Therapeutic Hypothermia Reduces Middle Cerebral Artery Flow Velocity in Patients with Severe Aneurysmal Subarachnoid Hemorrhage

Background

Transcranial Doppler (TCD) is widely used to detect and follow up cerebral vasospasm after subarachnoid hemorrhage (SAH). Therapeutic hypothermia might influence blood flow velocities assessed by TCD. The aim of the study was to evaluate the effect of hypothermia on Doppler blood flow velocity after SAH.

Methods

In 20 patients treated with hypothermia (33°) due to refractory intracranial hypertension or delayed cerebral ischemia (DCI), mean flow velocity of the middle cerebral artery (MFV_MCA) was assessed by TCD. Thirteen patients were treated with combined hypothermia and barbiturate coma and seven with hypothermia alone. MFV_MCA was obtained within 24 h before and after induction of hypothermia as well as before and after rewarming.

Results

Hypothermia was induced on average 5 days after SAH (range 1–12) and maintained for 144 h (range 29–270). After hypothermia induction, MFV_MCA decreased from 113.7 ± 49.0 to 93.8 ± 44.7 cm/s (p = 0.001). The decrease was independent of SAH-related complications and barbiturate coma. MFV_MCA further decreased by 28.2 cm/s between early and late hypothermia (p < 0.001). This second decrease was observed in patients with DCI (p < 0.001), but not in patients with intracranial hypertension (p = 0.715). Compared to late hypothermia, MFV_MCA remained unchanged after rewarming (65.6 ± 32.1 vs 70.3 ± 36.8 cm/s; p = 0.219). However, patients treated with hypothermia alone showed an increase in MFV_MCA after rewarming (p = 0.016).

Conclusion

Therapeutic hypothermia after SAH decreases Doppler blood flow velocity in both intracranial hypertension and DCI cases. The results can be the effect of hypothermia-related mechanisms or resolving cerebral vasospasm during prolonged hypothermia.     

The Effects of Fluid Balance and Colloid Administration on Outcomes in Patients with Aneurysmal Subarachnoid Hemorrhage: A Propensity Score-Matched Analysis

Background

Delayed ischemic neurological deficit (DIND) following aneurysmal subarachnoid hemorrhage (SAH) remains a significant cause of mortality and disability. The administration of colloids and the induction of a positive fluid balance during the vasospasm risk period remain controversial. Here, we compared DIND and outcomes among propensity score-matched cohorts who did and did not receive colloids and also tested the effect of a positive fluid balance on these endpoints.

Methods

Exploratory analysis was performed on 413 patients enrolled in CONSCIOUS-1, a prospective randomized trial of clazosentan for the prevention of angiographic vasospasm. Propensity score matching was performed on the basis of age, gender, pre-existing heart conditions, hypertension, nicotine use, World Federation of Neurosurgical Societies scores, aneurysm location, clazosentan treatment, subarachnoid clot burden, and severity of angiographic vasospasm. Inferential statistics were used for group-wise comparisons.

Results

One hundred twenty-three subjects were matched (41 received colloids, whereas 82 did not). The covariate balance and propensity score distributions were acceptable. There was no difference between the groups with respect to DIND (17 vs. 22 %; p = 0.64) or the presence (48 vs. 51 %; p = 0.71) or volume of delayed infarcts (volume >7.5 cm³; 62 vs. 48 %; p = 0.41). Similarly, no differences were found on multivariate analysis between patients who did and did not have a positive fluid balance, although patients with severe angiographic vasospasm had more delayed infarcts with a negative fluid balance (p = 0.01). Among all subjects, the administration of colloids and a positive fluid balance were associated with worse outcomes on the NIHSS (p = 0.04) and modified Rankin (p = 0.02) scales, respectively.

Conclusions

Colloid administration and induction of a positive fluid balance during the vasospasm risk period may be associated with poor outcomes in specific patient groups. Patient selection is of utmost importance when managing the fluid status of patients with aneurysmal SAH.     

Early Systemic Procalcitonin Levels in Patients with Aneurysmal Subarachnoid Hemorrhage

Background

Early (≤24 h) systemic procalcitonin (PCT) levels are predictive for unfavorable neurological outcome in patients after out-of-hospital cardiac arrest (OHCA). Subarachnoid hemorrhage (SAH) due to aneurysm rupture might lead to a cerebral perfusion stop similar to OHCA. The current study analyzed the association of early PCT levels and outcome in patients after SAH.

