Magnesium and Hematoma Expansion in Intracerebral Hemorrhage: A FAST-MAG Randomized Trial Analysis.

BACKGROUND: Observational studies suggest that magnesium may have hemostatic effects. FAST-MAG (Field Administration of Stroke Therapy-Magnesium) was a pragmatic clinical trial of magnesium sulfate administered prehospital for acute clinical stroke syndromes and included patients with intracerebral hemorrhage. Exploratory secondary analysis by the treatment group found no reduction in hematoma expansion (HE) associated with magnesium treatment in intracerebral hemorrhage but did not consider serum magnesium levels achieved. We analyzed FAST-MAG intracerebral hemorrhage data for associations between serum magnesium level, HE, and early neurological deterioration, accounting for groupwise biases. METHODS: HE was defined as hematoma volume increase ≥3 mL within 24 hours and early neurological deterioration as ≥1-point Glasgow Coma Scale decline from arrival to hospital day 4. Comparing treatment and placebo groups confirmed biased availability of neuroimaging data. Therefore, HE and neurological deterioration were analyzed and stratified by treatment and placebo groups using univariate tests and adjusted logistic regression. RESULTS: Spontaneous intracerebral hemorrhage was present in 381 patients. Placebo patients had fewer serial neuroimaging studies available (123 [65.4%] versus 145 [75.1%]; P=0.038). Necessary data were available in 104 magnesium- and 85 placebo-treated patients (age, 64.9 [13.0] years; 67.7% male). In the magnesium group, higher magnesium level was associated with less HE (adjusted odds ratio, 0.64 per mg/dL [95% CI, 0.42-0.93]) and less neurological deterioration (adjusted odds ratio, 0.54 per mg/dL [95% CI, 0.33-0.82]). In the placebo group, magnesium level was not associated with either HE or neurological deterioration. CONCLUSIONS: Magnesium may exhibit a hemostatic effect that was only observable in the FAST-MAG magnesium treatment group. Equipoise should be maintained, and specific trials are needed. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00059332.

Neurologic Manifestations of Long COVID Differ Based on Acute COVID-19 Severity.

OBJECTIVE: To characterize neurologic manifestations in post-hospitalization Neuro-PASC (PNP) and non-hospitalized Neuro-PASC (NNP) patients. METHODS: Prospective study of the first 100 consecutive PNP and 500 NNP patients evaluated at a Neuro-COVID-19 clinic between 5/2020 and 8/2021. RESULTS: PNP were older than NNP patients (mean 53.9 vs 44.9 y; p < 0.0001) with a higher prevalence of pre-existing comorbidities. An average 6.8 months from onset, the main neurologic symptoms were "brain fog" (81.2%), headache (70.3%), and dizziness (49.5%) with only anosmia, dysgeusia and myalgias being more frequent in the NNP compared to the PNP group (59 vs 39%, 57.6 vs 39% and 50.4 vs 33%, all p < 0.003). Moreover, 85.8% of patients experienced fatigue. PNP more frequently had an abnormal neurologic exam than NNP patients (62.2 vs 37%, p < 0.0001). Both groups had impaired quality of life in cognitive, fatigue, sleep, anxiety, and depression domains. PNP patients performed worse on processing speed, attention, and working memory tasks than NNP patients (T-score 41.5 vs 55, 42.5 vs 47 and 45.5 vs 49, all p < 0.001) and a US normative population. NNP patients had lower results in attention task only. Subjective impression of cognitive ability correlated with cognitive test results in NNP but not in PNP patients. INTERPRETATION: PNP and NNP patients both experience persistent neurologic symptoms affecting their quality of life. However, they harbor significant differences in demographics, comorbidities, neurologic symptoms and findings, as well as pattern of cognitive dysfunction. Such differences suggest distinct etiologies of Neuro-PASC in these populations warranting targeted interventions. ANN NEUROL 2023;94:146-159.

Plasma proteomics show altered inflammatory and mitochondrial proteins in patients with neurologic symptoms of post-acute sequelae of SARS-CoV-2 infection.

