神经炎症在动脉瘤性蛛网膜下腔出血后早期脑损伤中的作用

早期脑损伤(early brain injury,EBI)是影响动脉瘤性蛛网膜下腔出血(aneurysmal subarachnoid hemorrhage,aSAH)患者预后的重要因素之一.目前aSAH后EBI产生机制尚不明确,神经炎症可能为其主要驱动因素,其作用机制包括:红细胞降解产物和激活的小胶质细胞诱导神经炎症...     

蛛网膜下腔出血早期脑损伤发病 机制综述

【摘要】 自发性蛛网膜下腔出血是常见的脑血管疾病,死亡率及致残率高。尽管药物及外科手术
技术逐渐进步,但是并没有明显改善存活患者的功能预后。传统的观点认为血管痉挛是蛛网膜下腔
出血死亡及致残的主要原因,近年来针对血管痉挛的治疗也有了巨大的进步,但是患者的预后仍然
很差。目前国外许多研究发现,早期脑损伤可能是蛛网膜下腔出血预后不良的主要因素。     

Brain Iron Metabolism and Brain Injury Following Subarachnoid Hemorrhage: iCeFISH-Pilot (CSF Iron in SAH)

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.     

丁苯酞注射液对动脉瘤性蛛网膜下腔出血早期脑损伤的作用与机制探讨

目的 探讨丁苯酞注射液对动脉瘤性蛛网膜下腔出血（aneurysmal subarachnoid hemorrhages,aSAH） 患者早期脑损伤的作用与机制。     

Effect of Gastrodin on Early Brain Injury and Neurological Outcome After Subarachnoid Hemorrhage in Rats

Gastrodin is a phenolic glycoside that has been demonstrated to provide neuroprotection in preclinical models of central nervous system disease, but its effect in subarachnoid hemorrhage(SAH) remains unclear. In this study, we showed that intraperitoneal administration of gastrodin(100 mg/kg per day) significantly attenuated the SAH-induced neurological deficit, brain edema, and increased blood-brain barrier permeability in rats. Meanwhile, gastrodin treatment significantly reduced the SAHinduced elevation of glutamate concentration in the cerebrospinal fluid and the intracellular Ca~(2+) overload.Moreover, gastrodin suppressed the SAH-induced microglial activation, astrocyte activation, and neuronal apoptosis. Mechanistically, gastrodin significantly reduced the oxidative stress and inflammatory response, up-regulated the expression of nuclear factor erythroid 2–related factor2, heme oxygenase-1, phospho-Akt and B-cell lymphoma2, and down-regulated the expression of BCL2-associated X protein and cleaved caspase-3. Our results suggested that the administration of gastrodin provides neuroprotection against early brain injury after experimental SAH.     

Characteristics of MRI Findings after Subarachnoid Hemorrhage and D-Dimer as a Predictive Value for Early Brain Injury

BackgroundThe pathological mechanisms of early brain injury (EBI) have remained obscure. Several studies have reported on the neuroradiological findings of EBI. However, to our knowledge, no study has attempted to explore the mechanism of EBI after subarachnoid hemorrhage (SAH). Therefore, this study evaluates whether the initial plasma D-dimer levels were associated with EBI, classifies magnetic resonance imaging (MRI) findings, and speculates about the mechanism of EBI.MethodsThis study included 97 patients hospitalized within 24 h from the onset of nontraumatic SAH. The patients underwent MRI within 0–5 days from onset (before vasospasm) to detect EBI. EBI was radiologically defined as diffusion-weighted imaging (DWI)-positive lesions that appear dark on apparent diffusion coefficient maps, excluding procedure-related lesions. EBI, plasma D-dimer levels, and clinical features were retrospectively investigated.ResultsElevated D-dimer levels were associated with poor outcomes. Patients with EBI had significantly higher D-dimer levels than those without EBI. EBI was detected in 24 patients (27.3%) of all, and in 22 (45%) of 49 patients with World Federation of Neurosurgical Societies (WFNS) grade 4–5 SAH. EBI was frequently observed in the paramedian frontal lobe. There were several types of the pathology in EBI, including widespread symmetrical cerebral cortex lesions, focal cortex lesions, periventricular injury, and other lesions impossible to classify due to unknown mechanisms such as thrombotic complication and microcirculatory disturbance, ultra-early spasm, and spreading depolarization.ConclusionsThis study suggests that D-dimer levels predict poor outcomes in patients with SAH and that EBI was associated high D-dimer levels.     

