that cerebrospinal fluid (CSF) adrenomedullin concentration would be increased after severe TBI in infants and children, and that increases in adrenomedullin would be associated with alterations in CBF. We also investigated whether posttraumatic CSF adrenomedullin concentration was associated with relevant clinical variables (CBF, age, Glasgow Coma Scale [GCS] score, mechanism of injury, and outcome). Total adrenomedullin concentration was measured using a radioimmunometric assay. Sixty-six samples of ventricular CSF from 21 pediatric patients were collected during the first 10 days after severe TBI (GCS score < 8). Control CSF was obtained from children (n = 10) undergoing lumbar puncture without TBI or meningitis. Patients received standard neurointensive care, including CSF drainage. CBF was measured using Xenon computed tomography (CT) in 11 of 21 patients. Adrenomedullin concentration was markedly increased in CSF of infants and children after severe TBI vs control (median 4.5 versus 1.0 fmol/mL, p < 0.05). Sixty-two of 66 CSF samples (93.9%) from head-injured infants and children had a total adrenomedullin concentration that was greater than the median value for controls. Increases in CSF adrenomedullin were most commonly observed early after TBI. CBF was positively correlated with CSF adrenomedullin concentration (p < 0.001), but this relationship was not significant when controlling for the effect of time. CSF adrenomedullin was not significantly associated with other selected clinical variables. We conclude adrenomedullin is markedly increased in the CSF of infants and children early after severe TBI. We speculate that adrenomedullin participates in the regulation of CBF after severe TBI.
Assuntos
Lesões Encefálicas/líquido cefalorraquidiano , Peptídeos/líquido cefalorraquidiano , Adrenomedulina , Circulação Cerebrovascular , Criança , Pré-Escolar , Escala de Coma de Glasgow , Humanos , Lactente , Valor Preditivo dos TestesRESUMO
Fever above 38 degrees C that occurs in patients with acute neurosurgical diseases appears to worsen secondary brain injury and ultimate neurologic outcomes. Laboratory investigations are quite clear regarding the adverse effects of fever in terms not only of functional outcomes, but also histologic and neurochemical injury. Several preliminary clinical studies also suggest worsened neurologic outcomes in patients who are febrile compared to those who are not. Unfortunately, however, a large prospective study of 428 patients with acute neurosurgical diseases has shown that fever is extraordinarily common during the first seven days after subarachnoid hemorrhage, stroke, and TBI. The ability to eliminate fever in most of these patients during the first five to seven days after their injury would seem desirable. Based on a phase-I trial, it appears that intravascular cooling is a promising new method for avoiding fever in the neurosurgical ICU.
Assuntos
Lesões Encefálicas/terapia , Febre/terapia , Temperatura Corporal , Lesões Encefálicas/fisiopatologia , Febre/etiologia , Humanos , Hipotermia Induzida , Unidades de Terapia IntensivaRESUMO
Chronic frontal lobe functional deficits after traumatic brain injury (TBI) may be associated with altered catecholamine systems in the frontal cortex. To test this, tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH) levels were examined by immunohistochemistry and Western blot at 1, 7, 14, and 28 days after TBI or sham surgery. No alterations in DBH levels were observed by Western blot at any time point examined, but there was a significant increase in TH expression 28 days after TBI (optical density 334 +/- 68% or 3.3-fold, ipsilateral and 218 +/- 39% or 2.2-fold, contralateral) relative to the sham controls. The increase in TH may reflect a compensatory response of dopaminergic neurons to upregulate their synthesizing capacity and increase the efficiency of dopamine neurotransmission chronically after TBI.
