Lessons Learned from Phase II and Phase III Trials Investigating Therapeutic Agents for Cerebral Ischemia Associated with Aneurysmal Subarachnoid Hemorrhage.

One of the challenges in bringing new therapeutic agents (since nimodipine) in for the treatment of cerebral ischemia associated with aneurysmal subarachnoid hemorrhage (aSAH) is the incongruence in therapeutic benefit observed between phase II and subsequent phase III clinical trials. Therefore, identifying areas for improvement in the methodology and interpretation of results is necessary to increase the value of phase II trials. We performed a systematic review of phase II trials that continued into phase III trials, evaluating a therapeutic agent for the treatment of cerebral ischemia associated with aSAH. We followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines for systematic reviews, and review was based on a peer-reviewed protocol (International Prospective Register of Systematic Reviews no. 222965). A total of nine phase III trials involving 7,088 patients were performed based on eight phase II trials involving 1558 patients. The following therapeutic agents were evaluated in the selected phase II and phase III trials: intravenous tirilazad, intravenous nicardipine, intravenous clazosentan, intravenous magnesium, oral statins, and intraventricular nimodipine. Shortcomings in several design elements of the phase II aSAH trials were identified that may explain the incongruence between phase II and phase III trial results. We suggest the consideration of the following strategies to improve phase II design: increased focus on the selection of surrogate markers of efficacy, selection of the optimal dose and timing of intervention, adjustment for exaggerated estimate of treatment effect in sample size calculations, use of prespecified go/no-go criteria using futility design, use of multicenter design, enrichment of the study population, use of concurrent control or placebo group, and use of innovative trial designs such as seamless phase II to III design. Modifying the design of phase II trials on the basis of lessons learned from previous phase II and phase III trial combinations is necessary to plan more effective phase III trials.

Therapeutic Use of Music and Television in Neurocritical Care: A Practice Survey.

INTRODUCTION: Although health care providers often play music via radio, or play television, to calm and soothe patients, limited research is available to guide practice. METHOD: This study used a 17-item practice survey that was distributed electronically to neurocritical care society members in July 2014. Responses were collated and analyzed using SAS (Version 9.3). RESULTS: There were 118 completed responses, including from 71 attending physicians, 9 resident or fellow physicians, 30 nurses, and 8 affiliate professional members. The majority of respondents sometimes or always play music (65%) and agree that music is therapeutic (70%). However, there was no clear practice pattern regarding when or why music or TV should be used as an intervention in the neurocritical care unit. CONCLUSION: The use of music and TV is a common intervention in the neurocritical care unit but lacks a strong scientific foundation and is associated with a high practice variance.

Ketamine for refractory status epilepticus: a case of possible ketamine-induced neurotoxicity.

A 44-year-old man with treated neurosyphilis presented with subclinical status epilepticus (SE) refractory to intravenous high-dose lorazepam, phenytoin, and valproic acid over 4 days. Ketamine infusion was instituted after low-dose propofol sedation with gradual control of electrographic seizures over 72h. Reevaluation 3 months later revealed diffuse cerebellar and worsened cerebral atrophy, consistent with animal models of N-methyl-D-aspartate antagonist-mediated neurotoxicity. Animal studies of prolonged ketamine therapy are required before widespread human use in SE.