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Priorities for Clinical Research in the Treatment of Acute, non-Traumatic Intracerebral Hemorrhage Workshop


 

Priorities for Clinical Research in the Treatment of Acute, non-Traumatic Intracerebral Hemorrhage Workshop
November 17-18, 2003
Wyndham Washington Hotel
1400 M Street, NW, Washington, DC

Intracerebral hemorrhage (ICH) is a particularly lethal stroke type. Mortality approaches 50% and disability in survivors is common. In November 2003, a National Institutes of Neurological Diseases and Stroke (NINDS) workshop was convened in Washington DC to discuss research priorities in the ICH field. Non-traumatic, spontaneous ICH was the focus. Invited participants were asked to look into the future and suggest approaches to further the field toward therapy for the acute ICH patient. The scope was limited to clinical research priorities with only a modest examination of basic science, epidemiology and rehabilitation, all critically important topics worthy of separate workshops.

The participants (see Appendix) were divided into six sub-groups: 1. current state of ICH research, 2. basic science priorities, 3. medical priorities, 4. surgical priorities, 5. imaging priorities, and 6. clinical research methodology challenges in ICH. Each group prepared a document prior to the workshop and then the document was edited based on feedback at the workshop.

Current State of ICH Research

Hematoma Growth

There is now evidence that early hematoma growth is common in patients with normal coagulation profiles, and is associated with worse outcome. Hematoma growth primarily occurs within the first few hours of the onset of bleeding (up to 40% in the first 3 hours) and is rare after 24 hours.

Potential interventions to prevent hematoma growth focus on administration of agents to reduce bleeding. Two Phase IIA dose-escalation studies of synthetic activated Factor VII have been completed within 4 hours of acute ICH to patients with normal coagulation status. These studies demonstrated safety and feasibility but a low rate of hematoma extension in the placebo arm. A larger phase IIB dose-ranging (placebo, 40, 80, 160 mcg/kg) "proof-of-concept" study with 100 patients/group is currently underway.

Surgical evacuation/decompression

A clear benefit for surgery has not been identified. Most neurosurgeons and neurologists agree that surgical evacuation of life threatening cerebellar hematomas is beneficial. Some also extend this belief to lobar hematomas. Treatment of patients presenting with ganglionic hematomas, however, remains controversial. In addition to microsurgery, contemporary neurosurgeons also have access to minimally invasive techniques including stereotactic localization, endoscopic techniques, and adjunctive thrombolytic infusions. Mendelow and colleagues have allowed physician choice in terms of specific procedures in the STICH trial. There were 1033 patients with spontaneous supra-tentorial intracerebral hemorrhage randomized from 27 countries. There were 23.8% favorable outcomes in the "Initial Conservative Treatment" group compared with 26.1% in the "Early Surgery" group. These differences were not significant (Odds Ratio 0.89 with 95% confidence interval 0.66 and 1.19). There was no difference in mortality (63.7% compared with 62.6%).

Blood pressure

There remains a logical, but unproven concern that hypertension promotes re-bleeding. Yet, simultaneously there is fear that treating acute hypertension in this setting will exacerbate or induce ischemia. One PET study found stable peri-hematomal CBF with PET during a 15-20% reduction in MAP of hypertensive patients (MAP >120 mm Hg) with small to moderate sized hemorrhages. While these data suggest that modest reduction in BP does not adversely affect the cerebral circulation, the clinical safety and efficacy of this intervention remain to be established.

Perihematomal Ischemia

The presence of an "ischemic penumbra" surrounding an ICH has long been assumed, based on the belief that the hematoma compresses surrounding tissue and that CBF was reduced in experimental models of ICH. Several recent PET and MRI studies however, have questioned the existence of such a penumbra. These data suggest that ischemia is unlikely to be an important issue in small and moderate sized hemorrhages.

Intraventricular Extension

A pilot trial of urokinase and ventricular drainage in patients with primary intraventricular hemorrhage initially showed promising results (36). This study led to a subsequent double-blinded, placebo controlled multicenter trial of 48 patients treated with external ventricular drainage and t-PA versus placebo. Mortality was substantially lower than the severity-adjusted, predicted mortality: rt-PA (19% vs 76%) and placebo (23% vs 75%). The primary efficacy variable was the rate of clot resolution. The active treatment group demonstrated 18% per day clot reduction vs. 8% per day in the placebo group.

Basic Science Priorities

Development of appropriate animal models of ICH is imperative. New model systems that do not induce artificial changes in brain are needed. Porcine and primate models enable study of white matter injury while primate studies most closely mimic human ICH. Models must characterize spontaneous intracerebral hemorrhage including the elements of ventricular extension, lobar localization and vascular rupture.

Study of the cellular and molecular phenomena associated with hemorrhagic transformation and spontaneous ICH is needed. The time course of injury development is critical. There is remarkably little published in human ICH pathology. Axonal injury and hemorrhage into white matter requires further attention. Studies suggest inflammation may be involved in ICH pathology, but these may be model limited and are poorly characterized.