Persistent symptoms of COVID-19 survivors constitute long COVID syndrome, also called post-acute sequelae of SARS-CoV-2 infection (PASC). Neurologic manifestations of PASC (Neuro-PASC) are particularly debilitating, long lasting, and poorly understood. To gain insight into the pathogenesis of PASC, we leveraged a well-characterized group of Neuro-PASC (NP) patients seen at our Neuro-COVID-19 clinic who had mild acute COVID-19 and never required hospitalization to investigate their plasma proteome. Using the SomaLogic platform, SomaScan, the plasma concentration of >7000 proteins was measured from 92 unvaccinated individuals, including 48 NP patients, 20 COVID-19 convalescents (CC) without lingering symptoms, and 24 unexposed healthy controls (HC) to interrogate underlying pathobiology and potential biomarkers of PASC. We analyzed the plasma proteome based on post-COVID-19 status, neurologic and non-neurologic symptoms, as well as subjective and objective standardized tests for changes in quality-of-life (QoL) and cognition associated with Neuro-PASC. The plasma proteome of NP patients differed from CC and HC subjects more substantially than post-COVID-19 groups (NP and CC combined) differed from HC. Proteomic differences in NP patients 3-9 months following acute COVID-19 showed alterations in inflammatory proteins and pathways relative to CC and HC subjects. Proteomic associations with Neuro-PASC symptoms of brain fog and fatigue included changes in markers of DNA repair, oxidative stress, and neutrophil degranulation. Furthermore, we discovered a correlation between NP patients lower subjective impression of recovery to pre-COVID-19 baseline with an increase in the concentration of the oxidative phosphorylation protein COX7A1, which was also associated with neurologic symptoms and fatigue, as well as impairment in QoL and cognitive dysfunction. Finally, we identified other oxidative phosphorylation-associated proteins correlating with central nervous system symptoms. Our results suggest ongoing inflammatory changes and mitochondrial involvement in Neuro-PASC and pave the way for biomarker validation for use in monitoring and development of therapeutic intervention for this debilitating condition.

Household income is associated with functional outcomes in a multi-institutional cohort of patients with ischemic stroke and COVID-19.

OBJECTIVES: The COVID-19 pandemic has heightened awareness of health disparities associated with socioeconomic status (SES) across the United States. We examined whether household income is associated with functional outcomes after stroke and COVID-19. MATERIALS AND METHODS: This was a multi-institutional, retrospective cohort study of consecutively hospitalized patients with SARS-CoV-2 and radiographically confirmed stroke presenting from March through November 2020 to any of five comprehensive stroke centers in metropolitan Chicago, Illinois, USA. Zip-code-derived household income was dichotomized at the Chicago median. Logistic regression was used to examine the relationship between household income and good functional outcome (modified Rankin Scale 0-3 at discharge, after ischemic stroke). RESULTS: Across five hospitals, 159 patients were included. Black patients comprised 48.1%, White patients 38.6%, and Hispanic patients 27.7%. Median household income was $46,938 [IQR: $32,460-63,219]. Ischemic stroke occurred in 115 (72.3%) patients (median NIHSS 7, IQR: 0.5-18.5) and hemorrhagic stroke in 37 (23.7%). When controlling for age, sex, severe COVID-19, and NIHSS, patients with ischemic stroke and household income above the Chicago median were more likely to have a good functional outcome at discharge (OR 7.53, 95% CI 1.61 - 45.73; P=0.016). Race/ethnicity were not included in final adjusted models given collinearity with income. CONCLUSIONS: In this multi-institutional study of hospitalized patients with stroke, those residing in higher SES zip codes were more likely to have better functional outcomes, despite controlling for stroke severity and COVID-19 severity. This suggests that area-based SES factors may play a role in outcomes from stroke and COVID-19.

The Feasibility and Validity of Objective and Patient-Reported Measurements of Cognition During Early Critical Illness Recovery.