Assuntos
Lesões Encefálicas/metabolismo , Dopamina beta-Hidroxilase/metabolismo , Lobo Frontal/enzimologia , Lobo Frontal/lesões , Tirosina 3-Mono-Oxigenase/metabolismo , Animais , Western Blotting , Dopamina beta-Hidroxilase/análise , Lobo Frontal/química , Imuno-Histoquímica , Masculino , Ratos , Tirosina 3-Mono-Oxigenase/análiseRESUMO
DNA damage is a common sequela of traumatic brain injury (TBI). Available techniques for the in situ identification of DNA damage include DNA polymerase I-mediated biotin-dATP nick-translation (PANT), the Klenow fragment of DNA polymerase I-mediated biotin-dATP nick-end labeling (Klenow), and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL). While TUNEL has been widely utilized to detect primarily double-strand DNA breaks, the use of PANT to detect primarily single-strand DNA breaks and Klenow to detect both single- and double-strand DNA breaks has not been reported after TBI. Accordingly, coronal brain sections from naive rats and rats at 0, 0.5, 1, 2, 6, 24, and 72 h (n = 3-5/group) after controlled cortical impact with imposed secondary insult were processed using the PANT, Klenow, and TUNEL methods. Cells with DNA breaks were detected by PANT in the ipsilateral hemisphere as early as 0.5 h after injury and were maximal at 6 h (cortex = 66.3+/-15.8, dentate gyrus 58.6+/-12.8, CA1 = 15.8+/-5.9, CA3 = 12.8+/-4.2 cells/x 400 field, mean +/- SEM, all p < 0.05 versus naive). Cells with DNA breaks were detected by Klenow as early as 30 min and were maximal at 24 h (cortex = 56.3+/-14.3, dentate gyrus 78.0+/-16.7, CA1 = 25.8+/-4.7, CA3 = 29.3+/-15.1 cells/x 400 field, all p < 0.05 versus naive). Cells with DNA breaks were not detected by TUNEL until 2 h and were maximal at 24 h (cortex = 47.7+/-21.4, dentate gyrus 63.0+/-11.9, CA1 = 5.6+/-5.4, CA3 = 6.9+/-3.7 cells/x 400 field, cortex and dentate gyrus p < 0.05 versus naive). Dual-label immunofluorescence revealed that PANT-positive cells were predominately neurons. These data demonstrate that TBI results in extensive DNA damage, which includes both single- and double-strand breaks in injured cortex and hippocampus. The presence of multiple types of DNA breaks implicate several pathways in the evolution of DNA damage after TBI.
Assuntos
Lesões Encefálicas/genética , Dano ao DNA/genética , DNA Nucleotidilexotransferase/genética , DNA Polimerase I/genética , DNA de Cadeia Simples/genética , Animais , Lesões Encefálicas/patologia , Modelos Animais de Doenças , Marcação In Situ das Extremidades Cortadas , Masculino , Microscopia de Fluorescência , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
The influence of anesthetic agents on cerebral blood flow (CBF) was tested in normal rats. CBF is quantified with arterial spin-labeled MRI in rats anesthetized with either an opiate (fentanyl), a potent inhalation anesthetic agent (isoflurane), or a barbiturate (pentobarbital) using doses commonly employed in experimental paradigms. CBF values were found to be about 2.5-3 times lower in most regions analyzed during anesthesia with either fentanyl (with N(2)O/O(2)) or pentobarbital vs. isoflurane (with N(2)O/O(2)), in agreement with findings utilizing invasive measurement techniques. CBF was heterogeneous in rats anesthetized with isoflurane (with N(2)O/O(2)), but relatively homogeneous in rats anesthetized with either fentanyl (with N(2)O/O(2)) or pentobarbital, also in agreement with studies using other techniques. Magn Reson Med 46:202-206, 2001.
Assuntos
Anestesia Geral , Anestésicos , Encéfalo/anatomia & histologia , Circulação Cerebrovascular/efeitos dos fármacos , Fentanila , Isoflurano , Imageamento por Ressonância Magnética/métodos , Pentobarbital , Animais , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Cerebrovascular disruption frequently results from head and neck trauma. Injury to the extra- and intracranial carotid artery is uncommon but is associated with a high rate of death and permanent neurologic deficit. In this article, injuries to the carotid artery are reviewed with emphasis on the mechanisms, clinical manifestations, radiologic evaluation, and management of these traumatic lesions.
