Primary and Secondary Intracerebral Hemorrhage in Pregnant and Nonpregnant Young Adults by SMASH-UP Criteria.

BACKGROUND: Intracerebral hemorrhage (ICH) is a major cause of maternal morbidity, but its pathophysiology is poorly characterized. We investigated characteristics of pregnancy-associated ICH (P-ICH), compared with ICH in similar aged nonpregnant adults of both sexes. METHODS AND RESULTS: We performed a retrospective analysis of 134 adults aged 18 to 44 years admitted to our center with nontraumatic ICH from January 1, 2012, to December 31, 2021. We compared ICH characteristics among 3 groups: those with P-ICH (pregnant or within 12 months of end of pregnancy); nonpregnant women; and men. We categorized ICH pathogenesis according to a modified scheme, SMASH-UP (structural, medications, amyloid angiopathy, systemic, hypertension, undetermined, posterior reversible encephalopathy syndrome/reversible cerebral vasoconstriction syndrome), and calculated odds ratios and 95% CIs for primary (spontaneous small-vessel) ICH versus secondary ICH (structural lesions or coagulopathy related), using nonpregnant women as the reference. We also compared specific ICH pathogenesis by SMASH-UP criteria and functional outcomes between groups. Of 134 young adults with nontraumatic ICH, 25 (19%) had P-ICH, of which 60% occurred postpartum. Those with P-ICH had higher odds of primary ICH compared with nonpregnant women (adjusted odds ratio, 4.5 [95% CI, 1.4-14.7]). The odds of primary ICH did not differ between men and nonpregnant women. SMASH-UP pathogenesis for ICH differed significantly between groups (P<0.001). While the in-hospital mortality rate was lowest in the P-ICH group (4%) compared with nonpregnant women (13%) and men (24%), 1 in 4 patients with P-ICH were bedbound and dependent at the time of discharge. CONCLUSIONS: In our cohort of young adults with ICH, 1 in 5 was pregnancy related. P-ICH differed in pathogenesis compared with non-pregnancy-related ICH in young adults, suggesting unique pathophysiology.

Relationships of Hematocrit With Chronic Covert and Acute Symptomatic Lacunar Ischemic Lesions.

BACKGROUND AND OBJECTIVES: Red blood cell (RBC) concentrations are known to associate with ischemic stroke. It is unclear whether RBC concentrations associate specifically with small vessel disease lacunar infarcts. We investigated the hypothesis that RBC concentrations associate with both chronic covert and acute symptomatic brain MRI lacunar infarcts. METHODS: A cross-sectional observational analysis was performed across 2 cohorts with available hematocrit (as the assessment of RBC concentration exposure) and MRI outcome data. The primary setting was a population-based cohort of stroke-free, older adult (>50 years) participants from the Northern Manhattan Study (NOMAS) enrolled between 2003 and 2009. A second replication sample consisted of patients admitted with acute stroke and enrolled into the Columbia Stroke Registry (CSR) between 2005 and 2020. Associations of hematocrit with (1) chronic, covert lacunar infarcts and (2) symptomatic (i.e., acute) lacunar strokes were separately assessed from the NOMAS and CSR cohorts, respectively, using general additive models after adjusting for relevant covariates. RESULTS: Of 1,218 NOMAS participants analyzed, 6% had chronic, covert lacunar infarcts. The association between hematocrit and these covert lacunar infarcts was U-shaped (χ2 = 9.21 for nonlinear associations; p = 0.03), with people with hematocrit extremes being more likely to have covert lacunar infarcts. Of the 1,489 CSR patients analyzed, 23% had acute lacunar strokes. In this sample, only the relationships of increased hematocrit concentrations and lacunar strokes were replicated (adjusted coefficient ß = 0.020; SE = 0.009; p = 0.03). DISCUSSION: We identified relationships of hematocrit with MRI lacunar infarcts in both stroke-free and ischemic stroke cohorts, respectively. The relationship between increased hematocrit concentrations with lacunar infarcts was replicated in both cohorts. Further studies are required to clarify the mechanisms behind the relationships of hematocrit with ischemic cerebral small vessel disease.

