Delayed Ischemic Neurological Deficits Research Articles

A Comparison of Perioperative Complications and Outcomes in Patients Undergoing Cerebral Aneurysm Clipping Performed Ultra-Early (≤ 24 hours) versus Late (> 24 hours): A 7-Year Retrospective Study of 302 Patients

Abstract Objectives The intracerebral aneurysm with subarachnoid hemorrhage (SAH) has a high morbidity and mortality rate. This study aimed to compare the incidences of perioperative complications in ultra-early surgery (within 24 hours) with those in late surgery (> 24 hours). Methods Retrospective data were reviewed for 302 patients who underwent craniotomies with aneurysm clipping between January 2014 and December 2020. Perioperative data were obtained from the medical records and reviewed by the investigators. The complications were compared between ultra-early and late operations. We were interested in major complications such as delayed ischemic neurologic deficit (DIND), intraoperative aneurysm rupture (IAR), and anesthesia-related complications. The short-term (in hospital) and long-term (1 year) outcomes in patients with or without DIND and IAR were compared. The collected data was statistically analyzed. Results Three hundred and two patients were analyzed, and 264 patients had completed follow-up. The ultra-early cases (150 patients) had a higher American Society of Anesthesiologists physical status, a lower Glasgow Coma Scale, and higher Hunt and Hess scales. The surgeons operated on more cases of the anterior cerebral artery as ultra-early operations. The incidence rates of DIND, IAR, severe hemodynamic instability, and cardiac arrest were 5.6, 8.3, 6.3, and 0.3%, respectively, which were not different between groups. However, the reintubation rate was higher in the ultra-early surgery cases (0 vs. 3.3%, p = 0.023). The DIND and IAR patients had poorer short-term (in hospital) outcomes. Conclusions There were no differences in major complications between ultra-early and late craniotomy with aneurysm clipping. However, the reintubation rate was strikingly higher in the ultra-early group. Patients with major complications had early, unfavorable outcomes.

Recombinant soluble form of receptor for advanced glycation end products ameliorates microcirculation impairment and neuroinflammation after subarachnoid hemorrhage

Impaired cerebral microcirculation after subarachnoid hemorrhage (SAH) has been shown to be related to delayed ischemic neurological deficits (DIND). We previously demonstrated the involvement of the receptor for advanced glycation end products (RAGE) in the pathogenesis of SAH related neuronal death. In the present study, we aimed to investigate the therapeutic effects of a recombinant soluble form of RAGE (sRAGE) on microcirculation impairment following SAH. Intrathecal injection of autologous blood in rats, mixed primary astrocyte and microglia cultures exposed to hemolysates and endothelial cells ​(ECs) from human brain microvascular exposed to glia-conditioned medium or SAH patient's CSF were used as experimental SAH models in vivo and in vitro. The results indicated that intrathecal administration of recombinant sRAGE significantly ameliorated the vasoconstriction of cortical arterioles and associated perfusion impairment, brain edema, reduced cell death, endothelial dysfunction, and improved motor performance at 24 and 48 ​h after SAH induction in rats. The in vitro results further showed that recombinant sRAGE significantly reduced astrocyte swelling and microglia activation, in parallel with decreased mRNA expression levels of pro-inflammatory cytokines including interleukin-6 (IL-6) and interleukin-1β (IL-1β) in vitro. Moreover, the in vitro model of SAH-induced p-eNOS and eNOS suppression, along with stress fiber formation in brain microvascular ECs, was effectively reversed by sRAGE treatment and led to a decrease in cleaved-caspase 3 expression. In summary, recombinant sRAGE effectively lessened microcirculation impairment and vascular injury after SAH via the mechanism of anti-inflammation, which may provide a potential therapeutic strategy for SAH.

Evolving approaches in the management of patients with subarachnoid hemorrhage from 2002 to 2022: The impact of clazosentan and treatment modalities on outcomes

