Plasma Estrogen Levels Are Associated With Severity of Injury and Outcomes After Aneurysmal Subarachnoid Hemorrhage

Background:Biochemical mediators alter cerebral perfusion and have been implicated in delayed cerebral ischemia (DCI) and poor outcomes after aneurysmal subarachnoid hemorrhage (aSAH). Estrogens (estrone [E1] and estradiol [E2]) are mediators with neuroprotective properties that could play a role in DCI. This study explored associations between plasma estrogen levels and outcomes following aSAH.Methods:Plasma samples from 1–4, 4–6, and 7–10 days after hemorrhage from 99 adult aSAH patients were analyzed for estrogen levels using liquid chromatography tandem mass spectrometry. DCI was operationalized as radiographic/ultrasonic evidence of impaired cerebral blood flow accompanied by neurological deterioration. Outcomes were assessed using the Modified Rankin Scale at 3 and 12 months after hemorrhage. Statistical analysis included correlation, regression, and group-based trajectory.Results:Higher E1 and E2 levels were associated with higher Hunt and Hess grade (E1, p = .01; E2, p = .03), the presence of DCI (E1, p = .02; E2, p = .02), and poor 3-month outcomes (E1, p = .002; E2, p = .002). Trajectory analysis identified distinct populations over time for E1 (61% E1 high) and E2 (68% E2 high). Patients in higher trajectory groups had higher Fisher grades (E1, p = .008; E2, p = .01), more frequent DCI (E1, p = .04; E2, p = .08), and worse 3-month outcomes (E1, p = .01; E2, p = .004) than low groups.Conclusions:These results provide the first clinical evidence that plasma E1 and E2 concentrations are associated with severity of injury and outcomes after aSAH.

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20-HETE is Associated with Unfavorable Outcomes in Subarachnoid Hemorrhage Patients

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2015.75 ◽

2015 ◽

Vol 35 (9) ◽

pp. 1515-1522 ◽

Cited By ~ 19

Author(s):

Mark K Donnelly ◽

Elizabeth A Crago ◽

Yvette P Conley ◽

Jeffery R Balzer ◽

Dianxu Ren ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Medical Center ◽

Delayed Cerebral Ischemia ◽

University Of Pittsburgh ◽

Potential Contributor ◽

Csf Levels ◽

Novel Target ◽

Poor Outcomes

Emerging evidence has suggested that patients experiencing aneurysmal subarachnoid hemorrhage (aSAH) develop vascular dysregulation as a potential contributor to poor outcomes. Preclinical studies have implicated the novel microvascular constrictor, 20-hydroxyeicosatetraenoic acid (20-HETE) in aSAH pathogenesis, yet the translational relevance of 20-HETE in patients with aSAH is largely unknown. The goal of this research was to determine the relationship between 20-HETE cerebrospinal fluid (CSF) levels, gene variants in 20-HETE synthesis, and acute/long-term aSAH outcomes. In all, 363 adult patients (age 18 to 75) with aSAH were prospectively recruited from the University of Pittsburgh Medical Center neurovascular Intensive Care Unit. Patients were genotyped for polymorphic variants and cytochrome P450 (CYP)-eicosanoid CSF levels were measured over 14 days. Outcomes included delayed cerebral ischemia (DCI), clinical neurologic deterioration (CND), and modified Rankin Scores (MRS) at 3 and 12 months. Patients with CND and unfavorable 3-month MRS had 2.2- and 2.7-fold higher mean 20-HETE CSF levels, respectively. Patients in high/moderate 20-HETE trajectory groups (35.7%) were 2.5-, 2.1-, 3.1-, 3.3-, and 2.1-fold more likely to have unfavorable MRS at 3 months, unfavorable MRS at 12 months, mortality at 3 months, mortality at 12 months, and CND, respectively. These results showed that 20-HETE is associated with acute and long-term outcomes and suggest that 20-HETE may be a novel target in aSAH.

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Effects of Induced Hypertension on Cerebral Perfusion in Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage

Stroke ◽

10.1161/strokeaha.115.010537 ◽

2015 ◽

Vol 46 (11) ◽

pp. 3277-3281 ◽

Cited By ~ 34

Author(s):

Celine S. Gathier ◽

Jan Willem Dankbaar ◽

Mathieu van der Jagt ◽

Bon H. Verweij ◽

Annemarie W. Oldenbeuving ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Cerebral Ischemia ◽

Cerebral Perfusion ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Delayed Cerebral Ischemia ◽

Induced Hypertension

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Cerebral perfusion pressure threshold to prevent delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage

Journal of Clinical Neuroscience ◽

10.1016/j.jocn.2018.04.073 ◽

2018 ◽

Vol 54 ◽

pp. 29-32 ◽

Cited By ~ 4

Author(s):

Jiawei Cai ◽

Wenhua Fang ◽

Fuxiang Chen ◽

Zhangya Lin ◽

Yuanxiang Lin ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Cerebral Ischemia ◽

Cerebral Perfusion Pressure ◽

Cerebral Perfusion ◽

Perfusion Pressure ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Delayed Cerebral Ischemia ◽

Pressure Threshold

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Cerebrospinal Fluid 20-HETE Is Associated With Delayed Cerebral Ischemia and Poor Outcomes After Aneurysmal Subarachnoid Hemorrhage

Stroke ◽

10.1161/strokeaha.110.605816 ◽

2011 ◽

Vol 42 (7) ◽

pp. 1872-1877 ◽

Cited By ~ 34

Author(s):