Inter-Observer Agreement on the Diagnosis of Neurocardiogenic Injury Following Aneurysmal Subarachnoid Hemorrhage

Background

Neurocardiogenic injury results from increased sympathetic nervous system activation following acute brain injury. No diagnostic criteria for neurocardiogenic injury exist, and agreement has not been tested. We investigated the agreement by neurointensivists for the presence of neurocardiogenic injury on routine cardiac studies.

Methods

Six neurointensivists rated 100 consecutive cases of aneurysmal subarachnoid hemorrhage (aSAH) for the presence of neurocardiogenic injury. A fixed-panel design was employed for the agreement among the whole cohort, as well as stratified by modified Fisher Scale (mFs), Hunt and Hess grade, gender, and the presence of elevated cardiac enzymes. Overall percent agreement, paired agreement, and agreement above change (Fleiss’ Kappa) were calculated. Overall percent agreement between groups was compared using Chi square tests.

Results

Six raters completed the survey for a total 600 responses. Overall percent agreement was 79.3 %, and agreement among cases at least one rater thought had neurocardiogenic injury was 66.5 % (paired agreement). Fleiss’ Kappa was 0.66 (95 % CI, 0.1–0.71; p < 0.0001), indicating substantial agreement above chance. Similarly, on subgroup analysis, significant agreement beyond chance was seen in all groups (p < 0.001). Overall percent agreement was significantly better among mFs 3–4 compared to mFs ≤ 2 (81.3 vs. 63.6 %; p = 0.018) and among cases with positive cTI (96.9 vs. 70.1 %; p ≤ 0.001).

Conclusions

Overall, we demonstrated substantial agreement for the presence of neurocardiogenic injury on early cardiac studies following aSAH. However, inter-observer variability increased when evaluating patients without the objective finding of elevated cTI and among those with lower clinical and radiographic grades.     

Lactate and Lactate Dehydrogenase in Cistern as Biomarkers of Early Brain Injury and Delayed Cerebral Ischemia of Subarachnoid Hemorrhage

Objective: The pathophysiology of delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH) has not been fully evaluated. The aim of this study was to evaluate the dynamics of lactate and lactate dehydrogenase (LDH) in carotid cisternal cerebrospinal fluid (CSF), and to discuss their effectiveness as markers of early brain injury (EBI) and DCI following aSAH. Patients and Methods: Among 91 consecutive aSAH patients treated between January 2012 and March 2019 at National Hospital Organization Beppu Medical Center, 19 patients (20.9%) were eligible for this retrospective study. Concentrations of lactate and LDH in carotid cisternal CSF within 14 days after onset of aSAH were evaluated. Results: Six of the 19 patients (31.6%) had a history of DCI. Both lactate and LDH levels in carotid cisternal CSF were significantly higher in the DCI group than in the non-DCI group on postbleeding day (PBD) 1-2, 3-4, and 5-6. Interestingly, neither lactate nor LDH levels in blood differed significantly between DCI and non-DCI groups on PBD 1-2. Conclusions: Lactate and LDH concentrations in carotid cisternal CSF may vividly reflect the EBI and may thus represent predictive biomarkers of DCI following aSAH.     

