RESUMEN
Recovery from coma or disordered consciousness is a central issue in patients with acute brain injuries such as stroke, trauma, cardiac arrest, and brain infections. Yet, major gaps remain in the scientific underpinnings of coma and this has led to inaccuracy in prognostication and limited interventions for coma recovery. Even so, recent studies have begun to elucidate mechanisms of consciousness early and prolonged after acute brain injury and some pilot interventions have begun to be tested. The importance and scope of this led in 2019 to the development of the Curing Coma Campaign, an initiative of the Neurocritical Care Society designed to provide a platform for scientific collaboration across the patient care continuum and to empower a community for purposes of research, education, implementation science, and advocacy. Seen as a "grand challenge," the Curing Coma Campaign has developed an infrastructure of scientific working groups and operational modules, along with a 10-year roadmap.
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Lesiones Encefálicas , Coma , Coma/diagnóstico , Coma/terapia , Estado de Conciencia , HumanosRESUMEN
Background and Purpose: Aneurysmal subarachnoid hemorrhage (SAH) is associated with the development of delayed cognitive deficits. Neutrophil infiltration into the central nervous system is linked to the development of these deficits after SAH. It is however unclear how neutrophil activity influences central nervous system function in SAH. The present project aims to elucidate which neutrophil factors mediate central nervous system injury and cognitive deficits after SAH. Methods: Using a murine model of SAH and mice deficient in neutrophil effector functions, we determined which neutrophil effector function is critical to the development of deficits after SAH. In vivo and in vitro techniques were used to investigate possible pathways of neutrophils effect after SAH. Results: Our results show that mice lacking functional MPO (myeloperoxidase), a neutrophil enzyme, lack both the meningeal neutrophil infiltration (wild type, sham 872 cells/meninges versus SAH 3047, P=0.023; myeloperoxidase knockout [MPOKO], sham 1677 versus SAH 1636, P=NS) and erase the cognitive deficits on Barnes maze associated with SAH (MPOKO sham versus SAH, P=NS). The reintroduction of biologically active MPO, and its substrate hydrogen peroxide (H2O2), to the cerebrospinal fluid of MPOKO mice at the time of hemorrhage restores the spatial memory deficit observed after SAH (time to goal box MPOKO sham versus MPOKO+MPO/H2O2, P=0.001). We find evidence of changes in neurons, astrocytes, and microglia with MPO/H2O2 suggesting the effect of MPO may have complex interactions with many cell types. Neurons exposed to MPO/H2O2 show decreased calcium activity at baseline and after stimulation with potassium chloride. Although astrocytes and microglia are affected, changes seen in astrocytes are most consistent with inflammatory changes that likely affect neurons. Conclusions: These results implicate MPO as a mediator of neuronal dysfunction in SAH through its effect on both neurons and glia. These results show that, in SAH, the activity of innate immune cells in the meninges modulates the activity and function of the underlying brain tissue.
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Venas Cerebrales/lesiones , Neuronas/patología , Neutrófilos/enzimología , Peroxidasa/metabolismo , Hemorragia Subaracnoidea/patología , Animales , Astrocitos/patología , Señalización del Calcio , Trastornos del Conocimiento/etiología , Peróxido de Hidrógeno/líquido cefalorraquídeo , Peróxido de Hidrógeno/farmacología , Inflamación/patología , Aprendizaje por Laberinto , Trastornos de la Memoria/etiología , Trastornos de la Memoria/psicología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neuroglía/enzimología , Peroxidasa/genética , Memoria Espacial , Hemorragia Subaracnoidea/psicologíaRESUMEN
Coma and disorders of consciousness (DoC) are highly prevalent and constitute a burden for patients, families, and society worldwide. As part of the Curing Coma Campaign, the Neurocritical Care Society partnered with the National Institutes of Health to organize a symposium bringing together experts from all over the world to develop research targets for DoC. The conference was structured along six domains: (1) defining endotype/phenotypes, (2) biomarkers, (3) proof-of-concept clinical trials, (4) neuroprognostication, (5) long-term recovery, and (6) large datasets. This proceedings paper presents actionable research targets based on the presentations and discussions that occurred at the conference. We summarize the background, main research gaps, overall goals, the panel discussion of the approach, limitations and challenges, and deliverables that were identified.