ObjectiveThis study aimed to assess the changes in patient demographics, aneurysm characteristics, and treatment modalities for subarachnoid hemorrhage (SAH) over the past two decades. MethodsWe analyzed SAH 6,446 patients between 2002 and 2022, which was divided into three periods: 2002–2011 (FP), 2012–2021 (SP), and post-clazosentan 2022 (PC). The final cohort included 2878, 2016, and 152 patients in FP, SP, and PC groups, respectively. We examined patient demographics, surgical procedures, spasm prevention therapy, and delayed ischemic neurological deficits (DIND). ResultsThe mean age of the patients increased over the study period (64, 66, and 68 years in FP, SP, and PC groups, respectively). Clipping was the predominant method during FP (79 %); however, coiling surpassed clipping in 2022 (coiling vs. clipping, 47 % vs. 46.3 %). Before clazosentan introduction, fasudil was the primary spasm prevention treatment (>80 %); however, its use decreased (63.9 %) after clazosentan introduction. DIND varied across FP, SP, and PC groups (37.4 %, 24.2 %, and 16.7 % respectively). Age and generation were significantly associated with DIND and irreversibility. ConclusionRegarding the management of patients with SAH, shift from clipping to coiling, and the introduction of new spasm prevention treatments such as clazosentan were observed, led to a decrease in DIND.

Elevated levels of several chemokines in the cerebrospinal fluid of patients with subarachnoid hemorrhage are associated with worse clinical outcome.

Chemokines are small cytokines that exert chemotactic actions on immune cells and are involved in many inflammatory processes. The present study aims to provide insight in the role of this relatively unexplored family of proteins in the inflammatory pathophysiology of subarachnoid hemorrhage (SAH). Cerebrospinal fluid of 29 patients (17 female; mean age 57 years) was collected at days 1, 4 and 10 after SAH, centrifuged and frozen at -70°C. Analysis of 92 inflammation-related proteins was performed using Target 96 Inflammation ® assay (Olink Proteomics, Uppsala, Sweden) based on Proximity Extension Assay technology. The panel included 20 chemokines (CCL2 (or MCP-1), CCL3, CCL4, CCL7 (or MCP-3), CCL8 (or MCP-2), CCL11 (or Eotaxin), CCL13 (or MCP-4), CCL19, CCL20, CCL23, CCL25, CCL28, CXCL1, CXCL5, CXCL6, CXCL8 (or IL-8), CXCL9, CXCL10, CXCL11 and CX3CL1 (or Fractalkine)) that were analyzed for their temporal patterns of expression and compared in dichotomized clinical groups based on World Federation of Neurosurgical Societies (WFNS) admission score and amount of blood on admission CT based on Fisher scale; presence of delayed cerebral ischemia(DCI)/delayed ischemic neurological deficit (DIND); and clinical outcome based on Glasgow Outcome Scale. Protein expression levels were provided in output unit Normalized Protein Expression (NPX). ANOVA models were used for statistical analyses. Four temporal patterns of expression were observed (i.e., early, middle, late peak and no peak). Significantly higher day 10 mean NPX values were observed in patients with poor outcome (GOS 1-3) for chemokines CCL2, CCL4, CCL7, CCL11, CCL13, CCL19, CCL20, CXCL1, CXCL5, CXCL6 and CXCL8. In the WFNS 4-5 group, CCL11 showed significantly higher day 4 and day 10 mean NPX values and CCL25 significantly higher day 4 values. In patients with SAH Fisher 4, CCL11 showed significantly higher mean NPX values on days 1, 4 and 10. Finally, patients with DCI/DIND had significantly higher day 4 mean NPX values of CXCL5. Higher levels of multiple chemokines at the late stage of SAH seemed to correlate with worse clinical outcome. A few chemokines correlated with WFNS score, Fisher score and occurrence of DCI/DIND. Chemokines may be useful as biomarkers for describing the pathophysiology and prognosis of SAH. Further studies are needed to better understand their exact mechanism of action in the inflammatory cascade.

Dental Pulp Stem Cell-Derived Conditioned Medium Alleviates Subarachnoid Hemorrhage-Induced Microcirculation Impairment by Promoting M2 Microglia Polarization and Reducing Astrocyte Swelling.

