Research Departments & Organizations
Biomarkers, Pharmacological; Brain Edema; Brain Hemorrhage, Traumatic; Brain Infarction; Infarction, Middle Cerebral Artery; Neurology; Neurosciences; Neurosurgery; Quality of Health Care; Subarachnoid Hemorrhage; Trauma, Nervous System
Dr. Sheth's research focuses on the identification and translation of new therapies for patients with acute neurological injury such as stroke, brain hemorrhage, and trauma. The main focus of his group is to further the understanding of inflammation and swelling after acute central nervous system injury. His group is actively involved in developing new methods, including neuroimaging, to detect and follow brain swelling. He is also involved in leading several national clinical trials testing novel therapies directed at brain swelling. Dr. Sheth also studies medical decision making and prognostication in patients with acute neurological injury.
Specialized Terms: Brain edema; Stroke; Intracranial hemorrhage; Neurocritical Care; Critical care; Prognosis; Biomarkers; Clinical Trials
Extensive Research Description
The central mission of my research program is to 1. Improve our understanding of blood brain barrier injury, inflammation, and swelling after acute central nervous system injury and 2. Translate novel therapies to critically ill neurological patients in the hopes of improving what are all too often devastating outcomes.
For the early part of my career, I have partnered with Marc Simard, a vascular neurosurgeon at the University of Maryland, who discovered a new receptor in the brain, SUR1, expressed on all components of the neurovascular unit. Blockade at the capillary level reduces the formation of the space-occupying edema responsible for cell death. Small molecule-based therapy using the well-known and safe drug glyburide is effective in blocking this channel, thereby significantly reducing edema formation following ischemia.
With the direct purpose of translating this therapy using a novel approach in stroke (prevention of swelling), I have formed a research group working toward solving fundamental gaps in knowledge with the ability to reliably measure brain edema. In order to develop this intermediate endpoint, we have recently validated and published unique neuroimaging measures of brain swelling in patients with large stroke. In addition, we are exploring how novel therapies like glyburide may attenuate serum markers of injury at the blood-brain barrier. Early work in human patients suggests that MMP-9 levels are reduced in patients treated with glyburide, and this observation is associated with decreased swelling and hemorrhagic transformation. We continue to search for new pharmacodynamics markers of injury. Both areas of inquiry leverage existing collaborations with groups at Massachusetts General Hospital, Stanford University, and other institutions as well as groups here at Yale.
Our group has had the privilege of leading several phase II trials of IV glyburide in patients with large hemispheric infarction. GAMES-RP demonstrates that IV glyburide reduces neurological mortality, decreases midline shift, and reduces levels of MMP-9. These results are now to be carried forward in a global phase III study in patients with large stroke.
We continue to use clinical trials as a platform for both delivering improved outcomes to patients and also for returning to the laboratory to better understand mechanisms of disease. Below are some examples from our research group.
INTREPID (Impact of Fever Prevention in Brain Injured Patients) - This is a phase III study of over 1000 ischemic and hemorrhagic stroke patients testing the following hypothesis: does fever prevention, using an advanced cooling device, result in improved neurology outcomes in patients with severe stroke.
Saponimod in Intracerebral Hemorrhage - Related to our group's efforts towards characterizing edema formation in acute brain injury, we have partnered with several groups (Fu-Dong Shi - Barrow) to further understand the role of S1P modulation in ICH. S1P is a known target in multiple sclerosis, where via multiple mechanisms of action (prevention of lymphocyte egress, direct neuroprotection), drugs such as fingolimod are used in clinical practice. Recent evidence in several preclinical models of ICH suggests that S1P modulation may be beneficial in ICH. We are conducting a series of laboratory experiments that would support the framework for an early phase clinical trial and collaborating with Novartis to execute a 100 patient multinational multicenter phase II study to further understand the role of S1P modulation on secondary brain injury in ICH.
