Factor Xa Inhibitor-Related Intracranial Hemorrhage: Results From a Multicenter, Observational Cohort Receiving Prothrombin Complex Concentrates.

BACKGROUND: Since the approval of the oral factor Xa inhibitors, there have been concerns regarding the ability to neutralize their anticoagulant effects after intracranial hemorrhage (ICH). Multiple guidelines suggest using prothrombin complex concentrates (PCCs) in these patients on the basis of research that includes a limited number of patients with ICH. Given this, we aimed to evaluate the safety and efficacy of PCCs for factor Xa inhibitor-related ICH in a large, multicenter cohort of patients. METHODS: This was a multicenter, retrospective, observational cohort study of patients with apixaban- or rivaroxaban-related ICH who received PCCs between January 1, 2015, and March 1, 2019. The study had 2 primary analysis groups: safety and hemostatic efficacy. The safety analysis evaluated all patients meeting inclusion criteria for the occurrence of a thrombotic event, which were censored at hospital discharge or 30 days after PCC administration. Patients with intracerebral, subarachnoid, or subdural hemorrhages who had at least 1 follow-up image within 24 hours of PCC administration were assessed for hemostatic efficacy. The primary efficacy outcome was the percentage of patients with excellent or good hemostasis on the basis of the modified Sarode criteria. Secondary outcomes included an evaluation of in-hospital mortality, length of stay, infusion-related reactions, and thrombotic event occurrence during multiple predefined periods. RESULTS: A total of 663 patients were included and assessed for safety outcomes. Of these, 433 patients met criteria for hemostatic efficacy evaluation. We observed excellent or good hemostasis in 354 patients (81.8% [95% CI, 77.9-85.2]). Twenty-five (3.8%) patients had a total of 26 thrombotic events, of which 22 occurred in the first 14 days after PCC administration. One patient had documentation of an infusion-related reaction. For the full cohort of patients, in-hospital mortality was 19.0%, and the median intensive care unit and hospital lengths of stay were 2.0 and 6.0 days, respectively. CONCLUSIONS: Administration of PCCs after apixaban- and rivaroxaban-related ICH provided a high rate of excellent or good hemostasis (81.8%) coupled with a 3.8% thrombosis rate. Randomized, controlled trials evaluating the clinical efficacy of PCCs in patients with factor Xa inhibitor-related ICH are needed.

Hydrogen gas therapy improves survival rate and neurological deficits in subarachnoid hemorrhage rats: a pilot study.

The high morbidity, high mortality, and significant shortage of effective therapies for subarachnoid hemorrhage (SAH) have created an urgency to discover novel therapies. Human studies in Asia have established the safety of hydrogen gas in the treatment of hepatic, renal, pulmonary, and cardiac diseases. Mechanistically, hydrogen gas has been shown to affect oxidative stress, inflammation, and apoptosis. We hypothesized that hydrogen therapy would improve neurological function and increase survival rate in SAH. High dose hydrogen gas (66% at 3 L/min) was administered for 2 hours at 0.5, 8, and 18 hours after SAH. This treatment increased 72-hour survival rate and provided 24-hour neuroprotection after SAH in rats. To our knowledge, this is the first report demonstrating that high dose hydrogen gas therapy reduces mortality and improves outcome after SAH. Our results correlate well with the proposed mechanisms of hydrogen gas therapy within the literature. We outline four pathways and downstream targets of hydrogen gas potentially responsible for our results. A potentially complex network of pathways responsible for the efficacy of hydrogen gas therapy, along with a limited mechanistic understanding of these pathways, justifies further investigation to provide a basis for clinical trials and the advancement of hydrogen gas therapy in humans. This study was approved by the Institutional Animal Care and Use Committee of Loma Linda University, USA (Approval No. 8160016) in May 2016.

Outcomes Following Possible Undiagnosed Aneurysmal Subarachnoid Hemorrhage: A Contemporary Analysis.

