Identifying Patients at Risk for Vasospasm After Aneurysmal Subarachnoid Hemorrhage Using Genetic Sequencing

Introduction: Sanguinate is a dual-action oxygen transfer and carbon monoxide-releasing agent with efficacy in animal models of focal brain ischemia and established safety in health volunteers. We performed a dose-escalation study in subarachnoid hemorrhage (SAH) patients at risk for delayed cerebral ischemia (DCI) to evaluate tolerability and explore efficacy in improving cerebral blood flow (CBF) and flow-metabolism balance to vulnerable brain regions. Methods: 12 subjects were studied over three dose tiers: 160mg/kg, 240 mg/kg, and 320 mg/kg, with close safety evaluation prior to proceeding to higher doses. After baseline 15 O-PET measurement of global and regional CBF and oxygen extraction fraction (OEF), Sanguinate was infused over two hours; PET was repeated immediately after and again at 24-hours. Vulnerable brain regions were defined as those with baseline OEF ≥ 0.5. Results: Sanguinate infusion resulted in a significant but transient rise in mean arterial pressure (115±15 to 127±13 mm Hg) that was not dose-dependent. No adverse physiologic or clinical effects were observed with infusion at any dose. Global CBF did not rise significantly after Sanguinate (42.6±7 to 45.9±9 ml/100g/min, p=0.18). However, in the 28% of regions classified as vulnerable, Sanguinate resulted in a significant rise in CBF (42.2±11 to 51.2±18) and reduction in OEF (0.6±0.1 to 0.5±0.11, both p<0.001). The increase in regional CBF was only seen with the two higher doses but OEF improved in all tiers. However, response was attenuated at 24-hours. Conclusions: We safely administered a novel oxygen transport and vasodilating agent to a cohort of patients with SAH. Sanguinate infusion appeared to improve CBF and flow-metabolism balance in vulnerable brain regions and warrants further study in those at-risk for DCI. Higher or repeat dosing may be required for sustained efficacy.

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Invasive Multimodal Neuromonitoring in Aneurysmal Subarachnoid Hemorrhage: A Systematic Review

Stroke ◽

10.1161/strokeaha.121.034633 ◽

2021 ◽

Author(s):

Michael Veldeman ◽

Walid Albanna ◽

Miriam Weiss ◽

Soojin Park ◽

Anke Hoellig ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Trend Analysis ◽

Oxygen Tension ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Delayed Cerebral Ischemia ◽

Case Series ◽

Diagnostic Value ◽

Cerebral Microdialysis ◽

Treatment Support ◽

Patients At Risk

Background and Purpose: Aneurysmal subarachnoid hemorrhage is a devastating disease leaving surviving patients often severely disabled. Delayed cerebral ischemia (DCI) has been identified as one of the main contributors to poor clinical outcome after subarachnoid hemorrhage. The objective of this review is to summarize existing clinical evidence assessing the diagnostic value of invasive neuromonitoring (INM) in detecting DCI and provide an update of evidence since the 2014 consensus statement on multimodality monitoring in neurocritical care. Methods: Three invasive monitoring techniques were targeted in the data collection process: brain tissue oxygen tension (p ti O 2 ), cerebral microdialysis, and electrocorticography. Prospective and retrospective studies as well as case series (≥10 patients) were included as long as monitoring was used to detect DCI or guide DCI treatment. Results: Forty-seven studies reporting INM in the context of DCI were included (p ti O 2 : N=21; cerebral microdialysis: N=22; electrocorticography: N=4). Changes in brain oxygen tension are associated with angiographic vasospasm or reduction in regional cerebral blood flow. Metabolic monitoring with trend analysis of the lactate to pyruvate ratio using cerebral microdialysis, identifies patients at risk for DCI. Clusters of cortical spreading depolarizations are associated with clinical neurological worsening and cerebral infarction in selected patients receiving electrocorticography monitoring. Conclusions: Data supports the use of INM for the detection of DCI in selected patients. Generalizability to all subarachnoid hemorrhage patients is limited by design bias of available studies and lack of randomized trials. Continuous data recording with trend analysis and the combination of INM modalities can provide tailored treatment support in patients at high risk for DCI. Future trials should test interventions triggered by INM in relation to cerebral infarctions.