Methods

Data from 109 consecutive patients, admitted within 24 h after SAH, were analyzed. PCT levels were measured within 24 h after ictus. Clinical severity was determined using the World Federation of Neurological Societies (WFNS) scale and dichotomized into severe (grade 4–5) and non-severe (1–3). Neurological outcome after 3 months was assessed by the Glasgow outcome scale and dichotomized into unfavorable (1–3) and favorable (4–5). The predictive value was assessed using receiver operating curve (ROC) analysis.

Results

Systemic PCT levels were significantly higher in patients with severe SAH compared to those with non-severe SAH: 0.06 ± 0.04 versus 0.11 ± 0.11 μg/l (median ± interquartile range; p < 0.01). Patients with unfavorable outcome had significantly higher PCT levels compared to those with favorable outcome 0.09 ± 0.13 versus 0.07 ± 0.15 ng/ml (p < 0.01). ROC analysis showed an area under the curve of 0.66 (p < 0.01) for PCT, which was significantly lower than that of WFNS with 0.83 (p < 0.01).

Conclusions

Early PCT levels in patients with SAH might reflect the severity of the overall initial stress response. However, the predictive value is poor, especially compared to the reported predictive values in patients with OHCA. Early PCT levels might be of little use in predicting neurological outcome after SAH.     

Left Ventricular Dysfunction and Cerebral Infarction from Vasospasm After Subarachnoid Hemorrhage

Background

Although neurogenic stunned myocardium (NSM) after aneurysmal subarachnoid hemorrhage (SAH) is well described, its clinical significance remains poorly defined. We investigated the influence of left ventricular (LV) dysfunction and cerebral vasospasm on cerebral infarction, serious cardiovascular events, and functional outcome after SAH.

Methods

Of the 481 patients enrolled in the University Columbia SAH Outcomes Project between 10/96 and 05/02, we analyzed a subset of 119 patients with at least one echocardiogram, serial transcranial Doppler (TCD) data, and with no prior history of cardiac disease. LV dysfunction was defined as an ejection fraction <40% on echocardiography. Infarction from vasospasm was adjudicated by the study team after comprehensive review of all clinical and imaging data. Functional outcome was assessed at 15 and 90 days with the modified Rankin Scale (mRS).

Results

Eleven percent of patients had LV dysfunction (N = 13). Younger age, hydrocephalus, and complete filling of the quadrigeminal and fourth ventricles were associated with LV dysfunction (all P < 0.05). Despite a similar frequency of pre-existing hypertension, 0% of patients with LV dysfunction reported taking antihypertensive medication, compared to 35% of those without (P = 0.009). There was a significant association between LV dysfunction and infarction from vasospasm after adjusting for clinical grade, age, and peak TCD flow velocity (P = 0.03). Patients with LV dysfunction also had higher rates of hypotension requiring vasopressors (P = 0.001) and pulmonary edema (P = 0.002). However, there was no association between LV dysfunction and outcome at 14 days after adjustment for established prognostic variables.

Conclusions

LV dysfunction after SAH increases the risk of cerebral infarction from vasospasm, hypotension, and pulmonary edema, but with aggressive ICU support does not affect short-term survival or functional outcome. Antihypertensive medication may confer cardioprotection and reduce the risk of catecholamine-mediated injury after SAH.     

Cerebral Vasospasm and Delayed Cerebral Ischemia in Intraventricular Hemorrhage

Background

Intracerebral hemorrhage (ICH) with intraventricular extension (IVH) is a devastating disease with a particular high mortality. In some aspects, IVH may resemble subarachnoid hemorrhage. The incidence and role of cerebral vasospasm in ICH with IVH are poorly understood. Here, we aimed to analyze the incidence and relationship of cerebral vasospasm to clinical characteristics, in-hospital mortality, and functional outcome at 3 months in patients suffering ICH with IVH.

Methods

Patients with ICH and IVH treated on a neurological intensive care unit were prospectively enrolled in a single-center observational study. Vasospasm was defined using established ultrasound criteria. Delayed cerebral ischemia (DCI) was defined as a new hypodensity on follow-up cranial CT. Functional outcome at 3 months was assessed using the modified Rankin Scale.