Suboptimal Cerebral Perfusion is Associated with Ischemia After Intracerebral Hemorrhage.

BACKGROUND: Remote ischemic lesions on diffusion-weighted imaging (DWI) occur in one third of patients with intracerebral hemorrhage (ICH) and are associated with worse outcomes. The etiology is unclear and not solely due to blood pressure reduction. We hypothesized that impaired cerebrovascular autoregulation and hypoperfusion below individualized lower limits of autoregulation are associated with the presence of DWI lesions. METHODS: This was a retrospective, single-center study of all primary ICH with intraparenchymal pressure monitoring within 10 days from onset and subsequent magnetic resonance imaging. Pressure reactivity index was calculated as the correlation coefficient between mean arterial pressure and intracranial pressure. Optimal cerebral perfusion pressure (CPPopt) is the cerebral perfusion pressure (CPP) with the lowest corresponding pressure reactivity index. The difference between CPP and CPPopt, time spent below the lower limit of autoregulation (LLA), and time spent above the upper limit of autoregulation (ULA) were calculated by using mean hourly physiologic data. Univariate associations between physiologic parameters and DWI lesions were analyzed by using binary logistic regression. RESULTS: A total of 505 h of artifact-free data from seven patients without DWI lesions and 479 h from six patients with DWI lesions were analyzed. Patients with DWI lesions had higher intracranial pressure (17.50 vs. 10.92 mm Hg; odds ratio 1.14, confidence interval 1.01-1.29) but no difference in mean arterial pressure or CPP compared with patients without DWI lesions. The presence of DWI lesions was significantly associated with a greater percentage of time spent below the LLA (49.85% vs. 14.70%, odds ratio 5.77, confidence interval 1.88-17.75). No significant association was demonstrated between CPPopt, the difference between CPP and CPPopt, ULA, LLA, or time spent above the ULA between groups. CONCLUSIONS: Blood pressure reduction below the LLA is associated with ischemia after acute ICH. Individualized, autoregulation-informed targets for blood pressure reduction may provide a novel paradigm in acute management of ICH and require further study.

Red Blood Cell Transfusions Are Not Associated With Incident Complications or Poor Outcomes in Patients With Intracerebral Hemorrhage.

Background Anemia is associated with poor intracerebral hemorrhage (ICH) outcomes, yet the relationship of red blood cell (RBC) transfusions to ICH complications and functional outcomes remains unclear. We investigated the impact of RBC transfusion on hospital thromboembolic and infectious complications and outcomes in patients with ICH. Methods and Results Consecutive patients with spontaneous ICH enrolled in a single-center, prospective cohort study from 2009 to 2018 were assessed. Primary analyses assessed relationships of RBC transfusions on incident thromboembolic and infectious complications occurring after the transfusion. Secondary analyses assessed relationships of RBC transfusions with mortality and poor discharge modified Rankin Scale score 4 to 6. Multivariable logistic regression models adjusted for baseline demographics and medical disease severity (Acute Physiology and Chronic Health Evaluation II), and ICH severity (ICH score).Of 587 patients with ICH analyzed, 88 (15%) received at least one RBC transfusion. Patients receiving RBC transfusions had worse medical and ICH severity. Though patients receiving RBC transfusions had more complications at any point during the hospitalization (64.8% versus 35.9%), we found no association between RBC transfusion and incident complications in our regression models (adjusted odds ratio [aOR], 0.71 [95% CI, 0.42-1.20]). After adjusting for disease severity and other relevant covariates, we found no significant association between RBC transfusion and mortality (aOR, 0.87 [95% CI, 0.45-1.66]) or poor discharge modified Rankin Scale score (aOR, 2.45 [95% CI, 0.80-7.61]). Conclusions In our cohort with ICH, RBC transfusions were expectedly given to patients with higher medical and ICH severity. Taking disease severity and timing of transfusions into account, RBC transfusion was not associated with incident hospital complications or poor clinical ICH outcomes.