Aneurysmal subarachnoid hemorrhage (SAH) can cause severe neurological deficits and high mortality. Early brain edema following SAH contributes to the initiation of microcirculation impairment and may further lead to delayed ischemic neurologic deficit (DIND). This study aimed to investigate whether dental pulp stem cell conditioned medium (DPSC-CM) ameliorates SAH-induced microcirculation impairment and the underlying mechanisms. SAH was induced via intrathecal injection of fresh autologous blood in Wistar male adult rat. DPSC-CM or DPSC-CM + insulin growth factor-1 (IGF-1) antibody was randomly administered by intrathecal route 5min after SAH induction. To evaluate the underlying mechanisms of DPSC-CM in the treatment of SAH, primary rat astrocyte and microglia co-cultures were challenged with hemolysate or SAH-patient CSF in the presence or absence of DPSC-CM. The results showed that in vivo, DPSC-CM treatment decreased the brain water content, improved microcirculation impairment and enhanced functional recovery at 24h post-SAH. DPSC-CM treatment also alleviated the expressions of water channel protein aquaporin-4 (AQP4) and pro-inflammatory cytokines, and enhanced the expressions of anti-inflammatory factors in the cortical region. However, all the beneficial effects of DPSC-CM were abrogated after treatment with IGF-1 neutralizing antibody. The in vitro results further showed that DPSC-CM treatment reduced hemolysate/SAH-patient CSF-induced astrocyte swelling and promoted M2 microglia polarization, partially through IGF-1/AKT signaling. The data suggested that DPSC-CM significantly reduced brain edema and rescued microcirculation impairment with concomitant anti-inflammatory benefits after SAH, and may potentially be developed into a novel therapeutic strategy for SAH.

NT-proBNP and troponin I in high-grade aneurysmal subarachnoid hemorrhage: Relation to clinical course and outcome

PurposeTo investigate the association between two cardiac biomarkers, NT-proBNP and TnI, with intracranial pressure (ICP)−/cerebral perfusion pressure (CPP)-insults, cerebral pressure autoregulation, delayed ischemic neurological deficits (DIND), and clinical outcome after aneurysmal subarachnoid hemorrhage (aSAH). MethodsIn this retrospective study, 196 aSAH patients treated at the neurointensive care unit, Uppsala University Hospital, Sweden, 2011–2018, with ICP-monitoring and serial NT-proBNP and TnI measurements were included. The first 10 days were divided into early phase (day 1–3) and vasospasm phase (day 4–10). ResultsNT-proBNP and TnI were elevated above the reference interval at least once the first 10 days in 175 (89%) and 116 (59%) patients, respectively. In the vasospasm phase, higher NT-proBNP and TnI were associated with increased percentage of CPP below 60 mmHg. Higher TnI also correlated with more ICP-insults above 20 mmHg. NT-proBNP and TnI did not predict worse pressure autoregulation and DIND. Higher NT-proBNP and TnI were associated with mortality and unfavorable outcome in univariate, but not multivariate, analyses. ConclusionElevated NT-proBNP and TnI correlated with an increased burden of secondary ICP-/CPP-insults, but not with worse pressure autoregulation, DIND, and without independent association with clinical outcome.

Comparison of Symptomatic Vasospasm after Surgical Clipping and Endovascular Coiling.

Vasospasm, initial neurological damage, rebleeding, and periprocedural complications are associated prognostic factors for clinical outcomes after aneurysmal subarachnoid hemorrhage (SAH). In this study, factors related to delayed ischemic neurological deficit (DIND) are evaluated using data from our institute for the last 18 years. Data from 2001 to 2018 of patients with aneurysmal SAH who underwent surgical clipping (SC) or endovascular coiling (EC) within 7 days of onset were retrospectively analyzed. Cases of mortality within 5 days after treatment were excluded. Multivariate analysis was used to identify the risk factors for DIND. In total, 840 cases of SAH were assessed; among these cases, 384 (45.7%) and 456 (54.3%) were treated with SC and EC, respectively. The frequency of DIND in the EC group was significantly less than that in the SC group (11.8% vs. 17.7%; p = 0.016). In the results of multivariate analysis, internal carotid artery (ICA) aneurysm and hemorrhagic complications were the risk factors for DIND. Cilostazol administration and EC were significant factors for vasospasm prevention after aneurysmal SAH (odds ratio of ICA aneurysm: 1.59, hemorrhagic complications: 1.76, SC: 1.51, and cilostazol administration: 0.51, respectively). Cilostazol administration was also a significant factor in patients who were treated with EC. ICA aneurysm, treatment strategy, hemorrhagic complications, and cilostazol administration were associated with DIND. Oral administration of cilostazol and avoiding hemorrhagic complications were effective in DIND prevention. If both treatments are available for ruptured aneurysms, clinicians should choose EC on the basis of its ability to prevent DIND.