ASPIRE (Anticoagulation in ICH Survivors for Prevention and Recovery) - As many as 20% of ICH survivors have atrial fibrillation and are at high risk for cardioembolic stroke. However, whether or not anticoagulation may safely result in decreased stroke (ischemic and hemorrhagic) and mortality has never been tested in an adequately powered prospective trial. Several analyses from our group and others suggest that oral anticoagulation can improve outcomes in ICH survivors with AF
In addition, to the clinical trials above, we work with large administrative datasets (CMS, State Medicare), imaging cores, and multicenter observational studies (ERICH) in order to identify and support lines of inquiry that can elucidate improved treatments for patients with acute brain injury. We have also received support from the AHA to further the development and implementation of unique bedside neuroimaging capabilities that will also facilities rapid and effective bedside diagnosis and monitoring of primary and secondary brain injury.
|Diseases of the Cardiovascular System||Aneurysmal Subarachnoid Hemorrhage Trial RandOmizing Heparin (ASTROH)|
|Diseases of the Nervous System||Transforming Acute Stroke Detection through Real Time Neurological Monitoring|
|Diseases of the Nervous System||Impact of Fever Prevention in Brain Injured Patients (INTREPID)|
|Diseases of the Nervous System, Diseases of the Respiratory Systems||SETPOINT 2 Stroke-Related Early Tracheostomy versus Prolonged Orotracheal Intubation in Neurocritical Care Trial 2|
Pilot study of intravenous glyburide in patients with a large ischemic stroke.
Sheth KN, Kimberly WT, Elm JJ, Kent TA, Mandava P, Yoo AJ, Thomalla G, Campbell B, Donnan GA, Davis SM, Albers GW, Jacobson S, Simard JM, Stern BJ. Pilot study of intravenous glyburide in patients with a large ischemic stroke. Stroke; A Journal Of Cerebral Circulation 2014, 45:281-3. 2014
Safety and efficacy of intravenous glyburide on brain swelling after large hemispheric infarction (GAMES-RP): a randomised, double-blind, placebo-controlled phase 2 trial.
Sheth KN, Elm JJ, Molyneaux BJ, Hinson H, Beslow LA, Sze GK, Ostwaldt AC, Del Zoppo GJ, Simard JM, Jacobson S, Kimberly WT. Safety and efficacy of intravenous glyburide on brain swelling after large hemispheric infarction (GAMES-RP): a randomised, double-blind, placebo-controlled phase 2 trial. The Lancet. Neurology 2016, 15:1160-9. 2016
Brain Ischemia Suppresses Immunity in the Periphery and Brain via Different Neurogenic Innervations.
Liu Q, Jin WN, Liu Y, Shi K, Sun H, Zhang F, Zhang C, Gonzales RJ, Sheth KN, La Cava A, Shi FD. Brain Ischemia Suppresses Immunity in the Periphery and Brain via Different Neurogenic Innervations. Immunity 2017, 46:474-487. 2017
Predicting survival after acute civilian penetrating brain injuries: The SPIN score.
Muehlschlegel S, Ayturk D, Ahlawat A, Izzy S, Scalea TM, Stein DM, Emhoff T, Sheth KN. Predicting survival after acute civilian penetrating brain injuries: The SPIN score. Neurology 2016, 87:2244-2253. 2016
Glyburide is associated with attenuated vasogenic edema in stroke patients.
Kimberly WT, Battey TW, Pham L, Wu O, Yoo AJ, Furie KL, Singhal AB, Elm JJ, Stern BJ, Sheth KN. Glyburide is associated with attenuated vasogenic edema in stroke patients. Neurocritical Care 2014, 20:193-201. 2014
Intracranial pressure dose and outcome in traumatic brain injury.
Sheth KN, Stein DM, Aarabi B, Hu P, Kufera JA, Scalea TM, Hanley DF. Intracranial pressure dose and outcome in traumatic brain injury. Neurocritical Care 2013, 18:26-32. 2013