Treatment Of Delayed Cerebral Ischemia Research Articles

Cortical Spreading Depolarization and Delayed Cerebral Ischemia; Rethinking Secondary Neurological Injury in Subarachnoid Hemorrhage.

Poor outcomes in Subarachnoid Hemorrhage (SAH) are in part due to a unique form of secondary neurological injury known as Delayed Cerebral Ischemia (DCI). DCI is characterized by new neurological insults that continue to occur beyond 72 h after the onset of the hemorrhage. Historically, it was thought to be a consequence of hypoperfusion in the setting of vasospasm. However, DCI was found to occur even in the absence of radiographic evidence of vasospasm. More recent evidence indicates that catastrophic ionic disruptions known as Cortical Spreading Depolarizations (CSD) may be the culprits of DCI. CSDs occur in otherwise healthy brain tissue even without demonstrable vasospasm. Furthermore, CSDs often trigger a complex interplay of neuroinflammation, microthrombi formation, and vasoconstriction. CSDs may therefore represent measurable and modifiable prognostic factors in the prevention and treatment of DCI. Although Ketamine and Nimodipine have shown promise in the treatment and prevention of CSDs in SAH, further research is needed to determine the therapeutic potential of these as well as other agents.

Multidisciplinary and standardized management of patients with delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage

BackgroundThe appropriate management of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) remains uncertain. We aimed to evaluate the effect of implementing a standardized protocol for detection and management of DCI after aSAH on cerebral infarction and functional outcome.MethodsWe studied two cohorts of aSAH patients, one before (pre-implementation cohort: January 2012 to August 2014) and one after (post-implementation cohort: January 2016 to July 2018) implementation of a multidisciplinary approach, with standardized neurological and radiological assessment and risk-based medical treatment of DCI. We assessed the presence of new hypodensities on CT within 6 weeks after aSAH and categorized cerebral infarction into overall and DCI-related infarctions (hypodensities not within 48 h after IA repair and not attributable to aneurysm occlusion or intraparenchymal hematoma). Functional outcome was assessed at 3 months using the extended Glasgow outcome scale (eGOS), dichotomized into unfavorable (eGOS: 1–5) and favorable (eGOS: 6–8). We calculated odds ratios (OR) with corresponding 95% confidence intervals (CI’s), and adjusted for age, WFNS grade, Fisher score, and treatment modality (aOR).ResultsIn the post-implementation (n = 158) versus the pre-implementation (n = 143) cohort the rates for overall cerebral infarction were 29.1% vs 46.9% (aOR: 0.41 [0.24–0.69]), for DCI-related cerebral infarction 17.7% vs. 31.5% (aOR: 0.41 [0.23–0.76]), and for unfavorable functional outcome at 3 months 37.3% vs. 53.8% (aOR: 0.30 [0.17–0.54]). For patients with DCI, the rates for unfavorable functional outcomes at 3 months in the post-implementation versus the pre-implementation cohort were 42.3% vs. 77.8% (aOR: 0.1 [0.03–0.27]).ConclusionsA multidisciplinary approach with more frequent and standardized neurological assessment, standardized CT and CT perfusion monitoring, as well as tailored application of induced hypertension and invasive rescue therapy strategies, is associated with a significant reduction of cerebral infarction and unfavorable functional outcome after aneurysmal aSAH.

P.146 Exploring the Canadian management of aSAH and delayed cerebral ischemia

Background: Delayed Cerebral Ischemia (DCI) is a complication of aneurysmal subarachnoid hemorrhage (aSAH) and is associated with significant morbidity and mortality. A paucity of high-quality evidence is available to guide the management of DCI. As such, our objective was to evaluate practice patterns of Canadian physicians regarding the management of aSAH and DCI. Methods: The Canadian Neurosurgery Research Collaborative (CNRC) performed a cross-sectional survey of Canadian neurosurgeons, intensivists, and neurologists who manage aSAH. The survey was distributed to members of the Canadian Neurosurgical and Neurocritical Care Societies, respectively. Responses were analyzed using quantitative and qualitative methods. Results: The response rate was 129/340 (38%). Agreement among respondents included the need for intensive care unit admission, use of clinical and radiographic monitoring, and prophylaxis for prevention of DCI. Indications for starting hyperdynamic therapy varied. There was discrepancy in the proportion of patients felt to require intravenous milrinone, intra-arterial vasodilators, or physical angioplasty for treatment of DCI. Most respondents reported their facility does not utilize a standardized definition for DCI. Conclusions: DCI is an important clinical entity for which no consensus exists in management among Canadian practitioners. The CNRC calls for the development of national standards in the diagnosis and management of DCI.

