Evaluation of transport-related outcomes for neonatal transport teams with and without physicians.

OBJECTIVE: The aim of this study was to evaluate if the presence of a physician in the neonatal transport team (NTT) affects transport-related outcomes and procedural success. DESIGN: Retrospective cohort study with propensity score matching. SETTING: Canadian national study. PATIENTS: Neonatal transports from nontertiary centres between January 2014 and December 2017. INTERVENTIONS: Comparison of transports conducted by NTTs with physicians (MD Group) and without physicians (noMD Group). MAIN OUTCOME MEASURES: The primary outcome was the change in patient acuity as measured by the transport risk index of physiologic severity (TRIPS) score. Secondary outcomes included mortality within 24 hours of NICU admission, clinical complications during transport, procedural success, and stabilization time. RESULTS: Among 9,703 eligible cases, 899 neonatal transports attended by NTTs with physicians were compared to 899 neonatal transports without physicians using propensity score matching. No differences were seen in the improvement of TRIPS score or mortality ≤24 hours of NICU admission. The MD Group had more clinical complications (7.7% versus 5.0%, P=0.02). No differences were seen in success rates of invasive procedures. The MD Group had shorter stabilization times. In multivariable analysis, the MD Group was not a significant predictor for the improvement in TRIPS score after adjustment for covariates. CONCLUSIONS: Neonatal transports conducted by teams including physicians compared to teams without physicians, did not have higher improvement in TRIPS scores and had similar success rates for procedures. These results provide insights for the planning of the structure and training of specialized interfacility neonatal transport programs.

SAHIT Investigators--on the outcome of some subarachnoid hemorrhage clinical trials.

Outcome of patients with aneurysmal subarachnoid hemorrhage (SAH) has improved over the last decades. Yet, case fatality remains nearly 40% and survivors often have permanent neurological, cognitive and/or behavioural sequelae. Other than nimodipine drug or clinical trials have not consistently improved outcome. We formed a collaboration of SAH investigators to create a resource for prognostic analysis and for studies aimed at optimizing the design and analysis of phase 3 trials in aneurysmal SAH. We identified investigators with data from randomized, clinical trials of patients with aneurysmal SAH or prospectively collected single- or multicentre databases of aneurysmal SAH patients. Data are being collected and proposals to use the data and to design future phase 3 clinical trials are being discussed. This paper reviews some issues discussed at the first meeting of the SAH international trialists (SAHIT) repository meeting. Investigators contributed or have agreed to contribute data from several phase 3 trials including the tirilazad trials, intraoperative hypothermia for aneurysmal SAH trial, nicardipine clinical trials, international subarachnoid aneurysm trial, intravenous magnesium sulphate for aneurysmal SAH, magnesium for aneurysmal SAH and from prospectively-collected data from four institutions. The number of patients should reach 15,000. Some industry investigators refused to provide data and others reported that their institutional research ethics boards would not permit even deidentified or anonymized data to be included. Others reported conflict of interest that prevented them from submitting data. The problems with merging data were related to lack of common definitions and coding of variables, differences in outcome scales used, and times of assessment. Some questions for investigation that arose are discussed. SAHIT demonstrates the possibility of SAH investigators to contribute data for collaborative research. The problems are similar to those already documented in other similar collaborative efforts such as in head injury research. We encourage clinical trial and registry investigators to contact us and participate in SAHIT. Key issues moving forward will be to use common definitions (common data elements), outcomes analysis, and to prioritize research questions, among others.

Impact of global cerebral atrophy on clinical outcome after subarachnoid hemorrhage.