Ultrasound Perfusion Imaging for the Detection of Cerebral Hypoperfusion After Aneurysmal Subarachnoid Hemorrhage

BackgroundDelayed cerebral ischemia increases mortality and morbidity after aneurysmal subarachnoid hemorrhage (aSAH). Various techniques are applied to detect cerebral vasospasm and hypoperfusion. Contrast-enhanced ultrasound perfusion imaging (UPI) is able to detect cerebral hypoperfusion in acute ischemic stroke. This prospective study aimed to evaluate the use of UPI to enable detection of cerebral hypoperfusion after aSAH.MethodsWe prospectively enrolled patients with aSAH and performed UPI examinations every second day after aneurysm closure. Perfusion of the basal ganglia was outlined to normalize the perfusion records of the anterior and posterior middle cerebral artery territory. We applied various models to characterize longitudinal perfusion alterations in patients with delayed ischemic neurologic deficit (DIND) across the cohort and predict DIND by using a multilayer classification model.ResultsBetween August 2013 and December 2015, we included 30 patients into this prospective study. The left–right difference of time to peak (TTP) values showed a significant increase at day 10–12. Patients with DIND demonstrated a significant, 4.86 times increase of the left–right TTP ratio compared with a mean fold change in patients without DIND of 0.9 times (p = 0.032).ConclusionsUPI is feasible to enable detection of cerebral tissue hypoperfusion after aSAH, and the left–right difference of TTP values is the most indicative result of this finding.

Bilirubin Oxidation End Products (BOXes) Induce Neuronal Oxidative Stress Involving the Nrf2 Pathway.

Delayed ischemic neurological deficit (DIND) is a severe complication after subarachnoid hemorrhage (SAH). Previous studies have suggested that bilirubin oxidation end products (BOXes) are probably associated with the DIND after SAH, but there is a lack of direct evidence yet even on cellular levels. In the present study, we aim to explore the potential role of BOXes and the involved mechanisms in neuronal function. We synthesized high-purity (>97%) BOX A and BOX B isomers. The pharmacokinetics showed they are permeable to the blood-brain barrier. Exposure of a moderate concentration (10 or 30 μM) of BOX A or BOX B to isolated primary cortical neurons increased the production of reactive oxygen species. In the human neuroblastoma SH-SY5Y cells, BOX A and BOX B decreased the mitochondrial membrane potential and enhanced nuclear accumulation of the protein Nrf2 implicated in oxidative injury repair. In addition, both chemicals increased the mRNA and protein expression levels of multiple antioxidant response genes including Hmox1, Gsta3, Blvrb, Gclm, and Srxn1, indicating that the antioxidant response element (ARE) transcriptional cascade driven by Nrf2 is activated. In conclusion, we demonstrated that primary cortical neurons and neuroblastoma cells undergo an adaptive response against BOX A- and BOX B-mediated oxidative stress by activation of multiple antioxidant responses, in part through the Nrf2 pathway, which provides in-depth insights into the pathophysiological mechanism of DIND after SAH or other neurological dysfunctions related to cerebral hemorrhage.

Efficacy of Acupuncture Treatment to Prevent Cerebral Vasospasm After Subarachnoid Hemorrhage: A Double-Blind, Randomized Placebo-Controlled Trial.

Objectives: To investigate the efficacy of acupuncture in preventing cerebral vasospasm following aneurysmal subarachnoid hemorrhage (SAH) and explore its underlying mechanism. Design: A randomized, double-blinded, and placebo-controlled trial. Setting/Location: Subjects were recruited from Kyung Hee University Hospital at Gangdong, Seoul, Korea Subjects: A total of 50 patients admitted with acute SAH. Interventions: The study group received acupuncture treatments (n = 25), while the control group underwent mock transcutaneous electrical nerve stimulation and sham acupuncture (n = 25) six times/week for 2 weeks. Outcome measures: The primary outcome was the incidence of delayed ischemic neurologic deficit (DIND), and secondary measurements included angiographic vasospasm, vasospasm-related infarction, modified Rankin Scale score, and plasma nitric oxide (NO) and endothelin-1 (ET-1) levels. Results: The study group treated with acupuncture showed a lower incidence of DIND (9.1%) than the control group (20.8%); however, this difference in the incidence of DIND was not statistically significant. The study group demonstrated better clinical outcomes, especially in functional recovery. Significant alterations in plasma NO and ET-1 levels after the 2-week intervention were observed only in the study group. Conclusions: Their study shows that acupuncture treatment improved functional recovery after SAH and could potentially prevent cerebral vasospasm. These effects could be attributed to the recovery of endothelial dysfunction by acupuncture through modulating the plasma NO and ET-1 levels. The study protocol has been registered on www.clinicaltrials.gov (NCT02275949).

Appropriate Blood Pressure in Cerebral Aneurysm Clipping for Prevention of Delayed Ischemic Neurologic Deficits.