BACKGROUND: Cognitive outcomes are an important determinant of quality of life after critical illness, but methods to assess early cognitive impairment and cognition recovery are not established. The objective of this study was to assess the feasibility and validity of objective and patient-reported cognition assessments for generalized use during early recovery from critical illness. METHODS: Patients presented from the community with acute onset of either intracerebral hemorrhage (ICH) or sepsis as representative neurologic and systemic critical illnesses. Early cognitive assessments comprised the Glasgow Coma Scale (GCS), three NIH Toolbox cognition measures (Flanker Inhibitory Control and Attention Test, List Sorting Working Memory Test and Pattern Comparison Processing Speed Test) and two Patient Reported Outcomes Measurement Information System (PROMIS) cognition measures (Cognition-General Concerns and Cognition-Abilities) performed seven days after intensive care unit discharge or at hospital discharge, whichever occurred first. RESULTS: We enrolled 91 patients (53 with sepsis, 38 with ICH), and after attrition principally due to deaths, cognitive assessments were attempted in 73 cases. Median [interquartile range] Sequential Organ Failure Assessment scores for patients with sepsis was 7 [3, 11]. ICH cases included 13 lobar, 21 deep and 4 infratentorial hemorrhages with a median [IQR] ICH Score 2 [1, 2]. Patient-reported outcomes were successfully obtained in 42 (58% overall, 79% of sepsis and 34% of ICH) patients but scores were anomalously favorable (median 97th percentile compared to the general adult population). Analysis of the PROMIS item bank by four blinded, board-certified academic neurointensivists revealed a strong correlation between higher severity of reported symptoms and greater situational relevance of the items (ρ = 0.72, p = 0.002 correlation with expert item assessment), indicating poor construct validity in this population. NIH Toolbox tests were obtainable in only 9 (12%) patients, all of whom were unimpaired by GCS (score 15) and completed PROMIS assessments. Median scores were 5th percentile (interquartile range [2nd, 9th] percentile) and uncorrelated with self-reported symptoms. Shorter intensive care unit length of stay was associated with successful testing in both patients with ICH and sepsis, along with lower ICH Score in patients with ICH and absence of premorbid dementia in patients with sepsis (all p < 0.05). CONCLUSIONS: Methods of objective and patient-reported cognitive testing that have been validated for use in patients with chronic medical and neurologic illness were infeasible or yielded invalid results among a general sample of patients in this study who were in early recovery from neurologic and systemic critical illness. Longer critical illness duration and worse neurocognitive impairments, whether chronic or acute, reduced testing feasibility.

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.

Transcranial Doppler Ultrasound Evidence of Active Cerebral Embolization in COVID-19.

OBJECTIVE: To report six consecutive patients with confirmed coronavirus disease-2019 (COVID-19) who underwent Transcranial Doppler (TCD) ultrasonography evaluation for cerebral microemboli in the setting of suspected or confirmed acute ischemic stroke. METHODS: Patient data were obtained from medical records from Northwestern Memorial Hospital, Chicago, IL between May and June 2020. All patients with confirmed COVID-19 who underwent clinical TCD ultrasonography for microemboli detection were included. RESULTS: A total of eight TCD studies were performed in six patients with COVID-19 (4 men and 2 women, median age 65±5), four with confirmed ischemic stroke and two with refractory encephalopathy. Microemboli were detected in three male patients, two patients had suffered a confirmed ischemic stroke and one who developed prolonged encephalopathy. Microemboli of varying intensity were identified in multiple vascular territories in two patients, and microemboli persisted despite therapeutic anticoagulation in a third patient. Of the three patients without evidence of microemboli on TCD ultrasonography, two patients had suffered a confirmed ischemic stroke, while one remained with refractory encephalopathy. CONCLUSIONS: TCD ultrasonography for microemboli detection identified three patients with confirmed COVID-19 with evidence of cerebral arterial microemboli, including one who was therapeutically anticoagulated. TCD ultrasonography provides a non-invasive method for evaluating cerebral microemboli in patients with COVID-19 and may be useful in assessing response to treatment in cases with suspected or confirmed disorders of hypercoagulability. Further studies investigating the prevalence of cerebral microemboli and associated risk factors are needed to characterize their pathogenic mechanism and guide therapeutic interventions in hospitalized COVID-19 patients.

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.

Serum osmolality, cerebrospinal fluid specific gravity and overt hepatic encephalopathy severity in patients with liver failure.