OBJECT: Atrophy in specific brain areas correlates with poor neuropsychological outcome after subarachnoid hemorrhage (SAH). Few studies have compared global atrophy in SAH with outcome. The authors examined the relationship between global brain atrophy, clinical factors, and outcome after SAH. METHODS: This study was a post hoc exploratory analysis of the Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage (CONSCIOUS-1) trial, a randomized, double-blind, placebo-controlled trial of 413 patients with aneurysmal SAH. Patients with infarctions or areas of encephalomalacia on CT, and those with large clip/coil artifacts, were excluded. The 97 remaining patients underwent CT at baseline and 6 weeks, which was analyzed using voxel-based volumetric measurements. The percentage difference in volume between time points was compared against clinical variables. The relationship with clinical outcome was modeled using univariate and multivariate analysis. RESULTS: Older age, male sex, and systemic inflammatory response syndrome (SIRS) during intensive care stay were significantly associated with brain atrophy. Greater brain atrophy was significantly associated with poor outcome on the modified Rankin scale (mRS), severity of deficits on the National Institutes of Health Stroke Scale (NIHSS), worse executive functioning, and lower EuroQol Group-5D (EQ-5D) score. Adjusted for confounders, brain atrophy was not significantly associated with Mini-Mental State Examination and Functional Status Examination scores. Brain atrophy was not associated with angiographic vasospasm or delayed ischemic neurological deficit. CONCLUSIONS: Worse mRS score, NIHSS score, executive functioning, and EQ-5D scores were associated with greater brain atrophy and older age, male sex, and SIRS burden. These data suggest outcome is associated with factors that cause global brain injury independent of focal brain injury.

Subarachnoid Hemorrhage International Trialists data repository (SAHIT).

The outcome of patients with aneurysmal subarachnoid hemorrhage (SAH) has improved slowly over the past 25 years. This improvement may be due to early aneurysm repair by endovascular or open means, use of nimodipine, and better critical care management. Despite this improvement, mortality remains at about 40%, and many survivors have permanent neurologic, cognitive, and neuropsychologic deficits. Randomized clinical trials have tested pharmacologic therapies, but few have been successful. There are numerous explanations for the failure of these trials, including ineffective interventions, inadequate sample size, treatment side effects, and insensitive or inappropriate outcome measures. Outcome often is evaluated on a good-bad dichotomous scale that was developed for traumatic brain injury 40 years ago. To address these issues, we established the Subarachnoid Hemorrhage International Trialists (SAHIT) data repository. The primary aim of the SAHIT data repository is to provide a unique resource for prognostic analysis and for studies aimed at optimizing the design and analysis of phase III trials in aneurysmal SAH. With this aim in mind, we convened a multinational investigator meeting to explore merging individual patient data from multiple clinical trials and observational databases of patients with SAH and to create an agreement under which such a group of investigators could submit data and collaborate. We welcome collaboration with other investigators.

Global cerebral atrophy after subarachnoid hemorrhage: a possible marker of acute brain injury and assessment of its impact on outcome.

There is a correlation between poor neuropsychological outcome and focal regions of atrophy in patients with subarachnoid hemorrhage (SAH). No study has investigated the impact of global brain atrophy on outcome after SAH. In other neurological disorders, such as multiple sclerosis, a correlation has been found between global atrophy and outcome. This analysis of patients entered into a randomized clinical trial of clazosentan in patients with SAH (CONSCIOUS-1) investigated the relationship between global cerebral atrophy, clinical factors, and outcome.The 413 patients in the CONSCIOUS-1 study underwent cranial computed tomography (CT) on admission and 6 weeks after SAH. After patients with large clip/coil artefacts and those with infarctions on CT were excluded, 97 patients remained and had voxel-based volumetric measurements of the baseline and 6-week CT scans. The percentage difference in volume between times was taken and analysed against clinical variables. Relationships were modeled using univariate and multivariate analysis.Age, female gender, and higher body temperature during the patient's stay in the intensive care unit were significantly correlated with brain atrophy. Greater brain atrophy significantly correlated with poor outcome (modified Rankin scale), more severe neurological deficits on the National Institute of Health Stroke Scale (NIHSS), and poorer health status (EQ-5D).

Pharmacologic reduction of angiographic vasospasm in experimental subarachnoid hemorrhage: systematic review.

Animal models have been developed to simulate angiographic vasospasm secondary to subarachnoid hemorrhage (SAH) and to test pharmacologic treatments. Our aim was to evaluate the effect of pharmacologic treatments that have been tested in humans and in preclinical studies to determine if animal models inform results reported in humans. A systematic review and meta-analysis of SAH studies was performed. We investigated predictors of -translation from animals to humans with multivariate logistic regression. Pharmacologic reduction of vasospasm was effective in mice, rats, rabbits, dogs, nonhuman primates, and humans. Animal studies were generally of poor methodologic quality, and there was evidence of publication bias. Fresh blood injection to simulate SAH (vs. clot placement) and evaluation of vasospasm more than 3 days after SAH were independently associated with successful translation. We conclude that reduction of vasospasm is effective in animals and humans, and that injection of fresh blood and evaluation of vasospasm more than 3 days after SAH may be preferable for preclinical models.