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Coma , Estado de Conciencia , Biomarcadores , Coma/diagnóstico , Coma/terapia , Congresos como Asunto , Trastornos de la Conciencia/diagnóstico , Trastornos de la Conciencia/terapia , Humanos , National Institutes of Health (U.S.) , Estados UnidosRESUMEN
The Neurocritical Care Society and the Society of Critical Care Medicine have worked together to create a perspective regarding the Standards of Neurologic Critical Care Units (Moheet et al. in Neurocrit Care 29:145-160, 2018). The most neurologically ill or injured patients warrant the highest standard of care available; this supports the need for defining and establishing specialized neurological critical care units. Rather than interpreting the Standards as being exclusionary, it is most appropriate to embrace them in the setting of team-based care. Since there are many more patients than there are highly specialized beds, collaborative care and appropriate transfer agreements are essential in promoting excellent patient outcomes. This viewpoint addresses areas of clarification and emphasizes the need for collegiality and partnership in delivering the best specialty critical care to our patients.
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Enfermedad Crítica , Medicina , Cuidados Críticos , Humanos , Unidades de Cuidados IntensivosRESUMEN
Coma and disordered consciousness are common manifestations of acute neurological conditions and are among the most pervasive and challenging aspects of treatment in neurocritical care. Gaps exist in patient assessment, outcome prognostication, and treatment directed specifically at improving consciousness and cognitive recovery. In 2019, the Neurocritical Care Society (NCS) launched the Curing Coma Campaign in order to address the "grand challenge" of improving the management of patients with coma and decreased consciousness. One of the first steps was to bring together a Scientific Advisory Council including coma scientists, neurointensivists, neurorehabilitationists, and implementation experts in order to address the current scientific landscape and begin to develop a framework on how to move forward. This manuscript describes the proceedings of the first Curing Coma Campaign Scientific Advisory Council meeting which occurred in conjunction with the NCS Annual Meeting in October 2019 in Vancouver. Specifically, three major pillars were identified which should be considered: endotyping of coma and disorders of consciousness, biomarkers, and proof-of-concept clinical trials. Each is summarized with regard to current approach, benefits to the patient, family, and clinicians, and next steps. Integration of these three pillars will be essential to the success of the Curing Coma Campaign as will expanding the "curing coma community" to ensure broad participation of clinicians, scientists, and patient advocates with the goal of identifying and implementing treatments to fundamentally improve the outcome of patients.
