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BACKGROUND: Neutrophil-mediated inflammation in the acute phase of intracerebral hemorrhage (ICH) worsens outcome in preclinical studies. sICAM-1 (soluble intercellular adhesion molecule-1), an inducible ligand for integrins and cell-cell adhesion molecules, is critical for neutrophil extravasation. We aimed to determine whether serum levels of sICAM-1 are associated with worse outcomes after ICH. METHODS: We conducted a post hoc secondary analysis of an observational cohort using data from the FAST trial (Factor-VII for Acute Hemorrhagic Stroke Treatment). The study exposure was the admission serum level of sICAM-1. The coprimary outcomes were mortality and poor outcome (modified Rankin Scale score 4–6) at 90 days. Secondary radiological outcomes were hematoma expansion at 24 hours and perihematomal edema expansion at 72 hours. We used multiple linear and logistic regression analyses to test for associations between sICAM-1 and outcomes, after adjustment for demographics, ICH severity characteristics, change in the systolic blood pressure in the first 24 hours, treatment randomization arm, and the time from symptom onset to study drug administration. RESULTS: Of 841 patients, we included 507 (60%) with complete data. Hematoma expansion occurred in 169 (33%), while 242 (48%) had a poor outcome. In multivariable analyses, sICAM-1 was associated with mortality (odds ratio, 1.53 per SD increase [95% CI, 1.15–2.03]) and poor outcome (odds ratio, 1.34 per SD increase [CI, 1.06–1.69]). In multivariable analyses of secondary outcomes, sICAM-1 was associated with hematoma expansion (odds ratio, 1.35 per SD increase [CI, 1.11–1.66]), but was not associated with log-transformed perihematomal edema expansion at 72 hours. In additional analyses stratified by treatment assignment, similar results were noted in the recombinant activated factor-VII arm, but not in the placebo arm. CONCLUSIONS: Admission serum levels of sICAM-1 were associated with mortality, poor outcome, and hematoma expansion. Given the possibility of a biological interaction between recombinant activated factor-VII and sICAM-1, these findings highlight the need to further explore the role of sICAM-1 as a potential marker of poor ICH outcomes.

Background: Hematoma and perihematomal edema volumes are important radiographic markers in spontaneous intracerebral hemorrhage. Accurate, reliable, and efficient quantification of these volumes will be paramount to their utility as measures of treatment effect in future clinical studies. Both manual and semi-automated quantification methods of hematoma and perihematomal edema volumetry are time-consuming and susceptible to inter-rater variability. Efforts are now underway to develop a fully automated algorithm that can replace them. A (QUANTUM) study to establish inter-quantification method measurement equivalency, which deviates from the traditional use of measures of agreement and a comparison hypothesis testing paradigm to indirectly infer quantification method measurement equivalence, is described in this article. The Quantification of Hematoma and Perihematomal Edema Volumes in Intracerebral Hemorrhage study aims to determine whether a fully automated quantification method and a semi-automated quantification method for quantification of hematoma and perihematomal edema volumes are equivalent to the hematoma and perihematomal edema volumes of the manual quantification method. Methods/Design: Hematoma and perihematomal edema volumes of supratentorial intracerebral hemorrhage on 252 computed tomography scans will be prospectively quantified in random order by six raters using the fully automated, semi-automated, and manual quantification methods. Primary outcome measures for hematoma and perihematomal edema volumes will be quantified via computed tomography scan on admission (Discussion: By allowing direct equivalence hypothesis testing, the Quantification of Hematoma and Perihematomal Edema Volumes in Intracerebral Hemorrhage study offers advantages over radiology validation studies which utilize measures of agreement to indirectly infer measurement equivalence and studies which mistakenly try to infer measurement equivalence based on the failure of a comparison two-sided null hypothesis test to reach the significance level for rejection. The equivalence hypothesis testing paradigm applied to artificial intelligence application validation is relatively uncharted and warrants further investigation. The challenges encountered in the design of this study may influence future studies seeking to translate artificial intelligence medical technology into clinical practice.

Background and ObjectivesThere have been numerous reports of neurologic manifestations identified in hospitalized patients infected with SARS-CoV-2, the virus that causes COVID-19. Here, we identify the spectrum of associated neurologic symptoms and diagnoses, define the time course of their development, and examine readmission rates and mortality risk posthospitalization in a multiethnic urban cohort.MethodsWe identify the occurrence of new neurologic diagnoses among patients with laboratory-confirmed SARS-CoV-2 infection in New York City. A retrospective cohort study was performed on 532 cases (hospitalized patients with new neurologic diagnoses within 6 weeks of positive SARS-CoV-2 laboratory results between March 1, 2020, and August 31, 2020). We compare demographic and clinical features of the 532 cases with 532 controls (hospitalized COVID-19 patients without neurologic diagnoses) in a case-control study with one-to-one matching and examine hospital-related data and outcomes of death and readmission up to 6 months after acute hospitalization in a secondary case-only analysis.ResultsAmong the 532 cases, the most common new neurologic diagnoses included encephalopathy (478, 89.8%), stroke (66, 12.4%), and seizures (38, 7.1%). In the case-control study, cases were more likely than controls to be male (58.6% vs 52.8%, p = 0.05), had baseline neurologic comorbidities (36.3% vs 13.0%, p < 0.0001), and were to be treated in an intensive care unit (62.0% vs 9.6%, p < 0.0001). Of the 394 (74.1%) cases who survived acute hospitalization, more than half (220 of 394, 55.8%) were readmitted within 6 months, with a mortality rate of 23.2% during readmission.DiscussionHospitalized patients with SARS-CoV-2 and new neurologic diagnoses have significant morbidity and mortality postdischarge. Further research is needed to define the effect of neurologic diagnoses during acute hospitalization on longitudinal post-COVID-19–related symptoms including neurocognitive impairment.

Introduction: There are described differences in coagulation between females and males. Specifically, female sex is associated with greater platelet activation and stronger clotting characteristics. It is unclear whether there are relevant coagulation differences identifiable between female and male patients suffering from intracerebral hemorrhage (ICH). Hypothesis: Female sex will be associated with stronger clotting characteristics on whole blood viscoelastic hemostatic assay testing. Methods: Spontaneous ICH patients admitted and enrolled into a prospective observational ICH cohort study between 2009-2020 and who received baseline viscoelastic hemostatic assay testing (Rotational Thromboelastometry: ROTEM) were assessed. Patients with prior anticoagulant use, patients receiving hemorrhage control therapies prior to ROTEM, and secondary etiologies of ICH were excluded from the analysis. Female sex was assessed as the primary exposure variable. The following ROTEM clotting parameters were assessed as the outcome: Coagulation Time (CT) and Maximum Clot Firmness (MCF). We assessed relationships of female sex with these separate ROTEM parameters using multivariable linear regression analyses after adjusting for relevant covariates. Results: Of 57 ICH patients included for analyses, mean age was 65 (SD 14.1), 47% were female, and the median ICH volume was 20.6 mL (IQR 10.1-43.3). There were no baseline intergroup sex differences in demographics, age, or ICH characteristics. Female sex was associated with increased EXTEM MCF (ß 0.323, p Conclusions: We identified that female sex was associated with stronger clotting characteristics on ROTEM viscoelastic testing. Further work is required to clarify the clinical significance of these findings and their potential specific impacts on radiographic, complication, and clinical outcomes after ICH.