A Deep Learning Framework for Deriving Noninvasive Intracranial Pressure Waveforms from Transcranial Doppler.

Increased intracranial pressure (ICP) causes disability and mortality in the neurointensive care population. Current methods for monitoring ICP are invasive. We designed a deep learning framework using a domain adversarial neural network to estimate noninvasive ICP, from blood pressure, electrocardiogram, and cerebral blood flow velocity. Our model had a mean of median absolute error of 3.88 ± 3.26 mmHg for the domain adversarial neural network, and 3.94 ± 1.71 mmHg for the domain adversarial transformers. Compared with nonlinear approaches, such as support vector regression, this was 26.7% and 25.7% lower. Our proposed framework provides more accurate noninvasive ICP estimates than currently available. ANN NEUROL 2023;94:196-202.

Transfusion medicine approaches for spontaneous intracerebral hemorrhage patients.

PURPOSE OF REVIEW: Spontaneous intracerebral hemorrhage (ICH) is the deadliest stroke subtype. Acute treatments necessitate rapid hemorrhage control to minimize secondary brain injury. Here, we discuss the overlap of transfusion medicine and acute ICH care relating to diagnostic testing and therapies relevant for coagulopathy reversal and secondary brain injury prevention. RECENT FINDINGS: Hematoma expansion (HE) is the largest contributor to poor outcomes after ICH. Conventional coagulation assays to diagnose coagulopathy after ICH does not predict HE. Given the testing limitations, empiric pragmatic hemorrhage control therapies have been trialed but have not improved ICH outcomes, with some therapies even causing harm. It is still unknown whether faster administration of these therapies will improve outcomes. Alternative coagulation tests (e.g., viscoelastic hemostatic assays, amongst others) may identify coagulopathies relevant for HE, currently not diagnosed using conventional assays. This provides opportunities for rapid, targeted therapies. In parallel, ongoing work is investigating alternative treatments using transfusion-based or transfusion-sparing pharmacotherapies that can be implemented in hemorrhage control strategies after ICH. SUMMARY: Further work is needed to identify improved laboratory diagnostic approaches and transfusion medicine treatment strategies to prevent HE and optimize hemorrhage control in ICH patients, who appear particularly vulnerable to the impacts of transfusion medicine practices.

Relationships of Hemoglobin Concentration, Ischemic Lesions, and Clinical Outcomes in Patients With Intracerebral Hemorrhage.

BACKGROUND: Hemoglobin concentration and diffusion-weighted imaging (DWI) ischemic lesions are separately known to be associated with poor intracerebral hemorrhage (ICH) outcomes. While hemoglobin concentrations have known relationships with ischemic stroke, it is unclear whether hemoglobin concentration is associated with DWI ischemic lesions after ICH. We sought to investigate the hypothesis that hemoglobin concentrations would associate with DWI lesions after ICH and further investigated their relationships with clinical outcomes. METHODS: Supratentorial ICH patients enrolled between 2010 and 2016 to a prospective, multicenter, observational cohort study (ERICH study [Ethnic/Racial Variations of Intracerebral Hemorrhage]) were assessed. Patients from this study with baseline, admission hemoglobin, and hospitalization magnetic resonance imaging were analyzed. Hemoglobin was examined as the primary exposure variable defined as a continuous variable (g/dL). Magnetic resonance imaging DWI ischemic lesion presence was assessed as the primary radiographic outcome. Primary analyses assessed relationships of hemoglobin with DWI lesions. Secondary analyses assessed relationships of DWI lesions with poor 3-month outcomes (modified Rankin Scale score, 4-6). These analyses were performed using separate multivariable logistic regression models adjusting for relevant covariates. RESULTS: Of 917 patients with ICH analyzed, 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 odds ratio, 1.21 per 1 g/dL change in hemoglobin [95% CI, 1.07-1.37]) after adjusting for sex, race, ICH severity, time to magnetic resonance imaging, and acute blood pressure change. In secondary analyses, DWI lesions were associated with poor 3-month outcomes (adjusted odds ratio, 1.83 [95% CI, 1.24-2.69]) after adjusting for similar covariates. CONCLUSIONS: We identified novel relationships between higher baseline hemoglobin concentrations and DWI ischemic lesions in patients with ICH. Further studies are required to clarify the role of hemoglobin concentration on both cerebral small vessel disease pathophysiology and ICH outcomes.

