Anna Vilalta

Cooling the injured brain : How does moderate hypothermia influence the pathophysiology of traumatic brain injury

Neither any neuroprotective drug has been shown to be beneficial in improving the outcome of severe traumatic brain injury (TBI) nor has any prophylactically-induced moderate hypothermia shown any beneficial effect on outcome in severe TBI, despite the optimism generated by preclinical studies. This contrasts with the paradox that hypothermia still is the most powerful neuroprotective method in experimental models because of its ability to influence the multiple biochemical cascades that are set in motion after TBI. The aim of this short review is to highlight the most recent developments concerning the pathophysiology of severe TBI, to review new data on thermoregulation and induced hypothermia, the regulation of core and brain temperature in mammals and the multiplicity of effects of hypothermia in the pathophysiology of TBI. Many experimental studies in the last decade have again confirmed that moderate hypothermia confers protection against ischemic and non-ischemic brain hypoxia, traumatic brain injury, anoxic injury following resuscitation after cardiac arrest and other neurological insults. Many posttraumatic adverse events that occur in the injured brain at a cellular and molecular level are highly temperature-sensitive and are thus a good target for induced hypothermia. The basic mechanisms through which hypothermia protects the brain are clearly multifactorial and include at least the following: reduction in brain metabolic rate, effects on cerebral blood flow, reduction of the critical threshold for oxygen delivery, blockade of excitotoxic mechanisms, calcium antagonism, preservation of protein synthesis, reduction of brain thermopooling, a decrease in edema formation, modulation of the inflammatory response, neuroprotection of the white matter and modulation of apoptotic cell death. The new developments discussed in this review indicate that, by targeting many of the abnormal neurochemical cascades initiated after TBI, induced hypothermia may modulate neurotoxicity and, consequently, may play a unique role in opening up new therapeutic avenues for treating severe TBI and improving its devastating effects. Furthermore, greater understanding of the pathophysiology of TBI, new data from both basic and clinical research, the good clinical results obtained in randomized clinical trials in cardiac arrest and better and more reliable cooling methods have given hypothermia a second chance in treating TBI patients. A critical evaluation of hypothermia is therefore mandatory to elucidate the reasons for previous failures and to design further multicenter randomized clinical trials that would definitively confirm or refute the potential of this therapeutic modality in the management of severe traumatic brain injuries.

Brain extracellular fluid protein changes in acute stroke patients

In vivo human brain extracellular fluids (ECF) of acute stroke patients were investigated to assess the changes in protein levels associated with ischemic damages. Microdialysates (MDs) from the infarct core (IC), the penumbra (P), and the unaffected contralateral (CT) brain regions of patients suffering an ischemic stroke (n = 6) were compared using a shotgun proteomic approach based on isobaric tagging and mass spectrometry. Quantitative analysis showed 53 proteins with increased amounts in the IC or P with respect to the CT samples. Glutathione S-transferase P (GSTP1), peroxiredoxin-1 (PRDX1), and protein S100-B (S100B) were further assessed with ELISA on the blood of unrelated control (n = 14) and stroke (n = 14) patients. Significant increases of 8- (p = 0.0002), 20- (p = 0.0001), and 11-fold (p = 0.0093) were found, respectively. This study highlights the value of ECF as an efficient source to further discover blood stroke markers.

Normobaric Hyperoxia in Traumatic Brain Injury: Does Brain Metabolic State Influence the Response to Hyperoxic Challenge?

This study sought to investigate whether normobaric hyperoxia (NH) improves brain oxygenation and brain metabolism in the early phase of severe and moderate traumatic brain injury (TBI) and whether this effect occurs uniformly in all TBI patients. Thirty patients (9 women and 21 men) with a median initial Glasgow Coma Score (GCS) of 6 (range, 3-12) were monitored using a brain microdialysis (MD) catheter with a brain tissue oxygen sensor (PtiO(2)) placed in the least-injured hemisphere. The inspired oxygen fraction was increased to 100% for 2 h. Patients were divided into two groups: Group 1: patients with baseline brain lactate ≤3 mmol/L and Group 2: patients with baseline brain lactate >3 mmol/L, and therefore increased anaerobic metabolism in the brain. In Group 1, no significant changes in brain metabolic parameters were found after hyperoxic challenge, whereas a significant increase in glucose and a decrease in the lactate-pyruvate ratio (LPR) were found in Group 2. In this latter group of patients, brain glucose increased on average by 17.9% (95% CI, +9.2% to +26.6%, p<0.001) and LPR decreased by 11.6% (95% CI, -16.2% to -6.9%, p<0.001). The results of our study show that moderate and severe TBI may induce metabolic alterations in the brain, even in macroscopically normal brain tissue. We observed that NH increased PaO(2) and PtiO(2) and significantly decreased LPR in patients in whom baseline brain lactate levels were increased, suggesting that NH improved the brain redox state. In patients with normal baseline brain lactate levels, we did not find any significant changes in the metabolic variables after NH. This suggests that the baseline metabolic state should be taken into account when applying NH to patients with TBI. This maneuver may only be effective in a specific group of patients.