OBJECTIVES: Existing literature suggests that patients with aneurysmal subarachnoid hemorrhage (aSAH) and "sentinel" aSAH symptoms prompting healthcare evaluations prior to aSAH diagnosis are at increased risk of unfavorable neurologic outcomes and death. Accordingly, these encounters have been presumed to be unrecognized opportunities to diagnose aSAH and the worse outcomes representative of the added risks of delayed diagnoses. We sought to reinvestigate this paradigm among a contemporary cohort of patients with aSAH. METHODS: A case-control cohort was retrospectively assembled among patients diagnosed with aSAH between January 1, 2007 and June 30, 2013 within an integrated healthcare delivery system. Patients with a discrete clinical evaluation for headache or neck pain within 14 days prior to formal aSAH diagnosis were identified as cases, and the remaining patients served as controls. Modified Rankin Scale scores at 90 days and 1 year were determined by structured chart review. Multivariable logistic regression controlling for age, sex, ethnicity, presence of intracerebral or intraventricular hemorrhage at diagnosis, and aneurysm size was used to compare adjusted outcomes. Sensitivity analyses were performed using varying definitions of favorable neurologic outcomes, a restricted control subgroup of patients with normal mental status at hospital admission, inclusion of additional cases that were diagnosed outside of the integrated health system, and exclusion of patients without evidence of subarachnoid blood on initial noncontrast cranial computed tomography (CT) at the diagnostic encounter (i.e. "CT-negative" SAH). RESULTS: A total of 450 patients with aSAH were identified, 46 (10%) of whom had clinical evaluations for possible aSAH-related symptoms in the 14 days preceding formal diagnosis (cases). In contrast to prior reports, no differences were observed among cases compared to control patients in adjusted odds of death or unfavorable neurologic status at 90 days (0.35, 95% confidence interval [CI] = 0.11-1.15; 0.59, 95% CI = 0.22-1.60, respectively) or at 1 year (0.58, 95% CI = 0.19-1.73; 0.52, 95% CI = 0.18-1.51, respectively). Likewise, neither restricting the analysis to a control subgroup of patients with normal mental status at hospital admission, varying the dichotomous definition of unfavorable neurologic outcome, inclusion of cases diagnosed outside the integrated health system, or exclusion of patients with CT-negative SAH resulted in significant adjusted outcome differences. CONCLUSION: In a contemporary cohort of patients with aSAH, we observed no statistically significant increase in the adjusted odds of death or unfavorable neurologic outcomes among patients with clinical evaluations for possible aSAH-related symptoms in the 14 days preceding formal diagnosis of aSAH. While these findings cannot exclude a smaller risk difference than previously reported, they can help refine decision analyses and testing threshold determinations for patients with possible aSAH.

Development and validation of a score for evaluating comprehensive stroke care capabilities: J-ASPECT Study.

BACKGROUND: Although the Brain Attack Coalition recommended establishing centers of comprehensive care for stroke and cerebrovascular disease patients, a scoring system for such centers was lacking. We created and validated a comprehensive stroke center (CSC) score, adapted to Japanese circumstances. METHODS: Of the selected 1369 certified training institutions in Japan, 749 completed an acute stroke care capabilities survey. Hospital performance was determined using a 25-item score, evaluating 5 subcategories: personnel, diagnostic techniques, specific expertise, infrastructure, and education. Consistency and validity were examined using correlation coefficients and factorial analysis. RESULTS: The CSC score (median, 14; interquartile range, 11-18) varied according to hospital volume. The five subcategories showed moderate consistency (Cronbach's α = 0.765). A strong correlation existed between types of available personnel and specific expertise. Using the 2011 Japanese Diagnosis Procedure Combination database for patients hospitalized with stroke, four constructs were identified by factorial analysis (neurovascular surgery and intervention, vascular neurology, diagnostic neuroradiology, and neurocritical care and rehabilitation) that affected in-hospital mortality from ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage. The total CSC score was related to in-hospital mortality from ischemic stroke (odds ratio [OR], 0.973; 95% confidence interval [CI], 0.958-0.989), intracerebral hemorrhage (OR, 0.970; 95% CI, 0.950-0.990), and subarachnoid hemorrhage (OR, 0.951; 95% CI, 0.925-0.977), with varying contributions from the four constructs. CONCLUSIONS: The CSC score is a valid measure for assessing CSC capabilities, based on the availability of neurovascular surgery and intervention, vascular neurology, diagnostic neuroradiology, and critical care and rehabilitation services.

Enhanced Therapeutic Potential of Nano-Curcumin Against Subarachnoid Hemorrhage-Induced Blood-Brain Barrier Disruption Through Inhibition of Inflammatory Response and Oxidative Stress.

