Leucine-Rich Alpha-2-Glycoprotein 1 is a Systemic Biomarker of Early Brain Injury and Delayed Cerebral Ischemia After Subarachnoid Hemorrhage.

BACKGROUND: After subarachnoid hemorrhage (SAH), early brain injury (EBI) and delayed cerebral ischemia (DCI) lead to poor outcomes. Discovery of biomarkers indicative of disease severity and predictive of DCI is important. We tested whether leucine-rich alpha-2-glycoprotein 1 (LRG1) is a marker of severity, DCI, and functional outcomes after SAH. METHODS: We performed untargeted proteomics using mass spectrometry in plasma samples collected at < 48 h of SAH in two independent discovery cohorts (n = 27 and n = 45) and identified LRG1 as a biomarker for DCI. To validate our findings, we used enzyme-linked immunosorbent assay and confirmed this finding in an internal validation cohort of plasma from 72 study participants with SAH (22 DCI and 50 non-DCI). Further, we investigated the relationship between LRG1 and markers of EBI, DCI, and poor functional outcomes (quantified by the modified Rankin Scale). We also measured cerebrospinal fluid (CSF) levels of LRG1 and investigated its relationship to EBI, DCI, and clinical outcomes. RESULTS: Untargeted proteomics revealed higher plasma LRG1 levels across EBI severity and DCI in both discovery cohorts. In the validation cohort, the levels of LRG1 were higher in the DCI group compared with the non-DCI group (mean (SD): 95 [44] vs. 72 [38] pg/ml, p < 0.05, Student's t-test) and in study participants who proceeded to have poor functional outcomes (84 [39.3] vs. 72 [43.2] pg/ml, p < 0.05). Elevated plasma LRG1 levels were also associated with markers of EBI. However, CSF levels of LRG1 were not associated with EBI severity or the occurrence of DCI. CONCLUSIONS: Plasma LRG1 is a biomarker for EBI, DCI, and functional outcomes after SAH. Further studies to elucidate the role of LRG1 in the pathophysiology of SAH are needed.

Soluble Endoglin Stimulates Inflammatory and Angiogenic Responses in Microglia That Are Associated with Endothelial Dysfunction.

Increased soluble endoglin (sENG) has been observed in human brain arteriovenous malformations (bAVMs). In addition, the overexpression of sENG in concurrence with vascular endothelial growth factor (VEGF)-A has been shown to induce dysplastic vessel formation in mouse brains. However, the underlying mechanism of sENG-induced vascular malformations is not clear. The evidence suggests the role of sENG as a pro-inflammatory modulator, and increased microglial accumulation and inflammation have been observed in bAVMs. Therefore, we hypothesized that microglia mediate sENG-induced inflammation and endothelial cell (EC) dysfunction in bAVMs. In this study, we confirmed that the presence of sENG along with VEGF-A overexpression induced dysplastic vessel formation. Remarkably, we observed increased microglial activation around dysplastic vessels with the expression of NLRP3, an inflammasome marker. We found that sENG increased the gene expression of VEGF-A, pro-inflammatory cytokines/inflammasome mediators (TNF-α, IL-6, NLRP3, ASC, Caspase-1, and IL-1ß), and proteolytic enzyme (MMP-9) in BV2 microglia. The conditioned media from sENG-treated BV2 (BV2-sENG-CM) significantly increased levels of angiogenic factors (Notch-1 and TGFß) and pERK1/2 in ECs but it decreased the level of IL-17RD, an anti-angiogenic mediator. Finally, the BV2-sENG-CM significantly increased EC migration and tube formation. Together, our study demonstrates that sENG provokes microglia to express angiogenic/inflammatory molecules which may be involved in EC dysfunction. Our study corroborates the contribution of microglia to the pathology of sENG-associated vascular malformations.

Hypothermia for Patients Requiring Evacuation of Subdural Hematoma: A Multicenter Randomized Clinical Trial.