Results

129 patients with ICH and IVH were screened for the study. 62 patients entered the final analysis. The incidence of significant vasospasm was 37 %. A strong trend was found for the association between all cerebral vasospasm and DCI (P = 0.046). Early (up to 48 h) vasospasm was significantly associated with a DCI (P = 0.033). Overall mortality and outcome after 3 months did not differ between the groups.

Conclusion

Cerebral vasospasm seems to be a frequent complication after ICH with IVH and might be associated with DCI. Larger studies are warranted to confirm this hypothesis.     

Heart Rate Variability for Preclinical Detection of Secondary Complications After Subarachnoid Hemorrhage

Background

We sought to determine if monitoring heart rate variability (HRV) would enable preclinical detection of secondary complications after subarachnoid hemorrhage (SAH).

Methods

We studied 236 SAH patients admitted within the first 48 h of bleed onset, discharged after SAH day 5, and had continuous electrocardiogram records available. The diagnosis and date of onset of infections and DCI events were prospectively adjudicated and documented by the clinical team. Continuous ECG was collected at 240 Hz using a high-resolution data acquisition system. The Tompkins–Hamilton algorithm was used to identify R–R intervals excluding ectopic and abnormal beats. Time, frequency, and regularity domain calculations of HRV were generated over the first 48 h of ICU admission and 24 h prior to the onset of each patient’s first complication, or SAH day 6 for control patients. Clinical prediction rules to identify infection and DCI events were developed using bootstrap aggregation and cost-sensitive meta-classifiers.

Results

The combined infection and DCI model predicted events 24 h prior to clinical onset with high sensitivity (87 %) and moderate specificity (66 %), and was more sensitive than models that predicted either infection or DCI. Models including clinical and HRV variables together substantially improved diagnostic accuracy (AUC 0.83) compared to models with only HRV variables (AUC 0.61).

Conclusions

Changes in HRV after SAH reflect both delayed ischemic and infectious complications. Incorporation of concurrent disease severity measures substantially improves prediction compared to using HRV alone. Further research is needed to refine and prospectively evaluate real-time bedside HRV monitoring after SAH.     

Acute Effect of Intravenous Sildenafil on Cerebral Blood Flow in Patients with Vasospasm After Subarachnoid Hemorrhage

Background

The phosphodiesterase-5 inhibitor sildenafil has been shown to attenuate delayed cerebral ischemia (DCI) and improve neurologic function in experimental subarachnoid hemorrhage (SAH). We recently demonstrated that it could improve cerebral vasospasm (CVS) in humans after SAH. However, successful therapies for DCI must also restore cerebral blood flow (CBF) and/or autoregulatory capacity. In this study, we tested the effects of sildenafil on CBF in SAH patients at-risk for DCI.

Methods

Six subjects with angiographically confirmed CVS received 30-mg of intravenous sildenafil (mean 9 ± 2 days after aneurysmal SAH). Each underwent ¹⁵O-PET imaging to measure global and regional CBF at baseline and post-sildenafil.

Results

Mean arterial pressure declined by 10 mm Hg on average post-sildenafil (8 %, p = 0.01), while ICP was unchanged. There was no change in global CBF (mean 34.5 ± 7 ml/100g/min at baseline vs. 33.9 ± 8.0 ml/100g/min post-sildenafil, p = 0.84). The proportion of brain regions with low CBF (<25 ml/100g/min) was also unchanged after sildenafil infusion.

Conclusions

Infusion of sildenafil does not lead to a change in global or regional perfusion despite a significant reduction in cerebral perfusion pressure. While this could reflect the ineffectiveness of sildenafil-induced proximal vasodilatation to alter brain perfusion, it also suggests that cerebral autoregulatory function was preserved in this group. Future studies should assess whether sildenafil can restore or enhance autoregulation after SAH.

     

Brain Iron Metabolism and Brain Injury Following Subarachnoid Hemorrhage: iCeFISH-Pilot (CSF Iron in SAH)

Introduction

Iron-mediated oxidative damage has been implicated in the genesis of cerebral vasospasm in animal models of SAH. We sought to explore the relationship between levels of non-protein bound iron in cerebrospinal fluid and the development of brain injury in patients with aneurysmal SAH.

Methods

Patients admitted with aneurysmal subarachnoid hemorrhage to a Neurointensive care unit of an academic, tertiary medical center, with Hunt and Hess grades 2–4 requiring ventriculostomy insertion as part of their clinical management were included in this pilot study. Samples of cerebrospinal fluid (CSF) were obtained on days 1, 3, and 5. A fluorometric assay that relies on an oxidation sensitive probe was used to measure unbound iron, and levels of iron-handling proteins were measured by means of enzyme-linked immunosorbent assays. We prospectively collected and recorded demographic, clinical, and radiological data.

