167 High Throughput Metabolite Profiling Identifies Plasma Anandamide as a Biomarker of Functional Outcome After Aneurysmal Subarachnoid Hemorrhage

Neurosurgery ◽  
2017 ◽  
Vol 64 (CN_suppl_1) ◽  
pp. 242-243
Author(s):  
Christopher J Stapleton ◽  
Hannah Irvine ◽  
Zoe Wolcott ◽  
Aman B Patel ◽  
Jonathan Rosand ◽  
...  

Abstract INTRODUCTION The quantification of metabolites in plasma samples in patients with aneurysmal subarachnoid hemorrhage (aSAH) can highlight important alterations in critical metabolic pathways. As metabolites reflect changes associated with disease conditions, metabolite profiling (metabolomics) can identify candidate biomarkers for disease and potentially uncover pathways for intervention. METHODS We performed high throughput metabolite profiling across a broad spectrum of chemical classes (173 metabolites) on plasma samples taken from 119 patients with aSAH. Samples were drawn at 3 time points following ictus: 2–4, 7–10, and 12–14 days. Univariate and logistic regression analyses were performed to examine the relation of each metabolite with multiple outcome variables, including short- and long-term functional outcome (modified Rankin Scale, mRS). RESULTS >A good functional outcome (mRS 0–2) was found in 63.1% and 66.7% of patients at 30 and 90 days, respectively, following aSAH. Plasma concentrations of the endogenous cannabinoid anandamide during days 2–4 after aneurysmal SAH were decreased by 48.1% (P < 0.0001) and 57.6% (P <0.0001) in patients with mRS 0–2 at 30 and 90 days, respectively. A similar statistical result was noted with plasma anandamide concentrations averaged across all time periods. Logistic regression further demonstrated that anandamide remained an independent predictor of functional outcome (30 days: P = 0.04; 90 days: P = 0.03), even after adjusting for other factors that influence outcome, including age, World Federation of Neurological Surgeons grade (WFNS), Fisher grade, and symptomatic vasospasm. CONCLUSION Decreased plasma anandamide following aSAH predicts a good functional outcome at 30 and 90 days. While a role for anandamide in aneurysmal SAH has not been previously reported, elevated anandamide levels have been implicated in neuronal apoptosis and cerebral edema in the acutely injured brain. These data highlight the increasing capability of metabolomics techniques in profiling large-sized cohorts to illuminate novel markers of disease and potential metabolic regulators.

2020 ◽  
Vol 133 (6) ◽  
pp. 1842-1849 ◽  
Author(s):  
Christopher J. Stapleton ◽  
Animesh Acharjee ◽  
Hannah J. Irvine ◽  
Zoe C. Wolcott ◽  
Aman B. Patel ◽  
...  

OBJECTIVEMetabolite profiling (or metabolomics) can identify candidate biomarkers for disease and potentially uncover new pathways for intervention. The goal of this study was to identify potential biomarkers of functional outcome after subarachnoid hemorrhage (SAH).METHODSThe authors performed high-throughput metabolite profiling across a broad spectrum of chemical classes (163 metabolites) on plasma samples taken from 191 patients with SAH who presented to Massachusetts General Hospital between May 2011 and October 2016. Samples were drawn at 3 time points following ictus: 0–5, 6–10, and 11–14 days. Elastic net (EN) and LASSO (least absolute shrinkage and selection operator) machine learning analyses were performed to identify metabolites associated with 90-day functional outcomes as assessed by the modified Rankin Scale (mRS). Additional univariate and multivariate analyses were then conducted to further examine the relationship between metabolites and clinical variables and 90-day functional outcomes.RESULTSOne hundred thirty-seven (71.7%) patients with aneurysmal SAH met the criteria for inclusion. A good functional outcome (mRS score 0–2) at 90 days was found in 79 (57.7%) patients. Patients with good outcomes were younger (p = 0.002), had lower admission Hunt and Hess grades (p < 0.0001) and modified Fisher grades (p < 0.0001), and did not develop hydrocephalus (p < 0.0001) or delayed cerebral ischemia (DCI) (p = 0.049). EN and LASSO machine learning methods identified taurine as the leading metabolite associated with 90-day functional outcome (p < 0.0001). Plasma concentrations of the amino acid taurine from samples collected between days 0 and 5 after aneurysmal SAH were 21.9% (p = 0.002) higher in patients with good versus poor outcomes. Logistic regression demonstrated that taurine remained a significant predictor of functional outcome (p = 0.013; OR 3.41, 95% CI 1.28–11.4), after adjusting for age, Hunt and Hess grade, modified Fisher grade, hydrocephalus, and DCI.CONCLUSIONSElevated plasma taurine levels following aneurysmal SAH predict a good 90-day functional outcome. While experimental evidence in animals suggests that this effect may be mediated through downregulation of pro-inflammatory cytokines, additional studies are required to validate this hypothesis in humans.


