Fixed- Versus Variable-Dose Prothrombin Complex Concentrate for the Emergent Reversal of Vitamin K Antagonists: A Systematic Review and Meta-Analysis.

OBJECTIVES: Four-factor prothrombin complex concentrate (4-PCC) is recommended for rapid reversal of vitamin K antagonists (VKAs) such as warfarin, yet optimal dosing remains uncertain. DATA SOURCES: A systematic review was conducted of PubMed, Embase, and Ovid MEDLINE (Wolters Kluwer) databases from January 2000 to August 2023 for clinical studies comparing fixed- vs. variable-dose 4-PCC for emergent VKA reversal with at least one reported clinical outcome. STUDY SELECTION: Abstracts and full texts were assessed independently and in duplicate by two reviewers. DATA EXTRACTION: Data were extracted independently and in duplicate by two reviewers using predefined extraction forms. DATA SYNTHESIS: The analysis comprised three randomized trials and 16 cohort studies comprising a total of 323 participants in randomized trials (161 in fixed dosage and 162 in variable dosage) and 1912 patients in cohort studies (858 in fixed-dose and 1054 in variable dose). Extracranial bleeding was the predominant indication, while intracranial hemorrhage varied. Overall, a fixed-dose regimen may be associated with a lower dose of 4-PCC and results in a reduction in 4-PCC administration time compared with a variable-dose regimen. A fixed-dose regimen also likely results in increased clinical hemostasis. While there is no clear difference between the two regimens in terms of achieving a goal international normalized ratio (INR) less than 2, a fixed-dose regimen is less likely to achieve a goal INR less than 1.5. High certainty evidence indicates that the fixed-dose regimen reduces both mortality and the occurrence of thromboembolic events. Additional subgroup analyses provides exploratory data to guide future studies. CONCLUSIONS: A fixed-dose regimen for 4-PCC administration provides benefits over a variable-dose regimen in terms of dose reduction, faster administration time, improved clinical hemostasis, and reduced mortality and thromboembolic events. Further studies are warranted to better refine the optimal fixed-dose regimen.

Phenotypes of Patients with Intracerebral Hemorrhage, Complications, and Outcomes.

BACKGROUND: The objective of this study was to define clinically meaningful phenotypes of intracerebral hemorrhage (ICH) using machine learning. METHODS: We used patient data from two US medical centers and the Antihypertensive Treatment of Acute Cerebral Hemorrhage-II clinical trial. We used k-prototypes to partition patient admission data. We then used silhouette method calculations and elbow method heuristics to optimize the clusters. Associations between phenotypes, complications (e.g., seizures), and functional outcomes were assessed using the Kruskal-Wallis H-test or χ2 test. RESULTS: There were 916 patients; the mean age was 63.8 ± 14.1 years, and 426 patients were female (46.5%). Three distinct clinical phenotypes emerged: patients with small hematomas, elevated blood pressure, and Glasgow Coma Scale scores > 12 (n = 141, 26.6%); patients with hematoma expansion and elevated international normalized ratio (n = 204, 38.4%); and patients with median hematoma volumes of 24 (interquartile range 8.2-59.5) mL, who were more frequently Black or African American, and who were likely to have intraventricular hemorrhage (n = 186, 35.0%). There were associations between clinical phenotype and seizure (P = 0.024), length of stay (P = 0.001), discharge disposition (P < 0.001), and death or disability (modified Rankin Scale scores 4-6) at 3-months' follow-up (P < 0.001). We reproduced these three clinical phenotypes of ICH in an independent cohort (n = 385) for external validation. CONCLUSIONS: Machine learning identified three phenotypes of ICH that are clinically significant, associated with patient complications, and associated with functional outcomes. Cerebellar hematomas are an additional phenotype underrepresented in our data sources.

Recruitment in Acute Stroke Trials: Challenges and Potential Solutions.

Randomized clinical trials of acute stroke have led to major advances in acute stroke therapy over the past decade. Despite these successes, recruitment in acute trials is often difficult. We outline challenges in recruitment for acute stroke trials and present potential solutions, which can increase the speed and decrease the cost of identifying new treatments for acute stroke. One of the largest opportunities to increase the speed of enrollment and make trials more generalizable is expansion of inclusion criteria whose impact on expected recruitment can be assessed by epidemiologic and registry databases. Another barrier to recruitment besides the number of eligible patients is availability of study investigators limited to business hours, which may be helped by financial support for after-hours call. The wider use of telemedicine has accelerated quicker stroke treatment at many hospitals and has the potential to accelerate research enrollment but requires training of clinical investigators who are often inexperienced with this approach. Other potential solutions to enhance recruitment include rapid prehospital notification of clinical investigators of potential patients, use of mobile stroke units, advances in the process of emergency informed consent, storage of study medication in the emergency department, simplification of study treatments and data collection, education of physicians to improve equipoise and enthusiasm for randomization of patients within a trial, and clear recruitment plans, and even potentially coenrollment, when there are competing trials at sites. Without successful recruitment, scientific advances and clinical benefit for acute stroke patients will lag.