Results

A total of 12 patients were included in this analysis. Median Hunt and Hess score on admission was 3.5 (IQR: 1) and median modified Fisher scale score was 4 (IQR: 1). Seven of 12 patients (58 %) developed delayed cerebral ischemia (DCI). Day 5 non-transferrin bound iron (NTBI) (7.88 ± 1 vs. 3.58 ± 0.8, p = 0.02) and mean NTBI (7.39 ± 0.4 vs. 3.34 + 0.4 p = 0.03) were significantly higher in patients who developed DCI. Mean redox-active iron, as well as day 3 levels of redox-active iron correlated with development of angiographic vasospasm in logistic regression analysis (p = 0.02); while mean redox-active iron and lower levels of ceruloplasmin on days 3, 5, and peak concentration were correlated with development of deep cerebral infarcts.

Conclusions

Our preliminary data indicate a causal relationship between unbound iron and brain injury following SAH and suggest a possible protective role for ceruloplasmin in this setting, particularly in the prevention of cerebral ischemia. Further studies are needed to validate these findings and to probe their clinical significance.     

Is Transcranial Doppler Ultrasonography Old-fashioned?: One Institutional Validity Study

Objective

The purpose of this study is to investigate the correlation between various transcranial Doppler (TCD) ultrasonography parameters and clinical vasospasm after aneurysmal subarachnoid hemorrhage (SAH).

Methods

This study enrolled 40 patients presented with aneurysmal SAH between September 2006 and August 2007. We measured differences of mean blood flow velocity (BFVm), highest systolic blood flow velocity (BFVh), and Lindegaard ratio (LR) in the middle cerebral artery on TCD examination. These parameters were evaluated for correlation with clinical vasospasm by univariate analysis and the receiver operating characteristic analysis.

Results

Twelve patients (30%) developed clinical vasospasm. The best TCD parameters for the detection of clinical vasospasm were revealed to be differences of BFVm, BFVh, and LR values between 1^st TCD test and 3^rd TCD (7 cm/s, 11.5 cm/s, 0.45 respectively). The positive predictive value of any one of three parameters was 60% and the negative predictive value was 100%.

Conclusion

TCD is still considered a useful tool for screening clinical vasospasm. To confirm the predictive value of the above parameters, further prospective study will be needed.     

Transdermal Nicotine Replacement Therapy in Cigarette Smokers with Acute Subarachnoid Hemorrhage

Background

We evaluated the safety of nicotine replacement therapy (NRT) in active smokers with acute (aneurysmal) subarachnoid hemorrhage (SAH).

Methods

A retrospective observational cohort study was conducted in a prospectively collected database including all SAH patients admitted to an 18-bed neuro-ICU between January 1, 2001 and October 1, 2007. Univariate and multivariable models were constructed, employing stepwise logistic regression. The primary endpoint was 3-month mortality. Delayed cerebral ischemia (DCI) due to vasospasm, angiographic and TCD evidence of vasospasm, and delirium were secondary endpoints.

Results

Active cigarette smokers admitted with SAH included 128 that received NRT and 106 that did not. Patients were well-matched for age, admission Hunt-Hess Grade, radiographic findings, and APACHE II scores, but those who received NRT were more likely to be heavy smokers (>10 cigarettes daily), diabetic, heavy alcohol users, and to have cerebral edema on admission. NRT was associated in multivariate analysis with a lower risk of death at 3?months (OR 0.12, 95% CI 0.04?C0.37, P?P?=?0.006) and seizures (9 vs. 2%, P?=?0.024) were more common in patients who received NRT.

Conclusions

Despite vasoactive properties, administration of NRT among active smokers with acute SAH appeared to be safe, with similar rates of vasospasm and DCI, and a slightly higher rate of seizures. The association of NRT with lower mortality could be due to chance, to uncontrolled factors, or to a neuroprotective effect of nicotine in active smokers hospitalized with SAH, and should be tested prospectively.     

Impact of Percutaneous Transluminal Angioplasty for Treatment of Cerebral Vasospasm on Subarachnoid Hemorrhage Patient Outcomes

Background

Percutaneous transluminal angioplasty (PTA) has been introduced for treatment of symptomatic cerebral vasospasm in patients with subarachnoid hemorrhage (SAH). While angiographic improvement is consistently reported, clinical improvement following the procedure varies, and limited data is available regarding overall impact on outcome.