BACKGROUND AND AIMS: Hepatic encephalopathy (HE) is a leading contributor to morbidity in liver disease. While hyperammonaemia plays a key role, the mechanisms of cerebral toxicity are unclear. We hypothesized that serum hyperosmolality contributes to HE during acute (ALF) and acute-on-chronic liver failure (ACLF) through mechanisms that affect the water and solute composition of the cerebral environment. METHODS: We performed a retrospective analysis of serum osmolality, cerebral spinal fluid (CSF) solute density (specific gravity, determined from computed tomography attenuation) and clinical HE severity (Glasgow Coma Score [GCS]) at the time of intensive care admission in a prospectively identified cohort of liver failure patients with overt HE. RESULTS: Seventy-three patients (39 ALF and 34 ACLF) were included, of whom 28 (38%) were comatose. Serum osmolality (303.9 ± 15.4 mOsm/kg) was elevated despite normal serum sodium (136.6 ± 6.3 mEq/L). Increased osmolality was independently associated with more severe encephalopathy (ordinal adjusted OR 0.26 [95% CI 0.22, 0.31] for higher GCS per standard deviation increase in osmolality) and lower CSF-specific gravity (linear adjusted ß = -0.039 [95% CI -0.069, -0.009] Hounsfield unit per 1 mOsm/kg). CONCLUSIONS: In the context of related research, these data suggest that hyperosmolality increases brain exposure to metabolic toxins by blood-brain barrier alteration and may be a unique therapeutic target.

Natural History of Infratentorial Intracerebral Hemorrhages: Two Subgroups with Distinct Presentations and Outcomes.

BACKGROUND/OBJECTIVE: Infratentorial intracerebral hemorrhage (ICH) is associated with worse prognosis than supratentorial ICH; however, infratentorial ICH is often excluded or underrepresented in clinical trials of ICH. We sought to evaluate the natural history of infratentorial ICH stratified by brainstem or cerebellar location using a prospective observational study inclusive of all spontaneous ICH. METHODS: Using a prospective, single center cohort of patients with spontaneous ICH between 2008-2019, we conducted a descriptive analysis of baseline demographics, severity of injury scores, and long-term functional outcomes of infratentorial ICH stratified by cerebellar or brainstem location. RESULTS: Infratentorial ICH occurred in 82 (13%) of 632 patients in our ICH cohort. Among infratentorial ICH, cerebellar ICH occurred in 45 (55%) and brainstem ICH occurred in 37 (45%). Compared to cerebellar ICH, patients with brainstem ICH had significantly worse severity of injury scores, including lower admission Glasgow Coma Scale (median 14 [7.0 - 15.0] versus 4 [3.0 - 8.0], respectively; P < 0.001) and higher ICH Score (median 2 [1.0 - 3.0] versus 3 [2.75 - 4.0], respectively; P =  0.02). Patients with cerebellar ICH were more likely to be discharged home or to acute rehabilitation (OR 4.8, 95% CI 1.8 - 12.8) but there was no difference in in-hospital mortality (OR 0.4, 95% CI 0.1 - 1.1, P =  0.08) or cause of death (P =  0.5). Modified Rankin Scale scores at 3 months were significantly better in patients with cerebellar ICH compared to brainstem ICH (median 3.5 [1.8 - 6.0] versus median 6 [5.0 - 6.0], P =  0.03). CONCLUSIONS: Location of infratentorial ICH is an important determinant of admission severity and clinical outcome in unselected patients with ICH. Patients with cerebellar ICH have less severe symptoms at presentation and more favorable functional outcomes compared to patients with brainstem ICH.

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.

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.

Fever Burden and Health-Related Quality of Life After Intracerebral Hemorrhage.