Subarachnoid Hemorrhage, Delayed Cerebral Ischemia, and Milrinone Use in Canada.

Delayed cerebral ischemia (DCI) is a complication of aneurysmal subarachnoid hemorrhage (aSAH) and is associated with significant morbidity and mortality. There is little high-quality evidence available to guide the management of DCI. The Canadian Neurosurgery Research Collaborative (CNRC) is comprised of resident physicians who are positioned to capture national, multi-site data. The objective of this study was to evaluate practice patterns of Canadian physicians regarding the management of aSAH and DCI. We performed a cross-sectional survey of Canadian neurosurgeons, intensivists, and neurologists who manage aSAH. A 19-question electronic survey (Survey Monkey) was developed and validated by the CNRC following a DCI-related literature review (PubMed, Embase). The survey was distributed to members of the Canadian Neurosurgical Society and to Canadian members of the Neurocritical Care Society. Responses were analyzed using quantitative and qualitative methods. The response rate was 129/340 (38%). Agreement among respondents was limited to the need for intensive care unit admission, use of clinical and radiographic monitoring, and prophylaxis for the prevention of DCI. Several inconsistencies were identified. Indications for starting hyperdynamic therapy varied. There was discrepancy in the proportion of patients who felt to require IV milrinone, IA vasodilators, or physical angioplasty for treatment of DCI. Most respondents reported their facility does not utilize a standardized definition for DCI. DCI is an important clinical entity for which no homogeneity and standardization exists in management among Canadian practitioners. The CNRC calls for the development of national standards in the definition, identification, and treatment of DCI.

Targeting Hemoglobin to Reduce Delayed Cerebral Ischemia After Subarachnoid Hemorrhage.

Delayed cerebral ischemia (DCI) continues to be a sequela of aneurysmal subarachnoid hemorrhage (aSAH) that carries significant morbidity and mortality. Aside from nimodipine, no therapeutic agents are available to reduce the incidence of DCI. Pathophysiologic mechanisms contributing to DCI are poorly understood, but accumulating evidence over the years implicates several factors. Those have included microvessel vasoconstriction, microthrombosis, oxidative tissue damage, and cortical spreading depolarization as well as large vessel vasospasm. Common to these processes is red blood cell leakage into the cerebrospinal fluids (CSF) and subsequent lysis which releases hemoglobin, a central instigator in these events. This has led to the hypothesis that early blood removal may improve clinical outcome and reduce DCI. This paper will provide a narrative review of the evidence of hemoglobin as an instigator of DCI. It will also elaborate on available human data that discuss blood clearance and CSF drainage as a treatment of DCI. Finally, we will address a recent novel device that is currently being tested, the Neurapheresis CSF Management System™. This is an automated dual-lumen lumbar drainage system that has an option to filter CSF and return it to the patient.

Large practice variations in diagnosis and treatment of delayed cerebral ischemia after subarachnoid hemorrhage

Delayed cerebral ischemia (DCI) contributes to poor outcomes after subarachnoid hemorrhage (SAH). The pathophysiology of DCI is not fully understood, which has hindered the adoption of a uniform definition. Furthermore, a reliable diagnostic test and an effective evidence-based treatment are lacking. This could lead to variations in care. A web-based survey on the variations in the definition, diagnosis, and treatment of DCI was designed and sent to 314 intensivists, neurologists, and neurosurgeons of all 9 hospitals in the Netherlands who care for patients with SAH. The responders were categorized into physicians responsible for the coordination of SAH care and those who were not. For questions on the definition and diagnosis, only the responses from the coordinating physicians were evaluated. For the treatment questions, all the responses were evaluated. The response rate was 34% (106 of 314). All 9 hospitals were represented. Of the responses, 27 did not provide answers for the definition, diagnosis, or treatment questions; 79 responses were used for analysis. Signs of vasospasm were required by 21 of the 47 coordinating physicians (44%) when considering DCI. Of the 47 coordinating physicians, 24 (51%) did not use a diagnostic test results for a positive diagnosis of DCI. When patients were discharged within 21 days, 33 of the 73 responders (45%) did not provide a prescription for nimodipine continuation. Finally, all but one hospital had treated DCI with hypertension induction. We found large variations in the definition, diagnosis, and treatment of DCI in the Netherlands. In the absence of evidence-based treatment, standardization of management seems warranted in an effort to optimize DCI care.