Introduction: Hematocrit at both low and high extremes can result in both hypoxia and thrombosis respectively. While both scenarios may predispose to ischemia, it is unclear whether hematocrit associates with small vessel cerebrovascular lacunar infarcts. Hypothesis: Hematocrit levels will associate with both asymptomatic and symptomatic cerebrovascular lacunar infarcts in stroke-free participants and ischemic stroke patients, respectively. Methods: A cross sectional observational analysis of a prospective, population-based cohort study of stroke-free, older adult (>50) participants from the Northern Manhattan study (NOMAS) receiving baseline hematocrit testing and MRI between 2003-2008 were analyzed. A second, single center prospective cohort of admitted adult ischemic stroke patients receiving baseline hematocrit testing and MRI between 2005-2018 was evaluated. Associations of hematocrit with covert, asymptomatic chronic lacunar infarcts from stroke-free participants in NOMAS were assessed using general additive models after adjusting for relevant covariates. Separate analyses were performed to assess associations of hematocrit with symptomatic acute lacunar infarct stroke etiology using similar adjusted models for patients admitted and enrolled into the ischemic stroke registry. Results: Of 1218 NOMAS participants analyzed, 6% had covert chronic lacunar infarcts. The association between hematocrit and covert chronic lacunar infarcts was U-shaped (X2: 9.21; p-value: 0.03). In the 1489 patients from the ischemic stroke registry, 23% were identified to have symptomatic acute lacunar infarcts. Linear relationships were identified with higher hematocrit and symptomatic acute lacunar infarct etiology (adjusted coefficient beta: 0.020; standard error: 0.009; p=0.03). Conclusions: We identified relationships of hematocrit with both asymptomatic and symptomatic lacunar infarcts in both stroke-free and ischemic stroke cohorts, respectively. There may be a relevant role of red blood cell volumes with ischemic cerebral small vessel disease pathophysiology. However, further studies are required to clarify the mechanisms behind these relationships.

Introduction: Low hemoglobin is associated with stroke and poor cerebrovascular outcomes. It is unclear whether hemoglobin concentrations directly impact cerebrovascular health. Thus, we sought to investigate the role of hemoglobin concentration on cerebral hypoxia and blood brain barrier (BBB) function in murine models of anemia. Hypothesis: Low hemoglobin will cause relevant cerebral hypoxic changes and impair BBB function. Methods: Two different models of anemia and their respective controls were generated from 30 8-week-old, female C57/BL6 mice. The separate cohorts generated included: 1) an acute anemia model cohort via anti-TER119 injection (red blood cell hemolysis) compared to IgG control injected mice; 2) chronic anemia model cohort via iron-deficient chow compared to iron replete diet control. Hemoglobin concentrations were assessed using modified Drabkin assays. Mice were euthanized by intracardiac perfusion with saline and fixative and the brain was dissected and processed for histological analysis of vascular permeability (IgG), microglia number and activation (Iba1 and CD68), response to hypoxia (HIF1α) and endothelial markers of BBB function (GLUT1). Statistical analyses were performed using two-tailed Student's t-tests. Results: Hemoglobin concentrations were lower in our separate anemia model mice compared to their respective controls (acute anemia: 5.5 ± 4.02 vs 13.1 ± 1.69, p=0.007; chronic anemia: 7.9 ± 1.05 vs 11.9 ± 2.31, p=0.0006). Postmortem histological analyses revealed stronger microglial activation (p Conclusions: Anemic mice appear to display stronger microglial activation, greater HIF1α expression, and BBB dysfunction compared to non-anemic mice. Future studies will be needed to further clarify cellular and molecular mechanisms driving relationships between anemia, hypoxia, BBB dysfunction and clinical outcomes in cerebrovascular disease.

Introduction: Hemoglobin concentrations and diffusion weighted imaging (DWI) lesions are separately known to be associated with poor intracerebral hemorrhage (ICH) outcomes. Though hemoglobin concentrations are related to both hypoxia and thrombosis at their extremes, it is unknown whether hemoglobin concentrations relate to DWI lesions after ICH. Methods: Spontaneous, supratentorial ICH patients with available baseline hemoglobin and hospitalized MRI data enrolled into a multicenter cohort study between 2010-2016 were analyzed. Baseline hemoglobin was assessed as both a continuous variable (g/dL) and categorical variable (/=15 g/dL). Primary analyses assessed relationships of baseline hemoglobin with MRI DWI lesions. Secondary analyses assessed independent relationships of hemoglobin and DWI lesions with poor 3-month outcomes (modified Rankin Scale [mRS] 4-6). Separate multivariable regression models assessed these relationships after adjusting for relevant covariates. Results: Of 917 ICH patients analyzed, the mean baseline hemoglobin was 13.8 g/dL (+/-1.9), 60% were deep ICH, and DWI lesions were identified in 27% of the cohort. In our primary analyses, increased hemoglobin, defined as a continuous variable, was associated with DWI lesions (adjusted OR 1.21, 95% CI: 1.07-1.37) after adjusting for sex, race, ICH severity, time to MRI, and blood pressure treatment change. In secondary analyses, DWI lesions were associated with poor 3-month outcomes (adjusted OR 1.83, 95% CI: 1.24-2.69) adjusting for similar covariates. We identified associations of low hemoglobin categories, when referenced to hemoglobin 13 to /=15 g/dL) with poor outcomes were smaller and imprecise (adjusted OR 1.39, 95% CI: 0.89-2.17). Conclusions: We identified novel relationships between higher baseline hemoglobin concentrations and DWI lesions in ICH patients. Further studies are required to clarify the role of hemoglobin concentrations on both cerebral small vessel disease pathophysiology and ICH outcomes.

Introduction: Following intracerebral hemorrhage (ICH), elevated cerebral tissue iron concentrations are seen. It is unclear how peripheral serum iron concentrations change over time and how they relate to anemia after ICH. Given the known impacts of iron concentrations and anemia on clinical outcomes, we explored serum iron biomarker and hemoglobin concentration changes after acute ICH. Methods: A post hoc analysis of patients with available serial (baseline and 5 day) serum biomarker data from the multicenter, High Dose Deferoxamine in Intracerebral Hemorrhage (HI-DEF) trial was performed. Changes of serum hemoglobin, iron, transferrin, and ferritin were assessed using repeated measure ANOVA analyses. Deferoxamine treatment and poor 90 day modified Rankin Scale 4-6 were separately assessed as between subject factors for these laboratory changes. Results: Of 42 ICH patients analyzed, the mean age was 64, 62% were male, median ICH volume was 15.7mL (IQR 5.7-37.5), and baseline anemia was seen in 19%. We identified significant decrements of hemoglobin (mean difference -1.4 g/dL; 95%CI: -1.9 to -0.9; p Conclusions: Serum iron and hemoglobin concentrations decrease significantly over time following ICH. Patients with worse long term ICH outcomes had greater hemoglobin decrements during their hospitalization. The aggregate iron biomarker and hemoglobin concentration changes suggest anemia development may be due to anemia of inflammation. Further work is required to address the pathophysiologic difference between systemic and central iron homeostasis mechanisms following ICH and the impacts that ICH has on inflammation, systemic iron homeostasis, anemia, and clinical outcomes.

Introduction: Biological sex is known to impact cerebrovascular disease characteristics and clinical outcomes. While in intracerebral hemorrhage (ICH) it is known that biological sex impacts ICH incidence, it is less clear whether biological sex impacts ICH outcomes. Hypothesis: Female sex will be associated with ICH characteristics and clinical outcomes. Methods: Spontaneous ICH patients enrolled into a prospective observational ICH cohort study between 2009-2020 were assessed. Patients with prior anticoagulant use and secondary etiologies of ICH were excluded from the analysis. Female sex was assessed as the primary exposure variable. Primary analyses assessed relationships of female sex with radiographic outcomes: ICH location, ICH volume, hematoma expansion (>33% and/or >6mL). Secondary analyses assessed relationships of female sex with clinical outcomes: poor discharge neurological outcome (modified Rankin 4-6), and poor discharge disposition (skilled nursing facility, hospice, or inpatient death). Separate multivariable regression models assessed these relationships after adjusting for relevant covariates. Results: Of 504 ICH patients analyzed, mean age was 67 (SD 14.9), 46% were female, and median baseline ICH volume was 14.6 mL (IQR 4.98-35.0). In primary analyses, female sex was not associated with ICH volume or hematoma expansion but was associated with lobar ICH location (adjusted OR 1.72, 95% CI: 1.09-2.70). In secondary analyses, female sex was not associated with poor discharge neurological outcomes (adjusted OR 1.40, 95% CI: 0.74-2.64) after adjusting for race, ICH severity, and ICH location. However, there was an association of female sex with poor discharge disposition (adjusted OR 1.91, 95% CI: 1.15-3.16) after adjusting for similar covariates. Conclusions: While there were no clear intergroup sex differences in ICH severity or neurological outcomes, female sex was associated with worse discharge disposition. Further work is required to clarify whether these disposition differences are due to disease specific complications, characteristics, or if there are other social disparities responsible for these outcome differences.