BACKGROUND: Fever is associated with worse functional outcomes after intracerebral hemorrhage (ICH); however, there are few prospective data to quantify the relationship with health-related quality of life (HRQoL). We tested the hypothesis that increased burden of fever is independently associated with decreased HRQoL at follow-up. METHODS: In this prospective observational cohort study of 106 ICH patients admitted to a tertiary care hospital between 2011 and 2015, we recorded the highest core temperature each calendar day for 14 days after ICH onset. Fever burden was defined as the number of days with a fever ≥ 100.4 °F (38 °C). HRQoL outcomes were measured with Neuro-QoL domains of Cognitive Function and Mobility at 28 days, 3 months, and 1 year. Results were analyzed using mixed effects regression analysis. RESULTS: Each additional day with a fever was independently associated with lower Mobility HRQoL (T-score - 0.9, [- 1.6 to - 0.2]; p = 0.01) and Cognitive Function HRQoL (T-score - 1.3 [- 2.0 to - 0.6]; p = 0.001) after correction for National Institutes of Health Stroke Scale score on admission, age, and time to follow-up. CONCLUSIONS: Each additional day with a fever was predictive of worse HRQoL domains of Cognitive Function and Mobility after ICH up to 1 year. These data extend previous evidence on the negative association of fever and functional outcomes to the domains of Cognitive Function and Mobility HRQoL. HRQoL outcomes may be a sensitive and powerful way to measure the efficacy of fever control in future research.

Medication History versus Point-of-Care Platelet Activity Testing in Patients with Intracerebral Hemorrhage.

OBJECTIVE: We evaluated whether reduced platelet activity detected by point-of-care (POC) testing is a better predictor of hematoma expansion and poor functional outcomes in patients with intracerebral hemorrhage (ICH) than a history of antiplatelet medication exposure. METHODS: Patients presenting with spontaneous ICH were enrolled in a prospective observational cohort study that collected demographic, clinical, laboratory, and radiographic data. We measured platelet activity using the PFA-100 (Siemens AG, Germany) and VerifyNow-ASA (Accumetrics, CA) systems on admission. We performed univariate and adjusted multivariate analyses to assess the strength of association between those measures and (1) hematoma growth at 24 hours and (2) functional outcomes measured by the modified Rankin Scale (mRS) at 3 months. RESULTS: We identified 278 patients for analysis (mean age 65 ± 15, median ICH score 1 [interquartile range 0-2]), among whom 164 underwent initial neuroimaging within 6 hours of symptom onset. Univariate association with hematoma growth was stronger for antiplatelet medication history than POC measures, which was confirmed in multivariable models (ß 3.64 [95% confidence interval [CI] 1.02-6.26], P = .007), with a larger effect size measured in the under 6-hour subgroup (ß 7.20 [95% CI 3.35-11.1], P < .001). Moreover, antiplatelet medication history, but not POC measures of platelet activity, was independently associated with poor outcome at 3 months (mRS 4-6) in the under 6-hour subgroup (adjusted OR 3.6 [95% CI 1.2-11], P = .023). CONCLUSION: A history of antiplatelet medication use better identifies patients at risk for hematoma growth and poor functional outcomes than POC measures of platelet activity after spontaneous ICH.

Refining Prognosis for Intracerebral Hemorrhage by Early Reassessment.

BACKGROUND: Prognostic assessments, which are crucial for decision-making in critical illnesses, have shown unsatisfactory reliability. We compared the accuracy of a widely used prognostic score against a model derived from clinical data obtained 5 days after admission for patients with intracerebral hemorrhage (ICH), a condition for which prognostication has proven notoriously challenging and prone to bias. METHODS: Patients enrolled in a prospective observational cohort study of spontaneous ICH underwent hourly Glasgow Coma Scale (GCS) assessment. Outcome was measured at 3 months using the modified Rankin Scale (mRS). We analyzed the change in correlation between GCS and 3-month mRS scores from admission through day 5, and compared the performance of a parsimonious set of day 5 clinical variables against the ICH score. RESULTS: Data was collected on 254 subjects. The ICH score and day 5 GCS score were both correlated with 3-month mRS score (p < 0.001), but the correlation was stronger with day 5 GCS score (p < 0.05 by Fisher z-transformation). Premorbid mRS score, intraventricular hemorrhage and day 5 GCS score were independent predictors of outcome (all p < 0.05 in ordinal regression model). While ICH score correctly classified good (mRS 0-3) vs. poor (mRS 4-6) outcome in 73% of cases, the day 5 model correctly classified 83% of cases. CONCLUSIONS: A simple reassessment after 5 days of care significantly improves the accuracy of prognosticating outcome in patients with ICH. These data confirm the feasibility and potential utility of early reassessments in refining prognosis for patients who survive early stabilization of a severe neurologic injury.