BACKGROUND: Hypothermia is neuroprotective in some ischemia-reperfusion injuries. Ischemia-reperfusion injury may occur with traumatic subdural hematoma (SDH). This study aimed to determine whether early induction and maintenance of hypothermia in patients with acute SDH would lead to decreased ischemia-reperfusion injury and improve global neurologic outcome. METHODS: This international, multicenter randomized controlled trial enrolled adult patients with SDH requiring evacuation of hematoma within 6 h of injury. The intervention was controlled temperature management of hypothermia to 35 °C prior to dura opening followed by 33 °C for 48 h compared with normothermia (37 °C). Investigators randomly assigned patients at a 1:1 ratio between hypothermia and normothermia. Blinded evaluators assessed outcome using a 6-month Glasgow Outcome Scale Extended score. Investigators measured circulating glial fibrillary acidic protein and ubiquitin C-terminal hydrolase L1 levels. RESULTS: Independent statisticians performed an interim analysis of 31 patients to assess the predictive probability of success and the Data and Safety Monitoring Board recommended the early termination of the study because of futility. Thirty-two patients, 16 per arm, were analyzed. Favorable 6-month Glasgow Outcome Scale Extended outcomes were not statistically significantly different between hypothermia vs. normothermia groups (6 of 16, 38% vs. 4 of 16, 25%; odds ratio 1.8 [95% confidence interval 0.39 to ∞], p = .35). Plasma levels of glial fibrillary acidic protein (p = .036), but not ubiquitin C-terminal hydrolase L1 (p = .26), were lower in the patients with favorable outcome compared with those with unfavorable outcome, but differences were not identified by temperature group. Adverse events were similar between groups. CONCLUSIONS: This trial of hypothermia after acute SDH evacuation was terminated because of a low predictive probability of meeting the study objectives. There was no statistically significant difference in functional outcome identified between temperature groups.

Neostigmine for Treating Acute Colonic Pseudo-Obstruction in Neurocritically Ill Patients.

BACKGROUND AND PURPOSE: Acute colonic pseudo-obstruction (ACPO) is a common but understudied complication in neurocritically ill patients. The acetylcholinesterase inhibitor neostigmine can be used to treat ACPO in patients who do not respond to conventional treatment. This study investigated the effectiveness and adverse events when using neostigmine to manage ACPO in neurocritically ill patients. METHODS: This retrospective study investigated patients with ACPO who were treated using neostigmine in the neurological intensive-care units at two centers between March 2017 and August 2020. Neostigmine was administered intravenously or subcutaneously (at doses ranging from 0.25 mg to 2 mg) according to the protocols at the two centers. The outcomes were bowel movements and the changes in colon diameters on abdominal radiographs. Safety events such as bradycardia, vomiting, salivation, and sweating were evaluated. RESULTS: This study included 31 subjects with a mean age of 46.8 years (65.4% males). All patients had a bowel movement at a median of 120 minutes after administering neostigmine. The colon diameter decreased by a median of 17.5 mm (paired t-test: p<0.001) regardless of the dose and treatment protocols. Multilevel analysis confirmed that the mean colon diameter decreased from 66 mm pretreatment to 47.5 mm posttreatment (p<0.001), with an intraclass correlation coefficient of 13%. Three patients (9.7%) exhibited hypersalivation, sweating, bradycardia, and vomiting. Bradycardia (heart rate, 42 beats/minute) occurred in one patient (3.2%), and was successfully managed by injecting atropine. CONCLUSIONS: Neostigmine injection is a safe and effective treatment option for ACPO in neurocritically ill patients who fail to respond to conservative management.

Design and Rationale of a Prospective International Follow-Up Study on Intensive Care Survivors of COVID-19: The Long-Term Impact in Intensive Care Survivors of Coronavirus Disease-19-AFTERCOR.