Dysfunctional cerebral autoregulation often precedes delayed cerebral ischemia (DCI). Currently, there are no data-driven techniques that leverage this information to predict DCI in real time. Our hypothesis is that information using continuous updated analyses of multimodal neuromonitoring and cerebral autoregulation can be deployed to predict DCI.Time series values of intracranial pressure, brain tissue oxygenation, cerebral perfusion pressure (CPP), optimal CPP (CPPOpt), ΔCPP (CPP - CPPOpt), mean arterial pressure, and pressure reactivity index were combined and summarized as vectors. A validated temporal signal angle measurement was modified into a classification algorithm that incorporates hourly data. The time-varying temporal signal angle measurement (TTSAM) algorithm classifies DCI at varying time points by vectorizing and computing the angle between the test and reference time signals. The patient is classified as DCI+ if the error between the time-varying test vector and DCI+ reference vector is smaller than that between the time-varying test vector and DCI- reference vector. Finally, prediction at time point t is calculated as the majority voting over all the available signals. The leave-one-patient-out cross-validation technique was used to train and report the performance of the algorithms. The TTSAM and classifier performance was determined by balanced accuracy, F1 score, true positive, true negative, false positive, and false negative over time.One hundred thirty-one patients with aneurysmal subarachnoid hemorrhage who underwent multimodal neuromonitoring were identified from two centers (Columbia University: 52 [39.7%], Aachen University: 79 [60.3%]) and included in the analysis. Sixty-four (48.5%) patients had DCI, and DCI was diagnosed 7.2 ± 3.3 days after hemorrhage. The TTSAM algorithm achieved a balanced accuracy of 67.3% and an F1 score of 0.68 at 165 h (6.9 days) from bleed day with a true positive of 0.83, false positive of 0.16, true negative of 0.51, and false negative of 0.49.A TTSAM algorithm using multimodal neuromonitoring and cerebral autoregulation calculations shows promise to classify DCI in real time.

Background and ObjectivesAge-related cognitive impairment is driven by the complex interplay of neurovascular and neurodegenerative disease. There is a strong relationship between cerebral microbleeds (CMBs), cerebral amyloid angiopathy (CAA), and the cognitive decline observed in conditions such as Alzheimer disease. However, in the early, preclinical phase of cognitive impairment, the extent to which CMBs and underlying CAA affect volumetric changes in the brain related to neurodegenerative disease remains unclear.MethodsWe performed cross-sectional analyses from 3 large cohorts: The Northern Manhattan Study (NOMAS), Alzheimer's Disease Neuroimaging Initiative (ADNI), and the Epidemiology of Dementia in Singapore study (EDIS). We conducted a confirmatory analysis of 82 autopsied cases from the Brain Arterial Remodeling Study (BARS). We implemented multivariate regression analyses to study the association between 2 related markers of cerebrovascular disease—MRI-based CMBs and autopsy-based CAA—as independent variables and volumetric markers of neurodegeneration as dependent variables. NOMAS included mostly dementia-free participants age 55 years or older from northern Manhattan. ADNI included participants living in the United States age 55–90 years with a range of cognitive status. EDIS included community-based participants living in Singapore age 60 years and older with a range of cognitive status. BARS included postmortem pathologic samples.ResultsWe included 2,657 participants with available MRI data and 82 autopsy cases from BARS. In a meta-analysis of NOMAS, ADNI, and EDIS, superficial CMBs were associated with larger gray matter (β = 4.49 ± 1.13,p= 0.04) and white matter (β = 4.72 ± 2.1,p= 0.03) volumes. The association between superficial CMBs and larger white matter volume was more evident in participants with 1 CMB (β = 5.17 ± 2.47,p= 0.04) than in those with ≥2 CMBs (β = 1.97 ± 3.41,p= 0.56). In BARS, CAA was associated with increased cortical thickness (β = 6.5 ± 2.3,p= 0.016) but not with increased brain weight (β = 1.54 ± 1.29,p= 0.26).DiscussionSuperficial CMBs are associated with larger morphometric brain measures, specifically white matter volume. This association is strongest in brains with fewer CMBs, suggesting that the CMB/CAA contribution to neurodegeneration may not relate to tissue loss, at least in early stages of disease.

Little is known about the natural history of comatose patients with brain injury, as in many countries most of these patients die in the context of withdrawal of life-sustaining therapies (WLSTs). The accuracy of predicting recovery that is used to guide goals-of-care decisions is uncertain. We examined long-term outcomes of patients with ischemic or hemorrhagic stroke predicted by experienced clinicians to have no chance of meaningful recovery in Japan, where WLST in patients with isolated neurological disease is uncommon.We retrospectively reviewed the medical records of all patients admitted with acute ischemic stroke, intracerebral hemorrhage, or nontraumatic subarachnoid hemorrhage between January 2018 and December 2020 to a neurocritical care unit at Toda Medical Group Asaka Medical Center in Saitama, Japan. We screened for patients who were predicted by the attending physician on postinjury day 1-4 to have no chance of meaningful recovery. Primary outcome measures were disposition at hospital discharge and the ability to follow commands and functional outcomes measured by the Glasgow Outcome Scale-Extended (GOS-E), which was assessed 6 months after injury.From 860 screened patients, we identified 40 patients (14 with acute ischemic stroke, 19 with intracerebral hemorrhage, and 7 with subarachnoid hemorrhage) who were predicted to have no chance of meaningful recovery. Median age was 77 years (interquartile range 64-85), 53% (n = 21) were women, and 80% (n = 32) had no functional deficits prior to hospitalization. Six months after injury, 17 patients were dead, 14 lived in a long-term care hospital, 3 lived at home, 2 lived in a rehabilitation center, and 2 lived in a nursing home. Three patients reliably followed commands, two were in a vegetative state (GOS-E 2), four fully depended on others and required constant assistance (GOS-E 3), one could be left alone independently for 8 h per day but remained dependent (GOS-E 4), and one was independent and able to return to work-like activities (GOS-E 5).In the absence of WLST, almost half of the patients predicted shortly after the injury to have no chance of meaningful recovery were dead 6 months after the injury. A small minority of patients had good functional recovery, highlighting the need for more accurate neurological prognostication.

Objective To determine the ability of quantitative electroencephalography (QEEG) to improve the accuracy of predicting recovery of consciousness by post-cardiac arrest day 10. Methods Unconscious survivors of cardiac arrest undergoing daily clinical and EEG assessments through post-cardiac arrest day 10 were studied in a prospective observational cohort study. Power spectral density, local coherence, and permutation entropy were calculated from daily EEG clips following a painful stimulus. Recovery of consciousness was defined as following at least simple commands by day 10. We determined the impact of EEG metrics to predict recovery when analyzed with established predictors of recovery using partial least squares regression models. Explained variance analysis identified which features contributed most to the predictive model. Results 367 EEG epochs from 98 subjects were analyzed in conjunction with clinical measures. Highest prediction accuracy was achieved when adding QEEG features from post-arrest days 4–6 to established predictors (area under the receiver operating curve improved from 0.81 ± 0.04 to 0.86 ± 0.05). Prediction accuracy decreased from 0.84 ± 0.04 to 0.79 ± 0.04 when adding QEEG features from post-arrest days 1–3. Patients with recovery of command-following by day 10 showed higher coherence across the frequency spectrum and higher centro-occipital delta-frequency spectral power by days 4–6, and globally-higher theta range permutation entropy by days 7–10. Conclusions Adding quantitative EEG metrics to established predictors of recovery allows modest improvement of prediction accuracy for recovery of consciousness, when obtained within a week of cardiac arrest. Further research is needed to determine the best strategy for integration of QEEG data into prognostic models in this patient population.