Fall Risk Prediction Models During the Initial COVID-19 Surge: Could Predictive Analytics Be Used in a Resource-Constrained Environment?

During the first COVID surge, multiple changes in nurse staffing and workflows were made to support care delivery in a resource-constrained environment. We hypothesized that there was a higher rate of inpatient falls during the COVID surge. Furthermore, we predicted that an automated predictive analytic algorithm would perform as well as the Johns Hopkins Fall Risk Assessment. A retrospective review of falls for 3 months before and the first 3 months of the first COVID surge was conducted. We determined the total number of falls and the overall fall rate and examined the distribution of scores and accuracy of fall predictive models for both groups. There was a statistically significant increase in fall rate during the first 3 months of the COVID surge compared with the 3 prior months (2.48/1000 patient-days vs 1.89/1000 patient-days respectively; P = .041). The Johns Hopkins instrument had a greater sensitivity of 78.9% compared with 57.0% for the predictive analytic model. Specificity and accuracy of the predictive analytic model were higher than the Johns Hopkins instrument (71.3% vs 54.1% and 71.2% vs 54.3%, respectively). These findings suggest that the automated predictive analytic model could be used in a resource-constrained environment to accurately classify patients' risk of fall.

Magnesium Sulfate and Hematoma Expansion: An Ancillary Analysis of the FAST-MAG Randomized Trial.

BACKGROUND: Intracerebral hemorrhage (ICH) is the deadliest form of stroke. In observational studies, lower serum magnesium has been linked to more hematoma expansion (HE) and intracranial hemorrhage, implying that supplemental magnesium sulfate is a potential acute treatment for patients with ICH and could reduce HE. FAST-MAG (Field Administration of Stroke Therapy - Magnesium) was a clinical trial of magnesium sulfate started prehospital in patients with acute stroke within 2 hours of last known well enrolled. CT was not required prior to enrollment, and several hundred patients with acute ICH were enrolled. In this ancillary analysis, we assessed the effect of magnesium sulfate treatment upon HE in patients with acute ICH. METHODS: We retrospectively analyzed data that were prospectively collected in the FAST-MAG study. Patients received intravenous magnesium sulfate or matched placebo within 2 hours of onset. We compared HE among patients allocated to intravenous magnesium sulfate or placebo with a Mann-Whitney U. We used the same method to compare neurological deficit severity (National Institutes of Health Stroke Scale) and global disability (modified Rankin Scale) at 3 months. RESULTS: Among 268 patients with ICH meeting study entry criteria, mean 65.4±13/4 years, 33% were female, and 211 (79%) had a history of hypertension. Initial deficit severities were median (interquartile range) of 4 (3-5) on the Los Angeles Motor Scale in the field and National Institutes of Health Stroke Scale score of 16 (9.5-25.5) early after hospital arrival. Follow-up brain imaging was performed a median of 17.1 (11.3-22.7) hours after first scan. The magnesium and placebo groups did not statistically differ in hematoma volume on arrival, 10.1 (5.6-28.7) versus 12.4 (5.6-28.7) mL (P=0.6), or HE, 2.0 (0.1-7.4) versus 1.5 (-0.2 to 8) mL (P=0.5). There was no difference in functional outcomes (modified Rankin Scale score of 3-6), 59% versus 50% (P=0.5). CONCLUSIONS: Magnesium sulfate did not reduce HE or improve functional outcomes at 90 days. A benefit for patients with initial hypomagnesemia was not addressed. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT00059332.

Predicting Early Seizures After Intracerebral Hemorrhage with Machine Learning.

BACKGROUND: Seizures are a harmful complication of acute intracerebral hemorrhage (ICH). "Early" seizures in the first week after ICH are a risk factor for deterioration, later seizures, and herniation. Ideally, seizure medications after ICH would only be administered to patients with a high likelihood to have seizures. We developed and validated machine learning (ML) models to predict early seizures after ICH. METHODS: We used two large datasets to train and then validate our models in an entirely independent test set. The first model ("CAV") predicted early seizures from a subset of variables of the CAVE score (a prediction rule for later seizures)-cortical hematoma location, age less than 65 years, and hematoma volume greater than 10 mL-whereas early seizure was the dependent variable. We attempted to improve on the "CAV" model by adding anticoagulant use, antiplatelet use, Glasgow Coma Scale, international normalized ratio, and systolic blood pressure ("CAV + "). For each model we used logistic regression, lasso regression, support vector machines, boosted trees (Xgboost), and random forest models. Final model performance was reported as the area under the receiver operating characteristic curve (AUC) using receiver operating characteristic models for the test data. The setting of the study was two large academic institutions: institution 1, 634 patients; institution 2, 230 patients. There were no interventions. RESULTS: Early seizures were predicted across the ML models by the CAV score in test data, (AUC 0.72, 95% confidence interval 0.62-0.82). The ML model that predicted early seizure better in the test data was Xgboost (AUC 0.79, 95% confidence interval 0.71-0.87, p = 0.04) compared with the CAV model AUC. CONCLUSIONS: Early seizures after ICH are predictable. Models using cortical hematoma location, age less than 65 years, and hematoma volume greater than 10 mL had a good accuracy rate, and performance improved with more independent variables. Additional methods to predict seizures could improve patient selection for monitoring and prophylactic seizure medications.