Brain Perihematoma Genomic Profile Following Spontaneous Human Intracerebral Hemorrhage

Background Spontaneous intracerebral hemorrhage (ICH) represents about 15% of all strokes and is associated with high mortality rates. Our aim was to identify the gene expression changes and biological pathways altered in the brain following ICH. Methodology/Principal Findings Twelve brain samples were obtained from four deceased patients who suffered an ICH including perihematomal tissue (PH) and the corresponding contralateral white (CW) and grey (CG) matter. Affymetrix GeneChip platform for analysis of over 47,000 transcripts was conducted. Microarray Analysis Suite 5.0 was used to process array images and the Ingenuity Pathway Analysis System was used to analyze biological mechanisms and functions of the genes. We identified 468 genes in the PH areas displaying a different expression pattern with a fold change between −3.74 and +5.16 when compared to the contralateral areas (291 overexpressed and 177 underexpressed). The top genes which appeared most significantly overexpressed in the PH areas codify for cytokines, chemokines, coagulation factors, cell growth and proliferation factors while the underexpressed codify for proteins involved in cell cycle or neurotrophins. Validation and replication studies at gene and protein level in brain samples confirmed microarray results. Conclusions The genomic responses identified in this study provide valuable information about potential biomarkers and target molecules altered in the perihematomal regions.

Actualizaciones en los métodos de monitorización cerebral regional en los pacientes neurocríticos: presión tisular de oxígeno, microdiálisis cerebral y técnicas de espectroscopía por infrarrojos

Resumen El resultado final de los pacientes que han presentado un traumatismo craneoencefalico (TCE) depende de las lesiones primarias, pero tambien, y en gran medida, de las lesiones secundarias. El diagnostico de un gran numero de lesiones secundarias, y en especial de la isquemia cerebral, se centra en la monitorizacion simultanea de diversas variables encefalicas y sistemicas. En el momento actual, la monitorizacion continua de la presion intracraneal (PIC) se considera una medida indispensable en el manejo de los pacientes con un TCE grave que presentan cualquier tipo de lesion intracraneal. Sin embargo, la informacion que ofrece esta variable es insuficiente para diagnosticar los complejos procesos fisiopatologicos que caracterizan a las lesiones neurotraumaticas. Por ello, cada vez es mas frecuente complementar la neuromonitorizacion de los pacientes con un TCE con metodos de estimacion del flujo sanguineo cerebral (FSC) como el Doppler transcraneal o las tecnicas de oximetria yugular. Sin embargo, en el momento actual y en la cabecera del paciente, el conocimiento de la repercusion de las lesiones tisulares y de las medidas terapeuticas sobre el metabolismo cerebral requiere un acceso directo al parenquima encefalico. En esta revision nos centraremos en tres metodos de monitorizacion cerebral “regional”: la presion tisular de oxigeno, la microdialisis cerebral y las tecnicas transcutaneas de espectroscopia por infrarrojos. En cada caso se expondran los fundamentos del metodo en cuestion, los valores de referencia de los parametros monitorizados y una serie de recomendaciones sobre como pueden interpretarse sus resultados a la luz de los conocimientos actuales.

Moderate hypothermia in the management of severe traumatic brain injury: a good idea proved ineffective?

Many drugs with proven efficacy in the preclinical stage have failed to show any benefit in improving the outcome of severe traumatic brain injury (TBI) when tested in controlled clinical trials. Hypothermia is still the most powerful neuroprotective method in experimental models of TBI. Its ability to influence the multiple biochemical cascades that are set in motion after TBI is quite unique. In experimental models hypothermia protects against mechanical neuronal and axonal injury and improves behavioral outcome. Encouraging results from phase II and III clinical trials of hypothermia in TBI reported in the 1990s generated great enthusiasm. However, enthusiasm faded in 2001 after the final report of the multicenter phase III trial in which the neuroprotective effects of moderate hypothermia in TBI were formally tested. This study found no significant effect on outcome in the hypothermia group, leading many clinicians to lose interest in this therapy. The present article reviews the historical background of the use of hypothermia, presents the rationale for using both immediate and deferred hypothermia, and summarizes both experimental and clinical evidence supporting its potential benefits in the management of severe TBI. New technologies using intravascular methods to induce fast hypothermia have recently become available. Cooling either through the intravenous or intra-arterial route is an exciting alternative with great potential. We argue that moderate hypothermia is still the most powerful neuroprotective candidate for severe TBI and that it merits further research and discussion. We also defend the need for further clinical trials to prove or refute its potential for treating high intracranial pressure refractory to first level therapeutic measures. The premature abandonment of hypothermia could close new avenues for improving the devastating effects of TBI.