BACKGROUND: Electroencephalography (EEG) findings following cardiovascular collapse in death are uncertain. We aimed to characterize EEG changes immediately preceding and following cardiac death. METHODS: We retrospectively analyzed EEGs of patients who died from cardiac arrest while undergoing standard EEG monitoring in an intensive care unit. Patients with brain death preceding cardiac death were excluded. Three events during fatal cardiovascular failure were investigated: (1) last recorded QRS complex on electrocardiogram (QRS(0)), (2) cessation of cerebral blood flow (CBF(0)) estimated as the time that blood pressure and heart rate dropped below set thresholds, and (3) electrocerebral silence on EEG (EEG(0)). We evaluated EEG spectral power, coherence, and permutation entropy at these time points. RESULTS: Among 19 patients who died while undergoing EEG monitoring, seven (37%) had a comfort-measures-only status and 18 (95%) had a do-not-resuscitate status in place at the time of death. EEG(0) occurred at the time of QRS(0) in five patients and after QRS(0) in two patients (cohort median − 2.0, interquartile range − 8.0 to 0.0), whereas EEG(0) was seen at the time of CBF(0) in six patients and following CBF(0) in 11 patients (cohort median 2.0 min, interquartile range − 1.5 to 6.0). After CBF(0), full-spectrum log power (p < 0.001) and coherence (p < 0.001) decreased on EEG, whereas delta (p = 0.007) and theta (p = 0.007) permutation entropy increased. CONCLUSIONS: Rarely may patients have transient electrocerebral activity following the last recorded QRS (less than 5 min) and estimated cessation of cerebral blood flow. These results may have implications for discussions around cardiopulmonary resuscitation and organ donation.

Background Prevalence and etiology of unconsciousness are uncertain in hospitalized patients with coronavirus disease 2019 (COVID-19). We tested the hypothesis that increased inflammation in COVID-19 precedes coma, independent of medications, hypotension, and hypoxia. Methods We retrospectively assessed 3203 hospitalized patients with COVID-19 from March 2 through July 30, 2020, in New York City with the Glasgow Coma Scale and systemic inflammatory response syndrome (SIRS) scores. We applied hazard ratio (HR) modeling and mediation analysis to determine the risk of SIRS score elevation to precede coma, accounting for confounders. Results We obtained behavioral assessments in 3203 of 10,797 patients admitted to the hospital who tested positive for SARS-CoV-2. Of those patients, 1054 (32.9%) were comatose, which first developed on median hospital day 2 (interquartile range [IQR] 1–9). During their hospital stay, 1538 (48%) had a SIRS score of 2 or above at least once, and the median maximum SIRS score was 2 (IQR 1–2). A fivefold increased risk of coma (HR 5.05, 95% confidence interval 4.27–5.98) was seen for each day that patients with COVID-19 had elevated SIRS scores, independent of medication effects, hypotension, and hypoxia. The overall mortality in this population was 13.8% (n = 441). Coma was associated with death (odds ratio 7.77, 95% confidence interval 6.29–9.65) and increased length of stay (13 days [IQR 11.9–14.1] vs. 11 [IQR 9.6–12.4]), accounting for demographics. Conclusions Disorders of consciousness are common in hospitalized patients with severe COVID-19 and are associated with increased mortality and length of hospitalization. The underlying etiology of disorders of consciousness in this population is uncertain but, in addition to medication effects, may in part be linked to systemic inflammation. Supplementary Information The online version contains supplementary material available at 10.1007/s12028-021-01256-7.

Acute platelet transfusion after intracerebral hemorrhage (ICH) given in efforts to reverse antiplatelet medication effects and prevent ongoing bleeding does not appear to improve outcome and may be associated with harm. Although the underlying mechanisms are unclear, the influence of ABO-incompatible platelet transfusions on ICH outcomes has not been investigated. We hypothesized that patients with ICH who receive ABO-incompatible platelet transfusions would have worse platelet recovery (using absolute count increment [ACI]) and neurological outcomes (mortality and poor modified Rankin Scale [mRS 4-6]) than those receiving ABO-compatible transfusions. In a single-center cohort of consecutively admitted patients with ICH, we identified 125 patients receiving acute platelet transfusions, of whom 47 (38%) received an ABO-incompatible transfusion. Using quantile regression, we identified an association of ABO-incompatible platelet transfusion with lower platelet recovery (ACI, 2 × 103cells per μL vs 15 × 103cells per μL; adjusted coefficient β, −19; 95% confidence interval [CI], −35.55 to −4.44; P = .01). ABO-incompatible platelet transfusion was also associated with increased odds of mortality (adjusted odds ratio [OR], 2.59; 95% CI, 1.00-6.73; P = .05) and poor mRS (adjusted OR, 3.61; 95% CI, 0.97-13.42; P = .06); however, these estimates were imprecise. Together, these findings suggest the importance of ABO compatibility for platelet transfusions for ICH, but further investigation into the mechanism(s) underlying these observations is required.

Background and Purpose: Delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage negatively impacts long-term recovery but is often detected too late to prevent damage. We aim to develop hourly risk scores using routinely collected clinical data to detect DCI. Methods: A DCI classification model was trained using vital sign measurements (heart rate, blood pressure, respiratory rate, and oxygen saturation) and demographics routinely collected for clinical care. Twenty-two time-varying physiological measures were computed including mean, SD, and cross-correlation of heart rate time series with each of the other vitals. Classification was achieved using an ensemble approach with L2-regularized logistic regression, random forest, and support vector machines models. Classifier performance was determined by area under the receiver operating characteristic curves and confusion matrices. Hourly DCI risk scores were generated as the posterior probability at time t using the Ensemble classifier on cohorts recruited at 2 external institutions (n=38 and 40). Results: Three hundred ten patients were included in the training model (median, 54 years old [interquartile range, 45–65]; 80.2% women, 28.4% Hunt and Hess scale 4–5, 38.7% Modified Fisher Scale 3–4); 101 (33%) developed DCI with a median onset day 6 (interquartile range, 5–8). Classification accuracy before DCI onset was 0.83 (interquartile range, 0.76–0.83) area under the receiver operating characteristic curve. Risk scores applied to external institution datasets correctly predicted 64% and 91% of DCI events as early as 12 hours before clinical detection, with 2.7 and 1.6 true alerts for every false alert. Conclusions: An hourly risk score for DCI derived from routine vital signs may have the potential to alert clinicians to DCI, which could reduce neurological injury.

Background Laboratory monitoring is not recommended when subcutaneous unfractionated heparin (SQ-UFH) is administered at prophylactic doses. However, aPTT prolongation and associated hemorrhage has been reported in the neurocritically ill. At our institution, Neuroscience Intensive Care Unit (Neuro-ICU) patients with prolonged aPTT are further evaluated with a follow up aPTT and anti-factor Xa. Purpose The purpose of this study was to describe concordance between aPTT and anti-factor Xa in neurocritically ill patients receiving prophylactic SQ-UFH with evidence of aPTT prolongation. Methods A retrospective chart review of adult patients admitted to the Neuro-ICU from June 2017 to June 2019 was performed. Patients were included if they received SQ-UFH with aPTT levels and at least one anti-factor Xa level drawn within one hour of each other. Concordance between paired aPTT and anti-factor Xa was evaluated using Cohen’s weighted kappa. Results Forty two patients with 56 paired aPTT and anti-factor Xa levels were included. The most prescribed SQ-UFH regimen was 5000 units every 8 hours (60.7%) and anti-factor Xa levels were drawn a median (IQR) of 5.7 (3.1-10.7) hours after the SQ-UFH dose. Only 16 (28.6%) pairs were in concordance. The analysis showed a weighted kappa of .09; 95% CI [−.05 to .22] indicating poor agreement. Conclusions In neurocritically ill patients receiving prophylactic SQ-UFH with aPTT prolongation, there was poor concordance between aPTT and anti-factor Xa. This suggests that aPTT prolongation may not be solely driven by heparin activity and further evaluation of mechanistic drivers for coagulopathy in this population is necessary.