Background Delayed ischemic neurologic deficit (DNID) is a problem after cerebral aneurysm clipping. Intraoperative hypotension seems to be indicated as a risk factor, but it remains a controversial issue with varying low-blood pressure levels accepted. Methods A retrospective, hospital-based, case-control study was performed with patients who received general anesthesia for cerebral aneurysm clipping. 42 medical record charts were randomly selected and matched 1 : 2 (1 case with DNID : 2 controls without DNID) based on the type of general anesthetic techniques and severity of subarachnoid hemorrhage. The optimal cutoff points of hemodynamic response were calculated by the area under the curve. Results Data suggested that the optimal cutoff points for lowest blood pressure for prevention of DNID should be systolic blood pressure (SBP) of 95 mmHg (sensitivity of 78.6%; specificity of 53.6%), diastolic blood pressure (DBP) of 50 mmHg (sensitivity of 71.4%; specificity of 67.9%), and mean arterial pressure (MAP) of 61.7 mmHg (sensitivity of 85.7%; specificity of 35.7%). Furthermore, the optimal cutoff point mean difference baseline blood pressure was recommended as Δ SBP of 36 mmHg (sensitivity of 85.7%; specificity of 60.7%), Δ DBP of 27 mmHg (sensitivity of 92.9%; specificity of 71.4%), and Δ MAP of 32 mmHg (sensitivity of 92.9%; specificity of 85.7%). No significant difference between DNID and non-DNID groups was found for end-tidal carbon dioxide (ETCO2) and has poor diagnostic value for predicting DNID. Conclusion To prevent DNID, we recommend that optimal blood pressure should not be lower than 95 for SBP, 50 for DBP, and 61.7 mmHg for MAP. Additionally, we suggest that Δ SBP, Δ DBP, and Δ MAP should be less than 36, 27, and 32 mmHg, respectively.

Transcranial Doppler Sonography Defined Vasospasm, Ischemic Brain Lesions, and Delayed Ischemic Neurological Deficit in Younger and Elderly Patients after Aneurysmal Subarachnoid Hemorrhage

Vasospasm, delayed ischemic neurologic deficit (DIND), and ischemic brain lesions after acute subarachnoid hemorrhage (SAH) are associated with increased morbidity and mortality. The purpose of this study was to analyze age cutoffs for vasospasm, DIND, and ischemic brain lesions after SAH. This study included 292 aneurysmal SAH patients from January 2005 to December 2015. Patients' data were extracted from a prospective database with measurements of transcranial Doppler sonography. Any vasospasm was defined as a maximum mean flow velocity (MMFV) >120 cm/sec. Severe vasospasms were defined as at least 2 measurements of MMFVs >200 cm/sec or an increase of MMFV >50 cm/sec/24 hours over 2 consecutive days or a new neurologic deficit. All MMFVs >120 cm/sec in absence of severe vasospasm criteria were defined as mild vasospasm. Age-related cutoff values were calculated using receiver operating curve analysis. Any vasospasms occurred in 142 patients and thereof mild vasospasm in 86/142 (60.6%) patients and severe vasospasm in 56/142 patients (39.4%). Significantly higher incidences of any vasospasm (P = 0.005), severe vasospasm (P = 0.003), DIND (P = 0.031), and ischemic brain lesions (P = 0.04) were observed in patients aged <50 years. According to receiver operating curve analysis, the optimal age cutoff was 50 years for the presence of overall vasospasms, severe vasospasms, DIND, and ischemic brain lesions and 65 years for mild vasospasms. Higher incidences of any vasospasms, severe vasospasms, DIND, and ischemic brain lesions were observed in younger SAH patients.

A Case Report of Cerebral Vasospasm Following Elective Clipping of Unruptured Aneurysm: Pathogenetic Theories and Clinical Features of a Dangerous Underestimated Event