Intensive therapies of delayed cerebral ischemia after subarachnoid hemorrhage: a propensity-matched comparison of different center-driven strategies.

Intensive therapies of delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH) have still controversial and unproven benefit. We aimed to compare the overall efficacy of two different center-driven strategies for the treatment of DCI respectively with and without vasospasm angioplasty. Two hundred consecutive patients with aSAH were enrolled in each of two northern European centers. In an interventional center, vasospasm angioplasty was indicated as first line rather than rescue treatment of DCI using distal percutaneous balloon angioplasty technique combined with intravenous milrinone. In non-interventional center, induced hypertension was the only intensive therapy of DCI. Radiological DCI (new cerebral infarcts not visible on immediate post-treatment imaging), death at 1month, and favorable outcome at 6months (modified Rankin scale score ≤ 2) were retrospectively analyzed by independent observers and compared between two centers before and after propensity score (PS) matching for baseline characteristics. Baseline characteristics only differed between centers for age and rate of smokers and patients with chronic high blood pressure. In the interventional center, vasospasm angioplasty was performed in 38% of patients with median time from bleeding of 8days (Q1 = 6.5;Q3 = 10). There was no significant difference of incidence of radiological DCI (9% vs.14%, P = 0.11), death (8% vs. 9%, P = 0.4), and favorable outcome 74% vs. 72% (P = 0.4) between interventional and non-interventional centers before and after PS matching. Our results suggest either that there is no benefit, or might be minimal, of one between two different center-driven strategies for intensive treatment of DCI. Despite potential lack of power or unknown confounders in our study, these results question the use of such intensive therapies in daily practice without further optimization and validation.

Treatment of Subarachnoid Hemorrhage-associated Delayed Cerebral Ischemia With Milrinone: A Review and Proposal.

Delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage continues to be associated with high levels of morbidity and mortality. This complication had long been thought to occur secondary to severe cerebral vasospasm, but expert opinion now favors a multifactorial etiology, opening the possibility of new therapies. To date, no definitive treatment option for DCI has been recommended as standard of care, highlighting a need for further research into potential therapies. Milrinone has been identified as a promising therapeutic agent for DCI, possessing a mechanism of action for the reversal of cerebral vasospasm as well as potentially anti-inflammatory effects to treat the underlying etiology of DCI. Intra-arterial and intravenous administration of milrinone has been evaluated for the treatment of DCI in single-center case series and cohorts and appears safe and associated with improved clinical outcomes. Recent results have also brought attention to the potential outcome benefits of early, more aggressive dosing and titration of milrinone. Limitations exist within the available data, however, and questions remain about the generalizability of results across a broader spectrum of patients suffering from DCI. The development of a standardized protocol for milrinone use in DCI, specifically addressing areas requiring further clarification, is needed. Data generated from a standardized protocol may provide the impetus for a multicenter, randomized control trial. We review the current literature on milrinone for the treatment of DCI and propose a preliminary standardized protocol for further evaluation of both safety and efficacy of milrinone.

Abstract TP530: Transcranial Doppler Blood Velocities Kinetics During Treatment for Delayed Cerebral Ischemia in Patients With Subrachnoid Hemorrhage

