scholarly journals Intracerebral Iron Accumulation may be Associated with Secondary Brain Injury in Patients with Poor Grade Subarachnoid Hemorrhage

2021 ◽  
Author(s):  
Raimund Helbok ◽  
Verena Rass ◽  
Mario Kofler ◽  
Heribert Talasz ◽  
Alois Schiefecker ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Brain Injury ◽  
White Matter ◽  
Subarachnoid Space ◽  
Cerebral White Matter ◽  
Secondary Brain Injury ◽  
Wald Statistic ◽  
Poor Grade ◽  
Iron Load ◽  
Sum Score

Abstract Background The amount of intracranial blood is a strong predictor of poor outcome after subarachnoid hemorrhage (SAH). Here, we aimed to measure iron concentrations in the cerebral white matter, using the cerebral microdialysis (CMD) technique, and to associate iron levels with the local metabolic profile, complications, and functional outcome. Methods For the observational cohort study, 36 patients with consecutive poor grade SAH (Hunt & Hess grade of 4 or 5, Glasgow Coma Scale Score ≤ 8) undergoing multimodal neuromonitoring were analyzed for brain metabolic changes, including CMD iron levels quantified by graphite furnace atomic absorption spectrometry. The study time encompassed 14 days after admission. Statistical analysis was performed using generalized estimating equations. Results Patients were admitted in a poor clinical grade (n = 26, 72%) or deteriorated within 24 h (n = 10, 28%). The median blood volume in the subarachnoid space was high (SAH sum score = 26, interquartile range 20–28). Initial CMD iron was 44 µg/L (25–65 µg/L), which significantly decreased to a level of 25 µg/L (14–30 µg/L) at day 4 and then constantly increased over the remaining neuromonitoring days (p < 0.01). A higher intraventricular hemorrhage sum score (≥ 5) was associated with higher CMD iron levels (Wald-statistic = 4.1, df  = 1, p = 0.04) but not with the hemorrhage load in the subarachnoid space (p = 0.8). In patients developing vasospasm, the CMD iron load was higher, compared with patients without vasospasm (Wald-statistic = 4.1, degree of freedom = 1, p = 0.04), which was not true for delayed cerebral infarction (p = 0.4). Higher iron concentrations in the brain extracellular fluid (34 µg/L, 36–56 µg/L vs. 23 µg/L, 15–37 µg/L) were associated with mitochondrial dysfunction (CMD lactate to pyruvate ratio > 30 and CMD-pyruvate > 70 µM/L, p < 0.001). Brain extracellular iron load was not associated with functional outcome after 3 months (p > 0.5). Conclusions This study suggests that iron accumulates in the cerebral white matter in patients with poor grade SAH. These findings may support trials aiming to scavenger brain extracellular iron based on the hypothesis that iron-mediated neurotoxicity may contribute to acute and secondary brain injury following SAH.

Evidence for a conditioning effect of inhalational anesthetics on angiographic vasospasm after aneurysmal subarachnoid hemorrhage

2020 ◽  
Vol 133 (1) ◽  
pp. 152-158 ◽  
Author(s):  
Umeshkumar Athiraman ◽  
Diane Aum ◽  
Ananth K. Vellimana ◽  
Joshua W. Osbun ◽  
Rajat Dhar ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Subarachnoid Hemorrhage ◽  
Brain Injury ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Multivariate Logistic Regression Analysis ◽  
Secondary Brain Injury ◽  
Large Artery ◽  
Inhalational Anesthetics ◽  
Angiographic Vasospasm ◽  
Inhalational Anesthetic

OBJECTIVEDelayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (SAH) is characterized by large-artery vasospasm, distal autoregulatory dysfunction, cortical spreading depression, and microvessel thrombi. Large-artery vasospasm has been identified as an independent predictor of poor outcome in numerous studies. Recently, several animal studies have identified a strong protective role for inhalational anesthetics against secondary brain injury after SAH including DCI—a phenomenon referred to as anesthetic conditioning. The aim of the present study was to assess the potential role of inhalational anesthetics against cerebral vasospasm and DCI in patients suffering from an SAH.METHODSAfter IRB approval, data were collected retrospectively for all SAH patients admitted to the authors’ hospital between January 1, 2010, and December 31, 2013, who received general anesthesia with either inhalational anesthetics only (sevoflurane or desflurane) or combined inhalational (sevoflurane or desflurane) and intravenous (propofol) anesthetics during aneurysm treatment. The primary outcomes were development of angiographic vasospasm and development of DCI during hospitalization. Univariate and logistic regression analyses were performed to identify independent predictors of these endpoints.RESULTSThe cohort included 157 SAH patients whose mean age was 56 ± 14 (± SD). An inhalational anesthetic–only technique was employed in 119 patients (76%), while a combination of inhalational and intravenous anesthetics was employed in 34 patients (22%). As expected, patients in the inhalational anesthetic–only group were exposed to significantly more inhalational agent than patients in the combination anesthetic group (p < 0.05). Multivariate logistic regression analysis identified inhalational anesthetic–only technique (OR 0.35, 95% CI 0.14–0.89), Hunt and Hess grade (OR 1.51, 95% CI 1.03–2.22), and diabetes (OR 0.19, 95% CI 0.06–0.55) as significant predictors of angiographic vasospasm. In contradistinction, the inhalational anesthetic–only technique had no significant impact on the incidence of DCI or functional outcome at discharge, though greater exposure to desflurane (as measured by end-tidal concentration) was associated with a lower incidence of DCI.CONCLUSIONSThese data represent the first evidence in humans that inhalational anesthetics may exert a conditioning protective effect against angiographic vasospasm in SAH patients. Future studies will be needed to determine whether optimized inhalational anesthetic paradigms produce definitive protection against angiographic vasospasm; whether they protect against other events leading to secondary brain injury after SAH, including microvascular thrombi, autoregulatory dysfunction, blood-brain barrier breakdown, neuroinflammation, and neuronal cell death; and, if so, whether this protection ultimately improves patient outcome.

scholarly journals Stereotactic cisternal lavage in patients with aneurysmal subarachnoid hemorrhage with urokinase and nimodipine for the prevention of secondary brain injury (SPLASH): study protocol for a randomized controlled trial

Trials ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Roland Roelz ◽  
Fabian Schubach ◽  
Volker A. Coenen ◽  
Carolin Jenkner ◽  
Christian Scheiwe ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Subarachnoid Hemorrhage ◽  
Brain Injury ◽  
Neurological Outcome ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Standard Of Care ◽  
Secondary Brain Injury ◽  
Ringer’S Solution ◽  
Randomized Controlled ◽  
Therapy Protocol

Abstract Background Delayed cerebral infarction (DCI) is a major cause of death and poor neurological outcome in patients with aneurysmal subarachnoid hemorrhage (aSAH). Direct intrathecal therapies with fibrinolytic and spasmolytic drugs have appeared promising in clinical trials. However, access to the subarachnoid space for intrathecal drug administration is an unsolved problem so far, especially in patients with endovascular aneurysm securing. We investigate a therapy protocol based on stereotactic catheter ventriculocisternostomy (STX-VCS), a new approach to overcome this problem. The primary objective of this study is to assess whether cisternal lavage with urokinase, nimodipine, and Ringer’s solution administered via a stereotactically implanted catheter into the basal cisterns (= investigational treatment (IT)) is safe and improves neurological outcome in patients with aSAH. Methods This is a randomized, controlled, parallel-group, open-label phase II trial. Fifty-four patients with severe aSAH (WFNS grade ≥ 3) will be enrolled at one academic tertiary care center in Southern Germany. Patients will be randomized at a ratio of 1:1 to receive either standard of care only or standard of care plus the IT. The primary endpoint is the proportion of subjects with a favorable outcome on the Modified Rankin Scale (defined as mRS 0–3) at 6 months after aSAH. Further clinical and surrogate outcome parameters are defined as secondary endpoints. Discussion New approaches for the prevention and therapy of secondary brain injury in patients with aSAH are urgently needed. We propose this RCT to assess the clinical safety and efficacy of a novel therapy protocol for intrathecal administration of urokinase, nimodipine, and Ringer’s solution. Trial registration Deutsches Register Klinischer Studien (German Clinical Trials Register), DRKS00015645. Registered on 8 May 2019

scholarly journals White Matter Injury in Early Brain Injury after Subarachnoid Hemorrhage