2015 ◽  
Vol 122 (2) ◽  
pp. 414-418 ◽  
Author(s):  
Marianna Pegoli ◽  
Jay Mandrekar ◽  
Alejandro A. Rabinstein ◽  
Giuseppe Lanzino

OBJECT Case fatality rates after aneurysmal subarachnoid hemorrhage (aSAH) have decreased over time, and many patients treated with modern paradigms return to a normal life. However, there is little information on predictors of excellent functional outcome after aSAH. In this study, the authors investigated predictors of excellent outcome in a modern consecutive series of patients with aSAH. METHODS A retrospective review was conducted of patients with aSAH admitted between 2001 and 2013. The primary outcome measure was excellent functional outcome, defined as modified Rankin Scale (mRS) score of 0 or 1 at last follow-up within 1 year of aSAH. RESULTS Three hundred seventy-three patients were identified with posthospital follow-up. Excellent outcome was noted in 236 patients (63.3%), including an mRS score of 0 in 122 (32.7%) and an mRS score of 1 in 114 (30.6%). On univariate analysis, the following factors were associated with an excellent outcome: indicators of less severe bleeding, such as better World Federation of Neurosurgical Societies grade at any of the times of assessment, better modified Fisher grade, and absence of intracerebral hemorrhage (ICH), intraventricular hemorrhage (IVH), and symptomatic hydrocephalus; aneurysm treatment with coil embolization; absence of symptomatic vasospasm, delayed cerebral ischemia, and radiological infarction; absence of in-hospital seizures; lack of need for CSF diversion; fewer hours with fever; less severe anemia; and absence of transfusion. On multivariable analysis, the 4 variables that were most strongly associated with excellent outcome were presence of good clinical grade after neurological resuscitation, absence of ICH on initial CT scan, blood transfusion during the hospitalization, and radiological infarctions on final brain imaging. CONCLUSIONS Excellent outcomes (mRS score 0–1) can be achieved in the majority of patients with aSAH. The likelihood of excellent outcome is predicted by good clinical condition after resuscitation, absence of ICH on presentation, no evidence of infarction on brain imaging, and absence of blood transfusion during hospitalization.


Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Sean Neifert ◽  
Alexander Schupper ◽  
Michael Martini ◽  
Emily Chapman ◽  
William Shuman ◽  
...  

Introduction: Despite their high prevalence, prospective data on medical complications after aneurysmal subarachnoid hemorrhage (aSAH) and their contribution to functional outcome are sparse. We review rates of such events and correlate them to functional outcomes in three prospective datasets of patients with aSAH. Methods: Patients from two clinical trials (NEWTON-2, CONSCIOUS-1) and one clinical registry (Subarachnoid Hemorrhage Outcomes Project) were included. A good functional outcome was defined as a Glasgow Outcomes Scale (GOS) score of 4 or 5. Seventeen medical complications were assessed and their association with functional outcomes was determined with multivariable logistic regression. The variance in outcome explained by medical complications was calculated using difference in Nagelkerke’s R-squared. Results: Among the 1,430 patients, the most common complications were fever (564, 39%), anemia (410, 29%), and pneumonia (341, 24%). Patients who suffered any complication (OR: 0.45; 95% CI: 0.36 to 0.57; p<0.001) were less likely to have a good functional outcome in unadjusted analyses. In multivariable analysis, complications independently associated with lower rates of good functional outcome were anemia (OR: 0.60; 95% CI: 0.44 to 0.80; p<0.001), cardiac arrest (OR: 0.14; 95% CI: 0.05 to 0.37; p<0.001), pneumonia (OR: 0.48; 95% CI: 0.35 to 0.66; p<0.001), pulmonary edema (OR: 0.67; 95% CI: 0.45 to 0.99; p=0.047), and acute kidney injury (OR: 0.34; 95% CI: 0.12 to 0.98; p=0.047). A panel of eleven medical complications explained 8% of the variation in functional outcomes. Conclusions: Medical complications contribute to functional outcomes after aSAH, but their individual contributions to outcomes are relatively small. This should be noted when considering trials directed at preventing or treating any one complication and raises the question of studying comprehensive neurointensive care packages in the future.