Agitation, Delirium, and Cognitive Outcomes in Intracerebral Hemorrhage.

BACKGROUND: Delirium predicts higher long-term cognitive morbidity. We previously identified a cohort of patients with spontaneous intracerebral hemorrhage and delirium and found worse outcomes in health-related quality of life (HRQoL) in the domain of cognitive function. OBJECTIVE: We tested the hypothesis that agitation would have additional prognostic significance on later cognitive function HRQoL. METHODS: Prospective identification of 174 patients with acute intracerebral hemorrhage, measuring stroke severity, agitation, and delirium, with a standardized protocol and measures. HRQoL was assessed using the Neuro-QOL at 28 days, 3 months, and 1 year. Functional outcomes were measured with the modified Rankin Scale. RESULTS: Among the 81 patients with HRQoL follow-up data available, patients who had agitation and delirium had worse cognitive function HRQoL scores at 28 days (T scores for delirium with agitation 20.9 ± 7.3, delirium without agitation 30.4 ± 16.5, agitation without delirium 36.6 ± 17.5, and neither agitated nor delirious 40.3 ± 15.9; p = 0.03) and at 1 year (p = 0.006). The effect persisted in mixed models after correction for severity of neurologic injury, age, and time of assessment (p = 0.0006) and was not associated with medication use, seizures, or infection. CONCLUSIONS: The presence of agitation with delirium in patients with intracerebral hemorrhage may predict higher risk of unfavorable cognitive outcomes up to 1 year later.

23.4% Saline Decreases Brain Tissue Volume in Severe Hepatic Encephalopathy as Assessed by a Quantitative CT Marker.

OBJECTIVE: Cerebral edema is common in severe hepatic encephalopathy and may be life threatening. Bolus 23.4% hypertonic saline improves surveillance neuromonitoring scores, although its mechanism of action is not clearly established. We investigated the hypothesis that bolus hypertonic saline decreases cerebral edema in severe hepatic encephalopathy utilizing a quantitative technique to measure brain and cerebrospinal fluid volume changes. DESIGN: Retrospective analysis of serial CT scans, and clinical data for a case-control series were performed. SETTING: ICUs of a tertiary care hospital. PATIENTS: Patients with severe hepatic encephalopathy treated with 23.4% hypertonic saline and control patients who did not receive 23.4% hypertonic saline. INTERVENTIONS: 23.4% hypertonic saline bolus administration. MEASUREMENTS AND MAIN RESULTS: We used clinically obtained CT scans to measure volumes of the ventricles, intracranial cerebrospinal fluid, and brain using a previously validated semiautomated technique (Analyze Direct, Overland Park, KS). Volumes before and after 23.4% hypertonic saline were compared with Wilcoxon signed rank test. Associations among total cerebrospinal fluid volume, ventricular volume, serum sodium, and Glasgow Coma Scale scores were assessed using Spearman rank correlation test. Eleven patients with 18 administrations of 23.4% hypertonic saline met inclusion criteria. Total cerebrospinal fluid (median, 47.6 mL [35.1-69.4 mL] to 61.9 mL [47.7-87.0 mL]; p < 0.001) and ventricular volumes (median, 8.0 mL [6.9-9.5 mL] to 9.2 mL [7.8-11.9 mL]; p = 0.002) increased and Glasgow Coma Scale scores improved (median, 4 [3-6] to 7 [6-9]; p = 0.008) after 23.4% hypertonic saline. In contrast, total cerebrospinal fluid and ventricular volumes decreased in untreated control patients. Serum sodium increase was associated with increase in total cerebrospinal fluid volume (r = 0.83, p < 0.001), and change in total cerebrospinal fluid volume was associated with ventricular volume change (r = 0.86; p < 0.001). CONCLUSIONS: Total cerebrospinal fluid and ventricular volumes increased after 23.4% hypertonic saline, consistent with a reduction in brain tissue volume. Total cerebrospinal fluid and ventricular volume change may be useful quantitative measures to assess cerebral edema in severe hepatic encephalopathy.