Clinical prediction models for aneurysmal subarachnoid hemorrhage: a systematic review.

BACKGROUND: Clinical prediction models can enhance clinical decision-making and research. However, available prediction models in aneurysmal subarachnoid hemorrhage (aSAH) are rarely used. We evaluated the methodological validity of SAH prediction models and the relevance of the main predictors to identify potentially reliable models and to guide future attempts at model development. METHODS: We searched the EMBASE, MEDLINE, and Web of Science databases from January 1995 to June 2012 to identify studies that reported clinical prediction models for mortality and functional outcome in aSAH. Validated methods were used to minimize bias. RESULTS: Eleven studies were identified; 3 developed models from datasets of phase 3 clinical trials, the others from single hospital records. The median patient sample size was 340 (interquartile range 149-733). The main predictors used were age (n = 8), Fisher grade (n = 6), World Federation of Neurological Surgeons grade (n = 5), aneurysm size (n = 5), and Hunt and Hess grade (n = 3). Age was consistently dichotomized. Potential predictors were prescreened by univariate analysis in 36 % of studies. Only one study was penalized for model optimism. Details about model development were often insufficiently described and no published studies provided external validation. CONCLUSIONS: While clinical prediction models for aSAH use a few simple predictors, there are substantial methodological problems with the models and none have had external validation. This precludes the use of existing models for clinical or research purposes. We recommend further studies to develop and validate reliable clinical prediction models for aSAH.

Sliding dichotomy compared with fixed dichotomization of ordinal outcome scales in subarachnoid hemorrhage trials.

OBJECT: In randomized clinical trials of subarachnoid hemorrhage (SAH) in which the primary clinical outcomes are ordinal, it has been common practice to dichotomize the ordinal outcome scale into favorable versus unfavorable outcome. Using this strategy may increase sample sizes by reducing statistical power. Authors of the present study used SAH clinical trial data to determine if a sliding dichotomy would improve statistical power. METHODS: Available individual patient data from tirilazad (3552 patients), clazosentan (the Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage trial [CONSCIOUS-1], 413 patients), and subarachnoid aneurysm trials (the International Subarachnoid Aneurysm Trial [ISAT], 2089 patients) were analyzed. Treatment effect sizes were examined using conventional fixed dichotomy, sliding dichotomy (logical or median split methods), or proportional odds modeling. Whether sliding dichotomy affected the difference in outcomes between the several age and neurological grade groups was also evaluated. RESULTS: In the tirilazad data, there was no significant effect of treatment on outcome (fixed dichotomy: OR = 0.92, 95% CI 0.80-1.07; and sliding dichotomy: OR = 1.02, 95% CI 0.87-1.19). Sliding dichotomy reversed and increased the difference in outcome in favor of the placebo over clazosentan (fixed dichotomy: OR = 1.06, 95% CI 0.65-1.74; and sliding dichotomy: OR = 0.85, 95% CI 0.52-1.39). In the ISAT data, sliding dichotomy produced identical odds ratios compared with fixed dichotomy (fixed dichotomy vs sliding dichotomy, respectively: OR = 0.67, 95% CI 0.55-0.82 vs OR = 0.67, 95% CI 0.53-0.85). When considering the tirilazad and CONSCIOUS-1 groups based on age or World Federation of Neurosurgical Societies grade, no consistent effects of sliding dichotomy compared with fixed dichotomy were observed. CONCLUSIONS: There were differences among fixed dichotomy, sliding dichotomy, and proportional odds models in the magnitude and precision of odds ratios, but these differences were not as substantial as those seen when these methods were used in other conditions such as head injury. This finding suggests the need for different outcome scales for SAH.

Pharmacologic reduction of angiographic vasospasm in experimental subarachnoid hemorrhage: systematic review and meta-analysis.