2018 ◽  
Vol 28 (1) ◽  
pp. 26-35 ◽  
Author(s):  
Jinwei Pang ◽  
Jianhua Peng ◽  
Ping Yang ◽  
Li Kuai ◽  
Ligang Chen ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Brain Injury ◽  
White Matter ◽  
Early Brain Injury ◽  
Therapeutic Strategies ◽  
White Matter Injury ◽  
High Morbidity ◽  
Normal Brain ◽  
Neurological Outcomes ◽  
Multiple Substrates

Subarachnoid hemorrhage (SAH) is a major cause of high morbidity, disability, and mortality in the field of neurovascular disease. Most previous SAH studies have focused on improving cerebral blood flow, reducing cerebral vasospasm, reducing neuronal calcium overload, and other treatments. While these studies showed exciting findings in basic science, therapeutic strategies based on the findings have not significantly improved neurological outcomes in patients with SAH. Currently, the only drug proven to effectively reduce the neurological defects of SAH patients is nimodipine. Current advances in imaging technologies in the field of stroke have confirmed that white matter injury (WMI) plays an important role in the prognosis of types of stroke, and suggests that WMI protection is essential for functional recovery and poststroke rehabilitation. However, WMI injury in relation to SAH has remained obscure until recently. An increasing number of studies suggest that the current limitations for SAH treatment are probably linked to overlooked WMI in previous studies that focused only on neurons and gray matter. In this review, we discuss the biology and functions of white matter in the normal brain, and discuss the potential pathophysiology and mechanisms of early brain injury after SAH. Our review demonstrates that WMI encompasses multiple substrates, and, therefore, more than one pharmacological approach is necessary to preserve WMI and prevent neurobehavioral impairment after SAH. Strategies targeting both neuronal injury and WMI may potentially provide a novel future for SAH knowledge and treatment.

scholarly journals Cerebrospinal fluid hemoglobin drives subarachnoid hemorrhage-related secondary brain injury

2021 ◽  
Vol 1 ◽  
pp. 100310
Author(s):  
K. Akeret ◽  
R.M. Buzzi ◽  
C.A. Schaer ◽  
B.R. Thomson ◽  
F. Vallelian ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Subarachnoid Hemorrhage ◽  
Brain Injury ◽  
Secondary Brain Injury

Effect of heparin on secondary brain injury in patients with subarachnoid hemorrhage: an additional ‘H’ therapy in vasospasm treatment

2017 ◽  
Vol 9 (7) ◽  
pp. 659-663 ◽  
Author(s):  
Markus Bruder ◽  
Sae-Yeon Won ◽  
Sepide Kashefiolasl ◽  
Marlies Wagner ◽  
Nina Brawanski ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Brain Injury ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Favorable Outcome ◽  
Matched Pair ◽  
Control Group ◽  
High Morbidity ◽  
Secondary Brain Injury ◽  
Heparin Group ◽  
Vasomotor Function

ObjectiveSecondary brain injury leads to high morbidity and mortality rates in patients with aneurysmal subarachnoid hemorrhage (aSAH). However, evidence-based treatment strategies are sparse. Since heparin has various effects on neuroinflammation, microthromboembolism and vasomotor function, our objective was to determine whether heparin can be used as a multitarget prophylactic agent to ameliorate morbidity in SAH.MethodsBetween June 1999 and December 2014, 718 patients received endovascular treatment after rupture of an intracranial aneurysm at our institution; 197 of them were treated with continuous unfractionated heparin in therapeutic dosages after the endovascular procedure. We performed a matched pair analysis to evaluate the effect of heparin on cerebral vasospasm (CVS), cerebral infarction (CI), and outcome.ResultsThe rate of severe CVS was significantly reduced in the heparin group compared with the control group (14.2% vs 25.4%; p=0.005). CI and multiple ischemic lesions were less often present in patients with heparin treatment. These effects were enhanced if patients were treated with heparin for >48 hours, but the difference was not significant. Favorable outcome at 6-month follow-up was achieved in 69% in the heparin group and in 65% in the control group.ConclusionsPatients receiving unfractionated continuous heparin after endovascular aneurysm occlusion have a significant reduction in the rate of severe CVS, have CI less often, and tend to have a favorable outcome more often. Our findings support the potential beneficial effects of heparin as a multitarget therapy in patients with SAH, resulting in an additional ‘H’ therapy in vasospasm treatment.

