Acute stroke care is evolving from therapeutic nihilism towards the practice of rapidly reversing ischemia before infarction occurs. This proposal for a Specialized Program of Translational Research in Acute Stroke at the six Partners Hospitals will advance stroke care by its three integrated research projects, as well as through its impact on a large medical system with two academic medical centers, four community hospitals and 1500 stroke patients annually. Project 1: Brain infarction is related in part to impaired delivery of oxygen to the brain. We have discovered that normobaric hyperoxia in animal stroke models delays permanent brain injury. Preliminary studies in acute stroke patients treated with normobaric hyperoxia appear promising. Here we propose coordinated studies in both animal models and patients to test this widely accessible therapy for its safety when administered alone, or in combination with thrombolytic therapy. In a phase II randomized, double blind, trial we will test normobaric hyperoxia for its ability to improve neurologic deficits, and decrease the extent of ischemic damage in patients. Project II: Linked to our interest in oxygen as a therapy, here we propose to also investigate the role of oxidative processes in tissue destruction and secondary hemorrhage. Members of the SPOTRIAS team at Partners have investigated both the activation of matrix metalloproteinases (MMPs) in animals, and the serum markers of oxidative stress in acute stroke patients. Here we propose studies of serum and brain markers in the animal stroke models to compliment studies of MMP and oxidative serum markers in acute stroke patients as they relate to outcome, oxygen exposure, and reperfusion. This work will lay the foundation for the development of anti-oxidant therapy in acute stroke. Project III. Partners stroke researchers have developed methods of imaging ischemic changes in acute stroke patients. Here we propose to use CTperfusion technology to establish thresholds of blood flow and blood volume which delineate tissue which is salvageable with reperfusion from that which is not. The technique will be tested for its ability to contribute to prediction of clinical as well as tissue outcome. We hypothesize that by predicting tissue fate as a function of therapy, this widely accessible CT-based technique will direct clinical decisions in acute stroke patients and become a useful tool in large clinical trials examining novel therapies for their ability to salvage brain tissue. Each of these projects share overlapping lines of inquiry as well as common procedures for their execution. Projects 1 and 2 are truly translational in that animal studies are planned to enhance the clinical program. We believe that the integrating our strong stroke laboratory science with effective clinical stroke cores across the Partners network will give birth to a potent translational research center which efficiently brings new treatments to community practice. Project 1: Normobaric Hyperoxia in Ischemic Stroke PI: Aneesh B. Singhal, M.D. - P.I. DESCRIPTION (provided by applicant): Breathing high-flow oxygen at normal atmospheric pressure (Normobaric Oxygen Therapy, NBO) may be a simple strategy to sustain ischemic brain tissue ('buy time') until spontaneous or therapeutic reperfusion occurs, and thereby improve stroke outcome. By preventing early ischemic cell death, NBO may be a useful adjunctive therapy that extends the narrow (3-hour) time window for IV tissue plasminogen activator (tPA) therapy. Our recent rodent and pilot human stroke studies provide compelling evidence that early NBO confers potent neuroprotection. While the benefit appears to be transient, similar to that observed in prior hyperbaric oxygen studies, sustained benefit does occur if NBO-treated ischemic tissue is later reperfused. In this proposal (Spotrias Project 1), we aim to extend our preliminary work in a double blind, randomized, placebo-controlled clinical trial enrolling 240 acute (<9 hours) ischemic stroke patients over 5 years. Patients will receive either NBO or Room Air for 8 hours and undergo serial clincial assessments and CT scans. NBO's therapeutic potential will be assessed in an """"""""intention to treat"""""""" statistical analysis of change in NIHSS scores during therapy. The potential synergistic benefit of NBO with reperfusion will be assesed in patients who undergo a baseline and a 24-hour CT-perfusion scan to assess reperfusion, as part of Project 2 (Lev). Other secondary analyses will include an assessment of post-therapy clinical function scores, brain hemorrhage rates, and lesion volume growth on CT scans. In year 1 we will exclude tPA-treated patients and investigate the safety and utility of combined NBO with tPA in embolic (clot-based) rodent stroke models. If the combined therapy appears safe in rodents, and if the year 1 human data raises no safety concerns, we will include tPA-treated patients in the clinical trial of NBO. From these studies we hope to collect preliminary data and gain pilot experience for a future multi-center trial of NBO intiated by EMS at the scene. From a public health standpoint, these studies are significant because they will assess whether breathing high-flow oxygen, a potentially simple, practical, widely accessible, portable, and cost-effective therapy, can improve stroke outcomes either independently or by extending the time window for IV tPA.
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