Animal models have been developed to simulate angiographic vasospasm secondary to subarachnoid hemorrhage (SAH) and to test pharmacologic treatments. Our aim was to evaluate the effect of pharmacologic treatments that have been tested in humans and in preclinical studies to determine if animal models inform results reported in humans. A systematic review and meta-analysis of SAH studies was performed. We investigated predictors of translation from animals to humans with multivariate logistic regression. Pharmacologic reduction of vasospasm was effective in mice, rats, rabbits, dogs, nonhuman primates (standard mean difference of -1.74; 95% confidence interval -2.04 to -1.44) and humans. Animal studies were generally of poor methodologic quality and there was evidence of publication bias. Subgroup analysis by drug and species showed that statins, tissue plasminogen activator, erythropoietin, endothelin receptor antagonists, calcium channel antagonists, fasudil, and tirilazad were effective whereas magnesium was not. Only evaluation of vasospasm >3 days after SAH was independently associated with successful translation. We conclude that reduction of vasospasm is effective in animals and humans and that evaluation of vasospasm >3 days after SAH may be preferable for preclinical models.

Method of aneurysm treatment does not affect clot clearance after aneurysmal subarachnoid hemorrhage.

BACKGROUND: Patients undergoing neurosurgical clipping or endovascular coiling of a ruptured aneurysm may differ in their risk of vasospasm. OBJECTIVE: Because clot clearance affects vasospasm, we tested the hypothesis that clot clearance differs in patients depending on method of aneurysm treatment. METHODS: Exploratory analysis was performed on 413 patients from CONSCIOUS-1, a prospective randomized trial of clazosentan for the prevention of angiographic vasospasm in patients with aneurysmal subarachnoid hemorrhage (SAH). Clot clearance was measured by change in Hijdra score between baseline computed tomography and one performed 24 to 48 hours after aneurysm treatment. Angiographic vasospasm was assessed by the use of catheter angiography 7 to 11 days after SAH, and delayed ischemic neurological deficit (DIND) was determined clinically. Extended Glasgow Outcome Score (GOSE) was assessed 3 months after SAH, and poor outcome was defined as death, vegetative state, or severe disability. Multivariable ordinal and binary logistic regression were used. RESULTS: There was no significant difference in the rate of clot clearance between patients undergoing clipping or coiling (P = .56). Coiling was independently associated with decreased severity of angiographic vasospasm (odds ratio [OR] 0.53, 95% confidence interval [CI] 0.33-0.86), but not with DIND or GOSE. Greater clot clearance decreased the risk of severe angiographic vasospasm (OR 0.86, 95% CI 0.81-0.91), whereas higher baseline Hijdra score predicted increased angiographic vasospasm (OR 1.17, 95% CI 1.11-1.23) and poor GOSE (OR 1.09, 95% CI 1.04-1.14). CONCLUSION: Aneurysm coiling and increased clot clearance were independently associated with decreased severity of angiographic vasospasm in multivariate analysis, although no differences in clot clearance were seen between coiled and clipped patients.

Lower incidence of cerebral infarction correlates with improved functional outcome after aneurysmal subarachnoid hemorrhage.

Despite an undisputed association between vasospasm and delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage (SAH), there is debate if this association implies causality. It has been suggested that cerebral infarction is a better outcome measure than vasospasm in clinical trials and observational studies. To further investigate the relationship between infarction and outcome, we performed a systematic review and meta-analysis of all randomized, double-blind, placebo-controlled trials that studied the efficacy of pharmaceutical preventive strategies in SAH patients, and had both cerebral infarction and clinical outcome as outcome events. Effect sizes were expressed in (pooled) risk ratio (RR) estimates with corresponding 95% confidence intervals (CIs). Sensitivity analyses were performed for studies with a low risk of bias and for those who reported outcome at 3 months after SAH. Twenty-four studies including 8,552 patients were included. Pharmaceutical treatments decreased the incidence of both cerebral infarction (RR: 0.83; 95% CI: 0.74 to 0.93) and of poor functional outcome (RR: 0.92; 95% CI: 0.86 to 0.98). The sensitivity analyses did not change the results essentially. These data suggest that the previously observed association between cerebral infarction and functional outcome implies causality, and that cerebral infarction is a better outcome measure than vasospasm in clinical trials and observational studies.

Cerebral infarction after subarachnoid hemorrhage contributes to poor outcome by vasospasm-dependent and -independent effects.