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Trastornos de la Conciencia/terapia , Cuidados Críticos , Ciencia de la Implementación , Rehabilitación Neurológica , Neurología , Comités Consultivos , Biomarcadores , Ensayos Clínicos como Asunto , Coma/clasificación , Coma/fisiopatología , Coma/terapia , Trastornos de la Conciencia/clasificación , Trastornos de la Conciencia/fisiopatología , Humanos , Prueba de Estudio Conceptual , Participación de los InteresadosRESUMEN
Background and Purpose- The PILLAR (Extracorporeal Filtration of Subarachnoid Hemorrhage via Spinal Catheter) study is a first-in-human trial of cerebrospinal fluid (CSF) filtration in aneurysmal subarachnoid hemorrhage. The study evaluates the safety and feasibility of a novel filtration system to rapidly remove blood and blood breakdown products from CSF after securement of a ruptured aneurysm. Methods- Patients with aneurysmal subarachnoid hemorrhage had a dual-lumen lumbar, intrathecal catheter placed after aneurysm securement and received up to 24 hours of CSF filtration (neurapheresis therapy). The catheter aspirated blood-contaminated CSF from the lumbar cistern and returned filtered CSF to the thoracic subarachnoid space. Neuro checks were performed q2 hours, and CSF samples were collected for cell counts, total protein, and gram stain. Computed tomography scans were acquired at baseline and post-filtration. Clinical follow-up occurred at 2 weeks and 30 days. Results- Thirteen patients had a catheter placed (mean time 24:13 hours after ictus). The system processed 632.0 mL (180.6-1447.6 mL) CSF in 15:07 hours (5:32-24:00 hours) of filtration. The mean initial CSF red blood cell count, 2.78×105 cells/µL, reduced to 1.17×105 cells/µL after filtration (52.9% reduction), and total protein reduced 71%. Independent analysis of baseline and postfiltration computed tomographies found notable cisternal blood decrease, with 46.5% mean Hijdra Score reduction. Three mild, anticipated adverse events were reported. Conclusions- The initial safety and feasibility of Neurapheresis therapy in aneurysmal subarachnoid hemorrhage demonstrated the potential to safely filter CSF and remove blood and blood byproducts. Future studies are warranted. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT0287263.
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Aneurisma Roto/cirugía , Líquido Cefalorraquídeo , Hemorragia Subaracnoidea/líquido cefalorraquídeo , Hemorragia Subaracnoidea/cirugía , Adulto , Anciano , Aneurisma Roto/líquido cefalorraquídeo , Femenino , Humanos , Región Lumbosacra/cirugía , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
BACKGROUND: Early brain injury (EBI) following aneurysmal subarachnoid hemorrhage (SAH) is an important predictor of poor functional outcome, yet the underlying mechanism is not well understood. Animal studies suggest that platelet activation and inflammation with subsequent microthrombosis and ischemia may be a mechanism of EBI. METHODS: A prospective, hypothesis-driven study of spontaneous, SAH patients and controls was conducted. Platelet activation [thromboelastography maximum amplitude (MA)] and inflammation [C-reactive protein (CRP)] were measured serially over time during the first 72 h following SAH onset. Platelet activation and inflammatory markers were compared between controls and SAH patients with mild [Hunt-Hess (HH) 1-3] versus severe (HH 4-5) EBI. The association of these biomarkers with 3-month functional outcomes was evaluated. RESULTS: We enrolled 127 patients (106 SAH; 21 controls). Platelet activation and CRP increased incrementally with worse EBI/HH grade, and both increased over 72 h (all P < 0.01). Both were higher in severe versus mild EBI (MA 68.9 vs. 64.8 mm, P = 0.001; CRP 12.5 vs. 1.5 mg/L, P = 0.003) and compared to controls (both P < 0.003). Patients with delayed cerebral ischemia (DCI) had more platelet activation (66.6 vs. 64.9 in those without DCI, P = 0.02) within 72 h of ictus. At 3 months, death or severe disability was more likely with higher levels of platelet activation (mRS4-6 OR 1.18, 95 % CI 1.05-1.32, P = 0.007) and CRP (mRS4-6 OR 1.02, 95 % CI 1.00-1.03, P = 0.041). CONCLUSIONS: Platelet activation and inflammation occur acutely after SAH and are associated with worse EBI, DCI and poor 3-month functional outcomes. These markers may provide insight into the mechanism of EBI following SAH.