The resources that are needed include: translational research endeavors pairing laboratory discovery with early clinical investigation; and animal science collaboration to investigate new animal model systems.

Medical Priorities

A trial investigating blood pressure lowering in acute ICH to determine safety and efficacy in preventing rebleeding is needed. Therapeutic trials of coagulopathy reversal in acute ICH are also needed. The role of platelets warrants further attention.

Therapies to prevent rebleeding should be studied. A natural history study is needed to better identify those at risk for hematoma expansion. Further investigation of blocking development and treatment of cerebral edema should be studied. Hyperosmolar agents, cytoprotective agents and hypothermia may be useful therapies in acute ICH. The utility of ICP monitoring has not been systematically investigated.

Necessary resources include involvement of the hematology community in planning for therapeutic trials of ICH, and committed study groups interested in medical trials of ICH.

Surgical Priorities

Studies of minimally invasive surgical techniques including clot removal with and without thrombolytics, and clot removal with mechanical clot disruption are the highest surgical priority. Further, use of surgical adjuncts including robotic techniques, endoscopy, and intra-op and peri-op direct radiologic imaging may benefit surgical evacuation.

Use of local application of neuroprotective or restorative agents into the clot bed may allow direct targeted benefit. Suitable therapies include: hemostatic agents to prevent rebleeding; regional hypothermia; local delivery of protective and/or restorative agents; and polymer-based delivery systems of agents. Delayed restorative surgical procedures should be scrutinized including delayed administration intra-arterial or intra-cavity, and implantation of bionic interfaces to improve function.

The resources needed include programs to encourage young neurosurgeons to plan and participate in surgical trials of ICH, and collaborative support for development of devices for minimally invasive techniques.

Imaging Priorities

Real-time imaging techniques to determine ICH etiology and expansion are needed. These include labeling vessel and parenchymal cellular components for study; use of gradient echo imaging to detect historical hemorrhage profile, and magnets up to 8T to detect microhemorrhage to determine time course and pathophysiology of ICH. Hematoma growth can presumably be tracked with 3-D imaging.

Real-time techniques can also be used to examine peri-hematomal and global perfusion/hypo-perfusion. Rapid, continuous blood flow monitoring both locally and globally is ideal to monitor safety of blood pressure lowering in a trial, and may serve as bridge with animal models.

Studies of high-resolution tissue probes to determine tissue injury, response and recovery are needed. These may include: antibody tracers to examine the time course of cellular events; inflammatory biomarkers; markers of excitotoxicity; neural circuit images. Imaging may serve as a guide for directed therapy. Examples include drug carrying nanoparticles to cross the blood-brain barrier tagged for real-time imaging and direction.

The resources needed include development of molecular probes for components of the ICH pathway and techniques for these agents to traverse the blood-brain barrier and creation of a multicenter consortium with standardized imaging protocols, software, and hardware to be used for assembling a comprehensive repository for clinical and radiographic data following acute ICH.

Clinical Methodology Challenges

A focus on recruitment and the process of informed consent in ICH clinical trials is necessary. Neurosurgical and emergency physician involvement are critical. Establishment or use of existing networks dedicated to acute neurologic research recognizing that the emergency department is the site of most ICH research. Waiver of written informed consent and community consent issues should be systematically addressed.

Standardized medical care management in ICH trials is crucial. Further, experience of center relates to outcome. Choice of centers for trial is an important variable. Expertise and ability to generalize results should be considered. The role of Do Not Resuscitate orders on outcome in studies must be considered.

Analyses of trial data should stratify based on disease severity including ICH volume, GCS score and presence of intraventricular blood. Characteristics of trial patients should mimic population that the study's outcome is intended to generalize to. Choosing meaningful outcome parameters is critical. Outcome change from initial severity may be used rather than just final outcome. Surrogate markers known to predict outcome (e.g.. Residual clot volume) should be validated as surrogate outcome markers. Quality of life measures are needed that include severe disability states validated for ICH patients.

Resources Needed include presentation of ICH Workshop findings at emergency medicine, neurosurgery and neurology meetings and encouragement for their organization and participation in ICH trials. Further discussion of clinical methodology issues pertinent to ICH research among biostatistics and clinical methodology experts, and further encouragement of young investigators with quantitative backgrounds to enter this field.

Workshop Chairs

Marc R. Mayberg, M.D.
Professor and Chairman
Department of Neurosurgery
The Cleveland Clinic Foundation

Lewis B. Morgenstern, M.D.
Associate Professor
Department of Neurology
University of Michigan

Workshop Participants

Issam A. Awad, M.D.
Northwestern University
Evanston-Northwestern Hospital
Division on Neurosurgery

Edward Sander Connolly, M.D.
Associate Professor
Department of Neurological Surgery
Columbia University College of
Physicians and Surgeons

Michael DeGeorgia, M.D.
Director
Neurological Intensive Care Program
The Cleveland Clinic Foundation

Gregory J. del Zoppo, M.D.
Associate Professor
Department of Molecular and
Experimental Medicine
The Scripps Research Institute