Antiplatelet Medications and Biomarkers of Hemostasis May Explain the Association of Hematoma Appearance and Subsequent Hematoma Expansion After Intracerebral Hemorrhage.

BACKGROUND: To test the hypothesis that appearances of intracranial hematomas on diagnostic computed tomography (CT) are not idiosyncratic and reflect a biologically plausible mechanism, we evaluated the association between hematoma appearance on CT, biomarkers of platelet activity, and antiplatelet or anticoagulant medication use prior to admission. METHODS: We studied 330 consecutively identified patients from 2006 to 2019. Biomarkers of platelet activity (platelet aspirin assay) and medication history (aspirin, clopidogrel) were prospectively recorded on admission. A blinded interpreter recorded the presence of hematoma appearances from the diagnostic scan. Associations were tested with parametric or nonparametric statistics, as appropriate. RESULTS: The black hole sign (101, 30%) was most prevalent, followed by the island sign (57, 17%) and blend sign (32, 10%). There was reduced platelet activity in patients with a black hole sign (511 [430-610] vs. 562 [472-628] aspirin reaction units, P = 0.01) or island sign (505 [434-574] vs. 559 [462-629] aspirin reaction units, P = 0.004). Clopidogrel use prior to admission was associated with the black hole sign (odds ratio 2.25, 95% confidence interval 1.02-4.98, P = 0.04). CONCLUSIONS: In patients with acute intracerebral hemorrhage, hematoma appearances on CT are associated with biomarkers of platelet activity and clopidogrel use prior to admission. Appearances of intracranial hematomas on CT may reflect reduced hemostasis from antiplatelet medication use.

The Story of Intracerebral Hemorrhage: From Recalcitrant to Treatable Disease.

This invited special report is based on an award presentation at the World Stroke Organization/European Stroke Organization Conference in November of 2020 outlining progress in the acute management of intracerebral hemorrhage (ICH) over the past 35 years. ICH is the second most common and the deadliest type of stroke for which there is no scientifically proven medical or surgical treatment. Prospective studies from the 1990s onward have demonstrated that most growth of spontaneous ICH occurs within the first 2 to 3 hours and that growth of ICH and resulting volumes of ICH and intraventricular hemorrhage are modifiable factors that can improve outcome. Trials focusing on early treatment of elevated blood pressure have suggested a target systolic blood pressure of 140 mm Hg, but none of the trials were positive by their primary end point. Hemostatic agents to decrease bleeding in spontaneous ICH have included desmopressin, tranexamic acid, and rFVIIa (recombinant factor VIIa) without clear benefit, and platelet infusions which were associated with harm. Hemostatic agents delivered within the first several hours have the greatest impact on growth of ICH and potentially on outcome. No large Phase III surgical ICH trial has been positive by primary end point, but pooled analyses suggest that earlier ICH removal is more likely to be beneficial. Recent trials emphasize maximization of clot removal and minimizing brain injury from the surgical approach. The future of ICH therapy must focus on delivery of medical and surgical therapies as soon as possible if we are to improve outcomes.

Early Seizures Are Predictive of Worse Health-Related Quality of Life at Follow-Up After Intracerebral Hemorrhage.

