NeuroCritical Care Research
The primary thrust of the neurocritical care program is clinical and educational. However, we are seriously committed to provocative scholarly projects  dedicated to advancing our field. While our portfolio of projects is highly dynamic, our primary areas of present activity are listed in the following sections. Since the neurocritical care program is organizationally linked to the vascular neurology program, reference is made to the research delineated in the cerebrovascular section for further information about additional research on ischemic stroke (laboratory and clinical).For prospective trainees, there are two additional points to emphasize. We embrace working with medical students and residents, and many of the projects below have included trainees both in project design, formal presentation at national/international conferences, and manuscript preparation. In addition, these projects are derived from the present faculty in our section, and we are presently recruiting a third faculty who will bring additional areas of interest to our research endeavors, particularly in the laboratory.
Brain swelling is an important complication from acute liver failure (ALF), and it is a frequent cause of death in patients who suffer this complication. Some cases of acute liver failure spontaneously recover and some are so destructive that a liver transplant would be required to achieve survival. In either scenario, deterring brain swelling and optimizing brain perfusion when brain swelling does occur is a critical element in creating the option of good survivorship in patients with ALF.Since the conventional approaches to limiting brain swelling and lowering intracranial pressure (ICP) are not reliable in patients with ALF, we have been involved with several projects focused on this important treatable but life-threatening neurological complication. While monitoring ICP is an important step toward properly treating these patients, the ALF causes a coagulopathy that often creates hesitance for inserting an invasive device into the skull. Our extensive experience with this disease led to adopting a standardized approach to ICP monitor placement in ALF patients with coagulopathy. We have since systematically studied this approach and presented and published our results demonstrating the safe insertion of ICP monitors in ALF patients without causing significant hemorrhagic complications. This study has been an important step toward changing the clinical approach to optimizing brain perfusion and neurological outcome in ALF patients. In addition, hypothermia is a promising approach to limit brain swelling in patients with ALF in experimental animals and small human series. Given our experience and interest in both ALF and hypothermia, we have partnered with the well-established Acute Liver Failure Research Consortium and are involved with protocol development and organization for a multi-center clinical trial focused on this topic. We also have developed a strong interest in the role of continuous hemodialysis techniques to facilitate ammonia clearance, and we have a project dedicated to correlate dialysis flow rates to the quality of ammonia clearance.The mechanism of brain swelling from ALF relates, in part, to hyperammonemia. The liver usually creates urea from the ammonia produced as a byproduct of protein metabolism. When the liver acutely fails, ammonia accumulates and is an important contributing factor to the development of brain swelling. The elevated level of ammonia enhances the conversion of glutamic acid to glutamine within astrocytes (the supporting cells of the brain), and this (through several hypothesized mechanisms) leads to cellular swelling and, in aggregate, brain swelling. While it has been long hypothesized that ammonia is not toxic to neurons, we have recently demonstrated (and formally presented) the unique impact of hyperammonemia on specific brain cortical regions in human survivors. This has recently raised questions on whether high ammonia concentrations may have some toxic effects on neurons in addition to its role in astrocytic swelling.In order to more formally study the role of ammonia in causing brain swelling, we have teamed up with our departmental scientists, and colleagues at other institutions to establish an experimental model using fetal mouse brain organotypic cultures (FMBOTC). This method allows the architectural and physiological preservation of intact slices of brain in culture (absent blood flow) to study the impact of variable environmental conditions. We have employed FMBOTC to explore the dose-response relationship of ammonia concentrations to astrocytic swelling and the potential effect of other systemic mediators that may effect the potency of this relationship. Initial success in establishing this model has led to our formal presentation of our work and dedicating a focused laboratory effort on this topic. It is our hope that we will be able to use this model to discover important modifiable factors that have a critical but yet un-described role in the brain swelling associated with ALF. This, in turn, can potentially lead to new treatments for this deadly problem.