Curcumin and nano-curcumin both exhibit neuroprotective effects in early brain injury (EBI) after experimental subarachnoid hemorrhage (SAH). However, the mechanism that whether curcumin and its nanoparticles affect the blood-brain barrier (BBB) following SAH remains unclear. This study investigated the effect of curcumin and the poly(lactide-co-glycolide) (PLGA)-encapsulated curcumin nanoparticles (Cur-NPs) on BBB disruption and evaluated the possible mechanism underlying BBB dysfunction in EBI using the endovascular perforation rat SAH model. The results indicated that Cur-NPs showed enhanced therapeutic effects than that of curcumin in improving neurological function, reducing brain water content, and Evans blue dye extravasation after SAH. Mechanically, Cur-NPs attenuated BBB dysfunction after SAH by preventing the disruption of tight junction protein (ZO-1, occludin, and claudin-5). Cur-NPs also up-regulated glutamate transporter-1 and attenuated glutamate concentration of cerebrospinal fluid following SAH. Moreover, inhibition of inflammatory response and microglia activation both contributed to Cur-NPs' protective effects. Additionally, Cur-NPs markedly suppressed SAH-mediated oxidative stress and eventually reversed SAH-induced cell apoptosis in rats. Our findings revealed that the strategy of using Cur-NPs could be a promising way in improving neurological function in EBI after experimental rat SAH.

Astragaloside IV alleviates early brain injury following experimental subarachnoid hemorrhage in rats.

Astragaloside IV, one of the main effective components isolated from Astragalus membranaceus, has multiple neuroprotective properties, while the effects of astragaloside IV on the attenuation of subarachnoid hemorrhage (SAH)-induced early brain injury (EBI) and its possible mechanisms are unknown. In the present study, we aimed to determine whether astragaloside IV could inhibit oxidative stress, reduce neuronal apoptosis, and improve neurological deficits after experimental SAH in rats. Rats (n=68) were randomly divided into the following groups: Sham group, SAH group, SAH+vehicle group, and SAH+astragaloside IV group. Astragaloside IV or an equal volume of vehicle was administered at 1 h and 6 h after SAH, all the rats were subsequently sacrificed at 24 h after SAH. Mortality, neurological scores, and brain edema were assessed, biochemical tests and histological studies were also performed at that point. SAH induced an increase in the malondialdehyde (MDA) level, neuronal apoptosis, cleaved caspase 3, brain edema and decreased activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). Astragaloside IV treatment reversed these changes and improved neurobehavioral outcomes of SAH rats. Our findings suggested that astragaloside IV may alleviate EBI after SAH through antioxidative and anti-apoptotic effects.

Effect of prolonged therapeutic hypothermia on intracranial pressure, organ function, and hospital outcomes among patients with aneurysmal subarachnoid hemorrhage.

BACKGROUND: Global cerebral edema (GCE) with subsequent refractory intracranial hypertension complicates some cases of aneurysmal subarachnoid hemorrhage (aSAH), and typically is associated with poorer outcome. Treatment options for refractory intracranial pressure (ICP) cases are limited to decompressive hemicraniectomy (DHC) and targeted temperature management (TTM) with induced hypothermia (32-34 °C). No outcomes comparison between patients treated with either or both forms of refractory ICP therapy exists, and data on the effect of prolonged hypothermia on ICP and organ function among patients with aSAH are limited. METHODS: This is a retrospective study of aSAH patients who underwent DHC and/or prolonged hypothermia (greater than 48 h) for refractory ICP (i.e., ICP >20 mmHg after osmotherapy) in the intensive care unit of a single, tertiary-care academic center. RESULTS: Nineteen individuals with aSAH underwent TTM with or without DHC; sixteen patients underwent DHC alone. The patients in TTM group were younger (median age 44 years) than the DHC without TTM population (median age 60 years). TTM was started on median day 2 with a median duration of 7 days. There were no significant group differences in survival to discharge (59 % vs. 69 %) or in the mean modified Rankin score on follow-up (3.6 vs. 3.7), despite the TTM group having longer hospital length of stay (24 vs. 19 days, p = 0.03), longer duration of mechanical ventilation (20 vs. 9 days, p = 0.04), a higher cumulative fluid balance (12.8 vs. 5.1 L, p = 0.01), and higher APACHEII scores. The median maximal ICP decreased from 23.5 to 21 mmHg within 24 h of hypothermia initiation. There were no significant differences in other markers of end-organ function (respiratory, hematologic, renal, liver, and cardiac), infection rate, or adverse events between groups. CONCLUSIONS: Use of prolonged TTM among aSAH patients with GCE and refractory ICP elevations is associated with a longer duration of mechanical ventilation but is not different in terms of neurological outcomes measured by modified Rankin score or organ function outcomes compared to patients who received DHC alone.