Hemoglobin Concentration Impacts Viscoelastic Hemostatic Assays in ICU Admitted Patients.

OBJECTIVES: Low hemoglobin concentration impairs clinical hemostasis across several diseases. It is unclear whether hemoglobin impacts laboratory functional coagulation assessments. We evaluated the relationship of hemoglobin concentration on viscoelastic hemostatic assays in intracerebral hemorrhage (ICH) and perioperative patients admitted to an ICU. DESIGN: Observational cohort study and separate in vitro laboratory study. SETTING: Multicenter tertiary referral ICUs. PATIENTS: Two acute ICH cohorts receiving distinct testing modalities: rotational thromboelastometry (ROTEM) and thromboelastography (TEG), and a third surgical ICU cohort receiving ROTEM were evaluated to assess the generalizability of findings across disease processes and testing platforms. A separate in vitro ROTEM laboratory study was performed utilizing ICH patient blood samples. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Relationships between baseline hemoglobin and ROTEM/TEG results were separately assessed across patient cohorts using Spearman correlations and linear regression models. A separate in vitro study assessed ROTEM tracing changes after serial hemoglobin modifications from ICH patient blood samples. In both our ROTEM (n = 34) and TEG (n = 239) ICH cohorts, hemoglobin concentrations directly correlated with coagulation kinetics (ROTEM r: 0.46; p = 0.01; TEG r: 0.49; p < 0.0001) and inversely correlated with clot strength (ROTEM r: -0.52, p = 0.002; TEG r: -0.40, p < 0.0001). Similar relationships were identified in perioperative ICU admitted patients (n = 121). We continued to identify these relationships in linear regression models. When manipulating ICH patient blood samples to achieve lower hemoglobin concentrations in vitro, we similarly identified that lower hemoglobin concentrations resulted in progressively faster coagulation kinetics and greater clot strength on ROTEM tracings. CONCLUSIONS: Lower hemoglobin concentrations have a consistent, measurable impact on ROTEM/TEG testing in ICU admitted patients, which appear to be artifactual. It is possible that patients with low hemoglobin may appear to have normal viscoelastic parameters when, in fact, they have a mild hypocoagulable state. Further work is required to determine if these tests should be corrected for a patient's hemoglobin concentration.

