Disruption of thrombo-inflammatory response and activation of a distinct cytokine cluster after subarachnoid hemorrhage.

BACKGROUND: Unregulated inflammatory and thrombotic responses have been proposed to be important causes of early brain injury and worse clinical outcomes after subarachnoid hemorrhage (SAH). OBJECTIVE: We hypothesize that SAH is characterized by an increased inflammatory and thrombotic state and disruption of associations between these states. METHODS: This is a retrospective cohort study of 60 patients with SAH. 23 patients with unruptured aneurysms (UA) and 77 patients with traumatic brain injury (TBI) were chosen as controls. Plasma cytokine levels were measured using a 41-plex human immunoassay kit, and cytokine patterns associated with SAH, UA and TBI were identified using statistical and informatics methods. RESULTS: SAH was characterized by an increase in several cytokines and chemokines, platelet-derived factors, and growth factors. Cluster analysis identified several cytokine clusters common in SAH, UA and TBI groups - generally grouped as platelet-derived, vascular and pro-inflammatory clusters. In the UA group, the platelet-derived cluster had an inverse relationship with the inflammatory cluster which was absent in SAH. Additionally, a cluster comprising of growth and colony stimulating factors was unique to SAH. CONCLUSIONS: A cluster of cytokines involved in growth and colony stimulation was unique to SAH. Negative associations between the thrombotic and inflammatory molecules were observed in UA but not in SAH. Further studies to examine the pathophysiology behind the cluster unique to SAH and the associations between the thrombotic and inflammatory cytokines are required.

Assessment of the Relationship between Body Mass Index and Incidence of Venous Thromboembolism in Hospitalized Overweight and Obese Patients.

STUDY OBJECTIVE: To assess whether a positive linear association exists between body mass index (BMI) and incidence of venous thromboembolism (VTE) in overweight and obese hospitalized patients. DESIGN: Single-center retrospective observational cohort study. SETTING: Large academic tertiary care medical center. PATIENTS: A total of 1452 adults hospitalized between January 1, 2013, and December 31, 2014, who weighed more than 100 kg and had a BMI of 25 kg/m2 or greater on admission, and received heparin subcutaneously for VTE prophylaxis. Patients were categorized into four subgroups based on World Health Organization BMI classification: overweight (141 patients), obese class I (305 patients), obese class II (324 patients), and obese class III (682 patients). MEASUREMENTS AND MAIN RESULTS: The primary outcome was occurrence of VTE in each subgroup; all-cause mortality and length of hospital stay were secondary outcomes. A linear trend test did not show an association between occurrence of VTE and BMI of 25 kg/m2 or greater. VTE occurred in 7 (5%) of 141 patients in the overweight group, 5 (2%) of 305 in the obese class I group, 8 (3%) of 324 in the class II group, and 18 (3%) of 682 in the class III group (p=0.573). In addition, no linear association was noted between all-cause mortality or length of hospital stay and BMI of 25 kg/m2 or greater. Overall mortality was 10% (146/1452 patients). Ten deaths (7%) occurred in the overweight group, 45 (15%) in the obese class I group, 38 (12%) in the obese class II group, and 53 (8%) in the obese class III group (p=0.067). The median length of hospital stay was 5 days (interquartile range 3-9, p=0.122) for all patients. CONCLUSION: In overweight and obese hospitalized patients who weighed more than 100 kg and had a BMI of 25 kg/m2 or greater, the incidence of VTE did not increase incrementally with increasing severity of obesity.

Systematic model of peripheral inflammation after subarachnoid hemorrhage.

OBJECTIVE: To investigate inflammatory processes after aneurysmal subarachnoid hemorrhage (aSAH) with network models. METHODS: This is a retrospective observational study of serum samples from 45 participants with aSAH analyzed at multiple predetermined time points: <24 hours, 24 to 48 hours, 3 to 5 days, and 6 to 8 days after aSAH. Concentrations of cytokines were measured with a 41-plex human immunoassay kit, and the Pearson correlation coefficients between all possible cytokine pairs were computed. Systematic network models were constructed on the basis of correlations between cytokine pairs for all participants and across injury severity. Trends of individual cytokines and correlations between them were examined simultaneously. RESULTS: Network models revealed that systematic inflammatory activity peaks at 24 to 48 hours after the bleed. Individual cytokine levels changed significantly over time, exhibiting increasing, decreasing, and peaking trends. Platelet-derived growth factor (PDGF)-AA, PDGF-AB/BB, soluble CD40 ligand, and tumor necrosis factor-α (TNF-α) increased over time. Colony-stimulating factor (CSF) 3, interleukin (IL)-13, and FMS-like tyrosine kinase 3 ligand decreased over time. IL-6, IL-5, and IL-15 peaked and decreased. Some cytokines with insignificant trends show high correlations with other cytokines and vice versa. Many correlated cytokine clusters, including a platelet-derived factor cluster and an endothelial growth factor cluster, were observed at all times. Participants with higher clinical severity at admission had elevated levels of several proinflammatory and anti-inflammatory cytokines, including IL-6, CCL2, CCL11, CSF3, IL-8, IL-10, CX3CL1, and TNF-α, compared to those with lower clinical severity. CONCLUSIONS: Combining reductionist and systematic techniques may lead to a better understanding of the underlying complexities of the inflammatory reaction after aSAH.