Endovascular treatment: balloon angioplasty versus nimodipine intra-arterial for medically refractory cerebral vasospasm following aneurysmal subarachnoid hemorrhage.

Cerebral vasospasm (CV) accounts significant morbimortality after aneurysmal subarachnoid hemorrhage. The objective of this study was to compare the clinical outcome of patients with CV treated by 2 endovascular procedures: intra-arterial nimodipine angioplasty (IANA) and balloon angioplasty (BA). Between 2008 and June 2011, we performed 22 IANA and 8 BA in 30 patients. The mean age was 44 years and 60% was female. In 17 patients, the treatment was clipping, whereas 13 underwent coil treatment. The CV was severe in 63%, moderate in 30%, and mild in 7%. Good outcome between 2 groups was similar (P = .36). The clinical outcome according to the subgroups of CV severity and modality treatment was equivalent (P = .22). Mortality at 3 months was 16% and 20% at 1 year. We did not find differences in the clinical outcome despite the fact that both techniques produce adequate angiographic resolution of CV.

Incidence of subarachnoid haemorrhage: an Australian national hospital morbidity database analysis.

Incidences of subarachnoid haemorrhage (SAH) in Australia have been reported in regional studies with variable rates. We investigated the national SAH rate and evaluated the trend over the 10 years from 1998 to 2008. The crude SAH incidence, not related to trauma or arteriovenous malformation, was estimated at 10.3 cases per 100,000 person-years (95% confidence interval [CI]: 10.2-10.4). Females have a higher incidence of SAH (12.5 cases per 100,000; 95% CI: 12.3-12.8) compared to males (8.0 cases per 100,000; 95% CI: 7.8-8.3), with age-adjusted incidence increases with increasing age for both sexes. Less than 10% of SAH occurred in the first three decades of life. The peak age group for patients to experience SAH was between 45 years and 64 years, accounting for almost 45% of the overall annual SAH admissions. Aneurysms located in the anterior circulation were a more common source of rupture compared to those located in the posterior circulation (rate ratio 3.9; 95% CI: 3.6-4.2). Contrary to contemporary observations in the literature, we did not observe a decline in the incidence of SAH during this specified study period.

Treatment with Z-ligustilide, a component of Angelica sinensis, reduces brain injury after a subarachnoid hemorrhage in rats.

Subarachnoid hemorrhage (SAH) is a devastating stroke subtype accounting for approximately 3 to 7% of cases each year. Despite its rarity among the various stroke types, SAH is still responsible for approximately 25% of all stroke fatalities. Although various preventative and therapeutic interventions have been explored for potential neuroprotection after SAH, a considerable percentage of patients still experience serious neurologic and/or cognitive impairments as a result of the primary hemorrhage and/or secondary brain damage that occurs. Z-ligustilide (LIG), the primary lipophilic component of the Chinese traditional medicine radix Angelica sinensis, has been shown to reduce ischemic brain injury via antiapoptotic pathways. Accordingly, in our study, we investigated the neuroprotective potential of LIG after experimental SAH in rats. Rats with SAH that was induced using the established double hemorrhage model were studied with and without LIG treatment. Mortality, neurobehavioral evaluation, brain water content, blood-brain barrier (BBB) permeability, and vasospasm assessment of the basilar artery were measured on days 3 and 7 after injury. Additional testing was done to evaluate for apoptosis using TdT-mediated dUTP-biotin nick end labeling staining as well as immunohistochemistry and Western blotting to identify key proapoptotic/survival proteins, i.e., p53, Bax, Bcl-2, and cleaved caspase-3. The results showed that LIG treatment reduced mortality, neurobehavioral deficits, brain edema, BBB permeability, and cerebral vasospasm. In addition, treatment reduced the number of apoptotic cells in the surrounding brain injury site, which accompanied a marked down-regulation of proapoptotic proteins, p53, and cleaved caspase-3. Our data suggest that LIG may be an effective therapeutic modality for SAH victims by altering apoptotic mechanisms.

Tirilazad for aneurysmal subarachnoid haemorrhage.