scholarly journals Modeling the Encephalopathy of Prematurity in Animals: The Important Role of Translational Research

2012 ◽  
Vol 2012 ◽  
pp. 1-17 ◽  
Author(s):  
Hannah C. Kinney ◽  
Joseph J. Volpe
Keyword(s):  
Brain Injury ◽  
White Matter ◽  
Animal Models ◽  
Translational Research ◽  
Developmental Trajectories ◽  
Axonal Injury ◽  
White Matter Lesions ◽  
Human Condition ◽  
Cerebral White Matter

Translational research in preterm brain injury depends upon the delineation of the human neuropathology in order that animal models faithfully reiterate it, thereby ensuring direct relevance to the human condition. The major substrate of human preterm brain injury is the encephalopathy of prematurity that is characterized by gray and white matter lesions reflecting combined acquired insults, altered developmental trajectories, and reparative phenomena. Here we highlight the key features of human preterm brain development and the encephalopathy of prematurity that are critical for modeling in animals. The complete mimicry of the complex human neuropathology is difficult in animal models. Many models focus upon mechanisms related to a specific feature, for example, loss of premyelinating oligodendrocytes in the cerebral white matter. Nevertheless, animal models that simultaneously address oligodendrocyte, neuronal, and axonal injury carry the potential to decipher shared mechanisms and synergistic treatments to ameliorate the global consequences of the encephalopathy of prematurity.

scholarly journals Cerebrospinal fluid hemoglobin drives subarachnoid hemorrhage-related secondary brain injury

2021 ◽  
pp. 0271678X2110206
Author(s):  
Kevin Akeret ◽  
Raphael M Buzzi ◽  
Christian A Schaer ◽  
Bart R Thomson ◽  
Florence Vallelian ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Subarachnoid Hemorrhage ◽  
Brain Injury ◽  
Ex Vivo ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Unmet Need ◽  
Aneurysm Rupture ◽  
Secondary Brain Injury ◽  
Oxidative Potential ◽  
Macrophage Response

Secondary brain injury after aneurysmal subarachnoid hemorrhage (SAH-SBI) contributes to poor outcomes in patients after rupture of an intracranial aneurysm. The lack of diagnostic biomarkers and novel drug targets represent an unmet need. The aim of this study was to investigate the clinical and pathophysiological association between cerebrospinal fluid hemoglobin (CSF-Hb) and SAH-SBI. In a cohort of 47 patients, we collected daily CSF-samples within 14 days after aneurysm rupture. There was very strong evidence for a positive association between spectrophotometrically determined CSF-Hb and SAH-SBI. The accuracy of CSF-Hb to monitor for SAH-SBI markedly exceeded that of established methods (AUC: 0.89 [0.85-0.92]). Temporal proteome analysis revealed erythrolysis accompanied by an adaptive macrophage response as the two dominant biological processes in the CSF-space after aneurysm rupture. Ex-vivo experiments on the vasoconstrictive and oxidative potential of Hb revealed critical inflection points overlapping CSF-Hb thresholds in patients with SAH-SBI. Selective depletion and in-solution neutralization by haptoglobin or hemopexin efficiently attenuated the vasoconstrictive and lipid peroxidation activities of CSF-Hb. Collectively, the clinical association between high CSF-Hb levels and SAH-SBI, the underlying pathophysiological rationale, and the favorable effects of haptoglobin and hemopexin in ex-vivo experiments position CSF-Hb as a highly attractive biomarker and potential drug target.

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