1997 — 2001 |
Diringer, Michael N |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Focal Cerebral Ischemia in Acute Brain Injury
Each year approximately 2 million people suffer traumatic brain injuries (TBI) in the U.S. of these about 100,000 die and 90,000 are left with long-term disabilities. Advances in the management of these patients have reduced mortality but done little to ameliorate brain injury. Recent studies in severe TBI patients have suggested that reduced regional cerebral blood flow (rCBF) in the first few hours after injury contributes to secondary brain injury. in order to determine the role of cerebral ischemia in the pathophysiology of TBI, it is important to determine if the reduction in rCBF seen in TBI patients is due to a primary reduction in supply causing ischemia or merely represents a decline in rCBF secondary to reduced metabolic demands of injured brain tissue. Positron emission tomography (PET) is the only technology currently available that can quantify CBF and CMRO2 regionally in humans, and provide indices of the balance between CBF and CMRO2; oxygen extraction fraction OEF, differences in arteriovenous O2 content (A-VDO2), and cerebrovenous oxygen content (CvO2). Barnes-Jewish Hospital at Washington University Medical Center is a Level I trauma center which admits approximately 120 TB1 patients each year. A new Siemens ECAT EXACT HR 47 PET scanner has been installed in the Neurology/Neurosurgery Intensive Care Unit (NNICU) and is currently being used to study TBI patients. The presence of a PET scanner in the NNICU, combined with our extensive experience with the use of PET to detect ischemia, our expertise in the clinical management of TBI patients, and the large available patient patient population gives us a unique opportunity to address these issues. We propose to investigate the prevalence, severity, and duration of cerebral ischemia in severe TBI. Specifically we will measure regional CBF. CMRO2, CvO2, A-VDO2 and OEF using PET in 60 patients with severe head injury (GCS less then or equal to 8) within the first 12 hours after injury and again 24-72 hours latter. These investigations are critical to optimize treatment for these patients. If ischemia is a significant problem in TBI, then management of arterial hypertension and cerebral perfusion pressure will need to modified accordingly. In addition neuroprotective agents currently being studied in ischemic stroke may be useful in TBI as well.
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1997 — 2001 |
Diringer, Michael N |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Hyperventilation On Cerebral Blood Flow/Brain Oxygenation in Brain Injury
Each year approximately 2 million people suffer traumatic brain injuries (TBI) in the U.S. Of these about 100,000 die and 90,000 are left with long-term disabilities. Advances in the management of these patients have reduced mortality but done little to ameliorate brain injury. Recent studies in severe TBI patients have suggested that reduced regional cerebral blood flow (rCBF) in the first few hours after injury contributes to secondary brain injury. Additionally, the use of acute hyperventilation (HV) to treat elevated intracranial pressure following TBI may led to or exacerbate ischemia thus augmenting rather than preventing secondary CNS injury. In order to understand the impact of HV on brain oxygenation, it is important to determine if the reduction in rCBF seen in TBI patients produces brain oxygen deprivation severe enough to cause ischemic neuronal damage. The presence of a PET scanner in the NNICU at Barnes-Jewish Hospital, combined with our extensive experience with the use of PET to detect ischemia, our expertise in the clinical management of TBI patients, and the large available patient population gives us a unique opportunity to address these issues. We propose to investigate the impact of acute HV on cerebral blood flow and brain oxygenation in TBI. Specifically we will test the hypothesis that severe (PaCO2 of about 25 mm Hg) but not moderate (PaCO2 of about 30 mm Hg) hyperventilation following TBI can produce reduction in CBF potentially severe enough to cause cerebral energy failure (defined as CBF that is insufficient to meet metabolic needs). We will study 30 patients within 12 hours of non-penetrating severe head injury (GCS less then or equal of 8) who have just completed PET measurements of regional (CBF, CMRO2, OEF2 A-VDO2 and CvO3 as part of project 1. Patients with elevated ICP(18 - 25 mm Hg) at the time of the initial PET study will have repeat PET measurements of rCBF and CMRO2, OEF, A-VDO2, and CvO2, again after acute HV, Three groups of 10 patients each will be studied. The first group will have PaCPO2 lowered to 30+2 torr. If no patient develops cerebral ischemia potentially severe enough to cause energy failure the second group will have PaCO2 lowered to 25+2 torr. Otherwise, the second group will have PaCO2 lowered, in those patients with an initial PaCO2 greater then or equal to 35 torr, to 35=2 torr to determine if there is a safe threshold for HV. A third group of ten patients will serve as non- hyprventilated controls. These investigations are critical to determine the proper use of HV in the treatment of acute TBI.