Background and Importance: Angiographic-proven and clinically-evident cerebral vasospasm (CVS) after uneventful elective clipping of unruptured intracranial aneurysm (UIA) is a very rare and often underestimated event. To date, the knowledge of risk factors, pathophysiology, and demographic characteristics of these conditions are solely relegated to few case reports. With the aim of better characterize shared features and mechanism that could be involved in such event we also performed a review of the present literature and analyzed aneurysm’s features, surgical factors, treatments, recovery and of all reported cases of CVS after elective clipping. Clinical Presentation: We report a case of a cerebral vasospasm following elective clipping of a middle cerebral artery (MCA) bifurcation aneurysm in a 59-year-old woman who smoked next days after treatment, despite medical advice. We found ten cases comparable to ours with angiographic-proven and clinically evident cerebral vasospasm after uneventful elective clipping. Conclusion: Classic mechanisms of CVS following SAH have been widely studied. In all the cases we analyzed, no subarachnoid bleeding occurred, as demonstrated in pre and postoperative CT scans and intraoperatively. Various theories on the possible mechanism have been advanced. It seems reasonable that CVS following elective clipping of unruptured aneurysm is a multifactorial phenomenon. Although its pathogenesis is unclear, clinicians should keep in mind the existence of this event, that is rare, but it could be seen in the clinical practice of every neurosurgery ward. In our opinion, it’s worth to know this possible post-operative complication because, when suspected clinical signs and symptoms of delayed ischemic neurological deficit (DIND) arise after elective clipping, it’s important to make an early diagnosis of CVS owing to early treatments are critical to improve clinical outcome

Management of cerebral vasospasm in subarachnoid hemorrhage

Subarachnoid hemorrhage (SAH) has been shown to result in cerebral vasospasm at day 4 to day 14, which is the main cause of mortality and morbidity after SAH. Outcome after SAH depends on many factors, including the severity of the event, medical management, and prevention of several serious complications. The principal goal in management of vasospasm after SAH is to prevent delayed ischemic neurological deficit (DIND) by decreasing intracranial pressure (ICP), optimizing cerebral oxygen demand rate and improving cerebral blood flow (CBF). Therapeutic management has been applied to prevent or treat vasospasm, including hemodynamic therapy, and endovascular therapy. Endovascular therapies, including mechanical angioplasty and chemical angioplasty with administration of intra-arterial (IA) vasodilator, have been widely used and given a good outcome. The purpose of this article is to describe the management of vasospasm including medical management and endovascular treatment. This review will describe the treatment modalities and management strategies to treat vasospasm.Abbreviations: SAH – subarachnoid hemorrhage; aSAH – aneurysmal subarachnoid hemorrhage; TCD – transcranial Doppler; ROS – reactive oxygen species; ICAM – intercellular adhesion molecule; VCAM – vascular cell adhesion molecule; IL – interleukin; CTA – computed tomography angiography; MRA – magnetic resonance angiography; CBF – cerebral blood flow; DIND – delayed ischemic neurological deficit; RCT - randomized controlled trialsCitation: Prahaztuti D, Hidayati HB, Sani AF. Management of cerebral vasospasm in subarachnoid hemorrhage. Anaesth Pain &amp; Intensive Care 2018;22(3 Suppl 1):S58-S66.Received: 19 Oct 2018 Reviewed: 4, 11 Nov 2018 Accepted: 12 Nov 2018

Haptoglobin administration into the subarachnoid space prevents hemoglobin-induced cerebral vasospasm

Delayed ischemic neurological deficit (DIND) is a major driver of adverse outcomes in patients with aneurysmal subarachnoid hemorrhage (aSAH), defining an unmet need for therapeutic development. Cell-free hemoglobin that is released from erythrocytes into the cerebrospinal fluid (CSF) is suggested to cause vasoconstriction and neuronal toxicity, and correlates with the occurrence of DIND. Cell-free hemoglobin in the CSF of patients with aSAH disrupted dilatory NO signaling ex vivo in cerebral arteries, which shifted vascular tone balance from dilation to constriction. We found that selective removal of hemoglobin from patient CSF with a haptoglobin-affinity column or its sequestration in a soluble hemoglobin-haptoglobin complex was sufficient to restore physiological vascular responses. In a sheep model, administration of haptoglobin into the CSF inhibited hemoglobin-induced cerebral vasospasm and preserved vascular NO signaling. We identified 2 pathways of hemoglobin delocalization from CSF into the brain parenchyma and into the NO-sensitive compartment of small cerebral arteries. Both pathways were critical for hemoglobin toxicity and were interrupted by the large hemoglobin-haptoglobin complex that inhibited spatial requirements for hemoglobin reactions with NO in tissues. Collectively, our data show that compartmentalization of hemoglobin by haptoglobin provides a novel framework for innovation aimed at reducing hemoglobin-driven neurological damage after subarachnoid bleeding.

Delayed Ischemic Neurologic Deficit after Aneurysmal Subarachnoid Hemorrhage.