BACKGROUND AND PURPOSE: The pathogenesis of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage remains incompletely understood. It is generally assumed that it is caused by angiographic vasospasm. Our aim was to clarify the relationship among angiographic vasospasm, neurological worsening, cerebral infarction, and poor outcome and to investigate whether cerebral infarction also contributes to poor outcome by vasospasm-independent effects. METHODS: This exploratory analysis used data from 413 patients included in the Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage (CONSCIOUS-1) trial. We studied the incidence of neurological worsening, cerebral infarction, and poor outcome in patients with and without angiographic vasospasm. Path analysis implemented by structural equation modeling was performed to determine direct and indirect path coefficients. RESULTS: Of the 194 patients with moderate to severe vasospasm, 43% had neurological worsening of any cause, 20% had cerebral infarction, and 46% poor outcome. Path coefficients for direct effects on poor outcome were 0.20 for World Federation of Neurological Surgeons Grade 4 to 5, 0.13 for history of hypertension, 0.19 for angiographic vasospasm, 0.16 for neurological worsening, and 0.11 for new cerebral infarction. Cerebral infarction contributed to poor outcome by vasospasm-dependent and -independent effects. CONCLUSIONS: Our data show that the majority of patients with moderate to severe angiographic vasospasm did not have neurological worsening of any cause or cerebral infarction. Besides, cerebral infarction also has a direct effect on outcome independent of angiographic vasospasm. This suggests that other coexisting factors might be involved in the pathogenesis of delayed cerebral ischemia, which should also be an important research target to improve outcome after subarachnoid hemorrhage.

Angiographic vasospasm is strongly correlated with cerebral infarction after subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: The long-standing concept that delayed cerebral infarction after aneurysmal subarachnoid hemorrhage results exclusively from large artery vasospasm recently has been challenged. We used data from the CONSCIOUS-1 trial to determine the relationship between angiographic vasospasm and cerebral infarction after subarachnoid hemorrhage. METHODS: We performed a post hoc exploratory analysis of the CONSCIOUS-1 data. All patients underwent catheter angiography before treatment and 9±2 days after subarachnoid hemorrhage. CT was performed before and after aneurysm treatment, and 6 weeks after subarachnoid hemorrhage. Angiograms and CT scans were assessed by centralized blinded review. Angiographic vasospasm was classified as none/mild (0%-33% decrease in arterial diameter), moderate (34%-66%), or severe (≥67%). Infarctions were categorized as secondary to angiographic vasospasm, other, or unknown causes. Logistic regression was conducted to determine factors associated with infarction. RESULTS: Complete data were available for 381 of 413 patients (92%). Angiographic vasospasm was none/mild in 209 (55%) patients, moderate in 118 (31%), and severe in 54 (14%). Infarcts developed in 6 (3%) of 209 with no/mild, 12 (10%) of 118 patients with moderate, and 25 (46%) of 54 patients with severe vasospasm. Multivariate analysis found a strong association between angiographic vasospasm and cerebral infarction (OR, 9.3; 95% CI, 3.7-23.4). The significant association persisted after adjusting for admission neurological grade and aneurysm size. Method of aneurysm treatment was not associated with a significant difference in frequency of infarction. CONCLUSIONS: A strong association exists between angiographic vasospasm and cerebral infarction. Efforts directed at further reducing angiographic vasospasm are warranted.

Effect of pharmaceutical treatment on vasospasm, delayed cerebral ischemia, and clinical outcome in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis.

As it is often assumed that delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) is caused by vasospasm, clinical trials often focus on prevention of vasospasm with the aim to improve clinical outcome. However, the role of vasospasm in the pathogenesis of DCI and clinical outcome is possibly smaller than previously assumed. We performed a systematic review and meta-analysis on all randomized, double-blind, placebo-controlled trials that studied the effect of pharmaceutical preventive strategies on vasospasm, DCI, and clinical outcome in SAH patients to further investigate the relationship between vasospasm and clinical outcome. Effect sizes were expressed in pooled risk ratio (RR) estimates with corresponding 95% confidence intervals (CI). A total of 14 studies randomizing 4,235 patients were included. Despite a reduction of vasospasm (RR 0.80 (95% CI 0.70 to 0.92)), no statistically significant effect on poor outcome was observed (RR 0.93 (95% CI 0.85 to 1.03)). The variety of DCI definitions did not justify pooling the DCI data. We conclude that pharmaceutical treatments have significantly decreased the incidence of vasospasm, but not of poor clinical outcome. This dissociation between vasospasm and clinical outcome could result from methodological problems, sample size, insensitivity of clinical outcome measures, or from mechanisms other than vasospasm that also contribute to poor outcome.