Elizabeth A. Crago ◽

Bhavani P. Thampatty ◽

Paula R. Sherwood ◽

Chie-Wen J. Kuo ◽

Catherine Bender ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Subarachnoid Hemorrhage ◽

Cerebral Ischemia ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Delayed Cerebral Ischemia ◽

Poor Outcomes

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Diagnostic Threshold Values of Cerebral Perfusion Measured With Computed Tomography for Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage

Stroke ◽

10.1161/strokeaha.109.574392 ◽

2010 ◽

Vol 41 (9) ◽

pp. 1927-1932 ◽

Cited By ~ 71

Author(s):

Jan Willem Dankbaar ◽

Nicolien Karen de Rooij ◽

Mienke Rijsdijk ◽

Birgitta K. Velthuis ◽

Catharine J.M. Frijns ◽

...

Keyword(s):

Computed Tomography ◽

Subarachnoid Hemorrhage ◽

Cerebral Ischemia ◽

Cerebral Perfusion ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Delayed Cerebral Ischemia ◽

Threshold Values ◽

Diagnostic Threshold

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Aneurysmal Subarachnoid Hemorrhage and Vasospasm

AACN Advanced Critical Care ◽

10.4037/aacnacc2018491 ◽

2018 ◽

Vol 29 (2) ◽

pp. 163-174 ◽

Cited By ~ 4

Author(s):

Shannon K. Burns ◽

Kacie J. Brewer ◽

Courtney Jenkins ◽

Sally Miller

Keyword(s):

Subarachnoid Hemorrhage ◽

Cerebral Ischemia ◽

Aneurysmal Subarachnoid Hemorrhage ◽

External Ventricular Drain ◽

Delayed Cerebral Ischemia ◽

Endovascular Coiling ◽

Ruptured Aneurysms ◽

The Past ◽

Endovascular Interventions ◽

Poor Outcomes

Aneurysmal subarachnoid hemorrhage is potentially fatal and is associated with poor outcomes in many patients. Advances in neurosurgical and medical management of ruptured aneurysms have improved mortality rates in patients with aneurysmal subarachnoid hemorrhage. Surgical and endovascular interventions, such as external ventricular drain placement, aneurysm clipping, and endovascular coiling, have been developed over the past few decades. Patients with aneurysmal subarachnoid hemorrhage are also at risk for cerebral vasospasm and delayed cerebral ischemia. This article describes the diagnosis and treatment of aneurysmal subarachnoid hemorrhage, vasospasm, and cerebral ischemia. Concurrent medical considerations and ideas for future neuroinflammatory vasospasm research are also discussed.

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Relationship between vasospasm, cerebral perfusion, and delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage

Neuroradiology ◽

10.1007/s00234-009-0575-y ◽

2009 ◽

Vol 51 (12) ◽

pp. 813-819 ◽

Cited By ~ 138

Author(s):

Jan W. Dankbaar ◽

Mienke Rijsdijk ◽

Irene C. van der Schaaf ◽

Birgitta K. Velthuis ◽

Marieke J. H. Wermer ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Cerebral Ischemia ◽

Cerebral Perfusion ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Delayed Cerebral Ischemia

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Haptoglobin phenotype predicts the development of focal and global cerebral vasospasm and may influence outcomes after aneurysmal subarachnoid hemorrhage

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1412833112 ◽

2015 ◽

Vol 112 (4) ◽

pp. 1155-1160 ◽

Cited By ~ 33

Author(s):

Jenna L. Leclerc ◽

Spiros Blackburn ◽

Dan Neal ◽

Nicholas V. Mendez ◽

Jeffrey A. Wharton ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Cerebral Vasospasm ◽

Functional Outcomes ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Delayed Cerebral Ischemia ◽

Free Hemoglobin ◽

Disease States ◽

Critical Care Management ◽

Poor Outcomes ◽

Harmful Effects

Cerebral vasospasm (CV) and the resulting delayed cerebral ischemia (DCI) significantly contribute to poor outcomes following aneurysmal subarachnoid hemorrhage (aSAH). Free hemoglobin (Hb) within the subarachnoid space has been implicated in the pathogenesis of CV. Haptoglobin (Hp) binds free pro-oxidant Hb, thereby modulating its harmful effects. Humans can be of three Hp phenotypes: Hp1-1, Hp2-1, or Hp2-2. In several disease states, the Hp2-2 protein has been associated with reduced ability to protect against toxic free Hb. We hypothesized that individuals with the Hp2-2 phenotype would have more CV, DCI, mortality, and worse functional outcomes after aSAH. In a sample of 74 aSAH patients, Hp2-2 phenotype was significantly associated with increased focal moderate (P= 0.014) and severe (P= 0.008) CV and more global CV (P= 0.014) after controlling for covariates. Strong trends toward increased mortality (P= 0.079) and worse functional outcomes were seen for the Hp2-2 patients with modified Rankin scale at 6 wk (P= 0.076) and at 1 y (P= 0.051) and with Glasgow Outcome Scale Extended at discharge (P= 0.091) and at 1 y (P= 0.055). In conclusion, Hp2-2 phenotype is an independent risk factor for the development of both focal and global CV and also predicts poor functional outcomes and mortality after aSAH. Hp phenotyping may serve as a clinically useful tool in the critical care management of aSAH patients by allowing for early prediction of those patients who require increased vigilance due to their inherent genetic risk for the development of CV and resulting DCI and poor outcomes.

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