Assuntos
Lesões Encefálicas/cirurgia , Estenose das Carótidas/cirurgia , Revascularização Cerebral/métodos , Adulto , Fístula Arteriovenosa/diagnóstico , Fístula Arteriovenosa/cirurgia , Lesões Encefálicas/complicações , Lesões Encefálicas/diagnóstico , Dissecação da Artéria Carótida Interna/etiologia , Dissecação da Artéria Carótida Interna/cirurgia , Estenose das Carótidas/diagnóstico , Feminino , Humanos , Angiografia por Ressonância Magnética , Masculino , Lesões do Pescoço/complicações , Dissecação da Artéria Vertebral/etiologia , Dissecação da Artéria Vertebral/cirurgiaRESUMO
Adenosine analogs such as 2-chloroadenosine are potent cerebrovasodilators. Spin-labeled MRI was used to investigate the spatial distribution, dose-response, and timing of the effect of 2-chloroadenosine on cerebral blood flow (CBF) after intraparenchymal injection into rat brain. Sprague-Dawley rats (N = 10) were injected with 2-chloroadenosine at doses of 0.3, 6.0, or 12 nmoles, or saline vehicle (2-4 microL). CBF was serially quantified in a slice through the injection site in a circular (3.6 mm diameter) region of interest (ROI) around the injection and in ipsilateral hemispheric ROIs at approximately 90 min and approximately 180 min. Marked 3.77- and 3.93-fold increases in CBF (vs. vehicle) were seen in the circular ROI at approximately 90 min and approximately 180 min after 12-nmol injection, respectively. Similarly, 2.92- and 2.78-fold increases in hemispheric CBF were observed at approximately 90 min and approximately 180 min, respectively, after injection of 12 nmoles. Linear dose-response relationships were observed at both times after injection in both ROIs (all P < 0.01). Spin-labeling MRI assessment revealed that parenchymal injection of 2-chloroadenosine produces potent, dose-dependent, and sustained vasodilation over large areas of brain. This treatment and imaging paradigm should facilitate investigation of the effect of CBF promotion in models of traumatic and ischemic brain injury.
Assuntos
2-Cloroadenosina/farmacologia , Circulação Cerebrovascular/efeitos dos fármacos , Imageamento por Ressonância Magnética/métodos , Animais , Relação Dose-Resposta a Droga , Modelos Lineares , Masculino , Ratos , Ratos Sprague-Dawley , Fluxo Sanguíneo Regional/efeitos dos fármacos , Marcadores de SpinRESUMO
OBJECTIVE: Adenosine decreases the cerebral metabolic rate for oxygen and increases cerebral blood flow, and it may play an important role in cerebrometabolic and cerebrovascular responses to hypoperfusion after traumatic brain injury. Jugular venous oxygen saturation is monitored after traumatic brain injury to assess brain oxygen extraction, and desaturations may reflect secondary brain insults. We hypothesized that brain interstitial adenosine and related purine metabolites would be increased during jugular venous oxygen saturation desaturations (<50%) and determined associations between the purines, lactate, and glucose to assess the role of adenosine during secondary insults in humans. DESIGN: Study of critically ill adults with severe traumatic brain injury. SETTING: Adult neurointensive care unit. PATIENTS: We prospectively defined periods of normal saturation and desaturation in six patients after severe traumatic brain injury. INTERVENTIONS: During these periods, cerebral microdialysis samples of brain interstitial fluid were collected, and adenosine and purine metabolites were measured by high-pressure liquid chromatography. MEASUREMENTS AND MAIN RESULTS: Adenosine increased 3.1-fold and xanthine increased 2.5-fold during desaturation periods (both p <.05 vs. normal saturation period, signed rank). Adenosine, xanthine, hypoxanthine, and cyclic-adenosine monophosphate correlated with lactate over both study periods (r(2) =.32,.14,.31,.07, and.26, respectively, all p <.05, Pearson product moment correlation). CONCLUSION: The marked increases in interstitial brain adenosine that occur during jugular venous oxygen desaturations suggest that adenosine may play an important role during periods of secondary insults after traumatic brain injury. The correlation of these metabolites with lactate further suggests that adenosine is increased during periods of enhanced glycolytic metabolism.