OBJECTIVES: Early seizures are a common complication of intracerebral hemorrhage, occurring in ~10% of patients. However, the independent effect of early seizures on patient outcomes, particularly health-related quality of life, is unclear. Without a potential benefit to patient outcomes, the widespread use (~40%) of prophylactic seizure medications has no reasonable chance of improving patient outcomes. We tested the hypothesis that health-related quality of life at follow-up is different between patients with and without early seizures (and secondarily, with nonconvulsive status epilepticus) after intracerebral hemorrhage. DESIGN: Patients with intracerebral hemorrhage were enrolled in an observational cohort study that prospectively collected clinical data and health-related quality of life at follow-up. SETTING: Academic medical center. PATIENTS: One-hundred thirty-three patients whose health-related quality of life was assessed 3 months after intracerebral hemorrhage onset. MEASUREMENTS AND MAIN RESULTS: Health-related quality of life was obtained at 3 months after intracerebral hemorrhage onset. T Scores of health-related quality of life were modeled with multivariable linear models accounting for severity with the intracerebral hemorrhage Score and hematoma location. Health-related quality of life was measured with National Institutes of Health Patient Reported Outcomes Measurement Information System/Neuroquality of life, expressed in T Scores (U.S. normal 50 ± 10). The modified Rankin Scale (a global measure) was a secondary outcome. There were 12 patients (9%) with early seizures. T Scores of health-related quality of life at follow-up were lower (worse) in patients with early seizure compared with patients without an early seizure (44 [32.75-51.85] vs 30.25 [18.9-39.15]; p = 0.04); results for other domains of health-related quality of life were similar. The association persisted in multivariable models. There was no association between early seizures and prophylactic seizure medications (p = 0.4). Results for patients with nonconvulsive status epilepticus were similar. There was no association between early seizures and the modified Rankin Scale at 3 months. CONCLUSIONS: Early seizures and nonconvulsive status epilepticus were associated with lower health-related quality of life at follow-up in survivors of intracerebral hemorrhage.

Identifying Modifiable Predictors of Patient Outcomes After Intracerebral Hemorrhage with Machine Learning.

BACKGROUND/OBJECTIVE: Demonstrating a benefit of acute treatment to patients with intracerebral hemorrhage (ICH) requires identifying which patients have a potentially modifiable outcome, where treatment could favorably shift a patient's expected outcome. A decision rule for which patients have a modifiable outcome could improve the targeting of treatments. We sought to determine which patients with ICH have a modifiable outcome. METHODS: Patients with ICH were prospectively identified at two institutions. Data on hematoma volumes, medication histories, and other variables of interest were collected. ICH outcomes were evaluated using the modified Rankin Scale (mRS), assessed at 14 days and 3 months after ICH, with "good outcome" defined as 0-3 (independence or better) and "poor outcome" defined as 4-6 (dependence or worse). Supervised machine learning models identified the best predictors of good versus poor outcomes at Institution 1. Models were validated using repeated fivefold cross-validation as well as testing on the entirely independent sample at Institution 2. Model fit was assessed with area under the ROC curve (AUC). RESULTS: Model performance at Institution 1 was strong for both 14-day (AUC of 0.79 [0.77, 0.81] for decision tree, 0.85 [0.84, 0.87] for random forest) and 3 month (AUC of 0.75 [0.73, 0.77] for decision tree, 0.82 [0.80, 0.84] for random forest) outcomes. Independent predictors of functional outcome selected by the algorithms as important included hematoma volume at hospital admission, hematoma expansion, intraventricular hemorrhage, overall ICH Score, and Glasgow Coma Scale. Hematoma expansion was the only potentially modifiable independent predictor of outcome and was compatible with "good" or "poor" outcome in a subset of patients with low hematoma volumes, good Glasgow Coma scale and premorbid modified Rankin Scale scores. Models trained on harmonized data also predicted patient outcomes well at Institution 2 using decision tree (AUC 0.69 [0.63, 0.75]) and random forests (AUC 0.78 [0.72, 0.84]). CONCLUSIONS: Patient outcomes are predictable to a high level in patients with ICH, and hematoma expansion is the sole-modifiable predictor of these outcomes across two outcome types and modeling approaches. According to decision tree analyses predicting outcome at 3 months, patients with a high Glasgow Coma Scale score, less than 44.5 mL hematoma volume at admission, and relatively low premorbid modified Rankin Score in particular have a modifiable outcome and appear to be candidates for future interventions to improve outcomes after ICH.

Prothrombin Complex Concentrate for Emergent Reversal of Intracranial Hemorrhage in Patients with Ventricular Assist Devices.

BACKGROUND: Intracranial hemorrhage (ICH) is a devastating complication for patients with ventricular assist devices (VADs). The safety of emergent anticoagulation reversal with four-factor prothrombin complex concentrate (PCC) and optimal timing of anticoagulation resumption are not clear. In addition, lactate dehydrogenase (LDH) is used as a biomarker for thromboembolic risk, but its utility in guiding anticoagulation management after reversal with PCC has not be described. METHODS: We retrospectively reviewed a consecutive series of patients with VADs presenting with ICH between 2014 and 2020 who received four-factor PCC for rapid anticoagulation reversal. We collected the timing of PCC administration, timing of resumption of anticoagulation, survival, occurrence of thromboembolic events, and LDH levels throughout hospitalization. RESULTS: We identified 16 ICH events in 14 patients with VADs treated with rapid anticoagulation reversal using four-factor PCC (11 intraparenchymal, 4 subdural, 1 subarachnoid hemorrhage). PCC was administered at a mean of 3.3 ± 0.3 h after imaging diagnosis of ICH. Overall mortality was 63%. Survivors had higher presenting Glasgow Coma Scale (median 15, interquartile range [IQR] 15-15 versus 14, IQR 8-14.7, P = 0.041). In all six instances where the patient survived, anticoagulation was resumed on average 9.16 ± 1.62 days after reversal. There were no thromboembolic events prior to resumption of anticoagulation. Three events occurred after anticoagulation resumption and within 3 months of reversal: VAD thrombosis in a patient with thrombosis at the time of reversal, ischemic stroke, and readmission for elevated LDH in the setting of subtherapeutic international normalized ratio. CONCLUSIONS: Our limited series found no thromboembolic complications immediately following anticoagulation reversal with PCC prior to resumption of anticoagulation. LDH trends may be useful to monitor thromboembolic risk after reversal.