Background Obesity is a risk factor for pneumonia and acute respiratory distress syndrome. Objective To determine whether obesity is associated with intubation or death, inflammation, cardiac injury, or fibrinolysis in coronavirus disease 2019 (COVID-19). Design Retrospective cohort study. Setting A quaternary academic medical center and community hospital in New York City. Participants 2466 adults hospitalized with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection over a 45-day period with at least 47 days of in-hospital observation. Measurements Body mass index (BMI), admission biomarkers of inflammation (C-reactive protein [CRP] level and erythrocyte sedimentation rate [ESR]), cardiac injury (troponin level), and fibrinolysis (D-dimer level). The primary end point was a composite of intubation or death in time-to-event analysis. Results Over a median hospital length of stay of 7 days (interquartile range, 3 to 14 days), 533 patients (22%) were intubated, 627 (25%) died, and 59 (2%) remained hospitalized. Compared with overweight patients, patients with obesity had higher risk for intubation or death, with the highest risk among those with class 3 obesity (hazard ratio, 1.6 [95% CI, 1.1 to 2.1]). This association was primarily observed among patients younger than 65 years and not in older patients (P for interaction by age = 0.042). Body mass index was not associated with admission levels of biomarkers of inflammation, cardiac injury, or fibrinolysis. Limitations Body mass index was missing for 28% of patients. The primary analyses were conducted with multiple imputation for missing BMI. Upper bounding factor analysis suggested that the results are robust to possible selection bias. Conclusion Obesity is associated with increased risk for intubation or death from COVID-19 in adults younger than 65 years, but not in adults aged 65 years or older. Primary funding source National Institutes of Health.

Background Hematoma expansion (HE) is associated with poor outcome in patients with intracerebral hemorrhage (ICH), but the impact on patients with an left ventricular assist device (LVAD) is unknown. We aimed to define the occurrence of HE in the LVAD population and to determine the association between HE and mortality. Methods We performed a retrospective cohort study of LVAD patients and intentionally matched anticoagulated controls without LVAD admitted to Columbia University Irving Medical Center with ICH between 2008 and 2019. We compared HE occurrence between patients with an LVAD and those without an LVAD using regression modeling, adjusting for factors known to influence HE. We evaluated pump thrombosis following anticoagulation reversal. We examined the association between HE and hospital mortality using Poisson regression modeling adjusting for factors associated with poor outcome. Results Among 605 patients with an LVAD, we identified 28 patients with ICH meeting the study’s inclusion criteria. Our LVAD ICH cohort was predominantly male (71%), with a mean age of 56 ± 10 years. The median baseline hematoma size was 20.1 mL3 (interquartile range [IQR], 8.6–46.9 mL3), and the median ICH score was 1 (IQR, 1–2). There was no significant difference in occurrence of HE in LVAD patients and matched non-LVAD patients (adjusted odds ratio [OR], 1.3; 95% confidence interval [CI], 0.4–4.2). There was an association between HE and in-hospital mortality in LVAD patients (adjusted OR, 4.8; 95% CI, 1.4–6.2). Conclusions HE occurrence appears to be similar in LVAD and non-LVAD patients. HE has a significant impact on LVAD ICH mortality, underscoring the importance of adequate coagulopathy reversal and blood pressure management in these patients.

Background Impaired consciousness is common in intensive care unit (ICU) patients, and an individual’s degree of consciousness is crucial to determining their care and prognosis. However, there are no methods that continuously monitor consciousness and alert clinicians to changes. We investigated the use of physiological signals collected in the ICU to classify levels of consciousness in critically ill patients. Methods We studied 61 patients with subarachnoid hemorrhage (SAH) and 178 patients with intracerebral hemorrhage (ICH) from the neurological ICU at Columbia University Medical Center in a retrospective observational study of prospectively collected data. The level of consciousness was determined on the basis of neurological examination and mapped to comatose, vegetative state or unresponsive wakefulness syndrome (VS/UWS), minimally conscious minus state (MCS−), and command following. For each physiological signal, we extracted time-series features and performed classification using extreme gradient boosting on multiple clinically relevant tasks across subsets of physiological signals. We applied this approach independently on both SAH and ICH patient groups for three sets of variables: (1) a minimal set common to most hospital patients (e.g., heart rate), (2) variables available in most ICUs (e.g., body temperature), and (3) an extended set recorded mainly in neurological ICUs (absent for the ICH patient group; e.g., brain temperature). Results On the commonly performed classification task of VS/UWS versus MCS−, we achieved an area under the receiver operating characteristic curve (AUROC) in the SAH patient group of 0.72 (sensitivity 82%, specificity 57%; 95% confidence interval [CI] 0.63–0.81) using the extended set, 0.69 (sensitivity 83%, specificity 51%; 95% CI 0.59–0.78) on the variable set available in most ICUs, and 0.69 (sensitivity 56%, specificity 78%; 95% CI 0.60–0.78) on the minimal set. In the ICH patient group, AUROC was 0.64 (sensitivity 56%, specificity 65%; 95% CI 0.55–0.74) using the minimal set and 0.61 (sensitivity 50%, specificity 80%; 95% CI 0.51–0.71) using the variables available in most ICUs. Conclusions We find that physiological signals can be used to classify states of consciousness for patients in the ICU. Building on this with intraday assessments and increasing sensitivity and specificity may enable alarm systems that alert physicians to changes in consciousness and frequent monitoring of consciousness throughout the day, both of which may improve patient care and outcomes.

Introduction: Age-related cognitive impairment is driven by the complex interplay of neurovascular and neurodegenerative disease. There is a strong relationship between cerebral microbleeds (CMBs), cerebral amyloid angiopathy (CAA), and the cognitive decline observed in conditions such as Alzheimer’s disease. In the early, preclinical phase of cognitive impairment, the extent to which CMBs and underlying CAA impact volumetric changed in the brain related to neurodegenerative disease remains unclear. Methods: We performed cross-sectional analyses from 3 large cohorts: The Northern Manhattan Study (NOMAS), Alzheimer’s Disease Neuroimaging Initiative (ADNI), and the Epidemiology of Dementia in Singapore study (EDIS). We conducted a confirmatory analysis of 82 autopsied cases from the Brain Arterial Remodeling Study (BARS). We implemented multivariate regression analyses to study the association between two related markers of cerebrovascular disease – MRI-based CMBs and autopsy-based CAA, as independent variables, and volumetric markers of neurodegeneration, as dependent variables. Results: We included 2657 participants with available MRI data and 82 autopsy cases from the BARS. In a meta-analysis of NOMAS, ADNI and EDIS, superficial CMBs were associated with larger gray (β=4.49 ± 1.13, P=0.04) and white (β=4.72 ± 2.1, P=0.03) matter volumes. The association between superficial CMBs and larger white matter volume was more evident in participants with one CMB (B=5.17 ± 2.47, P=0.04) than in those with ≥ 2 CMBs (β=1.97 ± 3.41, P=0.56). In the BARS, CAA was associated with increased cortical thickness (β = 6.5 ± 2.3, P=0.016) but not with increased brain weight (β=1.54 ± 1.29, P=0.26). Discussion: Superficial CMBs are associated with larger morphometric brain measures. This association is strongest in brains with fewer CMBs, suggesting that the CMBs/CAA contribution to neurodegeneration may not relate to tissue loss, at least in early stages of disease.