The role of Transcranial Doppler (TCD) in monitoring patients with subarachnoid hemorrhage (SAH) for delayed cerebral ischemia (DCI) is well established. However, the response and kinetics of TCD blood flow velocities (BFV) to treatment of DCI has been scarcely investigated. We assessed the hypothesis that TCD BFV decrease progressively after treatment of DCI with vasopressors or inotropics. Methods: All patients with SAH admitted to a tertiary hospital neurocritical unit were evaluated with daily TCD exams for monitoring for DCI from June 2016 to June 2018. DCI was defined as the development of new focal neurological signs and/or deterioration in level of consciousness, lasting for more than 1 h, or the appearance of new infarctions on neuroimaging. Patients who developed DCI and were treated with vasopressors or inotropics were prospectively included in this study. TCD exams were performed immediately before (t0), 1 hour (t1) and 2 hours after (t2) the initiation of therapy for DCI by the same neurosonologist. Clinical and physiological data before and during exams were recorded. Results: 27 DCI treatments with either norepinephrine (n=12) or milrinone (n=15) in 21 patients were monitored. Patients were mainly females (88.9%, mean age 50.41+/- 12.52 year-old) with low grade clinical SAH (44.4% World Federation of Neurosurgeons Scale 1 and 2) but with high modified Fisher scores (81.1% with modified Fisher score of 3 and 4). DCI occurred 11.6+/- 3.4 days from the initial bleeding. Cerebral BFV significantly dropped after treatment (t0=158.08 +/- 42.84 cm/s; t1=146.71+/- 42.19 cm/s; t2=136.46+/-44.43 cm/s, p<0.01). There was also a significant drop in the National Institutes of Health stroke scale scores after therapy (t0= 13 [ 8, 19]; t1 12 [6, 19]; t2 9 [6, 19], p< 0.01). Patients treated with milrinone had a greater decline in cerebral BFV compared to those treated with norepinephrine (milrinone: t0 203.14+/- 49.41 cm/s; t1 183.14 +/-35.44 cm/s; t2= 167.86 +/- 37.55 cm/s, p=0.04 versus norepinephrine t0=156 +/- 27.45 cm/s; t1=164.58 +/- 40.48 cm/s; t2=159.0 +/- 48.24 cm/s, p=0.67). Conclusion: TCD BFV decrease progressively with hemodynamic therapy for DCI. Use of milrinone was associated with a greater decline in BFV when compared to norepinephrine.

Reduced Intravoxel Incoherent Motion Microvascular Perfusion Predicts Delayed Cerebral Ischemia and Vasospasm After Aneurysm Rupture

Proximal artery vasospasm and delayed cerebral ischemia (DCI) after cerebral aneurysm rupture result in reduced cerebral perfusion and microperfusion and significant morbidity and mortality. Intravoxel incoherent motion (IVIM) magnetic resonance imaging extracts microvascular perfusion information from a multi-b value diffusion-weighted sequence. We determined whether decreased IVIM perfusion may identify patients with proximal artery vasospasm and DCI. We performed a pilot retrospective cohort study of patients with ruptured cerebral aneurysms. Consecutive patients who underwent a brain magnetic resonance imaging with IVIM after ruptured aneurysm treatment were included. Patient demographic, treatment, imaging, and outcome data were determined by electronic medical record review. Primary outcome was DCI development with proximal artery vasospasm that required endovascular treatment. Secondary outcomes included mortality and clinical outcomes at 6 months. Sixteen patients (11 females, 69%; P=0.9) were included. There were no differences in age, neurological status, or comorbidities between patients who subsequently underwent endovascular treatment of DCI (10 patients; DCI+ group) and those who did not (6 patients; DCI- group). Compared with DCI- patients, DCI+ patients had decreased IVIM perfusion fraction f (0.09±0.03 versus 0.13±0.01; P=0.03), reduced diffusion coefficient D (0.82±0.05 versus 0.92±0.07×10-3 mm2/s; P=0.003), and reduced blood flow-related parameter fD* (1.18±0.40 versus 1.83±0.40×10-3 mm2/s; P=0.009). IVIM pseudodiffusion coefficient D* did not differ between DCI- (0.011±0.002) and DCI+ (0.013±0.005 mm2/s; P=0.4) patients. No differences in mortality or clinical outcome were identified. Decreased IVIM perfusion fraction f and blood flow-related parameter fD* correlate with DCI and proximal artery vasospasm development after cerebral aneurysm rupture.

Abstract 11383: Reversal of Post-stroke Cerebral Microvascular Dysfunction by Neuroprotective and Hyperdynamic Therapy for Experimental Subarachnoid Hemorrhage