Methods

The authors performed a retrospective analysis of all hospital admissions with aneurysmal SAH over a 6 year period. The length of stay, discharge outcomes (measured by modified Rankin scale [mRS] at discharge), and 1-year mortality among patients with SAH before (4 year period) and after (2 year period) institution of PTA for cerebral vasospasm were compared. Embolization for intracranial aneurysm was used as a therapeutic option throughout the study duration. The effect of institution of PTA for vasospasm after adjusting for age, clinical severity, and use of aneurysm embolization on both discharge outcomes and 1-year mortality in multivariate analysis was evaluated.

Results

A total of 146 patients with aneurysmal SAH were admitted during the study duration. There was no difference between the 89 patients admitted in pre-angioplasty period and 57 patients admitted in post-angioplasty period in regards to age, medical co-morbidities, and admission clinical severity of patients (measured by Hunt and Hess grade and Glasgow coma scale). A total of 18 (32%) patients underwent PTA with or without intra-arterial vasodilator treatment in the second period of the study. There was a non significant decrease in rates of severe disability and death (mRS 5–6) at discharge (45 vs. 33%, P = 0.09) and 1-year mortality (32 vs. 22%, P = 0.26) after introduction of PTA for cerebral vasospasm after adjusting for potential confounders. There was no significant difference between the two time periods in regards to length of stay.

Conclusion

A non significant trend was noted with reduced rate of severe disability and mortality at discharge and 1-year mortality after the introduction of PTA for cerebral vasospasm associated with SAH without increasing the length of hospital stay.     

Hyperacute Vasospasm After Aneurysmal Subarachnoid Hemorrhage

Background

Cerebral vasospasm after aneurysmal subarachnoid hemorrhage typically occurs 3–14 days after aneurysm rupture. We describe a series of patients who developed vasospasm within minutes of aneurysm rupture. This phenomenon, which we term, “hyperacute vasospasm,” has been reported in animal models of SAH, but hitherto has been poorly described in humans.

Methods

Eleven patients were identified from an institutional registry who had aneurysmal rupture during catheter cerebral angiography between 1997 and 2009. We quantified the degree of vasoconstriction using vascular diameter index (VDI). The change in VDI (delta VDI or DVDI) was calculated by determining the difference in VDI before and after the procedure. We also examined the relationship between hyperacute vasospasm and delayed cerebral ischemia.

Results

Ten of eleven (91 %) patients with intraoperative aneurysm rupture had cerebral vasoconstriction within minutes of intra-procedural aneurysmal rupture. Six of eleven patients (55 %) with hyperacute vasospasm developed delayed cerebral infarction.

Conclusions

Hyperacute vasospasm is likely common in patients with intraoperative aneurysm rupture and may be an unrecognized element of the natural history of aneurysmal subarachnoid hemorrhage. In this limited series, there was an association between hyperacute vasospasm and delayed cerebral infarction.

     

Post-subarachnoid Hemorrhage Vasospasm in Patients with Primary Headache Disorders

Background

Altered cerebral vasomotor reactivity leading to vasospasm can be seen both in patients with primary headache disorders (PHD) and in patients with subarachnoid hemorrhage (SAH). The pathogenesis of vasospasm in post-SAH patients and in headache disorder sufferers may be related. To address this hypothesis, we analyzed a large cohort of SAH patients to determine whether a diagnosis of PHD predisposes to vasospasm, delayed cerebral ischemia, or worsened clinical outcome.

Methods

Prospectively collected data from patients enrolled in the SAH Outcomes Project between 1996 and 2006 were analyzed. Patients were segregated based on whether they had a diagnosis of PHD or not and were subsequently compared for differences in clinical and radiographic outcome.

Results

A total of 921 SAH patients were analyzed, 265 of which had a diagnosis of PHD. In total, symptomatic vasospasm was seen in 17 %, while angiographic vasospasm was seen in 28 %. Vasospasm rates were similar among patients with a PHD and in those without a PHD (p > 0.05). However, on multivariate analysis new ischemic infarcts were more common in patients with a PHD as compared to patients without a PHD (p = 0.015). Functional outcomes at 3 months were similar among PHD and non-PHD patients (p > 0.05).