Assuntos
Adenosina/análise , Lesões Encefálicas/complicações , Espaço Extracelular/química , Hipóxia Encefálica/etiologia , Hipóxia Encefálica/metabolismo , Consumo de Oxigênio/fisiologia , Xantina/análise , Adenosina/fisiologia , Adolescente , Adulto , Gasometria , Glicemia/análise , Química Encefálica , Circulação Cerebrovascular/fisiologia , Cromatografia Líquida de Alta Pressão , Estado Terminal , AMP Cíclico/sangue , Glicólise , Humanos , Hipóxia Encefálica/diagnóstico , Veias Jugulares , Ácido Láctico/análise , Masculino , Microdiálise , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
In models of focal cerebral ischemia, adenoviral gene transfer is often attenuated or delayed versus naive. After controlled cortical impact (CCI)-induced traumatic brain injury in mice, CA1 and CA3 hippocampus exhibit delayed neuronal death by 3 days, with subsequent near complete loss of hippocampus by 21 days. We hypothesized that adenoviral-mediated expression of the reporter gene beta-Galactosidase (beta-Gal) in hippocampus would be attenuated after CCI in mice. C57BL6 mice (n = 16) were subjected to either CCI to left parietal cortex or sham (burr hole). Adenovirus carrying the beta-Gal gene (AdlacZ; 1 x 10(9) plaque-forming units [pfu]/mL) was then injected into left dorsal hippocampus. At 24 or 72 h, beta-Gal expression was quantified (mU/mg protein). Separate mice (n = 10) were used to study beta-Gal spatial distribution in brain sections. Beta-Gal expression in left hippocampus was similar in shams at 24 h (48.4 +/- 4.1) versus 72 h (68.8 +/- 8.8, not significant). CCI did not reduce beta-Gal expression in left hippocampus (68.8 +/- 8.8 versus 88.1 +/- 7.0 at 72 h, sham versus CCI, not significant). In contrast, CCI reduced beta-Gal expression in right (contralateral) hippocampus versus sham (p < 0.05 at both 24 and 72 h). Beta-Gal was seen in many cell types in ipsilateral hippocampus, including CA3 neurons. Despite eventual loss of ipsilateral hippocampus, adenovirus-mediated gene transfer was surprisingly robust early after CCI providing an opportunity to test novel genes targeting delayed hippocampal neuronal death.
Assuntos
Lesões Encefálicas/terapia , Regulação Viral da Expressão Gênica/fisiologia , Genes Reporter/fisiologia , Terapia Genética/métodos , Vetores Genéticos/fisiologia , Hipocampo/lesões , beta-Galactosidase/genética , Adenoviridae/genética , Animais , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Circulação Cerebrovascular/fisiologia , Modelos Animais de Doenças , Hipocampo/metabolismo , Hipocampo/patologia , Camundongos , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Degeneração Neural/prevenção & controle , Fatores de Crescimento Neural/biossíntese , Fatores de Crescimento Neural/genética , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , beta-Galactosidase/metabolismoRESUMO
BACKGROUND: Induction of hypothermia in patients with brain injury was shown to improve outcomes in small clinical studies, but the results were not definitive. To study this issue, we conducted a multicenter trial comparing the effects of hypothermia with those of normothermia in patients with acute brain injury. METHODS: The study subjects were 392 patients 16 to 65 years of age with coma after sustaining closed head injuries who were randomly assigned to be treated with hypothermia (body temperature, 33 degrees C), which was initiated within 6 hours after injury and maintained for 48 hours by means of surface cooling, or normothermia. All patients otherwise received standard treatment. The primary outcome measure was functional status six months after the injury. RESULTS: The mean age of the patients and the type and severity of injury in the two treatment groups were similar. The mean (+/-SD) time from injury to randomization was 4.3+/-1.1 hours in the hypothermia group and 4.1+/-1.2 hours in the normothermia group, and the mean time from injury to the achievement of the target temperature of 33 degrees C in the hypothermia group was 8.4+/-3.0 hours. The outcome was poor (defined as severe disability, a vegetative state, or death) in 57 percent of the patients in both groups. Mortality was 28 percent in the hypothermia group and 27 percent in the normothermia group (P=0.79). The patients in the hypothermia group had more hospital days with complications than the patients in the normothermia group. Fewer patients in the hypothermia group had high intracranial pressure than in the normothermia group. CONCLUSIONS: Treatment with hypothermia, with the body temperature reaching 33 degrees C within eight hours after injury, is not effective in improving outcomes in patients with severe brain injury.