BACKGROUND: Delayed cerebral ischaemia is a significant contributor to poor outcome (death or disability) in patients with aneurysmal subarachnoid haemorrhage (SAH). Tirilazad is considered to have neuroprotective properties in animal models of acute cerebral ischaemia. OBJECTIVES: To assess the efficacy and safety of tirilazad in patients with aneurysmal SAH. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (last searched October 2009); the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2009); MEDLINE (1966 to October 2009); EMBASE (1980 to October 2009); and the Stroke Trials Directory, the National Center for Complementary and Alternative Medicine, and the National Institute of Health Clinical Trials Database (searched October 2009). We handsearched 10 Chinese journals, searched the reference lists of relevant publications, and contacted the manufacturers of tirilazad. SELECTION CRITERIA: Randomised trials of tirilazad started within four days of SAH onset, compared with placebo or open control in patients with aneurysmal SAH documented by angiography and computerised tomography (CT) scan or cerebrospinal fluid examination, or both. DATA COLLECTION AND ANALYSIS: We extracted data relating to case fatality, poor outcome (death, vegetative state, or severe disability), delayed cerebral ischaemia (or symptomatic vasospasm), cerebral infarction and adverse events of treatments. We pooled the data using the Peto fixed-effect method for dichotomous data. MAIN RESULTS: We included five double-blind, placebo-controlled trials involving 3821 patients; there was no significant heterogeneity. Oral or intravenous nimodipine was used routinely as a background treatment in both groups in all trials. There was no significant difference between the two groups at the end of follow up for the primary outcome, death (odds ratio (OR) 0.89, 95% confidence interval (CI) 0.74 to 1.06), or in poor outcome (death, vegetative state or severe disability) (OR 1.04, 95% CI 0.90 to 1.21). During the treatment period, fewer patients developed delayed cerebral ischaemia in the tirilazad group than in the control group (OR 0.80, 95% CI 0.69 to 0.93). Subgroup analyses did not demonstrate any significant difference in effects of tirilazad on clinical outcomes. Leukocytosis and prolongation of Q-T interval occurred significantly more frequently in the treatment group in only one trial evaluating tirilazad at high dose. There was no significant difference in infusion site disorders or other laboratory parameters between the two groups. AUTHORS' CONCLUSIONS: There is no evidence that tirilazad, in addition to nimodipine, reduces mortality or improves poor outcome in patients with aneurysmal SAH.

Continuous selective intraarterial infusion of nimodipine for therapy of refractory cerebral vasospasm.

BACKGROUND: For endovascular treatment of vasospasm after aneurysmal subarachnoid hemorrhage (aSAH), an intraarterial treatment course with the calcium channel antagonist nimodipine infused for 30 min is proposed. As some patients still show ongoing vasospasm thereafter, we report on our experience with an extended time period of selective intraarterial nimodipine administration. METHODS: In nine patients with aSAH and refractory cerebral vasospasm, we left the catheter in place within the internal carotid artery after angiography. On the neurosurgical ICU, a continuous infusion of intraarterial nimodipine was commenced, combined with intraarterial heparin anticoagulation. Therapy was controlled with extended neuromonitoring techniques. RESULTS: Three patients died from refractory vasospasm and a fourth suffered lethal sepsis. Three patients survived in a good clinical condition, two of them without apparent neurologic deficit. The efficacy of intraarterial nimodipine was best verified with regional CBF monitoring. TCD failed to detect vasospasm in two patients and missed improvement in four. Brain tissue oxygenation increased in all patients, but was not indicative of vasospasm in one. CT perfusion reflected the treatment course adequately in the qualitative scans. CONCLUSION: Selective continuous intraarterial nimodipine treatment for refractory cerebral vasospasm after aSAH seems feasible and may add to the endovascular therapeutic options. Appropriate monitoring technology is essential for further investigation of this novel technique.

Influence of early antioxidant supplements on clinical evolution and organ function in critically ill cardiac surgery, major trauma, and subarachnoid hemorrhage patients.