Elevated Serum Leukocytes are Predictive of Cardiac Injury Following Aneurysmal Subarachnoid Hemorrhage

ObjectivesAneurysmal subarachnoid hemorrhage (aSAH) accounts for 5% of strokes but results in significant morbidity and mortality. In addition to systemic inflammation, up to half of patients develop cardiac injury; however, the relationship between systemic inflammation and cardiac injury after aSAH is unknown. We investigated changes in leukocyte counts in relation to cardiac dysfunctionMaterials and methodsWe reviewed the records of consecutive patients with SAH at our large academic medical referral center. The inclusion criteria were aSAH and available cardiac troponin I (cTnI) levels within 48 h of admission. The primary outcome was cardiac injury, defined as cTnI ≥0.04 ng/mL (lab reference range 0.01–0.03 ng/mL). We compared baseline characteristics, including serum leukocyte counts and performed univariable and multivariable logistic regression analysis to determine whether changes in leukocyte subpopulations predict cardiac injury.ResultsOf 288 SAH patients, 250 met inclusion criteria. Of these, 116 (46.4%) had elevated cTnI. In univariable analysis, total leukocyte count (p < 0.001), absolute neutrophil count (ANC, p < 0.001), and absolute monocyte count (p = 0.013), were associated with elevated cTnI. in multivariable analysis, total leukocyte count (OR=1.079, p = 0.037) and ANC (OR=1.081, p = 0.044) remained predictors of elevated cTnI. Adjusted ANC distinguishes between aSAH patients with normal and elevated TnI (area under the curve=0.766, p < 0.001) with specificity of 89.2%.ConclusionsElevated total leukocytes and ANC are independently associated with cardiac injury in aSAH. Systemic inflammatory responses after aSAH may play a role in cardiac dysfunction, warranting additional studies to further characterize how cardiac inflammation after aSAH drives subsequent morbidity and mortality.     

Neuroinflammation and Microvascular Dysfunction After Experimental Subarachnoid Hemorrhage: Emerging Components of Early Brain Injury Related to Outcome

Neurocritical Care - Aneurysmal subarachnoid hemorrhage has a high mortality rate and, for those who survive this devastating injury, can lead to lifelong impairment. Clinical trials have...     

Cerebral Microdialysis in Traumatic Brain Injury and Subarachnoid Hemorrhage: State of the Art

Cerebral microdialysis (CMD) is a laboratory tool that provides on-line analysis of brain biochemistry via a thin, fenestrated, double-lumen dialysis catheter that is inserted into the interstitium of the brain. A solute is slowly infused into the catheter at a constant velocity. The fenestrated membranes at the tip of the catheter permit free diffusion of molecules between the brain interstitium and the perfusate, which is subsequently collected for laboratory analysis. The major molecules studied using this method are glucose, lactate, pyruvate, glutamate, and glycerol. The collected substances provide insight into the neurochemical features of secondary injury following traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH) and valuable information about changes in brain metabolism within a short time frame. In this review, the authors detail the CMD technique and its associated markers and then describe pertinent findings from the literature about the clinical application of CMD in TBI and SAH.     

The Role of Depression in Verbal Memory Following Traumatic Brain Injury

The purpose of this study was to characterize the relationship between verbal memory and depression scores on the Personality Assessment Inventory following traumatic brain injury. Depression was associated with diminished delayed recall and recognition on the California Verbal Learning Test-II (CVLT-II), even after controlling for a neuropsychological composite score and/or a measure of motivation (i.e., the TOMM). There was no relationship between depression and recall on Verbal Paired Associates or Logical Memory when controlling for the same covariates. The findings were most consistent with depressed subjects failing to utilize the semantic organization of the CVLT-II list to enhance their learning.     

Fluoxetine is Neuroprotective in Early Brain Injury via its Antiinflammatory and Anti-apoptotic Effects in a Rat Experimental Subarachnoid Hemorrhage Model

Fluoxetine, an anti-depressant drug, has recently been shown to provide neuroprotection in central nervous system injury, but its roles in subarachnoid hemorrhage(SAH) remain unclear. In this study, we aimed to evaluate whether fluoxetine attenuates early brain injury(EBI) after SAH. We demonstrated that intraperitoneal injection of fluoxetine(10 mg/kg per day) significantly attenuated brain edema and blood-brain barrier(BBB) disruption, microglial activation, and neuronal apoptosis in EBI after experimental SAH, as evidenced by the reduction of brain water content and Evans blue dye extravasation, prevention of disruption of the tight junction proteins zonula occludens-1, claudin-5, and occludin, a decrease of cells staining positive for Iba-1, ED-1, and TUNEL and a decline in IL-1 b, IL-6, TNF-a, MDA, 3-nitrotyrosine, and 8-OHDG levels. Moreover, fluoxetine significantly improved the neurological deficits of EBI and long-term sensorimotor behavioral deficits following SAH in a rat model. These results indicated that fluoxetine has a neuroprotective effect after experimental SAH.     