Magnesium and Risk of Bleeding Complications From Ventriculostomy Insertion.

BACKGROUND AND PURPOSE: Hemorrhages are a serious complication of brain surgery, and magnesium has shown hemostatic properties in hemorrhagic stroke and non-neurological surgeries. External ventricular drain (EVD) insertion is an advantageous model of emergency neurosurgical hemorrhage risk because it is common, standardized, and the operator is blinded to the outcome during the procedure. We tested the hypothesis that low magnesium is associated with risk of hemorrhagic complications from EVD insertion. METHODS: Patients with spontaneous intracerebral hemorrhage and aneurysmal subarachnoid hemorrhage were enrolled in a prospective, observational study. Demographic and clinical variables were prospectively recorded, including serum magnesium measurements. Catheter tract hemorrhage (CTH) was measured on postoperative head computed tomography within 48 hours of EVD insertion. RESULTS: We observed 50 CTH among 327 EVD procedures (15.3%) distributed similarly among intracerebral hemorrhage (21/116 [18.1%]) and subarachnoid hemorrhage (29/211 [13.7%]). Magnesium was lower in patients with CTH compared with those without (median 1.8 versus 2.0 mg/dL, P<0.0001). Higher magnesium was associated with lower odds of CTH (odds ratio 0.67 per 0.1 mg/dL magnesium [95% CI, 0.56-0.78], P<0.0001) after adjustment for other risk factors, with similar effect in the intracerebral hemorrhage and subarachnoid hemorrhage subgroups. Preprocedural increase in magnesium (odds ratio 0.68 [0.52-0.85]) and dose of preprocedural magnesium sulfate (odds ratio 0.67 [0.40-0.97]) were associated with reduced CTH risk after adjustment for initial magnesium and other risk factors. CONCLUSIONS: Lower magnesium at the time of EVD insertion was an independent predictor of hemorrhagic complications. Baseline risk was attenuated by preprocedural increases in magnesium, suggesting a therapeutic opportunity.

Magnesium and Hemorrhage Volume in Patients With Aneurysmal Subarachnoid Hemorrhage.

OBJECTIVES: We tested the hypothesis that admission serum magnesium levels are associated with extent of hemorrhage in patients with aneurysmal subarachnoid hemorrhage. DESIGN: Single-center prospective observational study. SETTING: Tertiary hospital neurologic ICU. PATIENTS: Patients with aneurysmal subarachnoid hemorrhage. INTERVENTIONS: Clinically indicated CT scans and serum laboratory studies. MEASUREMENTS AND MAIN RESULTS: Demographic, clinical, laboratory, and radiographic data were analyzed. Extent of initial hemorrhage was graded semi-quantitatively on admission CT scans using the modified Fisher scale (grades: 0, no radiographic hemorrhage; 1, thin [< 1 mm in depth] subarachnoid hemorrhage; 2, thin subarachnoid hemorrhage with intraventricular hemorrhage; 3, thick [≥ 1 mm] subarachnoid hemorrhage; 4, thick subarachnoid hemorrhage with intraventricular hemorrhage). We used both ordinal (modified Fisher scale) and dichotomized (thick vs thin subarachnoid hemorrhage) univariate and adjusted logistic regression models to assess associations between serum magnesium and radiographic subarachnoid hemorrhage severity. Data from 354 patients (mean age 55 ± 14 yr, 28.5% male, median admission Glasgow Coma Scale 14 [10-15]) were analyzed. Mean magnesium was lower in patients with thick versus thin subarachnoid hemorrhage (1.92 vs 1.99 mg/dL; p = 0.022). A monotonic trend across categories of modified Fisher scale was found using analysis of variance and Spearman rank correlation (p = 0.015 and p = 0.008, respectively). In adjusted ordinal and binary regression models, lower magnesium levels were associated with higher modified Fisher scale (odds ratio 0.33 per 1 mg/dL increase; 95% CI, 0.14-0.77; p = 0.011) and with thick subarachnoid hemorrhage (odds ratio 0.29 per 1 mg/dL increase; 95% CI, 0.10-0.78; p = 0.015). CONCLUSIONS: These data support the hypothesis that magnesium influences hemorrhage severity in patients with aneurysmal subarachnoid hemorrhage, potentially through a hemostatic mechanism.