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Lesiones Encefálicas , Inflamación/sangre , Evaluación de Resultado en la Atención de Salud , Activación Plaquetaria/fisiología , Hemorragia Subaracnoidea , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores , Lesiones Encefálicas/sangre , Lesiones Encefálicas/etiología , Lesiones Encefálicas/inmunología , Lesiones Encefálicas/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Hemorragia Subaracnoidea/sangre , Hemorragia Subaracnoidea/complicaciones , Hemorragia Subaracnoidea/inmunología , Hemorragia Subaracnoidea/fisiopatología , Adulto JovenRESUMEN
Intracerebral hemorrhage (ICH) in patients with oral anticoagulation therapy is an increasingly prevalent problem in large part due to the aging population and the increased use of anticoagulants for patients at high risk of thrombosis. Warfarin has been virtually the only outpatient anticoagulant choice until fairly recently. The development of subcutaneously injected heparinoids, and more recently, of direct thrombin inhibitors, has made the treatment and prognostication of ICH in anticoagulated patients more difficult. In this review, we will review the current state of diagnosis, prognostication, and treatment for patients with this often-devastating type of bleeding. We will focus on warfarin therapy, because the preponderance of evidence comes from studies of warfarin treatment. Where there is evidence, we will contrast warfarin with some of the newer treatment modalities. We review the evidence of the 4 major reversal agents for warfarin, vitamin K, prothrombin complex concentrates, activated factor VII, and fresh frozen plasma as well as rational treatment choices. We offer possible treatments for the newer anticoagulants based on the limited evidence available. Finally, we review recommendations from the major societies and studies that support early and aggressive therapies in intensive care units with dedicated neurological specialists.
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Anticoagulantes/efectos adversos , Factores de Coagulación Sanguínea/uso terapéutico , Hemorragia Cerebral/inducido químicamente , Factor VIIa/uso terapéutico , Trombosis/tratamiento farmacológico , Vitamina K/uso terapéutico , Warfarina/efectos adversos , Administración Oral , Factores de Edad , Hemorragia Cerebral/diagnóstico por imagen , Hemorragia Cerebral/prevención & control , Cuidados Críticos , Humanos , Plasma , Tomografía Computarizada por Rayos XRESUMEN
Inflammation is an important part of the normal physiologic response to acute brain injury (ABI). How inflammation is manifest determines if it augments or hinders the resolution of ABI. Monitoring body temperature, the cellular arm of the inflammatory cascade, and inflammatory proteins may help guide therapy. This summary will address the utility of inflammation monitoring in brain-injured adults. An electronic literature search was conducted for English language articles describing the testing, utility, and optimal methods to measure inflammation in ABI. Ninety-four articles were included in this review. Current evidence suggests that control of inflammation after ABI may hold promise for advances in good outcomes. However, our understanding of how much inflammation is good and how much is deleterious is not yet clear. Several important concepts emerge form our review. First, while continuous temperature monitoring of core body temperature is recommended, temperature pattern alone is not useful in distinguishing infectious from noninfectious fever. Second, when targeted temperature management is used, shivering should be monitored at least hourly. Finally, white blood cell levels and protein markers of inflammation may have a limited role in distinguishing infectious from noninfectious fever. Our understanding of optimal use of inflammation monitoring after ABI is limited currently but is an area of active investigation.
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Lesiones Encefálicas/diagnóstico , Lesiones Encefálicas/metabolismo , Fiebre/diagnóstico , Mediadores de Inflamación/metabolismo , Biomarcadores/metabolismo , Lesiones Encefálicas/terapia , Cuidados Críticos , Fiebre/etiología , Humanos , Inmunidad Celular/fisiología , Inflamación/diagnóstico , Inflamación/etiología , Inflamación/terapia , Valor Predictivo de las Pruebas , Pronóstico , Tiritona/fisiologíaRESUMEN