Conclusion

A history of PHD is associated with an increased rate of ischemic infarcts during admission for SAH. Increased rates of vasospasm within small cerebral blood vessels may be implicated. Further studies are warranted to more closely link the mechanisms of vasospasm in PHD and SAH patients.     

Role of Endothelin-1 in Human Aneurysmal Subarachnoid Hemorrhage: Associations with Vasospasm and Delayed Cerebral Ischemia

Background

Endothelin-1 (ET-1) is a potent vasoconstrictor implicated in the pathogenesis of vasospasm and delayed cerebral ischemia (DCI) in aneurysmal subarachnoid hemorrhage (aSAH) patients. The aim of this study was to investigate the relationship between cerebrospinal fluid (CSF) ET-1 levels and angiographic vasospasm and DCI.

Methods

Patients with aSAH were consented (n?=?106). Cerebral vasospasm was determined by angiography. DCI was determined by transcranial Doppler (TCD) results and/or angiogram results with corresponding clinical deterioration. CSF ET-1 levels over 14?days after the initial insult was quantified by ELISA. ET-1 analysis included a group-based trajectory analysis and ET-1 exposure rate during 24, 48, and 72?h prior to, as well as 72?h post angiography, or clinical deterioration.

Results

Trajectory analysis revealed two distinct groups of subjects with 56% of patients in the low ET-1 trajectory group (mean at day 1?=?0.31?pg/ml; SE?=?0.04; mean at day 14?=?0.41?pg/ml; SE?=?0.15) and 44% of patients in the high ET-1 trajectory group (mean at day 1?=?0.65?pg/ml; SE?=?0.08; mean at day 14?=?0.61?pg/ml; SE?=?0.06). Furthermore, we observed that ET-1 exposure rate 72?h before angiography and clinical spasm was a significant predictor of both angiographic vasospasm and DCI, whereas, ET-1 exposure after angiography and clinical spasm was not associated with either angiographic vasospasm or DCI.

Conclusion

Based on these results we conclude that ET-1 concentrations are elevated in a sub-group of patients and that the acute (72?h prior to angiography and clinical neurological deterioration), but not chronic, elevations in CSF ET-1 concentrations are indicative of the pathogenic alterations of vasospasm and DCI in aSAH patients.     

High Risk of New Episode of Symptomatic Vasospasm in Unaffected Arteries in Subarachnoid Hemorrhage Patients Receiving Targeted Endovascular Treatment for Symptomatic Focal Vasospasm

Background

There is controversy whether asymptomatic vasospasm in other arteries should be concurrently treated (global treatment) in patients receiving targeted endovascular treatment [percutaneous-transluminal-angioplasty (PTA) and/or intra-arterial (IA) vasodilators] for focal symptomatic vasospasm.

Objective

To determine the rates of occurrence of new symptomatic vasospasm in previously asymptomatic arterial distributions among patients with aneurysmal subarachnoid hemorrhage (SAH) who underwent targeted endovascular treatment for focal symptomatic vasospasm.

Methods

We identified all patients with SAH who had received targeted endovascular treatment during a 4-year period. We ascertained any new occurrence of symptomatic vasosopasm requiring endovascular treatment in previously unaffected (and untreated) arterial distributions within the same hospitalization. Blinded reviewers quantitatively graded angiographic vasospasm (<25, 26–49, ≥50 %) in all major arteries for each patient at the time of targeted treatment.

Results

Of the 41 patients who received targeted endovascular treatment (PTA in 41 % and vasodilators in 59 %), 11 (27 %) developed new symptomatic vasospasm in previously asymptomatic vascular distributions requiring endovascular treatment. Moderate severity of angiographic vasospasm in asymptomatic arteries at the time of targeted treatment tended to predict the occurrence of new symptomatic vasospasm. The rate of death and disability at discharge [modified Rankin scale (mRS) of 3–6] was 82 % (9/11) among those who developed a new episode of symptomatic vasospasm compared with 70 % (21/30) in those who did not (P = 0.58).

Conclusions

High risk of new occurrence of ischemic symptoms in previously asymptomatic (and untreated) arterial distributions among patients receiving targeted treatment should be recognized. Further studies should evaluate the benefit of performing global endovascular treatment during the initial targeted endovascular treatment session.     