Delayed ischemic neurologic deficit (DIND) is the main preventable cause of poor outcomes in aneurysmal subarachnoid hemorrhage (SAH) patients. Of 50% of survivors from a SAH, approximately 30% of patients will present clinical vasospasm (VS). The cornerstone of the DIND management comprises prevention and early identification. Several diagnostic methods have been proposed differing in efficacy, invasiveness, and costs. Serial neurological examination is the most reliable method to detect a new neurological deficit. On the other hand, comatose patients require advanced monitoring methods which identify changes in the microcirculatory environment, brain autoregulation, and spreading depolarization. Multimodality monitoring with continuous electroencephalography, microdialysis, and intracranial pressure monitoring represents altogether the current state-of-art technology for the intensive care of SAH patients. Moreover, advances in genetic biomarkers to predict clinical VS have shown consistent accuracy which may in the near future allow the early prediction of DIND through a simple blood test. Several clinical trials have tested drugs with theoretical effects on DIND prevention or treatment. Nevertheless, nimodipine remains the Holy Grail in the prevention of clinical VS. Among rescue therapies, the endovascular treatment through intra-arterial vasodilator (verapamil or nicardipine) infusion is the most employed method for DIND reversal; however, there is no good quality evidence comparing results of intra-arterial infusion of vasodilators versus balloon angioplasty. Although we have addressed the most refined technology in the management of SAH and DIND, the clinical experience and strict follow-up in neurointensive care will be determinant for favorable long-term outcomes.

#48 Use of metformin during pregnancy and risk of major congenital malformations: Preliminary findings of a systematic review and meta-analysis

Clazosentan, an endothelin receptor antagonist, reduced vasospasm and delayed ischemic neurologic deficit (DIND) but did not improve outcome after subarachnoid hemorrhage (SAH) in clinical trials. However, a lack of dose-dependent analysis and potential overestimation of clazosentan's effect are concerning. We used stratified analysis and trial sequential analysis (TSA) of existing data to investigate the effects of clazosentan on SAH outcome.Studies from PubMed, Embase, and Cochrane were reviewed for eligibility. Primary outcomes were DIND requiring rescue therapy, all-cause mortality, and vasospasm-related morbidity at 6 weeks. Secondary outcomes were moderate-to-severe angiographic vasospasm, new cerebral infarction, and poor clinical outcome at 3 months. TSA was performed to assess the required information size and the α-spending monitoring boundary effect of relative risk (RR) reduction. A stratified analysis of clazosentan dosage was performed.Five studies (N = 2317) were included. Clazosentan significantly reduced the risk of DIND requiring rescue therapy (RR, 0.625; 95% confidence interval [CI], 0.462–0.846) and vasospasm (RR, 0.543; 95% CI, 0.464–0.635), but did not significantly affect mortality or vasospasm-related morbidity (RR, 0.775; 95% CI, 0.578–1.039), new cerebral infarction (RR, 0.604; 95% CI, 0.383–0.952), or outcome (RR, 1.131; 95% CI, 0.959–1.334). TSA revealed that the studies were underpowered to evaluate the effects of clazosentan on mortality and vasospasm-associated morbidity. We found 10–15 mg/h of clazosentan administration was associated with lower rates of vasospasm and new cerebral infarctions compared with 5 mg/h.Clazosentan reduced the risk of DIND requiring rescue therapy and moderate-to-severe vasospasm. Further meta-analyses based on individual patient data with different clazosentan doses and more refined outcome measures are necessary to clarify clazosentan's efficacy in improving post-SAH outcome.

Compartmentalisation of the inflammatory response following aneurysmal subarachnoid haemorrhage