Brain contusions induce a strong local overexpression of MMP-9. Results of a pilot study

BACKGROUND Brain contusions are inflammatory evolutive lesions that induce intracranial pressure increase and edema, contributing to neurological outcome. Matrix metalloproteinases (MMPs) 2 and 9 can degrade the majority of the extracellular matrix components, and are implicated in blood-brain barrier disruption and edema formation. The aim of this study was to investigate MMP-2 and MMP-9 profiles in human brain contusions using zymography. METHODS A prospective study was conducted in 20 traumatic brain injury patients where contusion brain tissue was resected. Brain tissues from lobectomies were used as controls. Brain homogenates were analysed by gelatin zymography and in situ zimography was performed to confirm results, on one control and one brain contusion tissue sample. FINDINGS MMP-2 and MMP-9 levels were higher in brain contusions when compared to controls. MMP-9 was high during the first 24 hours and at 48 to 96 hours, whereas MMP-2 was slightly high at 24 to 96 hours. In situ zymography confirmed gelatin zymography results. A relation between outcome and MMP-9 levels was found; MMP-9 levels were higher in patients with worst outcome. CONCLUSIONS Our results indicate strong time-dependent gelatinase expression primarily from MMP-9, suggesting that the inflammatory response induced by focal lesions should be considered as a new therapeutic target.

Detección de episodios de hipoxia tisular isquémica mediante la monitorización neurofisiológica intraoperatoria combinada con la monitorización de la oxigenación tisular en la cirugía aneurismática

Resumen Introduccion La neuromonitorizacion intraoperatoria en la cirugia aneurismatica puede ser de gran utilidad para determinar posiciones inadecuadas del clip que ocasionen un compromiso parcial o completo del flujo sanguineo cerebral en los territorios vasculares irrigados por las arterias relacionadas con el aneurisma. La visualizacion directa de estas arterias tras la aplicacion del clip quirurgico puede ser insuficiente para detectar esta situacion potencialmente deleterea. El conocimiento precoz de esta circunstancia permitiria al neurocirujano corregirla y evitar asi la hipoxia tisular cerebral isquemica. Mostramos, con el ejemplo de un caso clinico, la utilidad de la monitorizacion intraoperatoria de la presion tisular de oxigeno (PtiO2) y de los potenciales evocados somatosensoriales (PESS) para la deteccion de estas situaciones. Caso clinico Presentamos el caso de una mujer de 62 anos de edad, que debuto con una hemorragia subaracnoidea de origen aneurismatico. La arteriografia cerebral demostro la existencia de un aneurisma de la arteria comunicante posterior izquierda que fue tratado inicialmente por via endovascular con exclusion parcial del aneurisma. Por este motivo se decidio completar el tratamiento mediante cirugia programada. La paciente fue monitorizada intraoperatoriamente con un sensor de PtiO2 situado en el area de riesgo y con PESS. Tras la colocacion del clip se produjo una rapida caida de la presion parcial de oxigeno, asi como disminucion de la amplitud del potencial cortical del nervio tibial posterior izquierdo. El conocimiento de esta situacion, permitio detectar un atrapamiento de la arteria comunicante posterior. Tras corregir esta situacion reposicionando el clip quirurgico, ambas variables recuperaron sus valores basales. Conclusiones La monitorizacion intraoperatoria de la PtiO2 combinada con la monitorizacion neurofisiologica durante la cirugia aneurismatica ofrece, de una forma rapida y fiable, la deteccion precoz de fenomenos isquemicos ocasionados por mal posicionamiento del clip quirurgico.

Métodos globales de monitorización de la hemodinámica cerebral en el paciente neurocrítico: fundamentos, controversias y actualizaciones en las técnicas de oximetría yugular

Resumen El papel relevante que la hipoxia tisular cerebral juega en la fisiopatologia de los pacientes con un traumatismo craneoencefalico (TCE) justifica la necesidad de complementar la monitorizacion de estos pacientes con sistemas que aporten informacion sobre el flujo sanguineo y el metabolismo cerebral. En la busqueda de sistemas utiles en la cabecera del paciente, se han utilizado extrapolaciones del principio de Fick al encefalo, utilizando metodos que estiman el flujo sanguineo cerebral (FSC) a partir de la obtencion de muestras de sangre del bulbo de la yugular. En los ultimos anos, las tecnicas de oximetria yugular se han convertido en elementos de uso frecuente en las unidades que tratan pacientes con un TCE u otros pacientes neurocriticos, como los pacientes con una hemorragia subaracnoidea o con infartos masivos de la arteria cerebral media. El uso frecuente de estas tecnicas en las ultimas dos decadas, junto a la incorporacion de otros sistemas de neuromonitorizacion, permiten en la actualidad matizar la informacion que estos metodos globales proporcionan y definir mejor tanto sus indicaciones como sus limitaciones. El objetivo de esta revision es presentar los fundamentos y los conceptos basicos relacionados con la utilizacion clinica de las tecnicas de oximetria yugular en el paciente neurocritico. Tambien presentamos y discutimos la evidencia mas reciente que indica que determinadas variables, obtenidas de muestras de sangre del bulbo de la yugular, tales como las diferencias arterio-yugulares de lactatos (AVDL) y el indice lactato-oxigeno (LOI), a pesar de su amplia utilizacion en la practica clinica diaria, no ofrecen una informacion fiable sobre el metabolismo cerebral que permita la toma de decisiones terapeuticas.