INTRODUCTION: Oxidative stress is involved in the development of secondary tissue damage and organ failure. Micronutrients contributing to the antioxidant (AOX) defense exhibit low plasma levels during critical illness. The aim of this study was to investigate the impact of early AOX micronutrients on clinical outcome in intensive care unit (ICU) patients with conditions characterized by oxidative stress. METHODS: We conducted a prospective, randomized, double-blind, placebo-controlled, single-center trial in patients admitted to a university hospital ICU with organ failure after complicated cardiac surgery, major trauma, or subarachnoid hemorrhage. Stratification by diagnosis was performed before randomization. The intervention was intravenous supplements for 5 days (selenium 270 microg, zinc 30 mg, vitamin C 1.1 g, and vitamin B1 100 mg) with a double-loading dose on days 1 and 2 or placebo. RESULTS: Two hundred patients were included (102 AOX and 98 placebo). While age and gender did not differ, brain injury was more severe in the AOX trauma group (P = 0.019). Organ function endpoints did not differ: incidence of acute kidney failure and sequential organ failure assessment score decrease were similar (-3.2 +/- 3.2 versus -4.2 +/- 2.3 over the course of 5 days). Plasma concentrations of selenium, zinc, and glutathione peroxidase, low on admission, increased significantly to within normal values in the AOX group. C-reactive protein decreased faster in the AOX group (P = 0.039). Infectious complications did not differ. Length of hospital stay did not differ (16.5 versus 20 days), being shorter only in surviving AOX trauma patients (-10 days; P = 0.045). CONCLUSION: The AOX intervention did not reduce early organ dysfunction but significantly reduced the inflammatory response in cardiac surgery and trauma patients, which may prove beneficial in conditions with an intense inflammation. TRIALS REGISTRATION: Clinical Trials.gov RCT Register: NCT00515736.

Melatonin decreases mortality following severe subarachnoid hemorrhage.

Aneurysmal subarachnoid hemorrhage (SAH) is a devastating disease that is associated with significant morbidity and mortality. There is substantial evidence to suggest that oxidative stress is significant in the development of acute brain injury following SAH. Melatonin is a strong antioxidant that has low toxicity and easily passes through the blood-brain barrier. Previous studies have shown that melatonin provides neuroprotection in animal models of ischemic stroke. This study hypothesizes that melatonin will provide neuroprotection when administered 2 hr after SAH. The filament perforation model of SAH was performed in male Sprague-Dawley rats weighing between 300 and 380 g. Melatonin (15 or 150 mg/kg), or vehicle was given via intraperitoneal injection 2 hr after SAH. Mortality and neurologic deficits were assessed 24 hr after SAH. A significant reduction in 24-hr mortality was seen following treatment with high dose melatonin. There was no improvement in neurologic scores with treatment. Brain water content and lipid peroxidation were measured following the administration of high dose melatonin to identify a mechanism for the increased survival. High dose melatonin tended to reduce brain water content following SAH, but had no effect on the lipid peroxidation of brain samples. Large doses of melatonin significantly reduces mortality and brain water content in rats following SAH through a mechanism unrelated to oxidative stress.

Experimental subarachnoid hemorrhage in the rat: influences of nimodipine.

BACKGROUND: Traumatic subarachnoid hemorrhage is a common finding following traumatic brain injury. Clinical studies revealed a positive influence of Nimodipine. However, till now no experimental studies have been performed. The aim of the present study was to determine the influence of early Nimodipine administration on outcome and histological findings in the rat: METHODS: Diffuse brain injury was produced in Sprague-Dawley rats using a brass weight falling from a predetermined height. Traumatic subarachnoidal hemorrhage was produced by administration of heparin before the injury. A total number of 52 animals were divided in 4 groups. FINDINGS: Mortality increased following administration of heparin. Mortality was not reduced following administration of Nimodipine. The histological investigation revealed less cell loss in animals with administration of Nimodipine as well as increased GFAP immunoexpression. CONCLUSIONS: Administration of Heparin results in a marked traumatic subrachnoidal hemorrhage following diffuse traumatic brain injury. Administration of Nimodipine does not reduce overall mortality. However, histological investigations indicate a positive effect of Nimodipine on cell loss.

Magnesium sulfate: role as possible attenuating factor in vasospasm morbidity.