Prolonged external ventricular drainage (EVD) in patients with subarachnoid hemorrhage (SAH) leads to morbidity, whereas early removal can have untoward effects related to recurrent hydrocephalus. A metric to help determine the optimal time for EVD removal or ventriculoperitoneal shunt (VPS) placement would be beneficial in preventing the prolonged, unnecessary use of EVD. This study aimed to identify whether dynamics of cerebrospinal fluid (CSF) biometrics can temporally predict VPS dependency after SAH.This was a retrospective analysis of a prospective, single-center, observational study of patients with aneurysmal SAH who required EVD placement for hydrocephalus. Patients were divided into VPS-dependent (VPS+) and non-VPS dependent groups. We measured the bicaudate index (BCI) on all available computed tomography scans and calculated the change over time (ΔBCI). We analyzed the relationship of ΔBCI with CSF output by using Pearson's correlation. A k-nearest neighbor model of the relationship between ΔBCI and CSF output was computed to classify VPS.Fifty-eight patients met inclusion criteria. CSF output was significantly higher in the VPS+ group in the 7 days post EVD placement. There was a negative correlation between delta BCI and CSF output in the VPS+ group (negative delta BCI means ventricles become smaller) and a positive correlation in the VPS- group starting from days four to six after EVD placement (p 0.05). A weighted k-nearest neighbor model for classification had a sensitivity of 0.75, a specificity of 0.70, and an area under the receiver operating characteristic curve of 0.80.The correlation of ΔBCI and CSF output is a reliable intraindividual biometric for VPS dependency after SAH as early as days four to six after EVD placement. Our machine learning model leverages this relationship between ΔBCI and cumulative CSF output to predict VPS dependency. Early knowledge of VPS dependency could be studied to reduce EVD duration in many centers (intensive care unit length of stay).

ObjectiveTo evaluate the relationship between prior antiplatelet therapy (APT) and outcomes after primary intracerebral haemorrhage (ICH), and assess if it varies by haematoma location.MethodsWe pooled individual patient data from the Virtual International Stroke Trials Archive-ICH trials dataset, Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage III trial and the Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation Phase III trial. The exposure was APT preceding ICH diagnosis. The primary outcome was haematoma expansion at 72 hours. Secondary outcomes were admission haematoma volume, all-cause mortality, death or major disability (modified Rankin Scale (mRS) score ≥4) and shift in mRS distribution. Mixed-effects models were used to assess the relationship between APT and outcomes. Secondary analyses were stratified by ICH location and study cohort.ResultsAmong 1420 patients with ICH, there were 782 (55.1%) lobar and 596 (42.0%) deep haemorrhages. APT was reported in 284 (20.0%) patients. In adjusted regression models, prior APT was not associated with haematoma expansion (OR, 0.97; 95% CI 0.60 to 1.57), major disability or death (OR, 1.05; 95% CI 0.61 to 1.63), all-cause mortality (OR, 0.89; 95% CI 0.47 to 1.85), admission haematoma volume (beta, −0.17; SE, 0.09; p=0.07) and shift in mRS (p=0.43). In secondary analyses, APT was associated with admission haematoma volume in lobar ICH (beta, 0.25; SE, 0.12; p=0.03), but there was no relationship with other ICH outcomes when stratified by haematoma location or study cohort.ConclusionsIn a large heterogeneous cohort of patients with ICH, prior APT was not associated with haematoma expansion or functional outcomes after ICH, regardless of haematoma location. APT was associated with admission haematoma volumes in lobar ICH.

Background Infection and venous thromboembolism (VTE) are associated with worse outcomes after intracerebral hemorrhage (ICH). The relationship between infection and VTE in ICH patients is unclear. We hypothesized that infection would be associated with subsequent VTE after ICH. Methods We retrospectively studied consecutively admitted spontaneous primary ICH patients from 2009 to 2018 surviving beyond 24 h. The primary predictor variable was infection, diagnosed prior to VTE. The primary outcome was VTE. We used multivariable logistic regression models to estimate the odds ratios and 95% confidence intervals (OR, 95% CI) for VTE risk after infection of any type, after adjusting for ICH score, length of stay and days to deep venous thrombosis (DVT) prophylaxis. Similar analysis was done to estimate the association of infection subtypes, including respiratory and urinary and blood stream infections (BSI) with VTE. Results There were 414 patients (mean age 65 years, 47% female) that met were analyzed. Infection was diagnosed in 181 (44%) patients. Incident VTE was diagnosed in 36 (9%) patients, largely comprised of DVT (n = 32; 89%). Infection overall was associated with increased risk of subsequent VTE (adjusted OR 4.5, 95% CI 1.6–12.6). Respiratory (adjusted OR 5.7, 95% CI 2.8–11.7) and BSI (adjusted OR 4.0, 95% CI 1.3–11.0) were associated with future VTE. Urinary and other infections were not associated with subsequent VTE. Conclusions Infections are associated with subsequent risk of VTE among patients with ICH. Further investigation is required to elucidate mechanisms behind this association and to improve VTE prevention after ICH.

Background and Purpose— Perihematomal edema (PHE) is a promising surrogate marker of secondary brain injury in patients with spontaneous intracerebral hemorrhage, but it can be challenging to accurately and rapidly quantify. The aims of this study are to derive and internally validate a fully automated segmentation algorithm for volumetric analysis of PHE. Methods— Inpatient computed tomography scans of 400 consecutive adults with spontaneous, supratentorial intracerebral hemorrhage enrolled in the Intracerebral Hemorrhage Outcomes Project (2009–2018) were separated into training (n=360) and test (n=40) datasets. A fully automated segmentation algorithm was derived from manual segmentations in the training dataset using convolutional neural networks, and its performance was compared with that of manual and semiautomated segmentation methods in the test dataset. Results— The mean volumetric dice similarity coefficients for the fully automated segmentation algorithm were 0.838±0.294 and 0.843±0.293 with manual and semiautomated segmentation methods as reference standards, respectively. PHE volumes derived from the fully automated versus manual (r=0.959; P P P P P Conclusions— The fully automated segmentation algorithm accurately quantified PHE volumes from computed tomography scans of supratentorial intracerebral hemorrhage patients with high fidelity and greater efficiency compared with manual and semiautomated segmentation methods. External validation of fully automated segmentation for assessment of PHE is warranted.

Background Key dimensions of cardiac arrest-induced posttraumatic stress disorder (PTSD) symptoms include reexperiencing, avoidance, numbing, and hyperarousal. It remains unknown which dimensions are most predictive of outcome. Purpose To determine which dimensions of cardiac arrest-induced PTSD are predictive of clinical outcome within 13 months posthospital discharge. Methods PTSD symptoms were assessed in survivors of cardiac arrest who were able to complete psychological screening measures at hospital discharge via the PTSD Checklist-Specific scale, which queries for 17 symptoms using five levels of severity. Responses on items for each symptom dimension of the four-factor numbing model (reexperiencing, avoidance, numbing, and hyperarousal) were converted to Z-scores and treated as continuous predictors. The combined primary endpoint was all-cause mortality (ACM) or major adverse cardiovascular events (MACE; hospitalization for myocardial infarction, unstable angina, heart failure, emergency coronary revascularization, or urgent defibrillator/pacemaker placements) within 13 months postdischarge. Four bivariate Cox proportional hazards survival models evaluated associations between individual symptom dimensions and ACM/MACE. A multivariable model then evaluated whether significant bivariate predictors remained independent predictors of the primary outcome after adjusting for age, sex, comorbidities, premorbid psychiatric diagnoses, and initial cardiac rhythm. Results A total of 114 patients (59.6% men, 52.6% white, mean age: 54.6 ± 13 years) were included. In bivariate analyses, only hyperarousal was significantly associated with ACM/MACE. In a fully adjusted model, 1 standard deviation increase in hyperarousal symptoms corresponded to a two-times increased risk of experiencing ACM/MACE. Conclusions Greater level of hyperarousal symptoms was associated with a higher risk of ACM/MACE within 13 months postcardiac arrest. This initial evidence should be further investigated in a larger sample.