Introduction: Early brain injury characterized by microvascular dysfunction in cerebral vessels may play an important role in the development of delayed cerebral ischemia (DCI) or vasospasm after subarachnoid hemorrhage (SAH). However, little is known as to the microcirculatory mechanism(s) to treat post-SAH DCI. Hypothesis: To clarify the utility of neuroprotective and hyperdynamic therapy in relieving cerebral microcirculatory dysfunction affected by vasospasm after experimental SAH. Methods: Male C57BL/6 mice were subjected to SAH by endovascular perforation and minocycline for antibiotic and anti-inflammatory use was started. Closed cranial bone window was then made over the left somatosensory cortex. In vivo real-time imaging was performed using 2-photon laser-scanning microscopy at postoperative day 3 to record alterations on the level of cerebral microvessels and the effects of dobutamine hyperdynamic therapy at clinical dose were evaluated. Comparison was made with a group without minocycline administration. Results: According to the 3-dimentional observation, >50% of pial and penetrating arteries constricted moderately (25-50%) from day 2 to 3 after SAH, which was greater in number in a group without minocycline pretreatment (p>0.05). In areas close to the microvasospasm, blood cell flow as measured by line scan increased by 24% (range, from 7 to 39%) following dobutamine infusion. Reversal of flow stagnation by dobutamine was more prominently observed in animals with minocycline pretreatment in pial and penetrating arteries (1.2 ± 0.5 vs. 1.8 ± 1.0 mm/s, p<0.05). Diameters of the microvessels or location of microthrombi in precapillary arterioles were not affected in any of the groups (p>0.05). Conclusions: The data suggest that early neuroprotection followed by inotropic hemodynamic therapy can improve microcirculation in specific areas affected by microvasospasm, which may in part, explain novel therapeutic targets for the early treatment of DCI after SAH.

Effect of Hydroxyethyl Starch Solution on Incidence of Acute Kidney Injury in Patients Suffering from Cerebral Vasospasm Following Aneurysmal Subarachnoid Hemorrhage.

The application of third-generation hydroxyethyl starch (HES) solutions in critically ill patients suffering from aneurysmal subarachnoid hemorrhage (aSAH) was often part of the treatment of delayed cerebral ischemia (DCI). However, there is increasing evidence showing a correlation between the application of HES and the incidence of acute kidney injury (AKI). In a single-center retrospective analysis including 81 patients without a preexisting renal disorder suffering from aSAH who had received higher volumes of 6% HES 130/0.4 due to standard treatment of DCI, the incidence of AKI during intensive care unit (ICU) stay was recorded using AKIN criteria. Furthermore, the course of serum creatinine after discharge from ICU was observed. 6% HES 130/0.4 was given over a period of 12.9±7.1days resulting in a cumulative dose of 12543.2±7743.6mL. Four patients (4.9%) fulfilled AKIN criteria stage 1 during ICU stay. In two of these patients, serum creatinine was within normal range again on day of discharge. Five patients showed elevated levels of serum creatinine within 1 to 22months after hospitalization. A correlation between the amount of HES given and the incidence of AKI could not be found. The application of 6% HES 130/0.4 did not lead to an elevated incidence of AKI in patients without an elevated baseline serum creatinine. However, there is still a lack of high-level evidence as prospective randomized trials are missing yet.

Abstract TP436: Precision Medicine Using Quantitative Electroencephalography for Blood Pressure Augmentation in Penumbral Salvage After Subarachnoid Hemorrhage

Delayed cerebral ischemia (DCI) complicates aneurysmal subarachnoid hemorrhage (SAH) in 20 to 30 percent of cases. DCI is treated initially with hemodynamic augmentation to improve cerebral perfusion. AHA/ASA guidelines recommend induced hypertension in the treatment of DCI, but at the same time recognize that insufficient scientific data support this practice. There is little practical guidance on how to augment blood pressure - i.e. extent and duration of blood pressure augmentation. Oftentimes, intensivists determine blood pressure goals by serial neurologic exams, which may be limited in poor clinical grade SAH. We assessed the hypothesis that quantitative electroencephalography (EEG) has an adjunctive value to the clinical exam that can be used to monitor response to blood pressure augmentation in SAH. Three patients with aneurysmal SAH in the neurocritical care unit were connected to quantitative EEG. To detect a decline in neuronal activity, we measured the amount of EEG variability, reactivity, amplitude as well as the changes in alpha-delta ratio. Induced hypertension through fluid challenge and inotropic support was tailored to reach the clinical and/or electrographic ischemic threshold, i.e. blood pressure levels that ameliorated clinical examination or the EEG. Induced hypertension tailored to quantitative EEG data was tolerated well. We observed that neurologic examination of the patient (i.e. wakefulness, alertness, mental status, motor strength) following blood pressure augmentation correlated with quantitative EEG data. Furthermore, quantitative EEG added value to clinical exam, allowing for more precise increments in hemodynamic augmentation. Tapering of inotropic support was also done more safely and in a timely manner with EEG changes that preceded mild clinical impairments. In conclusion, we demonstrated in a case series that blood pressure augmentation can be guided by quantitative EEG data, which correlated with the neurologic exam. Further research can be done to determine if induced hypertension guided by quantitative EEG can reduce mortality and morbidity in patients with aneurysmal SAH.