BACKGROUND: Among the many complications of SAH, one of the most important is vasospasm. Several treatment alternatives have been proposed for this condition, with far-from-ideal results being obtained. Magnesium sulfate recently returned to the scene (with still unproven benefit) as an adjuvant in the treatment of vasospasm. METHODS: Seventy-two patients diagnosed with SAH by aneurysm rupture were submitted to microsurgery craniotomy and subdivided in 2 groups. Group 1, formed by 48 patients, received prophylactic hypervolemic and hemodilution therapy in addition to nimodipine. Group 2, composed of 24 patients, received the same treatment of group 1 with the addition of magnesium sulfate in continuous infusion from 120 to 150 mg a day, keeping serum magnesium levels close to double normal values. RESULTS: Age was 49 +/- 12.6 years. Ratio of female to male was 3.16:1. Most patients were admitted in a Hunt-Hess grade 2 (46.4%) and Fisher grade 3 (52.8%). Anterior communicating artery aneurysms were the most common in location (38.8%). Both groups were compared, and there was no statistical difference related to age, sex, and Glasgow, Fisher, or Hunt-Hess admission grades. No statistical difference in vasospasm incidence was found between the two groups. However, in group 1, vasospasm was correlated with a longer hospitalization time (P = .0003), different from group 2, in which patients with vasospasm receiving magnesium sulfate required less hospitalization time. CONCLUSION: Magnesium did not seem to interfere in vasospasm frequency but apparently acted favorably in decreasing morbidity and length of hospital stay.

Mechanisms of hyperbaric oxygen-induced neuroprotection in a rat model of subarachnoid hemorrhage.

Acute cerebral ischemia occurs after subarachnoid hemorrhage (SAH) because of increased intracranial pressure (ICP) and decreased cerebral perfusion pressure (CPP). The effect of hyperbaric oxygen (HBO) on physiological and clinical outcomes after SAH, as well as the expressions of hypoxia-inducible factor-1alpha (HIF-1alpha) and its target genes, such as BNIP3 and VEGF was evaluated. Eighty-five male SD rats (300 to 350 g) were randomly assigned to sham, SAH, and SAH+HBO groups. Subarachnoid hemorrhage was induced by endovascular perforation. Cortical cerebral blood flow (CBF), ICP, brain water content, brain swelling, neurologic function, and mortality were assessed. HBO (100% O2, 2.8 ATA for 2 h) was initiated at 1 h after SAH. Rats were sacrificed at 24 h to harvest tissues for Western blot or for histology. Apoptotic morphology accompanied by strong immunostaining of HIF-1alpha, VEGF, and BNIP3 were observed in the hippocampus and the cortex after SAH. Increased expressions of HIF-1alpha, VEGF, and BNIP3 were quantified by Western blot. HBO reduced the expressions of HIF-1alpha, VEGF, and BNIP3, diminished neuronal damage and improved CBF and neurologic function. HBO reduced early brain injury after SAH, probably by inhibition of HIF-1alpha and its target genes, which led to the decrease of apoptosis and preservation of the blood-brain barrier function.

Using routine data to complement and enhance the results of randomised controlled trials.

BACKGROUND: Randomised controlled trials (RCTs) are widely accepted as the best way to assess the outcomes and safety of medical interventions, but are sometimes not ethical, not feasible, or limited in the generalisability of their results. In such circumstances, routinely available data could help in several ways. Routine data could be used, for example, to conduct 'pseudo-trials', to estimate likely outcomes and required sample size to help design and conduct trials, or to examine whether the expected outcomes observed in an RCT will be realised in the general population. OBJECTIVES: The project was undertaken to explore how routinely assembled hospital data might complement or supplement RCTs to evaluate medical interventions: in contexts where RCTs are not feasible for defining the context and design of an RCT for assessing whether the benefits indicated by RCTs are achieved in wider clinical practice. METHODS: The project was based on the system of linked Scottish morbidity records, which cover 100% of acute hospital care episodes and statutory death records from 1981 to 1995. Three case studies were undertaken as a way of investigating the utility of these records in different applications. First, an attempt was made to analyse the link between the timing of surgery for subarachnoid haemorrhage (SAH) and subsequent outcomes (a question not easily susceptible to RCT design). A subsample was derived by excluding patients for which a diagnosis of SAH may not have been established or that may not have been admitted to a neurosurgical unit, and the data were assessed to attempt to inform the design of a trial of early versus late surgery. Transurethral prostatectomy (TURP), the second case study, has become the surgery of choice for benign prostatic hyperplasia without systematic assessment of its effectiveness and safety, and an RCT would now be considered unethical. However, there is a need to investigate long-term effects and the influence of co-morbidities on outcomes. A retrospective comparison of mortality and re-operation following either open prostatectomy (OPEN) or TURP was, therefore, undertaken. Patients for whom it was not possible to establish the initial procedure were excluded. The third case study compared coronary artery bypass grafting (CABG) with percutaneous transluminal angioplasty (PTCA) for coronary revascularisation. RCTs have been conducted in limited patient subgroups with short follow-up periods. A meta-analysis of RCTs could be augmented by routine data, which are available for large populations. This would allow assessment of subgroup effects, and outcomes over a long period. A subgroup of patients was therefore constructed for whom relevant routine data were available and who reflected the entry criteria for major RCTs, thus enabling a comparison between the results expected from this subgroup and those of the general population. RESULTS AND CONCLUSIONS: The uses of routine data in these contexts had strengths and weaknesses. The SAH study suggested a means of assessing outcomes and survival rates following haemorrhage, which could have value in informing the design of more precise trials and in evaluating changes in outcome following the introduction of new treatments such as embolisation. However, the potential of the data was not realised because their scope and content were insufficient. For example, lack of data on the time of onset of symptoms and patients' conditions at hospital admission made it difficult to establish the link between timing of surgery and the outcome, and there was insufficient information on patients' conditions at discharge to enable a comparison of outcomes. The prostatectomy study was able to address questions not answered by RCT literature because the large number of cases it included allowed exploration of subgroup effects. (ABSTRACT TRUNCATED)