Neurosurgery ◽  
2020 ◽  
Author(s):  
Isabel C Hostettler ◽  
Menelaos Pavlou ◽  
Gareth Ambler ◽  
Varinder S Alg ◽  
Stephen Bonner ◽  
...  

Abstract BACKGROUND Long-term outcome after subarachnoid hemorrhage, beyond the first few months, is difficult to predict, but has critical relevance to patients, their families, and carers. OBJECTIVE To assess the performance of the Subarachnoid Hemorrhage International Trialists (SAHIT) prediction models, which were initially designed to predict short-term (90 d) outcome, as predictors of long-term (2 yr) functional outcome after aneurysmal subarachnoid hemorrhage (aSAH). METHODS We included 1545 patients with angiographically-proven aSAH from the Genetic and Observational Subarachnoid Haemorrhage (GOSH) study recruited at 22 hospitals between 2011 and 2014. We collected data on age, WNFS grade on admission, history of hypertension, Fisher grade, aneurysm size and location, as well as treatment modality. Functional outcome was measured by the Glasgow Outcome Scale (GOS) with GOS 1 to 3 corresponding to unfavorable and 4 to 5 to favorable functional outcome, according to the SAHIT models. The SAHIT models were assessed for long-term outcome prediction by estimating measures of calibration (calibration slope) and discrimination (area under the receiver-operating characteristic curve [AUC]) in relation to poor clinical outcome. RESULTS Follow-up was standardized to 2 yr using imputation methods. All 3 SAHIT models demonstrated acceptable predictive performance for long-term functional outcome. The estimated AUC was 0.71 (95% CI: 0.65-0.76), 0.73 (95% CI: 0.68-0.77), and 0.74 (95% CI: 0.69-0.79) for the core, neuroimaging, and full models, respectively; the calibration slopes were 0.86, 0.84, and 0.89, indicating good calibration. CONCLUSION The SAHIT prediction models, incorporating simple factors available on hospital admission, show good predictive performance for long-term functional outcome after aSAH.


2009 ◽  
Vol 110 (3) ◽  
pp. 487-491 ◽  
Author(s):  
Markus Holling ◽  
Astrid Jeibmann ◽  
Joachim Gerss ◽  
Bernhard R. Fischer ◽  
Hansdetlef Wassmann ◽  
...  

Object Aneurysmal subarachnoid hemorrhage (SAH) carries a severe prognosis, which is often related to the development of cerebral vasospasm. Even though several clinical and radiological predictors of vasospasm and functional outcome have been established, the prognostic value of histopathological findings remains unclear. Methods Histopathological findings in resected distal aneurysm walls were examined, as were the clinical and radiological factors in a series of 91 patients who had been neurosurgically treated for aneurysmal SAH. The impact of the histological, clinical, and radiological factors on the occurrence of vasospasm and functional outcome at discharge was analyzed. Results Histopathological findings frequently included lymphocytic infiltrates (60%), fibrosis (60%), and necrosis (50%) of the resected aneurysm wall. On univariate analysis, clinical (Hunt and Hess grade) and radiological (aneurysm size) factors as well as histopathological features—namely, lymphocytic infiltrates and necrosis of the aneurysm wall—were significantly associated with the occurrence of vasospasm. On multivariate analysis, lymphocytic infiltrates (OR 6.35, 95% CI 2.32–17.36, p = 0.0001) and aneurysm size (OR 1.22, 95% CI 1.05–1.42, p = 0.009) remained the only factors predicting the development of vasospasm. A poor functional outcome at discharge was significantly associated with vasospasm, other clinical factors (Hunt and Hess grade, alcohol consumption, hyperglycemia, and elevated white blood cell count [WBC] at admission), and radiological factors (Fisher grade and aneurysm size), as well as with histopathological features (lymphocytic infiltrates [p = 0.0001] and necrosis of the aneurysm wall [p = 0.0015]). On multivariate analysis taking into account all clinical, radiological, and histological factors; vasospasm (OR 9.82, 95% CI 1.83–52.82, p = 0.008), Hunt and Hess grade (OR 5.61, 95% CI 2.29–13.74, p = 0.0001), patient age (OR 1.09, 95% CI 1.02–1.16, p = 0.0013), elevated WBC (OR 1.29, 95% CI 1.01–1.64, p = 0.04), and Fisher grade (OR 4.35, 95% CI 1.25–15.07, p = 0.015) best predicted functional outcome at discharge. Conclusions The demonstration of lymphocytic infiltrates in the resected aneurysm wall is of independent prognostic value for the development of vasospasm in patients with neurosurgically treated aneurysmal SAH. Thus, histopathology might complement other clinical and radiological factors in the identification of patients at risk.