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A Large Database Analysis of Rates of Aneurysm Screening, Elective Treatment, and Subarachnoid Hemorrhage in Patients With Polycystic Kidney Disease

Neurosurgery ◽

10.1093/neuros/nyy551 ◽

2018 ◽

Vol 85 (2) ◽

pp. E266-E274

Author(s):

D Andrew Wilkinson ◽

James F Burke ◽

Jeffrey L Nadel ◽

Cormac O Maher ◽

Neeraj Chaudhary ◽

...

Keyword(s):

At Risk ◽

Subarachnoid Hemorrhage ◽

Kidney Disease ◽

Polycystic Kidney Disease ◽

Incidence Rate Ratio ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Polycystic Kidney ◽

Database Analysis ◽

Professional Societies ◽

Elective Treatment

Abstract BACKGROUND Professional societies provide conflicting guidelines on aneurysm screening in patients with polycystic kidney disease (PKD), and the rate of subarachnoid hemorrhage (SAH) is poorly understood. OBJECTIVE To evaluate screening, elective treatment, and the rate of SAH in patients with known PKD. METHODS We examined longitudinally linked claims data from a large private insurer, identifying screening, elective treatment, aneurysmal subarachnoid hemorrhage (aSAH) and secured aneurysmal SAH (saSAH) in 2004 to 2014 amongst patients with known PKD. RESULTS We identified 20 704 patients diagnosed with PKD. Among patients with an initial PKD diagnosis, 51/446 (15.9%) underwent angiographic screening within 2 yr. Forty aneurysms were treated electively in 48 868 yr at risk in PKD patients (82/100K patient yr, 95% confidence interval [CI] 60-112) vs 24 elective treatments in 349 861 yr at risk in age- and sex-matched controls (7/100K patient yr, 95% CI 5-10, P < .0001). Eleven admissions for aSAH were identified in PKD patients (23/100K patient yr, 95% CI 13-41) and 22 admissions for aSAH in controls (6/100K patient yr, 95% CI 4-10), giving an incidence rate ratio (IRR) of 3.6 (95% CI 1.7-7.4, P < .0001) and a comorbidity-adjusted IRR of 3.1 (95% CI 1.4-6.9). The incidence of saSAH was proportionally even higher in PKD patients than controls, 16 vs 2/100K patient years, IRR 9.5 (95% CI 3.3-27.5, P < .0001). CONCLUSION Screening in PKD is performed only selectively, though resulting rates of elective treatment were over 10× those of controls. Despite screening and treatment, the rate of SAH remains significantly elevated over that of controls.

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Role of Computed Tomography in the Management of Vasospasm after Subarachnoid Hemorrhage

Neurosurgery ◽

10.1227/00006123-198409000-00009 ◽

1984 ◽

Vol 15 (3) ◽

pp. 344-353 ◽

Cited By ~ 71

Author(s):

Alberto Pasqualin ◽

Luisa Rosta ◽

Renato Da Pian ◽

Paolo Cavazzani ◽

Renato Scienza

Keyword(s):

Computed Tomography ◽

At Risk ◽

Subarachnoid Hemorrhage ◽

Subsequent Development ◽

Blood Collection ◽

Therapeutic Modalities ◽

Patients At Risk ◽

Definition Of ◽

Subarachnoid Blood

Abstract The role of computed tomography (CT) in the management of vasospasm from subarachnoid hemorrhage was evaluated in 242 consecutive cases with CT performed within 7 days after hemorrhage. Only 20% of these cases did not show a detectable subarachnoid hemorrhage on CT. Subsequent angiograms showed vessel narrowing in 56% of the cases; associated clinical deterioration was noted in 34% of the cases. On later CT, clear ischemic areas were detected in 20% of the cases. A strict correlation between the amount of cisternal blood and the subsequent development of vasospasm was observed: although absent or thin cisternal depositions were rarely associated with vasospasm, consistent or thick depositions were frequently linked to vasospasm (72% of the cases) and to ischemic disturbances (51% of the cases), as well as to clear ischemic areas on later CT (30% of the cases). Regarding the morphology of the cisternal blood collection, the risk of developing vasospasm was at its lowest (42%) for depositions only in the frontal interhemispheric fissure and was at its highest (79%) for depositions in multiple cisterns. The site of cisternal deposition corresponded closely to the area of ischemia on later CT. The persistence of subarachnoid blood more than 72 hours after hemorrhage probably increases the risk of vasospasm, although our data are not conclusive. The definition of a CT scan “at risk” for vasospasm—based on the previous findings—gives practical advantages: proper selection of patients in regard to timing of operation, closer observation and the possibility of prophylactic treatment in patients “at risk,” and more adequate evaluation of different therapeutic modalities for vasospasm. With regard to the last point, the incidence of vasospasm was not statistically different between two groups of patients uniformly “at risk”: the first group submitted to early operation and the second awaiting operation.