INTRODUCTION: Iron-mediated oxidative damage has been implicated in the genesis of cerebral vasospasm in animal models of SAH. We sought to explore the relationship between levels of non-protein bound iron in cerebrospinal fluid and the development of brain injury in patients with aneurysmal SAH. METHODS: Patients admitted with aneurysmal subarachnoid hemorrhage to a Neurointensive care unit of an academic, tertiary medical center, with Hunt and Hess grades 2-4 requiring ventriculostomy insertion as part of their clinical management were included in this pilot study. Samples of cerebrospinal fluid (CSF) were obtained on days 1, 3, and 5. A fluorometric assay that relies on an oxidation sensitive probe was used to measure unbound iron, and levels of iron-handling proteins were measured by means of enzyme-linked immunosorbent assays. We prospectively collected and recorded demographic, clinical, and radiological data. RESULTS: A total of 12 patients were included in this analysis. Median Hunt and Hess score on admission was 3.5 (IQR: 1) and median modified Fisher scale score was 4 (IQR: 1). Seven of 12 patients (58 %) developed delayed cerebral ischemia (DCI). Day 5 non-transferrin bound iron (NTBI) (7.88 ± 1 vs. 3.58 ± 0.8, p = 0.02) and mean NTBI (7.39 ± 0.4 vs. 3.34 + 0.4 p = 0.03) were significantly higher in patients who developed DCI. Mean redox-active iron, as well as day 3 levels of redox-active iron correlated with development of angiographic vasospasm in logistic regression analysis (p = 0.02); while mean redox-active iron and lower levels of ceruloplasmin on days 3, 5, and peak concentration were correlated with development of deep cerebral infarcts. CONCLUSIONS: Our preliminary data indicate a causal relationship between unbound iron and brain injury following SAH and suggest a possible protective role for ceruloplasmin in this setting, particularly in the prevention of cerebral ischemia. Further studies are needed to validate these findings and to probe their clinical significance.
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Isquemia Encefálica/metabolismo , Líquido Cefalorraquídeo/metabolismo , Hierro/metabolismo , Hemorragia Subaracnoidea/metabolismo , Vasoespasmo Intracraneal/metabolismo , Anciano , Isquemia Encefálica/etiología , Ceruloplasmina/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Hemorragia Subaracnoidea/complicaciones , Vasoespasmo Intracraneal/etiologíaRESUMEN
A variety of technologies have been developed to assist decision-making during the management of patients with acute brain injury who require intensive care. A large body of research has been generated describing these various technologies. The Neurocritical Care Society (NCS) in collaboration with the European Society of Intensive Care Medicine (ESICM), the Society for Critical Care Medicine (SCCM), and the Latin America Brain Injury Consortium (LABIC) organized an international, multidisciplinary consensus conference to perform a systematic review of the published literature to help develop evidence-based practice recommendations on bedside physiologic monitoring. This supplement contains a Consensus Summary Statement with recommendations and individual topic reviews on physiologic processes important in the care of acute brain injury. In this article we provide the evidentiary tables for select topics including systemic hemodynamics, intracranial pressure, brain and systemic oxygenation, EEG, brain metabolism, biomarkers, processes of care and monitoring in emerging economies to provide the clinician ready access to evidence that supports recommendations about neuromonitoring.
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Cuidados Críticos , Recolección de Datos , Medicina Basada en la Evidencia , Monitorización Neurofisiológica , Proyectos de Investigación , Consenso , Humanos , Internacionalidad , Sociedades MédicasRESUMEN
Careful patient monitoring using a variety of techniques including clinical and laboratory evaluation, bedside physiological monitoring with continuous or non-continuous techniques and imaging is fundamental to the care of patients who require neurocritical care. How best to perform and use bedside monitoring is still being elucidated. To create a basic platform for care and a foundation for further research the Neurocritical Care Society in collaboration with the European Society of Intensive Care Medicine, the Society for Critical Care Medicine and the Latin America Brain Injury Consortium organized an international, multidisciplinary consensus conference to develop recommendations about physiologic bedside monitoring. This supplement contains a Consensus Summary Statement with recommendations and individual topic reviews as a background to the recommendations. In this article, we highlight the recommendations and provide additional conclusions as an aid to the reader and to facilitate bedside care.