Factors Disrupting Melatonin Secretion Rhythms During Critical Illness.

OBJECTIVES: The circadian system modulates many important physiologic processes, synchronizing tissue-specific functions throughout the body. We sought to characterize acute alterations of circadian rhythms in critically ill patients and to evaluate associations between brain dysfunction, systemic multiple organ dysfunction, environmental stimuli that entrain the circadian rhythm (zeitgebers), rest-activity rhythms, and the central circadian rhythm-controlled melatonin secretion profile. DESIGN: Prospective study observing a cohort for 24-48 hours beginning within the first day of ICU admission. SETTING: Multiple specialized ICUs within an academic medical center. PATIENTS: Patients presenting from the community with acute onset of either intracerebral hemorrhage as a representative neurologic critical illness or sepsis as a representative systemic critical illness. Healthy control patients were studied in using modified constant routine in a clinical research unit. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Light, feeding, activity, medications, and other treatment exposures were evaluated along with validated measures of encephalopathy (Glasgow Coma Scale), multiple organ system function (Sequential Organ Failure Assessment score), and circadian rhythms (profiles of serum melatonin and its urinary metabolite 6-sulphatoxymelatonin). We studied 112 critically ill patients, including 53 with sepsis and 59 with intracerebral hemorrhage. Environmental exposures were abnormal, including light (dim), nutritional intake (reduced or absent and mistimed), and arousal stimuli (increased and mistimed). Melatonin amplitude and acrophase timing were generally preserved in awake patients but dampened and delayed with increasing encephalopathy severity. Melatonin hypersecretion was observed in patients exposed to catecholamine vasopressor infusions, but unaffected by sedatives. Change in vasopressor exposure was the only factor associated with changes in melatonin rhythms between days 1 and 2. CONCLUSIONS: Encephalopathy severity and adrenergic agonist medication exposure were the primary factors contributing to abnormal melatonin rhythms. Improvements in encephalopathy and medical stabilization did not rapidly normalize rhythms. Urinary 6-sulphatoxymelatonin is not a reliable measure of the central circadian rhythm in critically ill patients.

Why Physicians Prescribe Prophylactic Seizure Medications after Intracerebral Hemorrhage: An Adaptive Conjoint Analysis.

BACKGROUND: Seizures are a morbid complication of intracerebral hemorrhage (ICH) and increase the risk for herniation, status epilepticus, and worse patient outcomes. Prophylactic levetiracetam is administered to approximately 40% of patients with ICH. It is unclear which patients are consciously selected for treatment by physicians. We sought to determine how patients are selected for treatment with prophylactic levetiracetam after ICH. METHODS: We administered an adaptive conjoint analysis using decision making software to an NIH Stroke Trials Network Working Group. The adaptive conjoint analysis determines the most influential attributes for making a decision in an iterative, algorithm-driven process. We asked respondents which would most influence a decision to administer prophylactic levetiracetam. The attributes and their levels were taken from published phenotypes associated with prophylactic seizure medications and the likelihood of seizures after ICH: hematoma location (lobar or basal ganglia), hematoma volume (<=10 mL or >10 mL), level of consciousness (Glasgow Coma Scale 5-12 or Glasgow Coma Scale 13-15), age (<65 or ≥65 years), and race (White or Caucasian or Black/African American). The algorithm terminated when the attributes were ranked from most to least influential. RESULTS: The study sample included 27 respondents who completed the adaptive conjoint analysis out of 42 who responded to the survey with a mean age of 43.4 ± 9.4 years. The attribute with the greatest weight was hematoma location (30%), followed by reduced level of consciousness (24%), hematoma volume (19%), race (14%), and age (13%). Ranks of attributes were different (P < .001). CONCLUSIONS: The decision to administer prophylactic levetiracetam to patients with ICH is driven by lobar hematoma location and depressed level of consciousness. Future research on prophylactic seizure medication could focus on patients most likely to receive it.

Race, Socioeconomic Status, and Gastrostomy after Spontaneous Intracerebral Hemorrhage.