A simple prediction score system for malignant brain edema progression in large hemispheric infarction.

Malignant brain edema (MBE) due to hemispheric infarction can result in brain herniation, poor outcomes, and death; outcome may be improved if certain interventions, such as decompressive craniectomy, are performed early. We sought to generate a prediction score to easily identify those patients at high risk for MBE. 121 patients with large hemispheric infarction (LHI) (2011 to 2014) were included. Patients were divided into two groups: those who developed MBE and those who did not. Independent predictors of MBE were identified by logistic regression and a score was developed. Four factors were independently associated with MBE: baseline National Institutes of Health Stroke Scale (NIHSS) score (p = 0.048), Alberta Stroke Program Early Computed Tomography Score (ASPECTS) (p = 0.007), collateral score (CS) (p<0.001) and revascularization failure (p = 0.013). Points were assigned for each factor as follows: NIHSS ≤ 8 (= 0), 9-17 (= 1), ≥ 18 (= 2); ASPECTS≤ 7 (= 1), >8 (= 0); CS<2 (= 1), ≥2 (= 0); revascularization failure (= 1),success (= 0). The MBE Score (MBES) represents the sum of these individual points. Of 26 patients with a MBES of 0 to 1, none developed MBE. All patients with a MBES of 6 developed MBE. Both MBE development and functional outcomes were strongly associated with the MBES (p = 0.007 and 0.002, respectively). The MBE score is a simple reliable tool for the prediction of MBE.

Impact of practice change in reducing venous thromboembolism in neurocritical overweight patients: 2008-2014.

Publications regarding early initiating venous thromboembolism (VTE) prophylaxis have been available since the early 1990s. These recommendations became available in current guidelines on and after 2012. The purpose of this study is to review the practice change in reducing the incidence of VTE in brain injury patients from 2008 to 2014. This was a single-center, retrospective, observational, cohort study. Data was extracted from our data base that included patients over 100 kg from January 2008 to August 2014. Included were all patients admitted with a primary diagnosis of acute brain and spinal injury to neurocritical care unit. Clinical endpoints examined were incidence of bleeding and VTE. A total of 509 patients who met the inclusion criteria were divided into two groups: The previous group (n = 212) included patients from 2008 to 2010, and the recent group (n = 297) included patients from 2011 to 2014. The time for initiating VTE prophylaxis from admission was (median, IQR) 73 h (37-140) vs. 34 h (20-46); p < 0.01. There were no differences in major and minor bleeding complications. Discontinuation of VTE prophylaxis for association with progressive bleeding was not documented in any of the study patients. The incidence of VTE was 10 % (22/212) vs. 5 % (15/297); p = 0.02. In hospital LOS in days was 16 (10-26) vs. 7 (4-15); P < 0.01. In multivariable logistic regression analysis, only the time of the initiation VTE prophylaxis after admission was significantly associated with the occurrence of VTE (median, IQR) 70 h (37-158) vs. 36 h (20-63); OR 1.004, 95 % CI 1.001-1.007; P < 0.01. In this 6-year review of data, early initiation of VTE prophylaxis has decreased the incidence of VTE without clinically documented bleeding complications.

Endovascular Therapy for Acute Ischemic Stroke With Occlusion of the Middle Cerebral Artery M2 Segment.