Assuntos
Lesões Encefálicas/terapia , Hipotermia Induzida , Doença Aguda , Adolescente , Adulto , Idoso , Lesões Encefálicas/complicações , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/fisiopatologia , Escala de Coma de Glasgow , Humanos , Hipotermia/complicações , Pressão Intracraniana , Pessoa de Meia-Idade , Falha de TratamentoRESUMO
BACKGROUND: Excitotoxicity is an important mechanism in secondary neuronal injury after traumatic brain injury (TBI). Excitatory amino acids (EAAs) are increased in cerebrospinal fluid (CSF) in adults after TBI; however, studies in pediatric head trauma are lacking. We hypothesized that CSF glutamate, aspartate, and glycine would be increased after TBI in children and that these increases would be associated with age, child abuse, poor outcome, and cerebral ischemia. METHODS: EAAs were measured in 66 CSF samples from 18 children after severe TBI. Control samples were obtained from 19 children who received lumbar punctures to rule out meningitis. RESULTS: Peak and mean CSF glycine and peak CSF glutamate levels were increased versus control values. Subgroups of patients with TBI were compared by using univariate regression analysis. Massive increases in CSF glutamate were found in children <4 years old and in child abuse victims. Increased CSF glutamate and glycine were associated with poor outcome. A trend toward an association between high glutamate concentration and ischemic blood flow was observed. CONCLUSIONS: CSF EAAs are increased in infants and children with severe TBI. Young age and child abuse were associated with extremely high CSF glutamate concentrations after TBI. A possible role for excitotoxicity after pediatric TBI is supported.
Assuntos
Ácido Aspártico/líquido cefalorraquidiano , Lesões Encefálicas/líquido cefalorraquidiano , Lesões Encefálicas/etiologia , Ventrículos Cerebrais , Maus-Tratos Infantis , Aminoácidos Excitatórios/líquido cefalorraquidiano , Ácido Glutâmico/líquido cefalorraquidiano , Glicina/líquido cefalorraquidiano , Adolescente , Fatores Etários , Lesões Encefálicas/diagnóstico por imagem , Lesões Encefálicas/mortalidade , Isquemia Encefálica/etiologia , Estudos de Casos e Controles , Criança , Maus-Tratos Infantis/estatística & dados numéricos , Pré-Escolar , Pessoas com Deficiência/estatística & dados numéricos , Escala de Coma de Glasgow , Escala de Resultado de Glasgow , Humanos , Lactente , Prognóstico , Análise de Sobrevida , Fatores de Tempo , Tomografia Computadorizada por Raios XRESUMO
OBJECTIVES: To measure adenosine concentration in the cerebrospinal fluid of infants and children after severe traumatic brain injury and to evaluate the contribution of patient age, Glasgow Coma Scale score, mechanism of injury, Glasgow Outcome Score, and time after injury to cerebrospinal fluid adenosine concentrations. To evaluate the relationship between cerebrospinal fluid adenosine and glutamate concentrations in this population. DESIGN: Prospective survey. SETTING: Pediatric intensive care unit in a university-based children's hospital. PATIENTS: Twenty-seven critically ill infants and children who had severe traumatic brain injury (Glasgow Coma Scale < 8), who required placement of an intraventricular catheter and drainage of cerebrospinal fluid as part of their neurointensive care. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients ranged in age from 2 months to 14 yrs. Cerebrospinal fluid samples (n = 304) were collected from 27 patients during the first 7 days after traumatic brain injury. Control cerebrospinal fluid samples were obtained from lumbar puncture on 21 infants and children without traumatic brain injury or meningitis. Adenosine concentration was measured by using high-pressure liquid chromatography. Adenosine concentration was increased markedly in cerebrospinal fluid of children after traumatic brain injury vs. controls (p < .001). The increase in cerebrospinal fluid adenosine was independently associated with Glasgow Coma Scale < or = 4 vs. > 4 and time after injury (both p < .005). Cerebrospinal fluid adenosine concentration was not independently associated with either age (< or = 4 vs. > 4 yrs), mechanism of injury (abuse vs. other), or Glasgow Outcome Score (good/moderately disabled vs. severely disabled, vegetative, or dead). Of the 27 patients studied, 18 had cerebrospinal fluid glutamate concentration previously quantified by high-pressure liquid chromatography. There was a strong association between increases in cerebrospinal fluid adenosine and glutamate concentrations (p < .005) after injury. CONCLUSIONS: Cerebrospinal fluid adenosine concentration is increased in a time- and severity-dependent manner in infants and children after severe head injury. The association between cerebrospinal fluid adenosine and glutamate concentrations may reflect an endogenous attempt at neuroprotection against excitotoxicity after severe traumatic brain injury.
Assuntos
Adenosina/líquido cefalorraquidiano , Lesões Encefálicas/líquido cefalorraquidiano , Lesões Encefálicas/fisiopatologia , Adolescente , Lesões Encefálicas/etiologia , Estudos de Casos e Controles , Criança , Maus-Tratos Infantis , Pré-Escolar , Aminoácidos Excitatórios/líquido cefalorraquidiano , Escala de Coma de Glasgow , Escala de Resultado de Glasgow , Ácido Glutâmico/líquido cefalorraquidiano , Humanos , Lactente , Modelos Lineares , Análise Multivariada , Pennsylvania , Estudos Prospectivos , Fatores de TempoRESUMO
OBJECT: Intracranial hypertension remains a common complication of traumatic brain injury (TBI). Ventriculostomy drainage is a recommended therapy to decrease intracranial pressure (ICP), but little empirical evidence exists to guide treatment. The authors conducted a study to examine systematically the effect of cerebral spinal fluid (CSF) drainage on ICP and indices of cerebral perfusion. METHODS: Intracranial pressure, cerebral perfusion pressure (CPP), cerebral blood flow velocity (CBFV), and near-infrared spectroscopy-determined regional cerebral oxygenation (rSO2) were measured in 58 patients (with Glasgow Coma Scale scores < or = 8) before, during, and after ventriculostomy drainage. Three randomly ordered CSF drainage protocols varied in the volume of CSF removed (1 ml, 2 ml, and 3 ml). Physiological variables were time averaged in 1-minute blocks from baseline to 10 minutes after cessation of ventricular drainage. There was a significant dose-time interaction for ICP with the three-extraction volume protocol, with incremental decreases in ICP (F [20, 1055] = 6.10; p = 0.0001). There was a significant difference in the CPP depending on the amount of CSF removed (F [2, 1787] = 3.22; p = 0.040) and across time (F [10, 9.58] = 11.9; p = 0.0003) without a significant dose-time interaction. A 3-ml withdrawal of CSF resulted in a 10.1% decrease in ICP and a 2.2% increase in CPP, which were sustained for 10 minutes. There was no significant dose, time or dose-time interaction with CBFV or rSO2. CONCLUSIONS: Cerebrospinal fluid drainage (3 ml) significantly reduced ICP and increased CPP for at least 10 minutes. Analysis of these findings supports the use of ventriculostomy drainage as a means of at least temporarily reducing elevated ICP in patients with TBI.