Patient age and vasospasm after subarachnoid hemorrhage.

BACKGROUND: Subarachnoid hemorrhage (SAH) from a ruptured intracranial aneurysm is a devastating disease with high mortality and morbidity. The incidence of SAH increases with advancing age. OBJECTIVE: To determine whether age is an independent predictor of angiographic vasospasm, delayed ischemic neurological deficits (DINDs), or abnormal transcranial Doppler (TCD) measurements in patients with aneurysmal subarachnoid hemorrhage. METHODS: Data from CONSCIOUS-1 (Clazosentan to Overcome Neurological Ischemia and Infarct Occurring After Subarachnoid Hemorrhage study), a dose-finding study of clazosentan, were used. Data on angiographic vasospasm, DINDs, and TCD abnormalities were prospectively recorded as well as baseline characteristics and treatment data. Patient age was considered in 3 ways: as a continuous variable, dichotomized at age 65 years, and categorized by decade. Age was investigated as the main variable, whereas other possible confounding variables were adjusted for in the multiple logistic regression modeling with each of 3 dichotomized vasospasm outcome measures, presence or absence of angiographic vasospasm, DINDs, and TCD abnormalities as the dependent variable. RESULTS: The proportions of patients with angiographic vasospasm, DINDs, and TCD abnormalities were 45%, 19%, and 81%, respectively. Age, whether considered as a continuous, dichotomous, or a categorical variable, was not significantly associated with angiographic vasospasm, DINDs, or abnormal TCD measurements. CONCLUSION: Age does not seem to be a significant predictor for cerebral vasospasm after subarachnoid hemorrhage.

Endovascular treatment or neurosurgical clipping of ruptured intracranial aneurysms: effect on angiographic vasospasm, delayed ischemic neurological deficit, cerebral infarction, and clinical outcome.

BACKGROUND AND PURPOSE: The effects of aneurysm treatment modality (clipping or coiling) on the incidence of cerebral vasospasm and infarction after subarachnoid hemorrhage have not been clearly defined. We hypothesized that there may be a difference in angiographic and clinical vasospasm, cerebral infarction, and clinical outcome between patients undergoing clipping compared to coiling. METHODS: A retrospective, exploratory analysis of 413 patients randomized into the CONSCIOUS-1 trial was conducted. Patients underwent baseline and follow-up catheter angiography and computed tomography, as well as clinical assessments. Radiology end points were adjudicated by central blinded review, and angiographic vasospasm was quantified by measurements of arterial diameters on catheter angiography. The effect of method of aneurysm treatment (clipping [n=199] or coiling [n=214]) on angiographic vasospasm, delayed ischemic neurological deficit, cerebral infarction, and clinical outcome was analyzed using univariate and multivariate logistic regression. Propensity matching was used to adjust for differences in baseline risk factors between clipped and coiled patients. RESULTS: In all patients and the propensity-matched subset, aneurysm coiling was associated with a significantly reduced risk of angiographic vasospasm and delayed ischemic neurological deficit compared to clipping. Cerebral infarction and clinical outcome were not associated with clipping or coiling. CONCLUSIONS: In this exploratory analysis, aneurysm coiling was associated with less angiographic vasospasm and delayed ischemic neurological deficit than surgical clipping, whereas no effect on cerebral infarction or clinical outcome was observed. Whether this is attributable to differences in baseline risk factors between clipped and coiled patients or a true difference cannot be proven here.

Impact of systemic inflammatory response syndrome on vasospasm, cerebral infarction, and outcome after subarachnoid hemorrhage: exploratory analysis of CONSCIOUS-1 database.