Optimal Cerebral Perfusion Pressure and Brain Tissue Oxygen in Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Targeting a cerebral perfusion pressure optimal for cerebral autoregulation (CPPopt) has been gaining more attention to prevent secondary damage after acute neurological injury. Brain tissue oxygenation (PbtO2) can identify insufficient cerebral blood flow and secondary brain injury. Defining the relationship between CPPopt and PbtO2 after aneurysmal subarachnoid hemorrhage may result in (1) mechanistic insights into whether and how CPPopt-based strategies might be beneficial and (2) establishing support for the use of PbtO2 as an adjunctive monitor for adequate or optimal local perfusion. METHODS: We performed a retrospective analysis of a prospectively collected 2-center dataset of patients with aneurysmal subarachnoid hemorrhage with or without later diagnosis of delayed cerebral ischemia (DCI). CPPopt was calculated as the cerebral perfusion pressure (CPP) value corresponding to the lowest pressure reactivity index (moving correlation coefficient of mean arterial and intracranial pressure). The relationship of (hourly) deltaCPP (CPP-CPPopt) and PbtO2 was investigated using natural spline regression analysis. Data after DCI diagnosis were excluded. Brain tissue hypoxia was defined as PbtO2 <20 mmHg. RESULTS: One hundred thirty-one patients were included with a median of 44.0 (interquartile range, 20.8-78.3) hourly CPPopt/PbtO2 datapoints. The regression plot revealed a nonlinear relationship between PbtO2 and deltaCPP (P<0.001) with PbtO2 decrease with deltaCPP <0 mmHg and stable PbtO2 with deltaCPP ≥0mmHg, although there was substantial individual variation. Brain tissue hypoxia (34.6% of all measurements) was more frequent with deltaCPP <0 mmHg. These dynamics were similar in patients with or without DCI. CONCLUSIONS: We found a nonlinear relationship between PbtO2 and deviation of patients' CPP from CPPopt in aneurysmal subarachnoid hemorrhage patients in the pre-DCI period. CPP values below calculated CPPopt were associated with lower PbtO2. Nevertheless, the nature of PbtO2 measurements is complex, and the variability is high. Combined multimodality monitoring with CPP/CPPopt and PbtO2 should be recommended to redefine individual pressure targets (CPP/CPPopt) and retain the option to detect local perfusion deficits during DCI (PbtO2), which cannot be fulfilled by both measurements interchangeably.

A generalizable physiological model for detection of Delayed Cerebral Ischemia using Federated Learning.

Delayed cerebral ischemia (DCI) is a complication seen in patients with subarachnoid hemorrhage stroke. It is a major predictor of poor outcomes and is detected late. Machine learning models are shown to be useful for early detection, however training such models suffers from small sample sizes due to rarity of the condition. Here we propose a Federated Learning approach to train a DCI classifier across three institutions to overcome challenges of sharing data across hospitals. We developed a framework for federated feature selection and built a federated ensemble classifier. We compared the performance of FL model to that obtained by training separate models at each site. FL significantly improved performance at only two sites. We found that this was due to feature distribution differences across sites. FL improves performance in sites with similar feature distributions, however, FL can worsen performance in sites with heterogeneous distributions. The results highlight both the benefit of FL and the need to assess dataset distribution similarity before conducting FL.

Intraventricular Hemorrhage Expansion in the CLEAR III Trial: A Post Hoc Exploratory Analysis.

BACKGROUND: The objective of this study was to evaluate factors associated with intraventricular hemorrhage (IVH) expansion and its association with long-term outcomes. METHODS: We performed a post hoc analysis of the international, multi-center CLEAR III trial (Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage) which enrolled IVH patients between September 1, 2009, and January 31, 2015. The exposure was IVH expansion, defined as >1 mL increase in volume between baseline and stability computed tomography scans, before treatment randomization. We assessed factors associated with IVH expansion and secondarily assessed the relationship of IVH expansion with clinical outcomes: composite of death or major disability (modified Rankin Scale score, >3), and mortality alone at 6 months. The relationship of IVH expansion on ventriculoperitoneal shunt placement was additionally explored. Multivariable logistic regression was used for all analyses. RESULTS: Of 500 IVH patients analyzed, the mean age was 59 (±11) years old, 44% were female and 135 (27%) had IVH expansion. In multivariable regression models, factors associated with IVH expansion were baseline parenchymal intracerebral hemorrhage (ICH) volume (adjusted odds ratio [OR], 1.04 per 1 mL increase [95% CI, 1.01-1.08]), presence of parenchymal hematoma expansion: >33% (adjusted OR, 6.63 [95% CI, 3.92-11.24]), time to stability head CT (adjusted OR, 0.71 per 1 hour increase [95% CI, 0.54-0.94]), and thalamic hematoma location (adjusted OR, 1.68 [95% CI, 1.01-2.79]) while additionally adjusting for age, sex, and race. In secondary analyses, IVH expansion was associated with higher odds of poor 6-month outcomes (adjusted OR, 1.84 [95% CI, 1.12-3.02]) but not mortality (OR, 1.40 [95% CI, 0.78-2.50]) after adjusting for baseline ICH volume, thalamic ICH location, age, anticoagulant use, Glasgow Coma Scale score, any withdrawal of care order, and treatment randomization arm. However, there were no relationships of IVH expansion on subsequent ventriculoperitoneal shunt placement (adjusted OR, 1.02 [95% CI, 0.58-1.80]) after adjusting for similar covariates. CONCLUSIONS: In a clinical trial cohort of patients with large IVH, acute hematoma characteristics, specifically larger parenchymal volume, hematoma expansion, and thalamic ICH location were associated with IVH expansion. Given that IVH expansion resulted in poor functional outcomes, exploration of treatment approaches to optimize hemostasis and prevent IVH expansion, particularly in patients with thalamic ICH, require further study. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT00784134.