Michael N. Diringer, M.D.
Associate Professor
Department of Neurology and
Neurological Surgery
Washington University in St Louis
School of Medicine

Julian Hoff, M.D.
Professor and Chair
Department of Neurosurgery
University of Michigan
A. Alfred Taubman Health Care Center

Penelope M. Keyl, Ph.D.
President
Keyl Associates

Chelsea S. Kidwell, M.D.
Associate Professor
Department of Neurology
University of California, Los Angeles
Medical Center

Stefan A. Mayer, M.D.
Associate Professor
Division of Critical Care Neurology
The Neurological Institute of New York
Columbia University - Presbyterian
Medical Center

A. David Mendelow, Ph.D.
Professor and Department Head
Department of Neurosurgery
Newcastle General Hospital

Kenneth R. Wagner, Ph.D.
Research Associate Professor
Department of Neurology
Univesrity of Cincinnati
College of Medicine

Larry R. Wechsler, M.D.
Professor and Vice Chair
Department of Neurology
Director of the Stroke Institute
University of Pittsburgh
Medical Center Presbyterian

Howard Yonas, M.D.
Peter J. Jannetta Professor and Vice Chairman
Department of Neurological Surgery
University of Pittsburgh
Medical Center Presbyterian

Mario Zuccarello, M.D.
Professor
Department of Cerebrovascular
Surgery/Neurosurgery
University of Cincinnati
College of Medicine

Margo Warren
Chief, Public Liaison
Office of Communication and Public Liaison
National Institute of Neurological
Disorders and Stroke
National Institutes of Health

Katherine Woodbury-Harris, Ph.D.
National Institute of Neurological
Disorders and Stroke
National Institutes of Health
Neuroscience Center

Observers

Timothy D. Ardizzone, Ph.D.
Research Scientist
Department of Neurology
University of Cincinnati Medical Center

Jaroslaw A. Aronowski, Ph.D.
Associate Professor
Department of Neurology/Stroke Program
University of Texas Medical School
Health Science Center at Houston

Jonathan Rosand, M.D.
Neurology Clinical Trails Unit
Massachusetts General Hospital

Guohua Xi, M.D.
Assistant Research Scientist
Department of Neurosurgery
University of Michigan

Hunt Batjer, M.D.
Professor and Chair
Department of Neurological Surgery
Northwestern University
Feinberg School of Medicine

Kyra J. Becker, M.D.
Associate Professor
Department of Neurology
University of Washington
School of Medicine
Harborview Medical Center

Joseph P. Broderick, M.D.
Professor and Chairman
Department of Neurology
University of Cincinnati, College of Medicine
Medical Center

Jeffrey I. Frank, M.D.
Director
Neuromedical/Neurosurgical Intensive Care
Department of Neurology
University of Chicago

Steven M. Greenberg, M.D., Ph.D.
Associate Professor of Neurology
Co-Director of Neurology Clinical Trails Unit
Department of Neurology
Massachusetts General Hospital

James C. Grotta, M.D.
Professor and Director of Stroke Program
Department of Neurology
University of Texas Medical School
Health Science Center at Houston

Daniel F. Hanley, M.D.
Division Director and Jeffrey and
Harriet Professor
Department of Neurology
Division of Brain Injury Outcome
The Johns Hopkins University
School of Medicine

David W. Newell, M.D.
Professor
Department of Neurological Surgery
University of Washington School of Medicine
Harborview Medical Center

Christopher S. Ogilvy, M.D.
Director, Cerebrovascular Surgery
Department of Neurosurgery
Massachusetts General Hospital

Adnan I. Qureshi, M.D.
Professor
Department of Neurology and Neuroscience
Director, Cerebrovascular Program
University of Medicine and
Dentistry of New Jersey

Peter A. Rasmussen, M.D.
Head, Section of Cerebrovascular and
Endovascular Neurosurgery
Department of Neurosurgery
The Cleveland Clinic Foundation

NINDS Participants

Marian Emr
Director
Office of Communication and Public Liaison
National Institute of Neurological
Disorders and Stroke
National Institutes of Health

Thomas P. Jacobs, Ph.D.
Stroke Program Director
National Institute of Neurological
Disorders and Stroke
National Institutes of Health
Neuroscience Center

John R. Marler, M.D.
Associate Director of Clinical Trials
National Institute of Neurological
Disorders and Stroke
National Institutes of Health

Patricia H. Turner
Program Analyst
Office of Science Policy and Planning
National Institute of Neurological
Disorders and Stroke
National Institutes of Health

Christiana E. Hall, M.D.
Fellow
Stroke Program
Department of Neurology
University of Texas, Houston

David Harris
Research Coordinator
Department of Neurology
Johns Hopkins University

Richard F. Keep, Ph.D.
Research Professor
Department of Neurosurgery
University of Michigan

Ellen Magnis, M.B.A.
Director
American Stroke Association

Nichol A. McBee, M.P.H.
Research Coordinator
Department of Neurology
Johns Hopkins University

Last updated March 23, 2011