Background: In a disease that has only existed for 18 months, it is difficult to be fully informed of the long-term sequelae of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Evidence is growing that most organ systems can be affected by the virus, causing severe disabilities in survivors. The extent of the aftermath will declare itself over the next 5-10 years, but it is likely to be substantial with profound socio-economic impact on society. Methods: This is an international multi-center, prospective long-term follow-up study of patients who developed severe coronavirus disease-2019 (COVID-19) and were admitted to Intensive Care Units (ICUs). The study will be conducted at international tertiary hospitals. Patients will be monitored from time of ICU discharge up to 24 months. Information will be collected on demographics, co-existing illnesses before ICU admission, severity of illness during ICU admission and post-ICU quality of life as well as organ dysfunction and recovery. Statistical analysis will consist of patient trajectories over time for the key variables of quality of life and organ function. Using latent class analysis, we will determine if there are distinct patterns of patients in terms of recovery. Multivariable regression analyses will be used to examine associations between baseline characteristics and severity variables upon admission and discharge in the ICU, and how these impact outcomes at all follow-up time points up to 2 years. Ethics and Dissemination: The core study team and local principal investigators will ensure that the study adheres to all relevant national and local regulations, and that the necessary approvals are in place before a site may enroll patients. Clinical Trial Registration:anzctr.org.au: ACTRN12620000799954.

Time Course of Peripheral Leukocytosis and Clinical Outcomes After Aneurysmal Subarachnoid Hemorrhage.

Objective: Systemic inflammation after subarachnoid hemorrhage (SAH) is implicated in delayed cerebral ischemia (DCI) and adverse clinical outcomes. We hypothesize that early changes in peripheral leukocytes will be associated with outcomes after SAH. Methods: SAH patients admitted between January 2009 and December 2016 were enrolled into a prospective observational study and were assessed for Hunt Hess Scale (HHS) at admission, DCI, and modified Ranked Scale (mRS) at discharge. Total white blood cell (WBC) counts and each component of the differential cell count were determined on the day of admission (day 0) to 8 days after bleed (day 8). Global cerebral edema (GCE) was assessed on admission CT, and presence of any infection was determined. Statistical tests included student's t-test, Chi-square test, and multivariate logistic regression (MLR) models. Results: A total of 451 subjects were analyzed. Total WBCs and neutrophils decreased initially reaching a minimum at day 4-5 after SAH. Monocyte count increased gradually after SAH and peaked between day 6-8, while basophils and lymphocytes decreased initially from day 0 to 1 and steadily increased thereafter. Neutrophil to lymphocyte ratio (NLR) reached a peak on day 1 and decreased thereafter. WBCs, neutrophils, monocytes, and NLR were higher in patients with DCI and poor functional outcomes. WBCs, neutrophils, and NLR were higher in subjects who developed infections. In MLR models, neutrophils and monocytes were associated with DCI and worse functional outcomes, while NLR was only associated with worse functional outcomes. Occurrence of infection was associated with poor outcome. Neutrophils and NLR were associated with infection, while monocytes were not. Monocytes were higher in males, and ROC curve analysis revealed improved ability of monocytes to predict DCI and poor functional outcomes in male subjects. Conclusions: Monocytosis was associated with DCI and poor functional outcomes after SAH. The association between neutrophils and NLR and infection may impact outcomes. Early elevation in monocytes had an improved ability to predict DCI and poor functional outcomes in males, which was independent of the occurrence of infection.

Clinical Implications of Neurological Comorbidities and Complications in ICU Patients with COVID-19.

Clinical implications of neurological problems during intensive care unit (ICU) care for coronavirus disease 2019 (COVID-19) patients are unknown. This study aimed to describe the clinical implications of preexisting neurological comorbidities and new-onset neurological complications in ICU patients with COVID-19. ICU patients who were isolated and treated for COVID-19 between 19 February 2020 and 3 May 2020, from one tertiary hospital and one government-designated branch hospital were included. Clinical data including previous neurological disorders were extracted from electronic medical records. All neurological complications were evaluated by neurointensivists. Multiple logistic regression analysis was performed to investigate independent factors in ICU mortality. The median age of 52 ICU patients with COVID-19 was 73 years. Nineteen (36.5%) patients had preexisting neurological comorbidities, and new-onset neurological complications occurred in 23 (44.2%) during ICU admission. Patients with preexisting neurological comorbidities required tracheostomy more frequently and more ventilator and ICU days than those without. Patients with new-onset neurological complications experienced more medical complications and had higher ICU severity score and ICU mortality rates. New-onset neurological complications remained an independent factor for ICU mortality. Many COVID-19 patients in the ICU have preexisting neurological comorbidities, making them at a high risk of new-onset neurological complications.