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Lesiones Encefálicas/diagnóstico , Lesiones Encefálicas/fisiopatología , Cuidados Críticos , Monitorización Neurofisiológica , Análisis de los Gases de la Sangre , Lesiones Encefálicas/terapia , Circulación Cerebrovascular/fisiología , Protocolos Clínicos , Consenso , Electroencefalografía , Humanos , Internacionalidad , Presión Intracraneal/fisiología , Selección de Paciente , Sistemas de Atención de Punto , Sociedades MédicasRESUMEN
Neurocritical care depends, in part, on careful patient monitoring but as yet there are little data on what processes are the most important to monitor, how these should be monitored, and whether monitoring these processes is cost-effective and impacts outcome. At the same time, bioinformatics is a rapidly emerging field in critical care but as yet there is little agreement or standardization on what information is important and how it should be displayed and analyzed. The Neurocritical Care Society in collaboration with the European Society of Intensive Care Medicine, the Society for Critical Care Medicine, and the Latin America Brain Injury Consortium organized an international, multidisciplinary consensus conference to begin to address these needs. International experts from neurosurgery, neurocritical care, neurology, critical care, neuroanesthesiology, nursing, pharmacy, and informatics were recruited on the basis of their research, publication record, and expertise. They undertook a systematic literature review to develop recommendations about specific topics on physiologic processes important to the care of patients with disorders that require neurocritical care. This review does not make recommendations about treatment, imaging, and intraoperative monitoring. A multidisciplinary jury, selected for their expertise in clinical investigation and development of practice guidelines, guided this process. The GRADE system was used to develop recommendations based on literature review, discussion, integrating the literature with the participants' collective experience, and critical review by an impartial jury. Emphasis was placed on the principle that recommendations should be based on both data quality and on trade-offs and translation into clinical practice. Strong consideration was given to providing pragmatic guidance and recommendations for bedside neuromonitoring, even in the absence of high quality data.
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Cuidados Críticos , Monitoreo Fisiológico , Enfermedades del Sistema Nervioso/terapia , Biomarcadores , Consenso , Electrocardiografía , Electroencefalografía , Humanos , Presión Intracraneal , Enfermedades del Sistema Nervioso/metabolismo , Enfermedades del Sistema Nervioso/fisiopatología , Oximetría , Índice de Severidad de la Enfermedad , Sociedades Médicas , Índices de Gravedad del TraumaRESUMEN
Delayed deterioration associated with vasospasm (DDAV) after subarachnoid hemorrhage (SAH), (often called vasospasm) continues to be both a difficult entity to treat and a leading cause of morbidity in patients. Until recently, attention was focused on alleviating the vascular spasm. Recent evidence shows that vascular spasm may not account for all the morbidity of DDAV. There is renewed interest in looking for other potential targets for therapy. Inflammation has become a promising area of research for new treatments. This review explores the evidence that inflammation is a driver of DDAV by asking three questions: (1) If inflammation is important in the pathogenesis of the disease, what part or parts of the inflammatory response are involved? (2) When does inflammation occur in SAH? (3) In what compartment of the skull does the inflammation occur, the cerebrospinal fluid and meninges, the cerebral arteries, or the brain itself?
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Inflamación/etiología , Hemorragia Subaracnoidea/complicaciones , Vasoespasmo Intracraneal/etiología , Animales , Humanos , Inflamación/patologíaRESUMEN
There is increasing evidence that inflammation plays a role in the development of Delayed Deterioration associated with vasospasm (DDAV) after subarachnoid hemorrhage (SAH). Lipopolysaccharide (LPS) is an activator of the innate inflammatory system that causes DDAV in animal models. The effect of low-dose LPS has been shown to be protective in stroke models but has not been investigated in SAH. Two treatments were studied: (1) a single intraperitoneal dose of 0.6 mg/kg injected 24 h prior to SAH and (2) four daily doses administered prior to SAH. DDAV was determined by India ink angiography at day 6; behavioral testing was done in a different cohort of animals, and analysis of brain chemokine levels was accomplished by dot blot. Vessel caliber was improved compared to the SAH group in the single-injection group (ldLPS ×1) (p < 0.05). In the multiple-injection group (ldLPS ×4), the vessel caliber was similar to SAH (p < 0.05). ldLPS ×1 improved performance on the Barnes maze test, whereas the ldLPS ×4 was worse (p < 0.001). Brain levels of the inflammatory chemokine KC (keratinocyte-derived chemokine) were decreased in the ldLPS ×1 and increased in the ldLPS ×4 group. Single-injection low-dose LPS preconditioning was protective for delayed deterioration associated with vasospasm (DDAV), whereas the multiple-injection course exacerbated DDAV. This further supports that inflammation plays an important role in the development of DDAV, and that modulating the inflammatory system may be a potential target for future therapies in SAH.