Background and Purpose— Hematoma volume measurements influence prognosis and treatment decisions in patients with spontaneous intracerebral hemorrhage (ICH). The aims of this study are to derive and validate a fully automated segmentation algorithm for ICH volumetric analysis using deep learning methods. Methods— In-patient computed tomography scans of 300 consecutive adults (age ≥18 years) with spontaneous, supratentorial ICH who were enrolled in the ICHOP (Intracerebral Hemorrhage Outcomes Project; 2009–2018) were separated into training (n=260) and test (n=40) datasets. A fully automated segmentation algorithm was derived using convolutional neural networks, and it was trained on manual segmentations from the training dataset. The algorithm’s performance was assessed against manual and semiautomated segmentation methods in the test dataset. Results— The mean volumetric Dice similarity coefficients for the fully automated segmentation algorithm when tested against manual and semiautomated segmentation methods were 0.894±0.264 and 0.905±0.254, respectively. ICH volumes derived from fully automated versus manual ( R 2 =0.981; P R 2 =0.978; P R 2 =0.990; P P P Conclusions— The fully automated segmentation algorithm quantified hematoma volumes from computed tomography scans of supratentorial ICH patients with similar accuracy and substantially greater efficiency compared with manual and semiautomated segmentation methods. External validation of the fully automated segmentation algorithm is warranted.

A variety of genetic techniques have been devised to determine cell lineage relationships during tissue development. Some of these systems monitor cell lineages spatially and/or temporally without regard to gene expression by the cells, whereas others correlate gene expression with the lineage under study. The GAL4 Technique for Real-time and Clonal Expression (G-TRACE) system allows for rapid, fluorescent protein-based visualization of both current and past GAL4 expression patterns and is therefore amenable to genome-wide expression-based lineage screens. Here we describe the results from such a screen, performed by undergraduate students of the University of California, Los Angeles (UCLA) Undergraduate Research Consortium for Functional Genomics (URCFG) and high school summer scholars as part of a discovery-based education program. The results of the screen, which reveal novel expression-based lineage patterns within the brain, the imaginal disc epithelia, and the hematopoietic lymph gland, have been compiled into the G-TRACE Expression Database (GED), an online resource for use by the Drosophila research community. The impact of this discovery-based research experience on student learning gains was assessed independently and shown to be greater than that of similar programs conducted elsewhere. Furthermore, students participating in the URCFG showed considerably higher STEM retention rates than UCLA STEM students that did not participate in the URCFG, as well as STEM students nationwide.

This cohort study evaluates the mortality and functional outcome in patients with spontaneous intracerebral hemorrhage who received intraventricular alteplase vs those who received saline., Key Points Question Is intraventricular thrombolysis in patients with spontaneous intracerebral hemorrhage (ICH) and intraventricular hemorrhage (IVH) associated with reduced parenchymal ICH volume? Findings In this cohort study of 454 patients with ICH and IVH who were enrolled in a randomized clinical trial, intraventricular alteplase use was associated with a small reduction in the parenchymal ICH volume. However, no association was found between a change in parenchymal ICH volume and death or major disability. Meaning Findings of this study suggest that further exploration of the role of intraventricular thrombolysis in reducing parenchymal ICH volumes and potentially improving outcomes is warranted in patients with a moderate to large ICH with IVH and those with a thalamic ICH., Importance Intraventricular thrombolysis reduces intraventricular hemorrhage (IVH) volume in patients with spontaneous intracerebral hemorrhage (ICH), but it is unclear if a similar association with parenchymal ICH volume exists. Objective To evaluate the association between intraventricular alteplase use and ICH volume as well as the association between a change in parenchymal ICH volume and long-term functional outcomes. Design, Setting, and Participants This cohort study was a post hoc exploratory analysis of data from the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage phase 3 randomized clinical trial with blinded outcome assessments. Between September 1, 2009, and January 31, 2015, patients with ICH and IVH were randomized to receive either intraventricular alteplase or normal saline via an external ventricular drain. Participants with primary IVH were excluded. Data analyses were performed between January 1 and June 30, 2021. Exposure Randomization to receive intraventricular alteplase. Main Outcomes and Measures The primary outcome was the change in parenchymal ICH volume between the hematoma stability and end-of-treatment computed tomography scans. Secondary outcomes were a modified Rankin Scale score higher than 3 and mortality, both of which were assessed at 6 months. The association between alteplase and change in parenchymal ICH volume was assessed using multiple linear regression, whereas the associations between change in parenchymal ICH volume and 6-month outcomes were assessed using multiple logistic regression. Prespecified subgroup analyses were performed for baseline IVH volume, admission ICH volume, and ICH location. Results A total of 454 patients (254 men [55.9%]; mean [SD] age, 59 [11] years) were included in the study. Of these patients, 230 (50.7%) were randomized to receive alteplase and 224 (49.3%) to receive normal saline. The alteplase group had a greater mean (SD) reduction in parenchymal ICH volume compared with the saline group (1.8 [0.2] mL vs 0.4 [0.1] mL; P

Coronavirus disease-2019 (COVID-19) is associated with hypercoagulability that may cause thromobembolic complications. We describe our recent studies investigating the mechanisms of hypercoagulability in patients with severe COVID-19 requiring mechanical ventilation during the COVID-19 crisis in New York City in spring 2020. Using rotational thombelastometry we found that almost all patients with severe COVID-19 had signs of hypercoagulability compared with non-COVID-19 controls. Specifically, the maximal clot firmness in the fibrin-based extrinsically activated test was almost twice the upper limit of normal in COVID patients, indicating a fibrin-mediated cause for hypercoagulability. To better understand the mechanism of this hypercoagulability we measured the components of the fibrinolytic pathways. Fibrinogen, tissue plasminogen activator and plasminogen activator inhibitor-1, but not plasminogen levels were elevated in patients with severe COVID-19. Our studies indicate that hypercoagulability in COVID-19 may be because of decreased fibrinolysis resulting from inhibition of plasmin through high levels of plasminogen activator inhibitor-1. Clinicians creating treatment protocols for anticoagulation in critically ill COVID-19 patients should consider these potential mechanisms of hypercoaguability.

The Corona Virus Disease 2019 (COVID-19) pandemic represents an ongoing worldwide challenge. Exploratory studies evaluating the impact of COVID-19 infection on the plasma metabolome have been performed, often with small numbers of patients, and with or without relevant control data; however, determining the impact of biological and clinical variables remains critical to understanding potential markers of disease severity and progression. The present large study, including relevant controls, sought to understand independent and overlapping metabolic features of samples from acutely ill patients (n = 831), testing positive (n = 543) or negative (n = 288) for COVID-19. High-throughput metabolomics analyses were complemented with antigen and enzymatic activity assays on 831 plasma samples from acutely ill patients while in the emergency department, at admission, and during hospitalization. We then performed additional lipidomics analyses of the 60 subjects with the lowest and highest body mass index, either COVID-19 positive or negative. Omics data were correlated to detailed data on patient characteristics and clinical laboratory assays measuring coagulation, hematology and chemistry analytes. Significant changes in arginine/proline/citrulline, tryptophan/indole/kynurenine, fatty acid and acyl-carnitine metabolism emerged as highly relevant markers of disease severity, progression and prognosis as a function of biological and clinical variables in these patients. Further, machine learning models were trained by entering all metabolomics and clinical data from half of the COVID-19 patient cohort and then tested on the other half yielding ~ 78% prediction accuracy. Finally, the extensive amount of information accumulated in this large, prospective, observational study provides a foundation for follow-up mechanistic studies and data sharing opportunities, which will advance our understanding of the characteristics of the plasma metabolism in COVID-19 and other acute critical illnesses.