What's new in subarachnoid hemorrhage.

Aneurysmal subarachnoid haemorrhage (SAH) is a devastating disease first described in the era of Hippocrates. Despite advances in treatment, 1-month case fatality remains as high as 35 %, with around one-third of survivors needing lifelong care and a further third having residual cognitive impairment that affects functional status and quality of life. The immediate and delayed effects of SAH on outcome have recently been reviewed in Intensive Care Medicine [1]. There have been advances in the treatment of this devastating condition aimed at reducing early (mainly re-bleeding) or late complications, particularly delayed cerebral ischemia (DCI). The importance of treatment in high-volume centres by a multidisciplinary team cannot be over-emphasised [2]. Endovascular coiling of intracranial aneurysms represents a major advance in the treatment of SAH and allows minimally invasive and effective treatment. Flow-diverting stents, with or without coils, are an increasingly employed strategy that allows even complex aneurysm to be treated minimally invasively [3]. Clipping of the aneurysm remains an option in the minority of cases that cannot be secured via the endovascular route. Early aneurysm control reduces the risk of re-bleeding and allows maintenance of higher systemic blood pressure to prevent or treat cerebral hypoperfusion. Once the aneurysm is secured, the intensive care management of SAH involves optimization of systemic physiology, and prevention or treatment of DCI and non-neurological complications. Consensus guidelines on the critical care management of SAH have recently been published [2].

Continuous EEG monitoring in aneurysmal subarachnoid hemorrhage: a systematic review.

Continuous EEG (cEEG) may allow monitoring of patients with aneurysmal subarachnoid hemorrhage (SAH) for delayed cerebral ischemia (DCI) and seizures, including non-convulsive seizures (NCSz), and non-convulsive status epilepticus (NCSE). We aimed to evaluate: (a) the diagnostic accuracy of cEEG as a confirmatory test, (b) the prognostic value of EEG patterns suggestive of seizures and DCI, and (c) the effectiveness of intensified neuromonitoring using cEEG in terms of improved clinical outcome following SAH. A systematic review was performed with eligible studies selected from multiple indexing databases through June 2014. The methodological quality of these studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2. Eighteen studies were identified, including cEEG data from 481 patients with aneurysmal SAH. NCSz were diagnosed in 7-18% of patients; NCSE in 3-13%. NCSE was associated with increased age (mean age 68years) and mortality (82-100%) compared to the entire patient population (53.9years; mortality 13%; p values <0.05). DCI was diagnosed in 20-46% of patients. Quantitative EEG patterns suggestive of DCI included decreased alpha/delta ratio, relative alpha variability, and total power. All studies were subject to a high risk of bias concerning patient selection and cEEG methodology. cEEG monitoring following SAH detects an increased number of subclinical seizures and may predict DCI many hours in advance. NCSE is associated with high mortality and morbidity, whereas for DCI identified by cEEG this association is less clear. Prospective randomized controlled multicenter trials are needed to evaluate the benefits (or risks) of intensified treatment of seizures and DCI following SAH.

CT Perfusion and Delayed Cerebral Ischemia in Aneurysmal Subarachnoid Hemorrhage: A Systematic Review and Meta-Analysis

Delayed cerebral ischemia (DCI) is at presentation a diagnosis per exclusionem, and can only be confirmed with follow-up imaging. For treatment of DCI a diagnostic tool is needed. We performed a systematic review to evaluate the value of CT perfusion (CTP) in the prediction and diagnosis of DCI. We searched PubMed, Embase, and Cochrane databases to identify studies on the relationship between CTP and DCI. Eleven studies totaling 570 patients were included. On admission, cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), and time-to-peak (TTP) did not differ between patients who did and did not develop DCI. In the DCI time-window (4 to 14 days after subarachnoid hemorrhage (SAH)), DCI was associated with a decreased CBF (pooled mean difference -11.9 mL/100 g per minute (95% confidence interval (CI): -15.2 to -8.6)) and an increased MTT (pooled mean difference 1.5 seconds (0.9-2.2)). Cerebral blood volume did not differ and TTP was rarely reported. Perfusion thresholds reported in studies were comparable, although the corresponding test characteristics were moderate and differed between studies. We conclude that CTP can be used in the diagnosis but not in the prediction of DCI. A need exists to standardize the method for measuring perfusion with CTP after SAH, and optimize and validate perfusion thresholds.