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2003 — 2006 |
Diringer, Michael N |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Physiologic Response to Osmotic Therapy in Brain Edema
Acute brain injury is complicated by mass effect, a major cause of secondary injury by critically reducing cerebral perfusion pressure or producing tissue shifts which can lead to herniation. While the etiology and mechanisms responsible for this mass effect may differ considerably depending on the clinical condition, treatment options are limited. Traditionally osmotic agents have been the mainstay of medical treatment employing mannitol and recently hypertonic saline solutions. Despite numerous investigations and mannitors ubiquitous use, considerable controversy persists regarding its 1) mechanism of action (whether it reduces cerebral blood volume [CBV] or brain water), 2) differential effect in normal and abnormal brain, 3) effect on cerebral blood flow (CBF) and oxygen metabolism (CMRO2), 4) loss of efficacy over time, and 5) uptake into injured brain, which could lead to "rebound edema." In part because of some of these concerns, hypertonic saline (HS) has been introduced as an alternative agent; however, its physiologic effect and clinical efficacy compared to mannitol is unknown. Optimal use of these osmotic agents to treat brain swelling requires a detailed knowledge of their physiological effects in human subjects under the clinical conditions in which they are used. To this end, we will carry out the following Specific Aims: 1) measure the effect of a single bolus of mannitol or HS (23.4%) on regional CBF, CMRO2, CBV in patients with traumatic brain injury (TBI) and large hemispheric infarctions (LHI). We will measure CBF, CBV and CMRO2 using PET before and after a bolus of equi-osmolar (5.49 mOsm/kg ) doses of mannitol (1.0 gm/kg ) or HS (0.686 ml/kg), in 10 patients each with LHI and midline shift and 10 patients each with severe TBI; 2) measure the effect of a single bolus of mannitol or HS (23.4%) on regional brain volume in patients with LHI. In 20 patients we will measure regional change in brain volume using MRI before and after the same doses of mannitol and HS used in Aim 1. TBI patients will not be studied due to the MRI incompatibility of ICP monitors; 3) measure the extent that mannitol crosses the blood-brain-barrier in patients with TBI and LHI receiving osmotic therapy. In 15 patients with each entity we will measure blood: brain permeability of mannitol using PET and carbon-11 labeled-mannitol.
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2006 — 2007 |
Diringer, Michael N |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Clinic Pathophysiology of Acute Brain Injury
DESCRIPTION (provided by applicant): The overall goal of this Program Project is to investigate the pathophysiological changes that occur during injury and treatment in human subjects with acute brain damage. We will investigate three types of acute brain injury: intracerebral hemorrhage, ischemic stroke and head trauma. In Project 1, Dr. Allyson Zazutia will investigate the mechanism, extent and clinical importance of edema following intracerebral hemorrhage. In Project 2, Drs. William Powers and Venkatesh Aiyagari will use PET to determine the effect of pharmacologic reduction of systemic arterial pressure on regional cerebral blood flow in acute ischemic stroke. In Project 3, Drs. Michael Diringer and Robert Grubb will investigate the pathophysiological effects of mannitol and hypertonic saline on brain edema due to ischemic stroke and head trauma. The Imaging Core will perform acquisition, reconstruction, processing and archiving of the PET, MR and CT data for Projects 1,2 and 3 as well as validate recently developed MR methods of CBF and OEF estimation against gold-standard techniques. The Radiochemistry Core will provide radiopharmaceuticals for Projects 1,2 and 3 as well as construct a steady state oxygen-15 gas inhalation system to permit PET studies in subjects who are not endotracheally intubated or who cannot actively inhale. This Program Project draws on a combination of facilities and expertise at Washington University that is unique. It combines state-of-the art quantitative neuroimaging, expertise in the care of critically ill neurological patients and many years experience in studying cerebral blood flow and metabolism. This research will provide fundamentally important pathophysiological information to guide future research toward the most fruitful approaches for ameliorating the devastating impact of acute brain injury.