Endoscopic Third Ventriculostomy for Hydrocephalus Secondary to Extraventricular Obstruction in Thalamic Hemorrhage: A Case Series.

BACKGROUND: Intracranial hemorrhage carries significant morbidity and mortality, particularly if associated with hydrocephalus. Management of hydrocephalus includes temporary external ventricular drainage, with or without shunting. Thalamic location is an independent predictor of mortality and increases the likelihood of shunt dependence. OBJECTIVE: To determine whether endoscopic third ventriculostomy (ETV) can avoid the need for shunt placement and expedite recovery. METHODS: We prospectively identified thalamic intracranial hemorrhage patients who developed acute hydrocephalus requiring cerebrospinal fluid diversion by extraventricular drain placement from November 2017 to February 2019. Patients who failed an extraventricular drain clamping trial were then evaluated for eligibility for an ETV procedure. Patients who underwent ETV were then followed up for the development of hydrocephalus, need for shunting, and length of stay in the intensive care unit. RESULTS: Eight patients (7 males, 1 female) were prospectively enrolled. All patients underwent an ETV successfully. None of the patients required shunting. ETV was performed despite the presence of other factors that would have prevented shunt placement, including fever, leukocytosis, and gastrostomy tube placement. Seven patients who underwent ETV were evaluated at 3-mo follow-up and did not require shunting. CONCLUSION: ETV is a safe and effective technique for the management of hydrocephalus resulting from an extraventricular obstruction in thalamic hemorrhage. It can avoid the need for permanent shunting in this patient population. Larger studies should be conducted to validate and further analyze this intervention.

Fortifying the BBB: Border control by increasing regulators.

Treatment with exogenous regulatory T cells fortifies the blood-brain barrier after tissue plasminogen activator therapy in models of acute ischemic stroke.

Hung over? Maybe it's your overactive microglia.

Acute ethanol intake is associated with a mild suppression of microglial activity followed by a more robust inflammatory reaction during the withdrawal period.

The brain's immune system hibernates in response to systemic injury.

In a small cohort of prostatectomy patients, systemic inflammation influenced the brain's immune response and cognition.

Safety and Efficacy of High-Dose Unfractionated Heparin for Prevention of Venous Thromboembolism in Overweight and Obese Patients.

STUDY OBJECTIVE: To determine the safety and efficacy of high-dose subcutaneous unfractionated heparin (UFH) for prevention of venous thromboembolism (VTE) in overweight and obese patients. DESIGN: Single-center retrospective observational cohort study. SETTING: Large academic tertiary care medical center. PATIENTS: A total of 1335 adults who weighed more than 100 kg on admission and received either subcutaneous UFH 7500 units every 8 hours (751 patients [high-dose group]) or 5000 units every 8 hours (584 patients [low-dose group]) for VTE prophylaxis during their hospitalization between January 1, 2013, and August 31, 2014. MEASUREMENTS AND MAIN RESULTS: The incidences of VTE and bleeding complications were assessed in each group. Each group was further divided into four groups based on their body mass index (BMI): overweight (BMI 25-29.9 kg/m(2) ), obese class I (BMI 30-34.9 kg/m(2) ), obese class II (BMI 35-39.9 kg/m(2) ), and obese class III (BMI ≥ 40 kg/m(2) ). The incidence of VTE was similar for patients in the high-dose group versus those in the low-dose group for all BMI categories. Bleeding complications were significantly higher for patients in the high-dose group. The proportion of patients with at least a 2-g/dl hemoglobin drop from admission was higher in patients in the high-dose groups in obese classes II and III: obese class II, 46 (30%) of 152 patients in the high-dose group versus 30 (18%) of 171 patients in the low-dose group (p<0.01); obese class III, 109 (25%) of 432 patients in the high-dose group versus 31 (12%) of 249 patients in the low-dose group (p<0.01). In addition, the proportion of patients who received at least 2 units of packed red blood cell transfusion was significantly higher in patients in the high-dose group who were in obese class III: 47 (11%) of 432 in the high-dose group versus 13 (5%) of 249 in the low-dose group (p<0.01). CONCLUSION: Administering a higher dose of heparin to patients weighing more than 100 kg may not impart additional efficacy in reducing the incidence of VTE. However, it may increase the risk for bleeding.