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Relationship of the vascular territory affected by delayed cerebral ischemia and the location of the ruptured aneurysm in patients with aneurysmal subarachnoid hemorrhage

Neurosurgical Review ◽

10.1007/s10143-021-01522-4 ◽

2021 ◽

Author(s):

Helene Hurth ◽

Jochen Steiner ◽

Ulrich Birkenhauer ◽

Constantin Roder ◽

Till-Karsten Hauser ◽

...

Keyword(s):

At Risk ◽

Subarachnoid Hemorrhage ◽

Cerebral Ischemia ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Delayed Cerebral Ischemia ◽

Aneurysm Rupture ◽

Ruptured Aneurysm ◽

Vascular Territory ◽

Monitoring Methods ◽

Anterior Circulation

Abstract Objective To determine the area most at risk of delayed cerebral ischemia (DCI) in relation to the location of the ruptured aneurysm in patients with aneurysmal subarachnoid hemorrhage (aSAH) and, therefore, help to choose the site for focal multimodal neuromonitoring. Methods We retrospectively analyzed angiographic findings, CCT scans, and patient charts of patients who were admitted with aSAH to our neurosurgical intensive care unit between 2009 and 2017. DCI was defined as infarction on CCT 2–6 weeks after aSAH. Results DCI occurred in 17.9% out of 357 included patients. A DCI occurring in the vascular territory of the artery carrying the ruptured aneurysm was found in 81.0% of patients with anterior circulation aneurysms but only in 16.7% with posterior circulation aneurysms (Fisher’s exact, p=0.003). The vascular territory most frequently showing a DCI was the ipsilateral MCA territory (86.7%) in ICA aneurysms, the contra- (71.4%) and the ipsilateral (64.3%) ACA territory in ACA aneurysms, the right (93.8%) and the left (81.3%) ACA territory in AcomA aneurysms, and the ipsilateral MCA territory in MCA aneurysms (69.2%) as well as in VA/PICA/SCA aneurysms (100.0%). DCI after the rupture of a BA aneurysm occurred with 33.3% in 6 out of 8 vascular territories, respectively. DCI of multiple vascular territories occurred in 100.0% of BA aneurysms, 87.5% of AcomA aneurysms, 71.4% of ACA aneurysms, 40.0% of ICA aneurysms, 38.5% of MCA aneurysms, and 33.3% of VA/PICA/SCA aneurysms. Discussion Few studies exist that could determine the area most at risk of a DCI after an aSAH. Our data could identify the territory most at risk for DCI with a probability of > 60% except for BA aneurysms, which showed DCI in various areas and patients suffering from multiple DCIs. Either the ipsilateral ACA or MCA were affected by the DCI in about 80% of ACA and more than 90% of AcomA, ICA, MCA, and VA/PICA/SCA aneurysms. Therefore, local intraparenchymal neuromonitoring in the ACA/MCA watershed area might detect the vast majority of DCIs for all aneurysm locations, except for BA aneurysms. In ACA and AcomA aneurysms, bilateral DCI of the ACA territory was common, and bilateral probe positioning might be considered for monitoring high-risk patients. Non-focal monitoring methods might be preferably used after BA aneurysm rupture.

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Abstract TP418: Red Blood Cell Transfusion Increases Cerebral Oxygen Delivery After Subarachnoid Hemorrhage Regardless of Hemoglobin Level

Stroke ◽

10.1161/str.48.suppl_1.tp418 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Rajat Dhar ◽

Allyson Zazulia ◽

Tom Videen ◽

Colin P Derdeyn ◽

Michael Diringer

Keyword(s):