Dynamic Intracranial Pressure Waveform Morphology Predicts Ventriculitis.

BACKGROUND: 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 used a previously validated clinician-supervised active learning paradigm to identify metaclusters of triphasic, single-peak, or artifactual peaks. Metacluster 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, sex, and primary diagnosis. There were 1590 h of segmented data, including 396,130 dominant pulses in patients with ventriculitis and 557,435 pulses in patients without ventriculitis. There were significant differences in metacluster distribution comparing before culture-positivity versus during culture-positivity (p < 0.001) and after culture-positivity (p < 0.001). The classifier demonstrated good discrimination with median area under receiver operating characteristic 0.70 (interquartile range 0.55-0.80). There were 1.5 true alerts (ventriculitis detected) for every false alert. CONCLUSIONS: Intracranial pressure waveform morphology analysis can classify ventriculitis without cerebrospinal fluid sampling.

Cerebral Microbleeds and Acute Hematoma Characteristics in the ATACH-2 and MISTIE III Trials.

BACKGROUND AND OBJECTIVES: To study the relationship between the presence of cerebral microbleeds (CMBs) and acute hematoma characteristics among patients with primary intracerebral hemorrhage (ICH). METHODS: We pooled individual patient data from the Antihypertensive Treatment of Acute Cerebral Hemorrhage 2 (ATACH-2) trial and the Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation phase 3 (MISTIE III) trial. We included individuals with a brain MRI scan. Exposure was the presence of a CMB. The coprimary outcomes were admission ICH volume and hematoma expansion. Mixed-effects linear and logistic regression models were used, with demographics and comorbid conditions considered fixed effects and the study cohort treated as a random effect. Additional analyses assessed the relationship between CMB topography and number and hematoma characteristics. RESULTS: Of the 1,499 patients with ICH enrolled in the parent trials, 466 (31.1%) were included in this analysis, and 231 (49.6%) patients had CMBs. In adjusted models, presence of CMBs was associated with smaller ICH volume (ß = -0.26, 95% confidence interval [CI] -0.44 to -0.08) and lower odds of hematoma expansion (odds ratio 0.65, 95% CI 0.40-0.95; p = 0.04). The strength of association between CMBs and hematoma characteristics increased with increasing number of CMBs. The location of the CMBs and the severity of leukoaraiosis did not modify these results. DISCUSSION: In a pooled cohort of patients with ICH, our results are consistent with the hypothesis that more severe underlying small vessel disease, as represented by CMBs, leads to smaller baseline hematoma volumes and reduced hematoma expansion. Underlying cerebral small vessel disease may be of prognostic significance after ICH. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT01176565 and NCT01827046. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that the presence of microbleeds on MRI is associated with a smaller ICH volume at presentation and a lower rate of hematoma expansion on follow-up imaging.

Association Between Intraventricular Alteplase Use and Parenchymal Hematoma Volume in Patients With Spontaneous Intracerebral Hemorrhage and Intraventricular Hemorrhage.