The Potential Role of Neuromodulation in Subarachnoid Hemorrhage

ObjectivesAneurysmal subarachnoid hemorrhage (SAH) continues to be a difficult cerebrovascular disease with limited pharmacologic treatment options. Cerebral vasospasm (CV) and delayed cerebral ischemia (DCI) are leading causes of morbidity and mortality after SAH. Despite the advances in the understanding of its pathophysiology and tremendous efforts to date, nimodipine is currently the sole Food and Drug Administration–approved treatment for patients with SAH, with benefits that are marginal at best. The neuromodulation therapies are promising, especially those that target CV and DCI to improve functional outcomes. The aim of this review is therefore to summarize the available evidence for each type of neuromodulation for CV and DCI, with a special focus on its pathophysiological mechanisms, in addition to their clinical utility and drawbacks, which we hope will lead to future translational therapy options after SAH.Materials and MethodsWe conducted a comprehensive review of preclinical and clinical studies demonstrating the use of neuromodulation for SAH. The literature search was performed using PubMed, Embase, and ClinicalTrials.gov. A total of 21 articles published from 1992 to 2021 and eight clinical trials were chosen.ResultsThe studies reviewed provide a compelling demonstration that neuromodulation is a potentially useful strategy to target multiple mechanisms of DCI and thus to potentially improve functional outcomes from SAH. There are several types of neuromodulation that have been tested to treat CV and DCI, including the trigeminal/vagus/facial nerve stimulation, sphenopalatine ganglion and spinal cord stimulation, transcranial direct electrical stimulation, transcutaneous electrical neurostimulation, and electroacupuncture. Most of them are in the preclinical or early phases of clinical application; however, they show promising results.ConclusionsDCI has a complex pathogenesis, making the unique anatomical distribution and pleiotropic capabilities of various types of neuromodulation a promising field of study. We may be at the cusp of a breakthrough in the use of these techniques for the treatment of this stubbornly difficult disease.     

TSG-6 Attenuates Oxidative Stress-Induced Early Brain Injury in Subarachnoid Hemorrhage Partly by the HO-1 and Nox2 Pathways

BackgroundEarly brain injury (EBI) refers to acute brain injury during the first 72 h after subarachnoid hemorrhage (SAH), which is one of the major causes of poor prognosis after SAH. Here, we investigated the effect and the related mechanism of TSG-6 on EBI after SAH.Materials and methodsThe Sprague-Dawley rat model of SAH was developed by the endovascular perforation method. TSG-6 (5μg) was administered by an intraventricular injection within 1.5 h after SAH. The effects of TSG-6 on EBI were assessed by neurological score, brain water content (BWC) and TUNEL staining. Immunofluorescence staining was used to assay NF-κB/p-NF-κB expression in microglia. Protein expression levels of heme oxygenase-1 (HO-1), NADPH oxidase 2 (Nox2), Bcl-2, Bax, and cleaved-caspase-3 were measured to investigate the potential mechanism. The enzyme activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and the level of reactive oxygen species (ROS) were analyzed using commercially available kits.ResultsThe results showed that TSG-6 treatment alleviated the neurobehavioral dysfunction and reduced BWC and the number of TUNEL-positive neurons in EBI after SAH. TSG-6 decreased the ROS level and enhanced the enzyme activity of SOD and GSH-Px after SAH. Furthermore TSG-6 inhibited the NF-κB activation, increased the protein expression levels of HO-1 and Bcl-2 and decreased the expression levels of Nox2, Bax, and cleaved-caspase-3. The administration of TSG-6 siRNA abolished the protective effects of TSG-6 on EBI after SAH.ConclusionWe found that TSG-6 attenuated oxidative stress and apoptosis in EBI after SAH partly by inhibiting NF-κB and activating HO-1 pathway in brain tissue.     