IMPORTANCE: Randomized clinical trials have shown the superiority of endovascular therapy (EVT) compared with best medical management for acute ischemic strokes with large vessel occlusion (LVO) in the anterior circulation. However, of 1287 patients enrolled in 5 trials, 94 with isolated second (M2) segment occlusions were randomized and 51 of these received EVT, thereby limiting evidence for treating isolated M2 segment occlusions as reflected in American Heart Association guidelines. OBJECTIVE: To evaluate EVT safety and effectiveness in M2 occlusions in a cohort of patients with acute ischemic stroke. DESIGN, SETTING, AND PARTICIPANTS: This multicenter retrospective cohort study pooled patients with acute ischemic strokes and LVO isolated to M2 segments from 10 US centers. Patients with acute ischemic strokes and LVO in M2 segments presenting within 8 hours from their last known normal clinical status (LKN) from January 1, 2012, to April 30, 2015, were divided based on their treatment into EVT and medical management groups. Logistic regression was used to compare the 2 groups. Univariate and multivariate analyses evaluated associations with good outcome in the EVT group. MAIN OUTCOMES AND MEASURES: The primary outcome was the 90-day modified Rankin Scale score (range, 0-6; scores of 0-2 indicate a good outcome); the secondary outcome was symptomatic intracerebral hemorrhage. RESULTS: A total of 522 patients (256 men [49%]; 266 women [51%]; mean [SD] age, 68 [14.3] years) were identified, of whom 288 received EVT and 234 received best medical management. Patients in the medical management group were older (median [interquartile range] age, 73 [60-81] vs 68 [56-78] years) and had higher rates of intravenous tissue plasminogen activator treatment (174 [74.4%] vs 172 [59.7%]); otherwise the 2 groups were balanced. The rate of good outcomes was higher for EVT (181 [62.8%]) than for medical management (83 [35.4%]). The EVT group had 3 times the odds of a good outcome as the medical management group (odds ratio [OR], 3.1; 95% CI, 2.1-4.4; P < .001) even after adjustment for age, National Institute of Health Stroke Scale (NIHSS) score, Alberta Stroke Program Early Computed Tomographic Score (ASPECTS), intravenous tissue plasminogen activator treatment, and time from LKN to arrival in the emergency department (OR, 3.2; 95% CI, 2-5.2; P < .001). No statistical difference in symptomatic intracerebral hemorrhage was found (5.6% vs 2.1% for the EVT group vs the medical management group; P = .10). The treatment effect did not change after adjusting for center (OR, 3.3; 95% CI, 1.9-5.8; P < .001). Age, NIHSS score, ASPECTS, time from LKN to reperfusion, and successful reperfusion score of at least 2b (range, 0 [no perfusion] to 3 [full perfusion with filling of all distal branches]) were independently associated with good outcome of EVT. A linear association was found between good outcome and time from LKN to reperfusion. CONCLUSIONS AND RELEVANCE: Although a randomized clinical trial is needed to confirm these findings, available data suggest that EVT is reasonable, safe, and effective for LVO of the M2 segment relative to best medical management.

Quantification of Cerebral Edema After Subarachnoid Hemorrhage.

BACKGROUND: Global cerebral edema (GCE) is a manifestation of early brain injury (EBI) after subarachnoid hemorrhage (SAH) and is an independent risk factor for poor outcome. The lack of a quantitative method to measure GCE limits the study of its pathophysiology. The goal of this study is to develop a quantitative surrogate marker that represents GCE after SAH. METHODS: Patients with spontaneous SAH were enrolled into a prospective observational database. Initial CT scans were graded for GCE using established qualitative criteria. Selective sulcal volume (SSV) was defined as total mL of sulcal volumes on axial CT slices above the most cranial section of the lateral ventricles to the last visible section. Using a semiautomatic threshold approach, sulcal regions were traced out with manual adjustments when necessary. The volume of sulci in each slice was calculated and multiplied by the slice thickness and number of slices to calculate the SSV. All volumetric analysis was performed using Medical Image Processing, Analysis and Visualization Version 7.0.1 (MIPAV). RESULTS: A total of 109 subjects were included in our analysis. Mean selective sulcal volumes (SSV) differed between subjects with and without GCE 4.5 and 21.2 mL (P < 0.001). When separated into quartiles, the odds of qualitative GCE increases as SSV decreases. Compared to the highest SSV quartile, smaller SSV was associated with worse clinical outcomes. CONCLUSION: GCE can be quantified using volumetric analysis of SSV measurements on routine CT scans. Smaller SSV on admission is predictive of worse clinical outcomes. SSV may be an important marker of EBI after SAH.

Early depression screening is feasible in hospitalized stroke patients.

BACKGROUND AND PURPOSE: Post-stroke depression (PSD) is common but is not routinely assessed for in hospitalized patients. As a Comprehensive Stroke Center, we screen all stroke inpatients for depression, though the feasibility of early screening has not been established. We assessed the hypothesis that early depression screening in stroke patients is feasible. We also explored patient level factors associated with being screened for PSD and the presence of early PSD. METHODS: The medical records of all patients admitted with ischemic stroke (IS) or intracerebral hemorrhage (ICH) between 01/02/13 and 15/04/13 were reviewed. A depression screen, modified from the Patient Health Questionnaire-9, was administered (maximum score 27, higher scores indicating worse depression). Patients were eligible if they did not have a medical condition precluding screening. Feasibility was defined as screening 75% of all eligible patients. RESULTS: Of 303 IS and ICH inpatients, 70% (211) were eligible for screening, and 75% (158) of all eligible patients were screened. More than one-third of all patients screened positive for depression (score > 4). Women (OR 2.06, 95% CI 1.06-4.01) and younger patients (OR 0.97, 95% CI 0.96-0.99) were more likely to screen positive. Screening positive was not associated with poor discharge/day 7 outcome (mRS > 3; OR 1.45, 95% CI 0.74-2.83). CONCLUSIONS: Screening stroke inpatients for depression is feasible and early depression after stroke is common. Women and younger patients are more likely to experience early PSD. Our results provide preliminary evidence supporting continued screening for depression in hospitalized stroke patients.