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Lipopolisacáridos/administración & dosificación , Hemorragia Subaracnoidea/complicaciones , Vasoespasmo Intracraneal/etiología , Vasoespasmo Intracraneal/prevención & control , Análisis de Varianza , Animales , Encéfalo , Proteínas de Unión al Calcio/metabolismo , Carbono , Citocinas/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Molécula 1 de Adhesión Intercelular/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas de Microfilamentos/metabolismo , Actividad Motora/efectos de los fármacos , Desempeño Psicomotor/efectos de los fármacos , Hemorragia Subaracnoidea/tratamiento farmacológico , Hemorragia Subaracnoidea/patología , Factores de TiempoRESUMEN
BACKGROUND: Delayed deterioration associated with vasospasm (DDAV) after aneurismal subarachnoid hemorrhage (SAH) is a major cause of morbidity. We have previously shown that myeloid cell depletion before experimental SAH in a murine model ameliorates DDAV. In this study, we address whether systemic administration of lipopolysaccharide (LPS) worsens DDAV in a myeloid cell-dependent fashion. METHODS: We challenged mice in our experimental SAH model with LPS before hemorrhage and evaluated the degree of vasospasm on day 6 with India ink angiography; behavioral deficits by rotorod, Y-maze, and Barnes maze testing; microglial activation early after SAH by immunohistochemistry; and the brain levels of the chemokines CCL5 and KC at the time of vasospasm. Another group of animals were given the myeloid cell-depleting antibody against the neutrophil antigen Ly6G/C prior to LPS administration and SAH. RESULTS: LPS followed by SAH significantly worsens angiographic vasospasm as well as performance on the Barnes maze but not the Y-maze or rotorod tests. There was an increased activation of microglia in animals with LPS before SAH compared to SAH alone. Depletion of myeloid cells before LPS administration inhibited the development of vasospasm, improved the performance on behavioral tests, and reduced microglial activation. The chemokines CCL5 and KC were incrementally elevated in SAH and LPS SAH, but suppressed in animals with myeloid cell depletion. CONCLUSIONS: LPS administration before SAH worsens DDAV through a myeloid cell-dependent mechanism supporting studies in humans which show that systemic inflammation increases the likelihood of developing DDAV.