Recovery trajectories of clinically unresponsive patients with acute brain injury are largely uncertain. Brain activation in the absence of a behavioural response to spoken motor commands can be detected by EEG, also known as cognitive-motor dissociation. We aimed to explore the role of cognitive-motor dissociation in predicting time to recovery in patients with acute brain injury.In this observational cohort study, we prospectively studied two independent cohorts of clinically unresponsive patients (aged ≥18 years) with acute brain injury. Machine learning was applied to EEG recordings to diagnose cognitive-motor dissociation by detecting brain activation in response to verbal commands. Survival statistics and shift analyses were applied to the data to identify an association between cognitive-motor dissociation and time to and magnitude of recovery. The prediction accuracy of the model that was built using the derivation cohort was assessed using the validation cohort. Functional outcomes of all patients were assessed with the Glasgow Outcome Scale-Extended (GOS-E) at hospital discharge and at 3, 6, and 12 months after injury. Patients who underwent withdrawal of life-sustaining therapies were censored, and death was treated as a competing risk.Between July 1, 2014, and Sept 30, 2021, we screened 598 patients with acute brain injury and included 193 (32%) patients, of whom 100 were in the derivation cohort and 93 were in the validation cohort. At 12 months, 28 (15%) of 193 unresponsive patients had a GOS-E score of 4 or above. Cognitive-motor dissociation was seen in 27 (14%) patients and was an independent predictor of shorter time to good recovery (hazard ratio 5·6 [95% CI 2·5-12·5]), as was underlying traumatic brain injury or subdural haematoma (4·4 [1·4-14·0]), a Glasgow Coma Scale score on admission of greater than or equal to 8 (2·2 [1·0-4·7]), and younger age (1·0 [1·0-1·1]). Among patients discharged home or to a rehabilitation setting, those diagnosed with cognitive-motor dissociation consistently had higher scores on GOS-E indicating better functional recovery compared with those without cognitive-motor dissociation, which was seen as early as 3 months after the injury (odds ratio 4·5 [95% CI 2·0-33·6]).Recovery trajectories of clinically unresponsive patients diagnosed with cognitive-motor dissociation early after brain injury are distinctly different from those without cognitive-motor dissociation. A diagnosis of cognitive-motor dissociation could inform the counselling of families of clinically unresponsive patients, and it could help clinicians to identify patients who will benefit from rehabilitation.US National Institutes of Health.

Background The objective of this study was to evaluate the accuracy of seizure burden in patients with super-refractory status epilepticus (SRSE) by using quantitative electroencephalography (qEEG). Methods EEG recordings from 69 patients with SRSE (2009-2019) were reviewed and annotated for seizures by three groups of reviewers: two board-certified neurophysiologists using only raw EEG (gold standard), two neurocritical care providers with substantial experience in qEEG analysis (qEEG experts), and two inexperienced qEEG readers (qEEG novices) using only a qEEG trend panel. Results Raw EEG experts identified 35 (51%) patients with seizures, accounting for 2950 seizures (3,126 min). qEEG experts had a sensitivity of 93%, a specificity of 61%, a false positive rate of 6.5 per day, and good agreement (κ = 0.64) between both qEEG experts. qEEG novices had a sensitivity of 98.5%, a specificity of 13%, a false positive rate of 15 per day, and fair agreement (κ = 0.4) between both qEEG novices. Seizure burden was not different between the qEEG experts and the gold standard (3,257 vs. 3,126 min), whereas qEEG novices reported higher burden (6066 vs. 3126 min). Conclusions Both qEEG experts and novices had a high sensitivity but a low specificity for seizure detection in patients with SRSE. qEEG could be a useful tool for qEEG experts to estimate seizure burden in patients with SRSE.

OBJECTIVE: Intracranial pressure waveform morphology reflects compliance, which can be decreased by ventriculitis. We investigated whether morphologic analysis of intracranial pressure dynamics predicts the onset of ventriculitis. METHODS: Ventriculitis was defined as culture or Gram-stain positive cerebrospinal fluid warranting treatment. We developed a pipeline to automatically isolate segments of intracranial pressure waveforms from extraventricular catheters, extract dominant pulses, and obtain morphologically similar groupings. We utilized a previously validated clinician-supervised active learning paradigm to identify meta-clusters of triphasic, single-peak, and artifactual peaks. Meta-cluster distributions were concatenated with temperature and routine blood laboratory values to create feature vectors. A L2-regularized logistic regression classifier was trained to distinguish patients with ventriculitis from matched controls and the discriminative performance using area under receiver operating characteristic curve with bootstrapping cross-validation was reported. RESULTS: Fifty-eight patients were included for analysis. Twenty-seven patients with ventriculitis from two centers were identified. Thirty-one patients with catheters but without ventriculitis were selected as matched controls based on age, gender, and primary diagnosis. There were 1590 hours of segmented data including 396,130 dominant pulses in ventriculitis patients and 557,435 pulses in patients without ventriculitis. There were significant differences in meta-cluster distribution comparing before culture-positivity vs during culture-positivity (p

The association between impaired brain perfusion, cerebrovascular reactivity status and the risk of ictal events in patients with subarachnoid hemorrhage is unknown. We identified 13 subarachnoid hemorrhage (SAH) patients with seizures and 22 with ictal-interictal continuum (IIC), and compared multimodality physiological recordings to 38 similarly poor-grade SAH patients without ictal activity. We analyzed 10,179 cumulative minutes of seizure and 12,762 cumulative minutes of IIC. Cerebrovascular reactivity (PRx) was not different between subjects with seizures, IIC, or controls. Cerebral perfusion pressure (CPP) was higher in patients with seizures [99 ± 6.5, p = .005] and IIC [97 ± 8.5, p = .007] when compared to controls [89 ± 12.3]. DeltaCPP, defined as actual CPP minus optimal CPP (CPPopt), was also higher in the seizure group [8.3 ± 7.9, p = .0003] and IIC [8.1 ± 10.3, p = .0006] when compared to controls [−0.1 ± 5]. Time spent with supra-optimal CPP was higher in the seizure group [342 ± 213 min/day, p = .002] when compared to controls [154 ± 120 min/day]. In a temporal examination, a supra-optimal CPP preceded increased seizures and IIC in SAH patients, an hour before and continued to increase during the events [ p

ObjectiveStudies have independently shown associations of lower hemoglobin levels with larger admission intracerebral hemorrhage (ICH) volumes and worse outcomes. We investigated whether lower admission hemoglobin levels are associated with more hematoma expansion (HE) after ICH and whether this mediates lower hemoglobin levels' association with worse outcomes.MethodsConsecutive patients enrolled between 2009 and 2016 to a single-center prospective ICH cohort study with admission hemoglobin and neuroimaging data to calculate HE (>33% or >6 mL) were evaluated. The association of admission hemoglobin levels with HE and poor clinical outcomes using modified Rankin Scale (mRS 4–6) were assessed using separate multivariable logistic regression models. Mediation analysis investigated causal associations among hemoglobin, HE, and outcome.ResultsOf 256 patients with ICH meeting inclusion criteria, 63 (25%) had HE. Lower hemoglobin levels were associated with increased odds of HE (odds ratio [OR] 0.80 per 1.0 g/dL change of hemoglobin; 95% confidence interval [CI] 0.67–0.97) after adjusting for previously identified covariates of HE (admission hematoma volume, antithrombotic medication use, symptom onset to admission CT time) and hemoglobin (age, sex). Lower hemoglobin was also associated with worse 3-month outcomes (OR 0.76 per 1.0 g/dL change of hemoglobin; 95% CI 0.62–0.94) after adjusting for ICH score. Mediation analysis revealed that associations of lower hemoglobin with poor outcomes were mediated by HE (p = 0.01).ConclusionsFurther work is required to replicate the associations of lower admission hemoglobin levels with increased odds of HE mediating worse outcomes after ICH. If confirmed, an investigation into whether hemoglobin levels can be a modifiable target of treatment to improve ICH outcomes may be warranted.

Coagulopathy may be defined as the loss of balance between hemostatic and fibrinolytic processes resulting in excessive bleeding, intravascular thrombosis or abnormalities in coagulation testing. It is frequently encountered across a wide range of conditions seen in the neurocritical care unit and can contribute to poor outcomes. Early recognition and appropriate management are key, with traumatic brain injury, acute ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage presenting unique challenges to the neurointensivist. We will discuss techniques to assess coagulopathies as well as treatment strategies for the brain injured patient.