INTRODUCTION: Spontaneous intracerebral hemorrhage is a disabling form of stroke, and some patients will require nutritional interventions for dysphagia. We sought to determine if socioeconomic status indicators mediate whether minorities undergo gastrostomy tube placement. MATERIALS AND METHODS: Patients with spontaneous intracerebral hemorrhage were enrolled in a single center, observational cohort study from 2010 to 2017. A socioeconomic index score was imputed using neighborhood characteristics by patients' ZIP code, according to an established method utilizing 6 indicators of wealth/income, education, and occupation. Multivariable logistic regression models were generated and stratified by racial/ethnic groups to determine the association of socioeconomic status with gastrostomy tube placement. RESULTS: Among 512 patients, 93 (18.2%) underwent gastrostomy tube placement. There were 245 Whites, 220 Blacks, and 47 Hispanic. Blacks underwent the highest percentage of gastrostomy placement (22.7%), and Whites had the lowest percentage (13.5%). Among patients with gastrostomy, Blacks and Hispanics had lowest median socioeconomic index (-2.1 [IQR: -3.0, .7]; .7 [IQR: -1.6, 2.9], respectively, P < .001). Increasing intracerebral hemorrhage score was correlated with higher odds of gastrostomy across all groups (P values ≤ .01) but only Hispanics had reduced adjusted odds of gastrostomy with increasing socioeconomic index (OR .56; 95% .33-.84; P = .01). DISCUSSION: Racial/ethnic minorities had lower socioeconomic index and underwent more gastrostomy placement. Socioeconomic index was independently associated with gastrostomy only in Hispanics, in whom the odds of gastrostomy decreased with increasing socioeconomic index. Summary & Conclusion: Differences in utilization of gastrostomy were evident among minorities, and socioeconomic status may mediate this relationship among Hispanics.

Elevated Cerebrospinal Fluid Protein Is Associated with Unfavorable Functional Outcome in Spontaneous Subarachnoid Hemorrhage.

BACKGROUND/OBJECTIVE: Subarachnoid hemorrhage (SAH) is a devastating neurologic event for which markers to assess poor outcome are needed. Elevated cerebrospinal fluid (CSF) protein may result from inflammation and blood-brain barrier (BBB) disruption that occurs during SAH. We sought to determine if CSF protein level is associated with functional outcome after SAH. METHODS: We prospectively collected single-center demographic and clinical data for consecutive patients admitted with spontaneous SAH. Inclusion required an external ventricular drain and daily CSF protein and cellular counts starting within 48 hours of symptom onset and extending through 7 days after onset. Seven-day average CSF protein was determined from daily measured values after correcting for contemporaneous CSF red blood cell (RBC) count. Three-month functional outcome was assessed by telephone interview with good outcome defined as modified Rankin score 0-3. Variables univariately associated with outcome at P less than .25 and measures of hemorrhage volume were included for binary logistic regression model development. RESULTS: The study included 130 patients (88% aneurysmal SAH, 69% female, 54.8 ± 14.8 years, Glasgow Coma Scale [GCS] 14 [7-15]). Three-month outcome assessment was complete in 112 (86%) patients with good functional outcome in 74 (66%). CSF protein was lower in good outcome (35.3 [20.4-49.7] versus 80.5 [40.5-115.5] mg/dL; P < .001). CSF protein was not associated with cerebral vasospasm, but delayed radiographic infarction on 3 to 12-month neuroimaging was associated with higher CSF protein (46.3 [32.0-75.0] versus 30.2 [20.4-47.8] mg/dL; P = .023). Good 3-month outcome was independently associated with lower CSF protein (odds ratios [OR] .39 [.23-.70] for 75th versus 25th percentile of protein; P = .001) and higher admission GCS (OR 1.23 [1.10-1.37] for good outcome per GCS point increase; P < .001). Parenchymal hematoma predicted worse outcome (OR 6.31 [1.58-25.25]; P = .009). Results were similar after excluding nonaneurysmal SAH and after including CSF RBC count, CT score, and intraventricular hemorrhage volume in models. CONCLUSIONS: Elevated average CSF protein is associated with poor outcome after spontaneous SAH. Further research should investigate if elevated CSF protein identifies patients in whom mechanisms such as BBB disruption contribute to poor outcome.

Early Stroke Recognition and Time-based Emergency Care Performance Metrics for Intracerebral Hemorrhage.

BACKGROUND AND AIM: Performance measures have been extensively studied for acute ischemic stroke, leading to guideline-established benchmarks. Factors influencing care efficiency for intracerebral hemorrhage (ICH) are not well delineated. We sought to identify factors associated with early recognition of ICH and to assess the association between early recognition and completion of emergency care tasks. METHODS: Consecutive patients with spontaneous ICH were enrolled in an observational cohort study conducted from 2009 to 2017 at an urban comprehensive stroke center, excluding patient transferred from other hospitals. We used stroke team activation as the indicator of early recognition and measured completion times for multiple ICH-relevant performance metrics including door to computed tomography (CT) acquisition and door to hemostatic medication initiation. RESULTS: We studied 204 cases. All stroke-related performance times were faster in patients managed with stroke team activation compared to no activation, including quicker door to CT acquisition (median 24 versus 48 minutes, P < .001) and door to hemostatic medication initiation (63 versus 99 minutes, P = .005). These associations were confirmed in adjusted models. Stroke codes were activated in 43% of cases and were more likely in patients with shorter onset-to-arrival times, higher National Institutes of Health Stroke Scale scores, and higher Glasgow Coma Scale scores. CONCLUSIONS: Stroke team activation was associated with more rapid diagnostic and therapeutic interventions for patients with ICH, but activation did not occur in the majority of cases, implying absence of early recognition. A stroke team activation process improves care performance, but leveraging the advantages of existing systems will require improved triage tools to identify ICH in the acute setting.