Controlled trial of alpha-tocopherol and beta-carotene supplements on stroke incidence and mortality in male smokers.

Observational data suggest that diets rich in fruits and vegetables and with high serum levels of antioxidants are associated with decreased incidence and mortality of stroke. We studied the effects of alpha-tocopherol and beta-carotene supplementation. The incidence and mortality of stroke were examined in 28 519 male cigarette smokers aged 50 to 69 years without history of stroke who participated in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC Study). The daily supplementation was 50 mg alpha-tocopherol, 20 mg beta-carotene, both, or placebo. The median follow-up was 6.0 years. A total of 1057 men suffered from incident stroke: 85 men had subarachnoid hemorrhage; 112, intracerebral hemorrhage; 807, cerebral infarction; and 53, unspecified stroke. Deaths due to stroke within 3 months numbered 38, 50, 65, and 7, respectively (total 160). alpha-Tocopherol supplementation increased the risk of subarachnoid hemorrhage 50% (95% CI -3% to 132%, P=0.07) but decreased that of cerebral infarction 14% (95% CI -25% to -1%, P=0.03), whereas beta-carotene supplementation increased the risk of intracerebral hemorrhage 62% (95% CI 10% to 136%, P=0.01). alpha-Tocopherol supplementation also increased the risk of fatal subarachnoid hemorrhage 181% (95% CI 37% to 479%, P=0.01). The overall net effects of either supplementation on the incidence and mortality from total stroke were nonsignificant. alpha-Tocopherol supplementation increases the risk of fatal hemorrhagic strokes but prevents cerebral infarction. The effects may be due to the antiplatelet actions of alpha-tocopherol. beta-Carotene supplementation increases the risk of intracerebral hemorrhage, but no obvious mechanism is available.

Nimodipine in traumatic subarachnoid haemorrhage: a re-analysis of the HIT I and HIT II trials.

Two large randomised controlled trials have been performed to study the effect of the calcium antagonist nimodipine on the outcome of severe head injury, HIT I [1] amd HIT II [4]. Both trials showed a modest and statistically non-significant increase in the proportion of favourable outcomes in patients treated with nimodipine. A subgroup analysis of the HIT II trial [4, 5] suggested, however, that there could be a substantial protective effect of nimodipine in patients with traumatic subarachnoid haemorrhage (SAH). This report provides a re-analysis of the HIT I data to see whether it provides a re-analysis of the HIT I data to see whether in HIT II. This involved performing a central review of the CT scans for the HIT I patients, to identify those individuals with evidence of traumatic SAH. The sample size was small, but the HIT I data gave no support to the hypothesis that nimodipine is protective in the traumatic SAH subgroup, where 69% of patients had a poor outcome on placebo and 74% of patients had a poor outcome on nimodipine. The data do not exclude the possibility of a clinically relevant beneficial effect of nimodipine in the traumatic SAH subgroup, but further data are required to provide a definitive answer. In addition, we present a pooled analysis of the data from the two trials, which suggests that the overall benefit of treating unselected head injured patients with nimodipine is unlikely to be clinically relevant.