Nocturnal Desaturation in the Stroke Unit Is Associated With Wake-Up Ischemic Stroke.

BACKGROUND AND PURPOSE: Wake-up stroke (WUS) represents a quarter of all ischemic strokes and may be a specific subgroup. Nocturnal desaturation secondary to sleep-disordered breathing is an independent risk factor for stroke, but the association between nocturnal desaturation and WUS remains unclear. We investigated the relationship between nocturnal desaturation using oxygen desaturation index and WUS in patients with acute stroke in the stroke unit. METHODS: A total of 298 patients admitted for acute ischemic stroke to the stroke unit between July 2013 and May 2015 were enrolled. The oxygen desaturation index was calculated using pulse oximetry data sampled every 1 minute during 9 hours on the first night (10:00 pm-7:00 am) of the stroke unit admission, and nocturnal desaturation was defined as an oxygen desaturation index of 5 at least per hour. We compared the clinical characteristics and nocturnal desaturations between patients with and without WUS. RESULTS: Among all patients (age, 67.7±12.6 years; male, 54.4%), 26.5% patients had WUS. The proportion of nocturnal desaturation was significantly greater in patients admitted with WUS (29.1% versus 12.3%, P=0.001). The age, sex, risk factors except for hyperlipidemia, stroke severity, and stroke mechanisms were similar between the 2 groups. After adjustment for covariates, it was found that nocturnal desaturation was significantly more common in the WUS group (odds ratio, 3.25; 95% confidence interval, 1.63-6.46). CONCLUSIONS: Nocturnal desaturation was more frequently observed in patients admitted with WUS during the first night in the stroke unit. This suggests that nocturnal desaturation is a possible modifiable risk factor for the occurrence of WUS.

Therapeutic hypothermia after recanalization in patients with acute ischemic stroke.

BACKGROUND AND PURPOSE: Therapeutic hypothermia improves outcomes in experimental stroke models, especially after ischemia-reperfusion injury. We investigated the clinical and radiological effects of therapeutic hypothermia in acute ischemic stroke patients after recanalization. METHODS: A prospective cohort study at 2 stroke centers was performed. We enrolled patients with acute ischemic stroke in the anterior circulation with an initial National Institutes of Health Stroke Scale≥10 who had successful recanalization (≥thrombolysis in cerebral ischemia, 2b). Patients at center A underwent a mild hypothermia (34.5°C) protocol, which included mechanical ventilation, and 48-hour hypothermia and 48-hour rewarming. Patients at center B were treated according to the guidelines without hypothermia. Cerebral edema, hemorrhagic transformation, good outcome (3-month modified Rankin Scale, ≤2), mortality, and safety profiles were compared. Potential variables at baseline and during the therapy were analyzed to evaluate for independent predictors of good outcome. RESULTS: The hypothermia group (n=39) had less cerebral edema (P=0.001), hemorrhagic transformation (P=0.016), and better outcome (P=0.017) compared with the normothermia group (n=36). Mortality, hemicraniectomy rate, and medical complications were not statistically different. After adjustment for potential confounders, therapeutic hypothermia (odds ratio, 3.0; 95% confidence interval, 1.0-8.9; P=0.047) and distal occlusion (odds ratio, 7.3; 95% confidence interval; 1.3-40.3; P=0.022) were the independent predictors for good outcome. Absence of cerebral edema (odds ratio, 5.4; 95% confidence interval, 1.6-18.2; P=0.006) and no medical complications (odds ratio, 9.3; 95% confidence interval, 2.2-39.9; P=0.003) were also independent predictors for good outcome during the therapy. CONCLUSIONS: In patients with ischemic stroke, after successful recanalization, therapeutic hypothermia may reduce risk of cerebral edema and hemorrhagic transformation, and lead to improved clinical outcomes.