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Inflamación/inmunología , Lipopolisacáridos/toxicidad , Células Mieloides/inmunología , Hemorragia Subaracnoidea/inmunología , Vasoespasmo Intracraneal/inmunología , Animales , Quimiocinas/inmunología , Inmunidad Innata , Inflamación/complicaciones , Masculino , Ratones , Modelos Animales , Hemorragia Subaracnoidea/complicaciones , Vasoespasmo Intracraneal/etiologíaRESUMEN
OBJECTIVE: Delayed cerebral ischemia (DCI) is a potentially preventable cause of morbidity and mortality after aneurysmal subarachnoid hemorrhage (aSAH). The authors performed a meta-analysis to assess the effect of antiplatelet therapy (APT) on DCI in patients with aSAH. METHODS: A systematic review of the PubMed and MEDLINE databases was performed. Study inclusion criteria were 1) ≥ 5 aSAH patients; 2) direct comparison between aSAH management with APT and without APT; and 3) reporting of DCI, angiographic, or symptomatic vasospasm rates for patients treated with versus without APT. The primary efficacy outcome was DCI. The outcomes of the APT versus no-APT cohorts were compared. Bias was assessed using the Downs and Black checklist. RESULTS: The overall cohort comprised 2039 patients from 15 studies. DCI occurred less commonly in the APT compared with the no-APT cohort (pooled = 15.9% vs 28.6%; OR 0.47, p < 0.01). Angiographic (pooled = 51.6% vs 68.7%; OR 0.46, p < 0.01) and symptomatic (pooled = 23.6% vs 37.7%; OR 0.51, p = 0.01) vasospasm rates were lower in the APT cohort. In-hospital mortality (pooled = 1.7% vs 4.1%; OR 0.53, p = 0.01) and functional dependence (pooled = 21.0% vs 35.7%; OR 0.53, p < 0.01) rates were also lower in the APT cohort. Bleeding event rates were comparable between the two cohorts. Subgroup analysis of cilostazol monotherapy compared with no APT demonstrated a lower DCI rate in the cilostazol cohort (pooled = 10.6% vs 28.1%; OR 0.31, p < 0.01). Subgroup analysis of surgically treated aneurysms demonstrated a lower DCI rate for the APT cohort (pooled = 18.4% vs 33.9%; OR 0.43, p = 0.02). CONCLUSIONS: APT is associated with improved outcomes in aSAH without an increased risk of bleeding events, particularly in patients who underwent surgical aneurysm repair and those treated with cilostazol. Although study heterogeneity is the most significant limitation of the analysis, the findings suggest that APT is worth exploring in patients with aSAH, particularly in a randomized controlled trial setting.
RESUMEN
BACKGROUND AND PURPOSE: Aneurysmal SAH is often followed by delayed ischemic deficits attributable to cerebral vasospasm. Recent studies suggest a positive impact of statin therapy on the incidence of vasospasm. This study was designed to assess whether a history of prior use of statin therapy was associated with a lower risk of vasospasm in patients with SAH. METHODS: We performed a comprehensive retrospective review of patients with aneurysmal SAH between 1997 and 2004. Clinical demographics and imaging data for all patients were reviewed, and a logistic regression analysis was performed to identify the predictors of cerebral vasospasm, defined as a combination of clinical signs with radiographic confirmation. RESULTS: Three hundred eight patients were included. Mean age was higher in the group receiving statins (64 +/- 12 vs 54 +/- 12 years). Hunt and Hess scores and treatment modality were not significantly different between the groups. Vasospasm was observed in 31% of patients not taking a statin (n = 282) vs 23% taking a statin (n = 26), without achieving statistical significance. Discontinuation of the statin did not affect risk of vasospasm. CONCLUSIONS: Use of a statin prior to an aneurysmal SAH trended to reduce the incidence of subsequent vasospasm, without achieving statistical significance.
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Isquemia Encefálica/epidemiología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hemorragia Subaracnoidea/epidemiología , Vasoespasmo Intracraneal/epidemiología , Adulto , Anciano , Isquemia Encefálica/prevención & control , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estudios Retrospectivos , Factores de Riesgo , Hemorragia Subaracnoidea/cirugía , Vasoespasmo Intracraneal/prevención & controlRESUMEN
Subarachnoid hemorrhage (SAH) serves as a good model for the study of heart-brain interactions because it is associated with both a high incidence of arrhythmia and a low prevalence of coronary heart disease. The pathophysiology of cardiac abnormalities in SAH is unsettled. Initial theories focused on sustained stimulation of cardiomyocytes at sympathetic nerve endings, but recent data suggest that dysfunction of the parasympathetic nervous system may contribute as well. We believe that the coupling of catecholamine release with parasympathetic dysfunction may allow unchecked inflammation that leads to myocardial dysfunction and cell death. We have developed a novel murine model of SAH to explore these potential inflammatory underpinnings of cardiac damage in SAH.