Can CT Perfusion Guide Patient Selection for Treatment of Delayed Cerebral Ischemia?

Purpose: To evaluate qualitative and quantitative CT perfusion (CTP) for different treatment options of delayed cerebral ischemia (DCI) in aneurysmal SAH. Methods: Retrospective study of consecutive SAH patients enrolled in a prospective IRB-approved clinical trial. Qualitative analysis of CTP deficits were determined by two blinded neuroradiologists. Quantitative CTP was performed using standardized protocol with region-of-interest placement sampling the cortex. DCI was assessed by clinical and imaging criteria. Patients were classified into treatment groups: 1) hypertension-hemodilution-hypervolemia (HHH); 2) intra-arterial (IA) vasodilators and/or angioplasty; 3) no treatment. Mean quantitative CTP values were compared using ANOVA pairwise comparisons. Receiver operating characteristic (ROC) curves, standard error (SE) and optimal threshold values were calculated. Results: Ninety-six patients were classified into three treatment groups; 21% (19/96) HHH, 34% (33/96) IA-therapy and 46% (44/96) no treatment. DCI was diagnosed in 42% (40/96); of which 18% (7/40) received HHH, 80% (32/40) IA-therapy, and 2% (1/40) no treatment. CTP deficits were seen in 50% (48/96); occurring in 63% (12/19) HHH, 94% (31/33) IA-therapy, and 11% (5/44) no treatment. Presence of CTP deficits had 83% sensitivity, 89% specificity, 90% positive predictive and 81% negative predictive values for treatment. Mean quantitative CTP values revealed significant differences in CBF (p mL/100 gm/min (89% specificity, 71% sensitivity) for determining treatment. Conclusion: These initial findings of significant differences in CTP deficits for different treatment groups suggest that CTP may have a potential role in guiding patient selection for treatment of DCI.

Abstract 8897: Valid Cardiac Strategy for Reversing Focal Cerebral Ischemia Caused by Vasospasm after Subarachnoid Hemorrhage

Delayed cerebral ischemia (DCI) attributable to vasospasm is currently the leading cause of death and disability after subarachnoid hemorrhage (SAH). Therapeutic hemodynamic augmentation by increasing cardiac output (CO) is a valuable method for elevating cerebral blood flow and oxygenation in dysautoregulated territories affected by DCI. Our previous results suggest that the key for successful reversal of focal ischemia is to accomplish hemodynamic acceleration enough to improve cerebral microcirculation. We prospectively assessed more effective strategy for hyperdynamic therapy with dobutamine (DOB) either by intermittent dose-repetition or by continuous step-wise dose increments in the treatment of post-SAH DCI. Real-time CO and regional cerebral oxygenation (rSO 2 ) recordings during the therapy in conjunction with the assessment of neurological improvements were analyzed. Forty patients with SAH treated surgically within 24 hours of ictus and diagnosed to have DCI between postoperative days 4 and 14 were enrolled. DOB was administered at an initial dose of 3 µg/kg/min and then increased in 3 µg/kg/min increments until resolution of the neurologic symptoms. Once the DCI recurred, 1) the DOB dose was reduced to the level where CO and rSO 2 became stable to apply the same dose-repetition (LD) or 2) simply increased the same increments until maximal dose (18 µg/kg/min) (HD). A total of 158 DOB challenges were performed with a maximum therapeutic dose of 9 ± 3 µg/kg/min (LD) and 13 ± 4 µg/kg/min (HD) (p=0.001), respectively. In response to DOB, uptake and stabilization of rSO 2 accompanied by a rapid elevation of CO usually occur, followed by improvement of the symptoms. Calculated peak slope of the CO uptake were greater in LD than in HD (p&lt;0.05). Area under the ROC curve of peak CO slope to discriminate neurological responders for each challenge was not significantly different between the strategies (p&gt;0.05). Patients managed with LD experienced less numbers of tachycardia, arrhythmia and paralytic ileus than those with HD. In conclusion, repeat application strategy with low-dose DOB will play a key role of hyperdynamic therapy in effectively relieving focal ischemia with less drug-induced complications in patients suffering from DCI after SAH.