Early Predictors of Prolonged Stay in a Critical Care Unit Following Aneurysmal Subarachnoid Hemorrhage

Background

Aneurysmal subarachnoid hemorrhage (aSAH) is a neurologic emergency that typically warrants initial monitoring in a critical care setting. The aim of this study is to identify clinical and radiologic features on admission that predict a protracted critical care admission following aSAH.

Methods

Exploratory posthoc analysis was performed on the 413 patients enrolled in Clazosentan to Overcome Neurological iSChemia and Infarction OccUrring after Subarachnoid hemorrhage (CONSCIOUS-1), a prospective randomized control trial of clazosentan for the prevention of vasospasm after aSAH. The association between potential clinical and radiographic covariates, and the length of stay (LOS) in a critical care unit after aSAH was determined using a Cox proportional hazards model. Covariates with a significance level of p < 0.20, on univariate analysis, were entered into a multivariate forward conditional analysis to identify independent predictors of prolonged LOS.

Results

The mean LOS was 12.6 ± 10.6 days. On multivariate analysis, age (hazard ratio [HR] 1.01, 95 % confidence interval [CI] 1.00–1.02; p = 0.032), a history of hypertension (HR 1.30, CI 1.01–1.67; p = 0.045), and a World Federation of Neurosurgical Societies Score of IV–V on admission (HR 1.38, CI 1.05–1.81; p = 0.02) were the clinical features associated with a greater critical care LOS following aSAH. Intracerebral hemorrhage (HR 1.50, CI 1.03–2.21; p = 0.004) and increasing intraventricular clot burden (HR 1.08, CI 1.03–1.14; p = 0.037) on admission computed tomography were the radiologic features associated with prolonged LOS.

Conclusions

We have identified several early risk factors associated with a prolonged critical care stay following aSAH.     

Protocolized Brain Oxygen Optimization in Subarachnoid Hemorrhage

Neurocritical Care - Brain tissue hypoxia (PbtO2 &lt; 20&nbsp;mmHg) is common after subarachnoid hemorrhage (SAH) and associated with poor outcome. Recent data suggest that...     

Subarachnoid Hemorrhage Prevalence and Its Association with Short-Term Outcome in Pediatric Severe Traumatic Brain Injury

Background

Subarachnoid hemorrhage (SAH) is an independent prognostic indicator of outcome in adult severe traumatic brain injury (sTBI). There is a paucity of investigations on SAH in pediatric sTBI. The goal of this study was to determine in pediatric sTBI patients SAH prevalence, associated factors, and its relationship to short-term outcome.

Methods

We retrospectively analyzed 171 sTBI patients (pre-sedation GCS ≤8 and head MAIS ≥4) who underwent CT head imaging within the first 24 h of hospital admission. Data were analyzed with both univariate and multivariate techniques.

Results

SAH was found in 42 % of sTBI patients (n = 71/171), and it was more frequently associated with skull fractures, cerebral edema, diffuse axonal injury, contusion, and intraventricular hemorrhage (p < 0.05). Patients with SAH had higher Injury Severity Scores (p = 0.032) and a greater frequency of fixed pupil(s) on admission (p = 0.001). There were no significant differences in etiologies between sTBI patients with and without SAH. Worse disposition occurred in sTBI patients with SAH, including increased mortality (p = 0.009), increased episodes of central diabetes insipidus (p = 0.002), greater infection rates (p = 0.002), and fewer ventilator-free days (p = 0.001). In sTBI survivors, SAH was associated with increased lengths of stay (p < 0.001) and a higher level of care required on discharge (p = 0.004). Despite evidence that SAH is linked to poorer outcomes on univariate analyses, multivariate analysis failed to demonstrate an independent association between SAH and mortality (p = 0.969).

Conclusion

SAH was present in almost half of pediatric sTBI patients, and it was indicative of TBI severity and a higher level of care on discharge. SAH in pediatric patients was not independently associated with increased risk of mortality.