BACKGROUND: Systemic inflammatory response syndrome (SIRS) may develop after aneurysmal subarachnoid hemorrhage (SAH). We investigated factors associated with SIRS after SAH, whether SIRS was associated with complications of SAH such as vasospasm, cerebral infarction, and clinical outcome, and whether SIRS could contribute to a difference in outcome between patients treated by endovascular coiling or neurosurgical clipping of the ruptured aneurysm. METHODS: This was exploratory analysis of 413 patients in the CONSCIOUS-1 study. SIRS was diagnosed if the patient had at least 2 of 4 variables (hypothermia/fever, tachycardia, tachypnea, and leukocytosis/leukopenia) within 4 days of admission. Clinical outcome was measured on the Glasgow outcome scale 3 months after SAH. The relationship between clinical and radiologic variables and SIRS, angiographic vasospasm, delayed ischemic neurologic deficit (DIND), cerebral infarction, vasospasm-related infarction, and clinical outcome were modeled with uni- and multivariable analyses. RESULTS: 63% of patients developed SIRS. Many factors were associated with SIRS in univariate analysis, but only poor WFNS grade and pneumonia were independently associated with SIRS in multivariable analysis. SIRS burden (number of SIRS variables per day over the first 4 days) was associated with poor outcome, but not with angiographic vasospasm, DIND, or cerebral infarction. The method of aneurysm treatment was not associated with SIRS. CONCLUSION: SIRS was associated with poor outcome but not angiographic vasospasm, DIND, or cerebral infarction after SAH in the CONSCIOUS-1 data. There was no support for the notion that neurosurgical clipping is associated with a greater risk of SIRS than endovascular coiling.

Sample size estimates for clinical trials of vasospasm in subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Clinical trials for prevention of vasospasm after aneurysmal subarachnoid hemorrhage (SAH) seldom have improved overall outcome; one reason may be inadequate sample size. We used data from the tirilizad trials and the Columbia University subarachnoid hemorrhage outcomes project to estimate sample sizes for clinical trials for reduction of vasospasm after SAH, assuming trials must show effect on 90-day patient-centered outcome. METHODS: Sample size calculations were based on different definitions of vasospasm, enrichment strategies, sensitivity of short- and long-term outcome instruments for reflecting vasospasm-related morbidity, different event rates of vasospasm, calculation of effect size of vasospasm on outcome instruments, and different treatment effect sizes. Sensitivity analysis was performed for variable event rates of vasospasm for a given treatment effect size. Sample size tables were constructed for different rates of vasospasm and outcome instruments for a given treatment effect size. RESULTS: Vasospasm occurred in 12% to 30% of patients. Symptomatic deterioration and infarction from vasospasm exhibited the strongest relationship to mortality and morbidity after SAH. Enriching for vasospasm by selection of patients with thick SAH slightly decreased sample sizes. Assuming beta=0.80, alpha=0.05 (2-tailed) and treatment effect size of 50%, total sample size exceeds 5000 patients to demonstrate efficacy on 3-month patient-centered outcome (modified Rankin Scale). CONCLUSIONS: Clinical trials targeting vasospasm and using traditional patient-centered outcome require very high sample sizes and will therefore be costly, time-consuming, and impractical. This will hinder development of new treatment strategies.

Metaanalysis of tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage.

BACKGROUND: Tirilazad is a non-glucocorticoid, 21-aminosteriod that inhibits lipid peroxidation. It had neuroprotective effects in experimental ischemic stroke and reduced angiographic vasospasm after experimental subarachnoid hemorrhage (SAH). Five randomized clinical trials of tirilazad were conducted in patients with SAH. We performed a meta-analysis of these trials to assess the effect of tirilazad on unfavorable outcome, symptomatic vasospasm, and cerebral infarction after SAH. METHODS: Data from 3,797 patients were analyzed and modeled using random effect and Mantel-Haenszel meta-analyses and multivariable logistic regression to determine the effect of tirilazad on clinical outcome, symptomatic vasospasm, and cerebral infarction. Clinical outcome was assessed 3 months after SAH using the Glasgow outcome scale, and symptomatic vasospasm was defined by clinical criteria with laboratory and radiological exclusion of other causes of neurological deterioration. RESULTS: The five trials were randomized, double-blind, and placebo-controlled. Tirilazad did not significantly decrease unfavorable clinical outcome on the GOS (odds ratio [OR] 1.04, 95% confidence interval [CI] 0.89-1.20) or cerebral infarction (OR 1.04, 95% CI 0.89-1.22). There was a significant reduction in symptomatic vasospasm in patients treated with tirilazad (OR 0.80, 95% CI 0.69-0.93). There was no heterogeneity across the five trials. CONCLUSION: Tirilazad had no effect on clinical outcome but did decrease symptomatic vasospasm in five trials of aneurysmal SAH. The dissociation between clinical outcome and symptomatic vasospasm deserves further investigation.