Admission Heart Rate Variability is Associated with Fever Development in Patients with Intracerebral Hemorrhage.

BACKGROUND: Fever is associated with worse outcome after intracerebral hemorrhage (ICH). Autonomic dysfunction, commonly seen after brain injury, results in reduced heart rate variability (HRV). We sought to investigate whether HRV was associated with the development of fever in patients with ICH. METHODS: We prospectively enrolled consecutive patients with spontaneous ICH in a single-center observational study. We included patients who presented directly to our emergency department after symptom onset, had a 10-second electrocardiogram (EKG) performed within 24 h of admission, and were in sinus rhythm. Patient temperature was recorded every 1-4 h. We defined being febrile as having a temperature of ≥ 38 °C within the first 14 days, and fever burden as the number of febrile days. HRV was defined by the standard deviation of the R-R interval (SDNN) measured on the admission EKG. Univariate associations were determined by Fisher's exact, Mann-Whitney U, or Spearman's rho correlation tests. Variables associated with fever at p ≤ 0.2 were entered in a logistic regression model of being febrile within 14 days. RESULTS: There were 248 patients (median age 63 [54-74] years, 125 [50.4%] female, median ICH Score 1 [0-2]) who met the inclusion criteria. Febrile patients had lower HRV (median SDNN: 1.72 [1.08-3.60] vs. 2.55 [1.58-5.72] msec, p = 0.001). Lower HRV was associated with more febrile days (R = - 0.22, p < 0.001). After adjustment, lower HRV was independently associated with greater odds of fever occurrence (OR 0.92 [95% CI 0.87-0.97] with each msec increase in SDNN, p = 0.002). CONCLUSIONS: HRV measured on 10-second EKGs is a potential early marker of parasympathetic nervous system dysfunction and is associated with subsequent fever occurrence after ICH. Detecting early parasympathetic dysfunction may afford opportunities to improve ICH outcome by targeting therapies at fever prevention.

Prophylactic Seizure Medication and Health-Related Quality of Life After Intracerebral Hemorrhage.

OBJECTIVES: Prophylactic levetiracetam is currently used in ~40% of patients with intracerebral hemorrhage, and the potential impact of levetircetam on health-related quality of life is unknown. We tested the hypothesis that prophylactic levetiracetam is independently associated with differences in cognitive function health-related quality of life. DESIGN: Patients with intracerebral hemorrhage were enrolled in a prospective cohort study. We performed mixed models for T-scores of health-related quality of life, referenced to the U.S. population at 50 ± 10, accounting for severity of injury and time to follow-up. SETTING: Academic medical center. PATIENTS: One-hundred forty-two survivors of intracerebral hemorrhage. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: T-scores of Neuro-Quality of Life Cognitive Function v2.0 was the primary outcome, whereas Neuro-Quality of Life Mobility v1.0 and modified Rankin Scale (a global functional scale) were secondary measures. We prospectively documented if prophylactic levetiracetam was administered and retrieved administration data from the electronic health record. Patients who received prophylactic levetiracetam had worse cognitive function health-related quality of life (T-score 5.1 points lower; p = 0.01) after adjustment for age (p = 0.3), National Institutes of Health Stroke Scale (p < 0.000001), lobar hematoma (p = 0.9), and time of assessment; statistical models controlling for prophylactic levetiracetam and the Intracerebral Hemorrhage Score, a global measure of intracerebral hemorrhage severity, yielded similar results. Lower T-scores of cognitive function health-related quality of life at 3 months were correlated with more total levetiracetam dosage (p = 0.01) and more administered doses of levetiracetam in the hospital (p = 0.03). Patients who received prophylactic levetiracetam were more likely to have a lobar hematoma (27/38 vs 19/104; p < 0.001), undergo electroencephalography monitoring (15/38 vs 21/104; p = 0.02), but not more likely to have clinical seizures (4/38 vs 7/104; p = 0.5). Levetiracetam was not independently associated with the modified Rankin Scale scores or mobility health-related quality of life (p > 0.1). CONCLUSIONS: Prophylactic levetiracetam was independently associated with lower cognitive function health-related quality of life at follow-up after intracerebral hemorrhage.