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 < .001). In the primary analysis, alteplase use was associated with a change in the parenchymal ICH volume in the unadjusted analysis per 1-mL change (ß, 1.37; 95% CI, 0.92-1.81; P < .001) and in multivariable linear regression analysis that was adjusted for demographic characteristics, stability ICH and IVH volumes, ICH location, and time to first dose of study drug per 1-mL change (ß, 1.20; 95% CI, 0.79-1.62; P < .001). In the secondary analyses, no association was found between change in parenchymal ICH volume and poor outcome (odds ratio [OR], 0.97; 95% CI 0.87-1.10; P = .64) or mortality (OR, 0.97; 95% CI 0.99-1.08; P = .59). Similar results were observed in the subgroup analyses. Conclusions and Relevance: This study found that intraventricular alteplase use in patients with a large IVH was associated with a small reduction in parenchymal ICH volume, but this association did not translate into improved functional outcomes or mortality. Intraventricular thrombolysis should be examined in patients with moderate to large ICH with IVH, especially in a thalamic location.

Dynamic Detection of Delayed Cerebral Ischemia: A Study in 3 Centers.

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.

The Impact of Age and BMI on the VWF/ADAMTS13 Axis and Simultaneous Thrombin and Plasmin Generation in Hospitalized COVID-19 Patients.

Aging and obesity independently contribute toward an endothelial dysfunction that results in an imbalanced VWF to ADAMTS13 ratio. In addition, plasma thrombin and plasmin generation are elevated and reduced, respectively, with increasing age and also with increasing body mass index (BMI). The severity risk of Corona Virus Disease 2019 (COVID-19) increases in adults older than 65 and in individuals with certain pre-existing health conditions, including obesity (>30 kg/m2). The present cross-sectional study focused on an analysis of the VWF/ADAMTS13 axis, including measurements of von Willebrand factor (VWF) antigen (VWF:AG), VWF collagen binding activity (VWF:CBA), Factor VIII antigen, ADAMTS13 antigen, and ADAMTS13 activity, in addition to thrombin and plasmin generation potential, in a demographically diverse population of COVID-19 negative (-) (n = 288) and COVID-19 positive (+) (n = 543) patient plasmas collected at the time of hospital presentation. Data were analyzed as a whole, and then after dividing patients by age (<65 and ≥65) and independently by BMI [<18.5, 18.5-24.9, 25-29.9, >30 (kg/m2)]. These analyses suggest that VWF parameters (i.e., the VWF/ADAMTS13 activity ratio) and thrombin and plasmin generation differed in COVID-19 (+), as compared to COVID-19 (-) patient plasma. Further, age (≥65) more than BMI contributed to aberrant plasma indicators of endothelial coagulopathy. Based on these findings, evaluating both the VWF/ADAMTS13 axis, along with thrombin and plasmin generation, could provide insight into the extent of endothelial dysfunction as well as the plasmatic imbalance in coagulation and fibrinolysis potential, particularly for at-risk patient populations.

Hypercoagulable viscoelastic blood clot characteristics in critically ill coronavirus disease 2019 patients and associations with thrombotic complications.