Spontaneous and traumatic intracerebral hemorrhages are considered acute intracranial mass lesions (AICML) and can cause catastrophic brain injury. However, surgical hematoma evacuation can lead to stabilization. While proper patient selection for invasive procedures is challenging, it is clear that timing is everything. Unnecessary delays in the diagnosis and treatment of brain hemorrhage in patients who can benefit from evacuation procedures can lead to worse brain injury, outcome and, sometimes, unnecessary death.Most of these spontaneous and traumatic hemorrhages occur outside a hospital in “the field.” Unfortunately, however, there is no reliable, sensitive, and specific method for in field identification of AICML. While clinical and situational factors can help discriminate between those patients more likely to have central nervous system injury, they do not reliably identify those, specifically, with mass lesions. This distinction can be important in a variety of settings. For example, patients with intracerebral hemorrhage should be selectively triaged to medical centers with neurocritical care and neurosurgical services able to accomplish acute hemorrhage evacuation or ventricular drain insertion. In a war zone, early identification of AICML from trauma (e.g. subdural hematoma, epidural hematoma, etc.) can facilitate appropriate triage for those patients (soldiers and civilians) who acutely require neurosurgical intervention. Delays in appropriate triage in these two example scenarios can increase a patient’s extent of brain injury and mortality. Unfortunately, it is not practical to have neuroimaging (e.g. computerized axial tomography or magnetic resonance imaging) available on all ambulances.We are spearheading the development and assessment of practical tools that may be helpful in early identification of patients with AICML in the field or emergency department. We are approaching this challenge with two projects. Through an intellectual partnership with a team of scientists, we are facilitating the development and preliminarily testing of a simple and inexpensive device that could accomplish detection of AICML. After several planning meetings, we have embarked on the first stage of this project which involves device design and prototype development. We are now preparing the in-vitro testing of the device. After secondary refinements we will design and carry-out in-vivo experiments on the device and its sensitivity to detect experimental models of intra-axial and extra-axial brain hemorrhages. Ultimately, we hope to bring the device to human testing.We are also involved with project development that will apply a new technology to better assess specific autonomic functions likely to be affected by AICML. This new technology is automated, inexpensive, and has promise to facilitate early discrimination of AICML in the field and emergency departments.
We have had a long-standing interest in brain swelling after large hemispheric supratentorial hemispheric infarctions (LHI). Some of our early work, presentations, and publications were instrumental in changing the thinking about the mechanisms of deterioration after LHI and the ideal approach to medical management. We eventually accomplished funding from the National Institutes of Health for a multi-center clinical trial we designed and coordinated on the role of surgical decompression (hemicraniectomy) for brain swelling from LHI (HeADDFIRST).This was the first randomized, control clinical trial on the topic, and the design of this study was used to design several similar European trials on the same topic. The results of our trial, HeADDFIRST, demonstrated a set of criteria that sensitively discriminate between those patients with low and high mortality from LHI. It also showed that the medical treatment protocol accomplished the lowest mortality every reported in patients with strokes of this magnitude; half of that reported in the literature (including those patients in the recent European trial on the same subject that did not similarly standardize the medical treatment). We continue to explore the results of this study to develop new insights into how to better approach patients with this life-threatening complication.Our experience with hemicraniectomy and the surgical protocol we developed for the procedure has led our facility in discovering other patients who may benefit from this procedure. We have since published our application of this procedure in children with LHI as well as in patients with brain swelling from acute disseminated encephalomyelitis. In addition, last year we described our series of patients with surgical decompression and insights on how to approach its more safe application with more uniform benefit to patients.
Brain cooling is the most promising approach to protect the brain from injury due to low blood flow (ischemia). Most lay public is familiar with the miraculous stories of exciting survival from near drowning in ice cold bodies of water. The capacity of cooling to limit brain injury from ischemia has been validated in numerous experimental models. More recently, human trials on systemic cooling after cardiac arrest (global cerebral ischemia) have shown significant benefit to neurological outcome such that it has become a standard of care for select patients. The most applicable and successful approach to brain cooling is cooling that involves lowering the temperature of the whole body (systemic hypothermia) through external cooling devices or indwelling cooling catheters (we were part of one of the clinical trials that showed the benefit of one of these devices in controlling body temperature in humans) in combination with systemic sedation and inhibition of reflex shivering. The undertaking of systemic cooling is cumbersome and requires escalation of medical care that carries inherent risks such as arrhythmia, pneumonia, and coagulopathy. While the typically dismal outcomes after cardiac arrest showed a favorable risk benefit ratio with systemic hypothermia, its risk profile is somewhat prohibitive with less extreme presentations as in the case of focal cerebral ischemia (ischemic stroke). Why not cool the brain selectively? The primary reason relates to the simple fact that we are made in a manner that protects the brain from “the elements” in the environment. In short, external cooling devices applied to the head simply do not cool the brain. However, we are presently a participant in a multi-center trial on a new promising device that uses a novel approach to selectively and rapidly cooling the brain, and, if successful and safe, it may lead to an exciting breakthrough in our ability to rapidly accomplish regional brain hypothermia in the acute setting.In addition to the above mentioned clinical trial, we have an exciting partnership with our colleague scientists at Argonne National Laboratories. Our collaborative research consortium with them, and development of innovative methods to establish regional hypothermia has been an important thrust of our work together. We are co-inventors with them on a now patented device for creating regional brain hypothermia. In addition, we are presently involved in an exciting initiative to develop a new approach to brain hypothermia to protect from reperfusion injury after recanalization of an occluded artery.