IntroductionThere is some evidence to suggest that a systemic and central nervous system (CNS) inflammatory response occurs following aneurysmal subarachnoid haemorrhage (aSAH) which may be related to the pathophysiology of early brain injury and delayed ischaemic neurological deficit (DIND). The aim of this study was to measure inflammatory mediator levels in plasma and cerebrospinal fluid (CSF) in the days following aSAH and to determine their association with aSAH, DIND and clinical outcome. Material and methodsPlasma and CSF samples were obtained prospectively from patients with aSAH on days 1–3, 5, 7 and 9 and profiled for interleukin (IL)-1α, IL-1β, IL-4, IL-6, IL-8, IL-10, IL-15, IL-17, IL-18, macrophage chemotactic protein (MCP)-1, vascular endothelial growth factor (VEGF) and tumour necrosis factor (TNF)-α. Plasma and CSF samples from non-aSAH patients undergoing spinal anaesthesia were used as controls. ResultsThe CSF levels of all cytokines investigated except for IL-1α were significantly higher in aSAH compared to controls in the first seven days of ictus. CSF levels of IL-1α (p = 0.014), IL-18 (p = 0.016), IL-6 (p = 0.0006) and IL-8 (p = 0.006) showed significant increases in the days following aSAH. Conversely IL-17 demonstrated a decrease. In particular, IL-4 was higher in the CSF of patients who had DIND at all time-points (p = 0.032). Plasma IL-6 and IL-8 levels were higher, and IL-1α levels lower, than controls at most time-points. All mediators demonstrated persistent elevation in the CSF compared to plasma apart from IL-1α and IL-18 which followed the opposite trend. Day 3 plasma IL-6 levels predicted poor outcome at six months (Exp(B) 1.12 1.03-1.22, P = 0.012), although this association was lost in the second analysis incorporating Fisher grade, WFNS grade and age. ConclusionThe post aSAH inflammatory response peaks on days 5–7 post ictus and remains largely compartmentalised within the CNS. IL-4 may have a particular association with DIND although its precise role in the pathophysiology of the disorder remains unclear. IL-6 predicted poor outcome but not independently of clinical grade, suggesting that it may be a surrogate marker of early brain injury.

Efficacy of Statins in Cerebral Vasospasm, Mortality, and Delayed Cerebral Ischemia in Patients with Aneurysmal Subarachnoid Hemorrhage: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Aneurysmal subarachnoid hemorrhage (aSAH) is an acute cerebrovascular disease with frequent cerebral vasospasm and delayed cerebral ischemia (DCI). The use of statins for patients with aSAH is controversial. The present study evaluated the efficacy of statins in aSAH-induced vasospasm, DCI, delayed ischemic neurological deficit (DIND), mortality, and other outcomes. A literature search was performed in PubMed, EMBASE, and the Cochrane Library. English reports of patients with aSAH who had been treated with statins without combination were included. The outcomes, including cerebral vasospasm, DIND, DCI, mortality, disability, and creatine kinase/alanine aminotransferase/aspartic transaminase elevation, were extracted for meta-analysis. A total of 13 studies, with 776 versus 821 patients treated with statins versus placebo, were retained for the statistical meta-analysis. The results showed that statin administration significantly reduced the frequency of vasospasm (relative risk [RR], 0.76; 95% confidence interval [CI], 0.63-0.91; P= 0.003), DIND (RR, 0.76; 95% CI, 0.63-0.91; P= 0.003), vasospasm-DCI (RR, 0.49; 95% CI, 0.32-0.74; P= 0.0008), and mortality (RR, 0.73; 95% CI, 0.54-0.98; P= 0.03). Statins showed insignificant efficacy in the prevention of disability (RR, 0.92; 95% CI, 0.71-1.20), a neurological poor prognosis (RR, 0.75; 95% CI, 0.45-1.27), and creatine kinase/alanine aminotransferase/aspartic transaminase elevation (RR, 1.90; 95% CI, 0.55-6.50). Statins significantly reduced the incidence of vasospasm, DIND, DCI, and mortality in individuals with aSAH, suggesting its efficacy in aSAH.

Abstract 46: RNA Expression Profiles From Whole Blood Associated With Vasospasm in Patients With Subarachnoid Hemorrhage

Background and Purpose: Though there are many biomarker studies of plasma and serum in patients with aneurysmal subarachnoid hemorrhage (SAH), few have examined cells in blood that might contribute to vasospasm and delayed ischemic neurological deficits (DIND). In this study we evaluate inflammatory and prothrombotic pathways by examining RNA expression in whole blood (including leukocytes, platelets) of SAH patients with vasospasm compared to those without vasospasm. Methods: Adult patients with aneurysmal SAH admitted to UCSF from 2003 to 2010 were enrolled. Patients with vasospasm (n=29) and without vasospasm (n=21) were matched for sex, race/ethnicity and aneurysm treatment method. Diagnosis of vasospasm was made by angiography. RNA expression was measured by Affymetrix Human Exon 1.0 ST Arrays. SAH patients with vasospasm were compared to those without vasospasm by ANCOVA to identify differential gene expression, exon expression and alternatively spliced transcript expression. Analyses were adjusted for age, batch, and days after SAH. Results: At the gene level there were 276 differentially expressed between SAH with vasospasm compared to patients without (P&lt;0.05,