Effect of Triple-H Prophylaxis on Global End-Diastolic Volume and Clinical Outcomes in Patients with Aneurysmal Subarachnoid Hemorrhage

Background

Although prophylactic triple-H therapy has been used in a number of institutions globally to prevent delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH), limited evidence is available for the effectiveness of triple-H therapy on hemodynamic variables. Recent studies have suggested an association between low global end-diastolic volume index (GEDI), measured using a transpulmonary thermodilution method, and DCI onset. The current study aimed at assessing the effects of prophylactic triple-H therapy on GEDI.

Methods

This prospective multicenter study included aneurysmal SAH patients admitted to 9 hospitals in Japan. The decision to administer prophylactic triple-H therapy and the management protocols were left to the physician in charge (physician-directed therapy) of each participating institution. The primary endpoints were the changes in the hemodynamic variables as analyzed using a generalized linear mixed model.

Results

Of 178 patients, 62 (34.8 %) received prophylactic triple-H therapy and 116 (65.2 %) did not. DCI was observed in 35 patients (19.7 %), with no significant difference between the two groups [15 (24.2 %) vs. 20 (17.2 %), p = 0.27]. Although a greater amount of fluid (p < 0.001) and a higher mean arterial pressure (p = 0.005) were observed in the triple-H group, no significant difference was observed between the groups in GEDI (p = 0.81) or cardiac output (p = 0.62).

Conclusions

Physician-directed prophylactic triple-H administration was not associated with improved clinical outcomes or quantitative hemodynamic indicators for intravascular volume. Further, GEDI-directed intervention studies are warranted to better define management algorithms for SAH patients with the aim of preventing DCI.     

Intraventricular Tissue Plasminogen Activator in Subarachnoid Hemorrhage Patients: A Prospective,Randomized, Placebo-Controlled Pilot Trial

Background

The quantity of subarachnoid (SAH) and intraventricular hemorrhage (IVH) occurring in the setting of a ruptured cerebral aneurysm is strongly associated with subsequent complications and poor outcomes.

Methods

We randomly allocated aneurysmal SAH patients with a modified Fisher score of 4, who had been treated with endovascular coil embolization and ventricular drainage, to receive either 2 mg intraventricular tissue plasminogen activator (TPA) every 12 h (maximum 10 mg) or placebo. Computed tomography scans were performed 12, 48, and 72 h after administration. Primary outcomes included feasibility (enrollment and consent rates), safety (assessed by prospectively screening for complications), and rate of intracranial blood clearance (measured using sequential IVH, modified Graeb, and SAH sum scores). Secondary outcomes included angiographic vasospasm, delayed cerebral ischemia, need for ventriculoperitoneal shunting, and 6-month neurological outcomes.

Results

Seventy-seven patients were screened, 17 were eligible, and 12 were randomized. The consent rate was 87 %. There were no cases of new intracranial hemorrhage complicating use of TPA. Models fit using generalized estimating equations demonstrated more rapid reduction in IVH volume (p = 0.009), modified Graeb score (p < 0.001), and SAH sum score (p < 0.001) among patients treated with TPA. SAH clearance at 48 h was enhanced by earlier drug administration (p = 0.02). There were no differences in secondary outcomes.

Conclusions

Intraventricular TPA accelerates clearance of SAH and IVH, especially when administered early. A larger-scale clinical trial of intraventricular TPA is feasible, will need to be conducted at multiple centers, and is required to determine whether this practice reduces complications and improves outcomes.     

pH-Sensitive NMDA Inhibitors Improve Outcome in a Murine Model of SAH

Background

Despite intensive research, neurological morbidity from delayed cerebral ischemia remains common after aneurysmal subarachnoid hemorrhage (SAH). In the current study, we evaluate the neuroprotective effects of a pH-dependent GluN2B subunit-selective NMDA receptor antagonist in a murine model of SAH.

Methods

Following induction of SAH, 12 ± 2 week old male C57-BL/6 mice received NP10075, a pH-dependent NMDA receptor antagonist, or vehicle. In a separate series of experiments, NP10075 and the non-pH sensitive NMDA antagonist, NP10191, were administered to normoglycemic and hyperglycemic mice. Both histological (right middle cerebral artery diameter, NeuN, and Fluoro-Jade B staining) and functional endpoints (rotarod latency and neuroseverity score) were evaluated to assess the therapeutic benefit of NP10075.