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2007 |
Diringer, Michael N |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Physiologic Response to Osmotic Therapy in Cerebral Edema Patients
Acute brain injury is complicated by mass effect, a major cause of secondary injury by critically reducing cerebral perfusion pressure or producing tissue shifts which can lead to herniation. While the etiology and mechanisms responsible for this mass effect may differ considerably depending on the clinical condition, treatment options are limited. Traditionally osmotic agents have been the mainstay of medical treatment employing mannitol and recently hypertonic saline solutions. Despite numerous investigations and mannitors ubiquitous use, considerable controversy persists regarding its 1) mechanism of action (whether it reduces cerebral blood volume [CBV] or brain water), 2) differential effect in normal and abnormal brain, 3) effect on cerebral blood flow (CBF) and oxygen metabolism (CMRO2), 4) loss of efficacy over time, and 5) uptake into injured brain, which could lead to "rebound edema." In part because of some of these concerns, hypertonic saline (HS) has been introduced as an alternative agent; however, its physiologic effect and clinical efficacy compared to mannitol is unknown. Optimal use of these osmotic agents to treat brain swelling requires a detailed knowledge of their physiological effects in human subjects under the clinical conditions in which they are used. To this end, we will carry out the following Specific Aims: 1) measure the effect of a single bolus of mannitol or HS (23.4%) on regional CBF, CMRO2, CBV in patients with traumatic brain injury (TBI) and large hemispheric infarctions (LHI). We will measure CBF, CBV and CMRO2 using PET before and after a bolus of equi-osmolar (5.49 mOsm/kg ) doses of mannitol (1.0 gm/kg ) or HS (0.686 ml/kg), in 10 patients each with LHI and midline shift and 10 patients each with severe TBI; 2) measure the effect of a single bolus of mannitol or HS (23.4%) on regional brain volume in patients with LHI. In 20 patients we will measure regional change in brain volume using MRI before and after the same doses of mannitol and HS used in Aim 1. TBI patients will not be studied due to the MRI incompatibility of ICP monitors; 3) measure the extent that mannitol crosses the blood-brain-barrier in patients with TBI and LHI receiving osmotic therapy. In 15 patients with each entity we will measure blood: brain permeability of mannitol using PET and carbon-11 labeled-mannitol.
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2008 — 2012 |
Diringer, Michael N |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Effect of Statins On Cerebral Blood Flow After Subarachnoid Hemorrhage (Sah)
The most common and potentially treatable cause of secondary neurological injury in this population in patients with aneurysmal subarachnoid hemorrhage (SAH) is delayed ischemic deficit (DID). This phenomenon is fundamentally a reduction of cerebral blood flow (CBF) below critical ischemic thresholds, occurring days after the onset of hemorrhage. Two important physiological processes involved in the CBF reduction are the severe narrowing of intracranial arteries (vasospasm) and a loss of normal autoregulatory function in the distal circulation. Recent preliminary studies have shown that early administration of statins can reduce the incidence of DID and symptomatic arterial vasospasm This benefit may be due an increase in cerebral blood flow, autoregulatory responses to low flow, or non-hemodynamic mechanisms. The primary objective of this project is to investigate the effect of statin therapy on CBF in 50 patients with aneurysmal SAH who are randomized evenly to receive or not receive statins in a blinded design. We will measure and compare global CBF after SAH between the two treatment groups using Positron Emission Tomography (PET) at two time points: between 3 and 5 days after onset of SAH and again at day 7. (Aim 1). We will compare autoregulatory function between treatment groups at days 7 (Aim 2). PET measurements of Oxygen Extraction Fraction (OEF) will also be made at baseline and 7 days and compared between groups (Aim 3). Secondary aims include the comparison between the two treatment groups of the incidence of symptomatic vasospasm, incidence of arteriographic vasospasm, and ultimate neurological outcome. More detailed analyses of hemodynamic and metabolic data will also be performed, including comparisons between treatment groups in regional CBF, OEF, Cerebral Blood Volume (CSV, measured in order to calculate OEF) and autoregulatory function for arterial territories with and without arteriographic vasospasm. We will determine if statin therapy improves CBF in patients with aneurysmal subarachnoid hemorrhage. This improvement, if present, may be due to improved basal CBF, improved autoregulatory function, or a mitigation of large arterial narrowing. The information gain from this study will help us to better understand the mechanism of action of statins. This knowledge may be useful in the design of future studies with statins and in the development of other therapies aimed at similar mechanisms.
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