Predictors of Outcome in Aneurysmal Subarachnoid Hemorrhage Patients: Observations From a Multicenter Data Set.

BACKGROUND AND PURPOSE: The mortality and morbidity after aneurysmal subarachnoid hemorrhage has improved because of better diagnosis, early treatment to secure the aneurysm, and better management of disease-specific complications. With these improvements in care, it is not clear if the previously identified independent predictors of a negative outcome have changed. The aim of this study was to identify the independent predictors of an unfavorable outcome (Glasgow Outcome Score 1, 2, and 3) in aneurysmal subarachnoid hemorrhage patients. METHODS: Univariate and multivariate analysis of prospectively collected data on patients presenting with an aneurysmal subarachnoid hemorrhage was performed. Outcome was assessed at discharge. Data were collected from 14 centers in the United Kingdom over a period of 4 years (September 2011-2015). RESULTS: The median age (interquartile range) at presentation of 3341 patients with aneurysmal subarachnoid hemorrhage was 55 (18) years. Most patients were female (n=2288 [68.5%]), presented in good grade (2397 [70%]; World Federation of Neurological Surgeons grade 1 and 2), and were treated by endovascular coiling (n=2600; 75%). The independent predictors of an unfavorable outcome (95% confidence interval [CI]) were increasing age (odds ratio [OR], 1.04; 95% CI, 1.03-1.05; P<0.001), World Federation of Neurological Surgeons grade (OR, 2.06; 95% CI, 1.91-2.22; P<0.001), preoperative rebleeding (OR, 7.41; 95% CI, 4.48-12.30; P<0.001), need for cerebrospinal fluid diversion (OR, 3.25; 95% CI, 2.58-4.09; P<0.001), and delayed cerebral ischemia (OR, 2.21; 95% CI, 1.72-2.83; P<0.001). CONCLUSIONS: These data suggest that potentially modifiable risk factors of preoperative rebleeding and delayed cerebral ischemia are associated with unfavorable outcomes. Understanding the reasons why patients requiring cerebrospinal fluid diversion have 3.25-fold higher adjusted odds of a poor outcome at discharge needs to be studied.

The effect of intravenous interleukin-1 receptor antagonist on inflammatory mediators in cerebrospinal fluid after subarachnoid haemorrhage: a phase II randomised controlled trial.

BACKGROUND: Interleukin-1 (IL-1) is a key mediator of ischaemic brain injury induced by stroke and subarachnoid haemorrhage (SAH). IL-1 receptor antagonist (IL-1Ra) limits brain injury in experimental stroke and reduces plasma inflammatory mediators associated with poor outcome in ischaemic stroke patients. Intravenous (IV) IL-1Ra crosses the blood-brain barrier (BBB) in patients with SAH, to achieve cerebrospinal fluid (CSF) concentrations that are neuroprotective in rats. METHODS: A small phase II, double-blind, randomised controlled study was carried out across two UK neurosurgical centres with the aim of recruiting 32 patients. Adult patients with aneurysmal SAH, requiring external ventricular drainage (EVD) within 72 hours of ictus, were eligible. Patients were randomised to receive IL-1Ra (500 mg bolus, then a 10 mg/kg/hr infusion for 24 hours) or placebo. Serial samples of CSF and plasma were taken and analysed for inflammatory mediators, with change in CSF IL-6 between 6 and 24 hours as the primary outcome measure. RESULTS: Six patients received IL-1Ra and seven received placebo. Concentrations of IL-6 in CSF and plasma were reduced by one standard deviation in the IL-1Ra group compared to the placebo group, between 6 and 24 hours, as predicted by the power calculation. This did not reach statistical significance (P = 0.08 and P = 0.06, respectively), since recruitment did not reach the target figure of 32. No adverse or serious adverse events reported were attributable to IL-1Ra. CONCLUSIONS: IL-1Ra appears safe in SAH patients. The concentration of IL-6 was lowered to the degree expected, in both CSF and plasma for patients treated with IL-1Ra.

Translational pharmacokinetics: challenges of an emerging approach to drug development in stroke.

INTRODUCTION: There is increasing recognition of the importance of translational pharmacokinetics in stroke research, lack of which has been cited as one of the main contributing factors to failure of Phase III trials. AREAS COVERED: The article reviews the translational issues in administration, distribution and sampling in the pharmacokinetics of putative therapeutic drugs in stroke. In addition, the role of translational pharmacometrics in drug development is discussed. The review uses the anti-inflammatory agent, IL-1 receptor antagonist, as an example. The reader will gain an insight into the pitfalls that are commonplace in translating pharmacokinetics from the preclinical to the clinical scenario. The reader will also gain an understanding of the complexities of blood-central nervous system (CNS) barriers in relation to brain pharmacokinetics and the increasing use of translational pharmacometrics in stroke research. EXPERT OPINION: The translation of preclinical to clinical pharmacokinetics is a discipline that is traditionally overlooked and is likely to be a key factor responsible for failure of clinical trials. With a clear comprehensive insight into the benefits and limitations of translational pharmacokinetics in stroke, translational pharmacokinetics can be safely used to enhance the efficacy of clinical trials in stroke and their likelihood of success.