Results

Administration of NP10075 was well tolerated and had minimal hemodynamic effects following SAH. Administration of the pH-sensitive NMDA antagonist NP10075, but not NP10191, was associated with a durable improvement in the functional performance of both normoglycemic and hyperglycemic animals. NP10075 was also associated with a reduction in vasospasm in the middle cerebral artery associated with hemorrhage. There was no significant difference between treatment with nimodipine + NP10075, as compared to NP10075 alone.

Conclusions

These data demonstrate that use of a pH-dependent NMDA antagonist has the potential to work selectively in areas of ischemia known to undergo acidic pH shifts, and thus may be associated with selective regional efficacy and fewer behavioral side effects than non-selective NMDA antagonists.     

Rosiglitazone Attenuates Cerebral Vasospasm and Provides Neuroprotection in an Experimental Rat Model of Subarachnoid Hemorrhage

Background

Glutamate and oxidative stress play important roles after subarachnoid hemorrhage (SAH). The ability to modulate glutamate transporter 1 (GLT-1) and the antioxidative effect of rosiglitazone have been demonstrated. We investigated the neuroprotective effect of rosiglitazone after SAH.

Methods

SAH was induced by double blood injection. The rats were randomly divided into sham, SAH + vehicle, and SAH + rosiglitazone groups and treated with dimethyl sulfoxide, dimethyl sulfoxide, and 6 mg/kg of rosiglitazone, respectively, at 2 and 12 h after SAH induction and then daily for 6 days. Cerebrospinal fluid dialysates were collected 30 min before SAH induction and then daily for 7 days for glutamate measurement. Mortality, body weight, and neurological scores were also measured daily. On day 7 after SAH, the wall thickness and the perimeter of the basilar artery (BA), neuron variability, GLT-1 levels, glial fibrillary acidic protein (GFAP) expression and activity, and malondialdehyde, superoxide dismutase, and catalase activities were also evaluated.

Results

Rosiglitazone improved survival (relative risk = 0.325) and neurological functions and reduced neuronal degeneration (5.7 ± 0.8 vs. 10.0 ± 0.9; P < 0.001) compared with the SAH + vehicle group. Rosiglitazone also lowered glutamate levels by 43.5-fold and upregulated GLT-1 expression by 1.5-fold and astrocyte activity by 1.8-fold compared with the SAH + vehicle group. The increase in BA wall thickness was significantly attenuated by rosiglitazone, whereas the perimeter of the BA was increased. In addition, rosiglitazone abated the 1.9-fold increase in malondialdehyde levels and the 1.6-fold increase in catalase activity after SAH.

Conclusion

Rosiglitazone reduced SAH mortality, neurological deficits, body weight loss, GFAP loss, and cerebral vasospasm by preventing the neurotoxicity induced by glutamate and oxidative stress.     

SSRI/SNRI Use is Not Associated with Increased Risk of Delayed Cerebral Ischemia After aSAH

Background

To determine the effect of selective serotonin reuptake inhibitor (SSRI)/selective norepinephrine reuptake inhibitor (SNRI) use on the risk of symptomatic vasospasm and delayed cerebral ischemia (DCI) in patients hospitalized with aneurysmal subarachnoid hemorrhage (aSAH).

Methods

Retrospective review of consecutive patients with aSAH at Mayo Clinic, Rochester from January 2001 to December 2013. The variables collected and analyzed included age, sex, SSRI/SNRI use, active smoking, transfusion, modified Fisher score, WFNS grade, and outcome at discharge. Multivariate logistic regression analysis was used to evaluate factors associated with DCI, symptomatic vasospasm, and poor outcome (modified Rankin score 3–6) within 1 year.

Results

579 [females 363 (62.7 %)] patients with a median age of 55 (IQR 47–65) years were admitted with aSAH during the study period. WFNS at nadir was IV–V in 240 (41.5 %), and modified Fisher score was 3–4 in 434 (75.0 %). 81 (13.9 %) patients had been prescribed an SSRI or SNRI prior to admission and all continued to receive these medications during hospitalization. Symptomatic vasospasm was present in 154 (26.4 %), radiological infarction in 172 (29.5 %), and DCI in 250 (42.9 %) patients. SSRI/SNRI use was not associated with the occurrence of DCI (p = 0.458), symptomatic vasospasm (p = 0.097), radiological infarction (p = 0.972), or poor functional outcome at 3 months (p = 0.376).

Conclusions

The use of SSRI/SNRI prior to and during hospitalization is not associated with DCI or functional outcome in patients with aSAH.