2012 ◽  
Vol 117 (1) ◽  
pp. 15-19 ◽  
Author(s):  
Elias A. Giraldo ◽  
Jay N. Mandrekar ◽  
Mark N. Rubin ◽  
Stefan A. Dupont ◽  
Yi Zhang ◽  
...  

Object Timing of clinical grading has not been fully studied in patients with aneurysmal subarachnoid hemorrhage (SAH). The primary objective of this study was to identify at which time point clinical assessment using the World Federation of Neurosurgical Societies (WFNS) grading scale and the Glasgow Coma Scale (GCS) is most predictive of poor functional outcome. Methods This study is a retrospective cohort study on the association between poor outcome and clinical grading determined at presentation, nadir, and postresuscitation. Poor functional outcome was defined as a Glasgow Outcome Scale score of 1–3 at 6 months after SAH. Results The authors identified 186 consecutive patients admitted to a teaching hospital between January 2002 and June 2008. The patients' mean age (± SD) was 56.9 ± 13.7 years, and 63% were women. Twenty-four percent had poor functional outcome (the mortality rate was 17%). On univariable logistic regression analyses, GCS score determined at presentation (OR 0.80, p < 0.0001), nadir (OR 0.73, p < 0.0001), and postresuscitation (OR 0.53, p < 0.0001); modified Fisher scale (OR 2.21, p = 0.0013); WFNS grade assessed at presentation (OR 1.92, p < 0.0001), nadir (OR 3.51, < 0.0001), and postresuscitation (OR 3.91, p < 0.0001); intracerebral hematoma on initial CT (OR 4.55, p < 0.0002); acute hydrocephalus (OR 2.29, p = 0.0375); and cerebral infarction (OR 4.84, p < 0.0001) were associated with poor outcome. On multivariable logistic regression analysis, only cerebral infarction (OR 5.80, p = 0.0013) and WFNS grade postresuscitation (OR 3.43, p < 0.0001) were associated with poor outcome. Receiver operating characteristic/area under the curve (AUC) analysis demonstrated that WFNS grade determined postresuscitation had a stronger association with poor outcome (AUC 0.90) than WFNS grade assessed upon admission or at nadir. Conclusions Timing of WFNS grade assessment affects its prognostic value. Outcome after aneurysmal SAH is best predicted by assessing WFNS grade after neurological resuscitation.


2017 ◽  
Vol 126 (5) ◽  
pp. 1545-1551 ◽  
Author(s):  
Fawaz Al-Mufti ◽  
David Roh ◽  
Shouri Lahiri ◽  
Emma Meyers ◽  
Jens Witsch ◽  
...  

OBJECTIVEThe clinical significance of cerebral ultra-early angiographic vasospasm (UEAV), defined as cerebral arterial narrowing within the first 48 hours of aneurysmal subarachnoid hemorrhage (aSAH), remains poorly characterized. The authors sought to determine its frequency, predictors, and impact on functional outcome.METHODSThe authors prospectively studied UEAV in a cohort of 1286 consecutively admitted patients with aSAH between August 1996 and June 2013. Admission clinical, radiographic, and acute clinical course information was documented during patient hospitalization. Functional outcome was assessed at 3 months using the modified Rankin Scale. Logistic regression and Cox proportional hazards models were generated to assess predictors of UEAV and its relationship to delayed cerebral ischemia (DCI) and outcome. Multiple imputation methods were used to address data lost to follow-up.RESULTSThe cohort incidence rate of UEAV was 4.6%. Multivariable logistic regression analysis revealed that younger age, sentinel bleed, and poor admission clinical grade were significantly associated with UEAV. Patients with UEAV had a 2-fold increased risk of DCI (odds ratio [OR] 2.3, 95% confidence interval [CI] 1.4–3.9, p = 0.002) and cerebral infarction (OR 2.0, 95% CI 1.0–3.9, p = 0.04), after adjusting for known predictors. Excluding patients who experienced sentinel bleeding did not change this effect. Patients with UEAV also had a significantly higher hazard for DCI in a multivariable model. UEAV was not found to be significantly associated with poor functional outcome (OR 0.8, 95% CI 0.4–1.6, p = 0.5).CONCLUSIONSUEAV may be less frequent than has been reported previously. Patients who exhibit UEAV are at higher risk for refractory DCI that results in cerebral infarction. These patients may benefit from earlier monitoring for signs of DCI and more aggressive treatment. Further study is needed to determine the long-term functional significance of UEAV.


Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Sean Neifert ◽  
Eric Oermann ◽  
J D Mocco ◽  
Michael M Todd ◽  
James Torner ◽  
...  

Introduction: Subarachnoid hemorrhage (SAH) mortality is decreasing, but data on functional outcomes over time is lacking. Methods: We created trends of good (Glasgow Outcomes Scale [GOS] of 4 or 5) and optimal (GOS of 5) functional outcomes and mortality (GOS of 1) using linear regression in 15 SAH trials and registries from 1982 to 2014. Models adjusted for age, sex, history of hypertension, World Federation of Neurological Surgeons grade, Fisher grade, aneurysm size, location, and repair modality, and whether data was from a clinical trial or registry. Analyses were repeated separately for the clinical trials and registries. Missing data were handled with multiple imputation. Results: Overall, 13,343 SAH patients were included. 9,524 (71%) patients had good functional outcome, while 1,608 (12%) died. There was a 0.6% adjusted improvement (95% confidence interval [CI]: 0.5% to 0.7%; p<0.001) per year in good functional outcome and a 0.1% adjusted reduction (95% CI: -0.2% to -0.08%; p<0.001) per year in mortality. For patients enrolled in clinical trials, there was no change good functional outcomes (0%; 95% CI: -0.2% to 0.1%; p=0.923) or mortality (0.0% change per year; 95% CI: -0.09% to 0.1%; p=0.676). Clinical registry patients experienced a 1.2% improvement (95% CI: 1.0% to 1.4%; p<0.001) in good functional outcome and a 0.3% reduction (95% CI: -0.4% to -0.1%; p<0.001) in mortality. Conclusions: SAH morbidity and mortality decreased from the 1980s to 2010s. This data can be helpful for researchers planning trials, clinicians discussing expected outcomes with patients and family members, and healthcare administrators planning resource utilization.


2003 ◽  
Vol 98 (6) ◽  
pp. 1222-1226 ◽  
Author(s):  
Matthew J. McGirt ◽  
John C. Mavropoulos ◽  
Laura Y. McGirt ◽  
Michael J. Alexander ◽  
Allan H. Friedman ◽  
...  

Object. The identification of patients at an increased risk for cerebral vasospasm after subarachnoid hemorrhage (SAH) may allow for more aggressive treatment and improved patient outcomes. Note, however, that blood clot size on admission remains the only factor consistently demonstrated to increase the risk of cerebral vasospasm after SAH. The goal of this study was to assess whether clinical, radiographic, or serological variables could be used to identify patients at an increased risk for cerebral vasospasm. Methods. A retrospective review was conducted in all patients with aneurysmal or spontaneous nonaneurysmal SAH who were admitted to the authors' institution between 1995 and 2001. Underlying vascular diseases (hypertension or chronic diabetes mellitus), Hunt and Hess and Fisher grades, patient age, aneurysm location, craniotomy compared with endovascular aneurysm stabilization, medications on admission, postoperative steroid agent use, and the occurrence of fever, hydrocephalus, or leukocytosis were assessed as predictors of vasospasm. Two hundred twenty-four patients were treated for SAH during the review period. One hundred one patients (45%) developed symptomatic vasospasm. Peak vasospasm occurred 5.8 ± 3 days after SAH. There were four independent predictors of vasospasm: Fisher Grade 3 SAH (odds ratio [OR] 7.5, 95% confidence interval [CI] 3.5–15.8), peak serum leukocyte count (OR 1.09, 95% CI 1.02–1.16), rupture of a posterior cerebral artery (PCA) aneurysm (OR 0.05, 95% CI 0.01–0.41), and spontaneous nonaneurysmal SAH (OR 0.14, 95% CI 0.04–0.45). A serum leukocyte count greater than 15 × 109/L was independently associated with a 3.3-fold increase in the likelihood of developing vasospasm (OR 3.33, 95% CI 1.74–6.38). Conclusions. During this 7-year period, spontaneous nonaneurysmal SAH and ruptured PCA aneurysms decreased the odds of developing vasospasm sevenfold and 20-fold, respectively. The presence of Fisher Grade 3 SAH on admission or a peak leukocyte count greater than 15 × 109/L increased the odds of vasospasm sevenfold and threefold, respectively. Monitoring of the serum leukocyte count may allow for early diagnosis and treatment of vasospasm.


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