At Risk ◽

Subarachnoid Hemorrhage ◽

Oxygen Delivery ◽

Delayed Cerebral Ischemia ◽

Brain Regions ◽

Oxygen Extraction Fraction ◽

Red Blood Cell Transfusion ◽

Cerebral Oxygen ◽

Arterial Blood ◽

Patients At Risk

Introduction: Impaired oxygen delivery (DO 2 ), as a result of reduced cerebral blood flow (CBF), is the hallmark of delayed cerebral ischemia (DCI) following subarachnoid hemorrhage (SAH). Anemia further contributes to reductions in DO 2 and places the brain at risk for infarction. Transfusion, by raising hemoglobin (Hgb) and oxygen content of arterial blood, may be able to reduce the risk of ischemia. However, it is unknown whether an Hgb threshold exists above which CBF will fall sufficient to negate any benefit of transfusion on DO 2 . In this physiologic proof-of-principle study we evaluated whether transfusion improves DO 2 and reduces brain vulnerable to ischemia across a broad range of Hgb values. Methods: 47 SAH patients with/at-risk for DCI with Hgb 7-13 g/dl were transfused 1 unit of red blood cells (RBCs). 15 O-PET imaging was used to measure CBF, DO 2 , and oxygen extraction fraction (OEF) before and after transfusion. Vulnerable brain regions were defined as those with baseline DO 2 < 4.5 ml/100g/min (equivalent to CBF of 25 ml/100g/min at low-normal Hgb). Results: Baseline Hgb was 9.7 g/dl (range 6.9-12.5) and CBF was 43±11 ml/100g/min. After transfusion, Hgb rose by 12% and global DO 2 by 10% (from 5.0 to 5.5 ml/100g/min, p=0.001), with CBF only marginally lower; response to transfusion was not dependent on Hgb level. Transfusion resulted in a greater (16%) rise in DO 2 , associated with a larger reduction in OEF, in vulnerable brain regions (p=0.005 for low vs. normal regions), even after adjusting for Hgb. Number of vulnerable regions was reduced from median 9 to 4 per patient (p=0.005). Conclusions: Transfusion of RBCs to patients at-risk for DCI improves cerebral oxygen delivery, preferentially to vulnerable regions and reduces brain at-risk for ischemia. This physiologic benefit does not appear limited to those with severe anemia but persists to Hgb as high as 13 g/dl. Our findings suggest that restrictive transfusion practices may not be appropriate in this population. Prospective trials are needed to determine if these physiologic benefits outweigh risks of transfusion and translate into clinical prevention of DCI.

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Effect of transluminal angioplasty on cerebral blood flow in the management of symptomatic vasospasm following aneurysmal subarachnoid hemorrhage

Journal of Neurosurgery ◽

10.3171/jns.1997.86.5.0830 ◽

1997 ◽

Vol 86 (5) ◽

pp. 830-839 ◽

Cited By ~ 106

Author(s):

Andrew D. Firlik ◽

Anthony M. Kaufmann ◽

Charles A. Jungreis ◽

Howard Yonas

Keyword(s):

At Risk ◽

Blood Flow ◽

Cerebral Blood Flow ◽

Subarachnoid Hemorrhage ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Transluminal Angioplasty ◽

T Test ◽

Neurological Deficits ◽

Symptomatic Vasospasm ◽

The Mean

✓ In this study the authors have examined the effects of transluminal angioplasty on cerebral blood flow (CBF) in the management of intractable vasospasm following aneurysmal subarachnoid hemorrhage (SAH). Fourteen consecutively enrolled patients underwent attempted angioplasty with or without intraarterial infusion of papaverine. Twelve patients underwent pre- and postangioplasty xenon-enhanced computerized tomography (Xe-CT) scanning to measure regional CBF in 55 to 65 regions of interest (ROIs) per patient. Angioplasty was possible in 13 (93%) of 14 patients, with angiographically demonstrated improvement in all 13. Twelve (92%) of the 13 patients were neurologically improved following angioplasty; seven (58%) of the 12 patients who improved had a complete reversal of all delayed ischemic deficits. Angioplasty significantly decreased the mean number of ROIs at risk (11.4 ROIs pre- and 0.9 ROIs postangioplasty) (p < 0.00005, t-test). All patients had a reduction in the number of ROIs at risk after angioplasty; six (50%) of 12 no longer had any ROIs remaining at risk after angioplasty. Angioplasty significantly increased the mean CBF within at-risk ROIs (13 ml/100 g/minute pre- and 44 ml/100 g/minute postangioplasty) (p < 0.00005, t-test). All patients experienced an improvement in mean CBF in at-risk ROIs after angioplasty, with the mean CBF improving to above 20 ml/100 g/minute in all cases. No differences in the degree of improvement were found in patients who received intraarterial papaverine compared with those who did not. In the majority of patients with refractory vasospasm following SAH, angioplasty effectively dilated spastic arteries, reversed delayed neurological deficits, and significantly improved CBF in areas of brain at risk of infarction.

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