In addition to our projects on AICML, we are involved with several projects that relate to the triage and management of intracerebral hemorrhage (ICH). The Emergency Medical Services (EMS) triage system in Chicago and many other cities, requires ambulances to transfer non-trauma patients to the nearest emergency department. Unfortunately, those with ICH often end up in urban or community hospitals without any acute neurological/neurosurgical services. The only economically feasible way to preferentially triage ICH patients to appropriate medical centers with acute neurological/neurosurgical services is to have a method to enhance the in-field detection of ICH. Our work on AICML detection (see above) is one approach to rectify this problem.While we are working on technology that can help with acute in-field detection of ICH, we have done important work defining the present state of ICH care in urban emergency and community departments without acute neurological/neurosurgical services. We did initial work defining delays in acute definitive management of ICH patients related to hospital-to-hospital transfers due to the initial triage of ICH patients to hospitals with inadequate neurological resources. As a follow-up to that foundational work, we developed a stroke triage survey tool. We have personally surveyed emergency doctors at key urban and community medical centers without acute neurological/neurosurgical services and asked them to identify their inadequacies in this clinical area, share their perceptions of the impact of their clinical limitations on ICH patient outcome, and their reflections on methods to better triage ICH patients. Doctors who work in these emergency departments plainly stated that patients highly suspected to have suffered ICH should not be sent to their hospitals, and that patients have suffered worse outcome (including death) because of their inability to acutely treat these patients. This work has been accepted for formal presentation to an upcoming international conference and serves as an important foundation for the exciting movement within the stroke community to change the approach to triage of stroke patients. We also have an interest in some of the readily detectable and modifiable factors that may contribute to ICH expansion. One of these factors is abnormal platelet function, and we have recently described a consecutive series of patients with platelet dysfunction in patient with acute ICH – many without known previously exposure to anti-platelet agents. This work has recently been formally presented and adds to a growing body of literature that promises to shed new insights into the potential role of acute platelet function screening in ICH patients and the role for restoration with medication and/or platelet transfusion.The prognosis of motor outcome is an important consideration in acute decision making with ICH. An emerging magnetic resonance image acquisition and processing technique called diffusion tensor imaging (DTI) shows promise as a tool to estimate motor recoverability after ICH. In partnership with our neuroradiologists, neurosurgeons, and a physicist at the Illinois Institute of Technology we have demonstrated the feasibility of DTI acquisition in critically ill ICH patients as a step toward more widely studying its practical utility in clinical decision support. The results of this exploration were recently presented at an international conference.
Our group has a unique expertise in brain death diagnosis and management. We have made provocative clinical observations in brain death that have been formally presented and published, and we have been instrumental in facilitating the evolution, understanding and approach to brain death. More recently, we have become interested in the process of solid organ donation after cardiac death (DCD), and we have systematically studies both pitfalls in the process as well as the neurological spectrum of patients considered ideal candidates for DCD. Our work has been formally presented at international meetings as the foundation for the development of more definitive projects on the topic. This work (and other related projects) underscores our clinical and scholarly interest in neurological prognostication, brain death, end-of-life decision making, and neuroethics.
Neurocritical care patients usually have increased metabolic demands, but our observations have suggested that we do not always meet their enhanced metabolic demand with proper nourishment. This can have a negative impact on patient outcome and increase the risk of complications and prolongation of hospitalization. In order to study this problem further we established a partnership with our Nutrition Department colleagues to systematically quantify patients’ daily nutritional needs and our success in accomplishing delivery to those targets. So far, we have shown that it is presently taking 5 days to achieve nutritional support toward those targets and there are various modifiable factors that can improve on this performance. We also disproved certain dogmatic concepts that have historically led to sluggishness in meeting the nutritional goals for individual patients. We recently formally presented our preliminary work on the topic and are reporting those results. This, in turn, will lead to our next phase on an interventional study to improve our adequacy in more rapidly accomplishing necessary nutritional support in our neurocritical care patients.
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