Management of Delayed Cerebral Ischemia after Subarachnoid Hemorrhage

The purpose of this article is to describe the modern management of delayed cerebral ischemia (DCI) in patients with aneurysmal subarachnoid hemorrhage (SAH). SAH causes an inflammatory reaction to blood products in the basal cisterns of the brain, which may produce cerebral ischemia and strokes through progressive narrowing of the cerebral artery lumen. This process, known as cerebral vasospasm, is the most common cause of DCI after SAH. Untreated DCI may result in strokes, which account for a significant portion of the death and long-term disability after SAH. A number of publications, including two recent consensus statements, have clarified many best practices for defining, diagnosing, monitoring, preventing, and treating DCI. DCI is best defined as new onset of focal or global neurologic deficits or strokes not attributable to another cause. In addition to the clinical examination, radiographic studies such as transcranial Doppler ultrasonography, CT angiography, and CT perfusion may have a role in determining which patients are at high risk for developing DCI. The mainstay of prevention and treatment of DCI is maintenance of euvolemia, which can be a difficult therapeutic target to measure. Hemodynamic augmentation with induced hypertension with or without inotropic support has become the first-line treatment of DCI. The ideal method of measuring hemodynamic values and volume status in patients with DCI remains elusive. In patients who do not adequately respond to or cannot tolerate hemodynamic augmentation, endovascular therapy (intraarterial vasodilators and balloon angioplasty) is a complementary strategy. Optimal triggers for escalation and de-escalation of therapies for DCI have not been well defined. Recent guidelines and consensus statements have clarified many aspects of prevention, monitoring, and treatment of DCI after SAH. Controversies continue regarding the optimal methods for measurement of volume status, the role of invasive neuromonitoring, and the targets for hemodynamic augmentation therapy.

Microthrombosis after experimental subarachnoid hemorrhage: Time course and effect of red blood cell-bound thrombin-activated pro-urokinase and clazosentan

Delayed cerebral ischemia (DCI) is a significant cause of morbidity and mortality for patients surviving the rupture of an intracranial aneurysm. Despite an association between vasospasm and DCI, thrombosis and thromboembolism may also contribute to DCI. In this study we investigate the time course of intravascular microclot formation after experimental subarachnoid hemorrhage (SAH) and assess the effects of the following two drugs on microclot burden: mutant thrombin-activated urokinase-type plasminogen activator (scFv/uPA-T), which is bound to red blood cells for use as a thromboprophylactic agent, and clazosentan, an endothelin antagonist. In the first study, adult male C57BL/6 mice were sacrificed at 24 (n=5), 48 (n=6), 72 (n=8), and 96 (n=3) hours after SAH induced by filament perforation of the anterior cerebral artery. Sham animals (n=5) underwent filament insertion without puncture. In the second study, animals received scFv/uPA-T (n=5) 3hours after hemorrhage, clazosentan (n=5) by bolus and subcutaneous pump after SAH just prior to skin closure, or a combination of scFv/uPA-T and clazosentan (n=4). Control (n=6) and sham (n=5) animals received saline alone. All animals were sacrificed at 48hours and underwent intra-cardiac perfusion with 4% paraformaldehyde. The brains were then extracted and sliced coronally on a cryostat and processed for immunohistochemistry. An antibody recognizing thrombin–anti-thrombin complexes was used to detect microclots on coronal slices. Microclot burden was calculated for each animal and compared among groups. Following SAH, positive anti-thrombin staining was detected bilaterally in the following brain regions, in order of decreasing frequency: cortex; hippocampus; hypothalamus; basal ganglia. Few microclots were found in the shams. Microclot burden peaked at 48hours and then decreased gradually. Animals receiving scFv/uPA-T and scFv/uPA-T+clazosentan had a lower microclot burden than controls, whereas animals receiving clazosentan alone had a higher microclot burden (p<0.005). The overall mortality rate in the time course study was 40%; mortality was highest among control animals in the second study. Intravascular microclots form in a delayed fashion after experimental SAH. Microclots may be safely reduced using a novel form of thromboprophylaxis provided by RBC-targeted scFv/uPA-T and represent a potential target for therapeutic intervention in the treatment of DCI.