BACKGROUND: Critically ill coronavirus disease 2019 (COVID-19) patients have frequent thrombotic complications and laboratory evidence of hypercoagulability. The relationship of coagulation tests and thrombosis requires investigation to identify best diagnostic and treatment approaches. We assessed for hypercoagulable characteristics in critically ill COVID-19 patients using rotational thromboelastometry (ROTEM) and explored relationships of D-dimer and ROTEM measurements with thrombotic complications. METHODS: Critically ill adult COVID-19 patients receiving ROTEM testing between March and April 2020 were analyzed. Patients receiving therapeutic anticoagulation before ROTEM were excluded. Rotational thromboelastometry measurements from COVID-19 patients were compared with non-COVID-19 patients matched by age, sex, and body mass index. Intergroup differences in ROTEM measurements were assessed using t tests. Correlations of D-dimer levels to ROTEM measurements were assessed in COVID-19 patients who had available concurrent testing. Intergroup differences of D-dimer and ROTEM measurements were explored in COVID-19 patients with and without thrombosis. RESULTS: Of 30 COVID-19 patients receiving ROTEM, we identified hypercoagulability from elevated fibrinogen compared with non-COVID-19 patients (fibrinogen assay maximum clot firmness [MCF], 47 ± 13 mm vs. 20 ± 7 mm; mean intergroup difference, 27.4 mm; 95% confidence interval [CI], 22.1-32.7 mm; p < 0.0001). In our COVID-19 cohort, thrombotic complications were identified in 33%. In COVID-19 patients developing thrombotic complications, we identified higher D-dimer levels (17.5 ± 4.3 µg/mL vs. 8.0 ± 6.3 µg/mL; mean difference, 9.5 µg/mL; 95% CI, 13.9-5.1; p < 0.0001) but lower fibrinogen assay MCF (39.7 ± 10.8 mm vs. 50.1 ± 12.0 mm; mean difference, -11.2 mm; 95% CI, -2.1 to -20.2; p = 0.02) compared with patients without thrombosis. We identified negative correlations of D-dimer levels and ROTEM MCF in these patients (r = -0.61; p = 0.001). CONCLUSION: We identified elevated D-dimer levels and hypercoagulable blood clot characteristics from increased fibrinogen on ROTEM testing in critically ill COVID-19 patients. However, we identified lower, albeit still hypercoagulable, ROTEM measurements of fibrinogen in COVID-19 patients with thrombotic complications compared with those without. Further work is required to externally validate these findings and to investigate the mechanistic drivers for these relationships to identify best diagnostic and treatment approaches for these patients. LEVEL OF EVIDENCE: Epidemiologic, level IV.

Prior antiplatelet therapy and haematoma expansion after primary intracerebral haemorrhage: an individual patient-level analysis of CLEAR III, MISTIE III and VISTA-ICH.

OBJECTIVE: To evaluate the relationship between prior antiplatelet therapy (APT) and outcomes after primary intracerebral haemorrhage (ICH), and assess if it varies by haematoma location. METHODS: We 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. RESULTS: Among 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. CONCLUSIONS: In 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.

Red Blood Cell Transfusions and Outcomes After Intracerebral Hemorrhage.

BACKGROUND: Low red blood cell (RBC) levels are associated with worse intracerebral hemorrhage (ICH) outcomes. However, relationships of RBC transfusions on ICH outcomes are unclear given the overlap of RBC transfusion, comorbidities, and disease severity. We investigated RBC transfusion relationships on ICH outcomes while accounting for comorbidities and disease severity. METHODS: ICH hospitalizations between 2002 and 2011 and RBC transfusion exposure were identified from the Nationwide Inpatient Sample using ICD-9-CM codes. Logistic regression was used to study the relationship between RBC transfusion on outcomes after adjusting for demographics, baseline comorbidities, and markers of disease severity. Additional sensitivity analyses stratified by comorbidity burden and disease severity were performed. RESULTS: Of 597,046 ICH hospitalizations, RBC transfusions were administered in 22,904 (4%). RBC transfusion was associated with higher odds of in-hospital mortality (adjusted OR: 1.22 [95%CI: 1.10-1.35]). In sensitivity analyses, RBC transfusions resulted in poor outcomes regardless of the comorbidity burden, but attenuation in this relationship was notable with lower comorbidities (adjusted OR 1.43 [95%CI: 1.34-1.51] vs 1.18 [95%CI: 1.10-1.29]). There were no associations of RBC transfusions with poor outcomes in hospitalizations without mechanical ventilation (adjusted OR 0.88 [95%CI: 0.83-1.13]) and in cases requiring ventriculostomy drains (adjusted OR 1.05 [95%CI: 0.97-1.10]). CONCLUSIONS: In a large, nationally representative sample, RBC transfusion was associated with poor ICH outcomes. However, there were variations in this relationship based on comorbidities and disease severity. Additional prospective studies are required to assess direct risks and benefits from RBC transfusions in ICH.