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RHAIR Organizing Committee Robert Silbergleit, MD Edward Sloan, MD, MPH Lance B. Becker, MD Clifton Callaway, MD, PhD Edward C. Jauch, MD, MS Patrick Lyden, MD Robert W. Neumar, MD, PhD Phillip A. Scott, MD Terry Vanden Hoek, MD David Wright, MD
Barriers
This panel was asked to lead
a discussion on: What are the barriers to and opportunities for initiating multidisciplinary emergent hypothermic resuscitation research efforts? Does the need for early initiation of therapy make waiver of informed consent necessary, feasible, or worth the effort? What is needed to initiate hypothermia very early in a patient's treatment? What are the advantages and disadvantages of starting cooling in the emergency department versus the intensive care unit? What is the role of technology in cooling more rapidly? Is using new technology to cool patients ever a barrier to performing hypothermia research? Are we studying the devices or the concept of induced hypothermia? Does every study of hypothermia need a new IDE? Where should the funding for this research come from? BARRIERS Dr. Guy L. Clifton What are barriers to multidisciplinary
emergent hypothermic resuscitation research? Waiver of informed consent
is necessary. What is needed to initiate
hypothermia very early in a patient's treatment? What are the advantages
and disadvantages of starting cooling in the ED vs. the ICU? Is using new technology
to cool patients ever a barrier to performing hypothermia research? We are simultaneously studying
the devices used and the concept of induced hypothermia. Where should funding come
from?
Markgraf CG, Clifton GL. Treatment
window for hypothermia in brain injury. J Neurosurg 95:979-983, 2001. Clifton GL, Knudson P, McDonald
M. Waiver of consent in studies of acute brain injury. J Neurotrauma 19(10):1121-1126,
2002. Clifton GL, Miller ER, Choi
SC, Levin HS, McCauley S, Smith KR, Muizelaar, JP, Marion DW, Luerssen
TG. Hypothermia on Admission in Patients with Severe Brain Injury. J Neurotrauma,
19(3):293-301, 2002.
Definition of hypothermia Other hypometabolic strategies Aim of hypometabolic strategies Aim of hypometabolic strategies Hypometabolic strategies:
clinical application
This panel was asked to lead
a discussion on: What are the critical questions
of science to be answered in the next 5 years for hypothermia? Should
the focus be on mechanisms of action? Can we define optimal temperatures,
durations of therapy, and rates of re-warming? Do these differ from one
disease state to another or from one patient to another? Can hypothermia
be induced or supplemented pharmacologically? Can cooling be performed
non-invasively? Are there important questions of genomics and proteonomics
related to hypothermia? QUESTIONS What degree of hypothermia
is optimal for improving outcomes after cerebral injury? Almost all physiological processes
are affected by hypothermia. Reduced temperature will reduce the metabolic
demands of the brain, presumably improving mismatch between substrate
supply and demand in low-flow states. Inasmuch as reduced metabolism contributes
to the beneficial effects of hypothermia, the lower the temperature the
better. For global brain ischemia, this central role for lowered metabolism
is supported by data about intraischemic hypothermia, but it is not supported
by the beneficial effects of hypothermia induced after reperfusion. Post-reperfusion
hypothermia may provide its maximal benefit at a level of 32-34ºC.
This observation suggests that post-reperfusion cooling may alter the
balance between specific metabolic pathways that have a differential sensitivity
to temperature. If cooling proceeds too far, all processes are inhibited
without any additional benefit. Mechanistic studies should look for candidate
processes that are affected over this temperature range. How quickly must hypothermia be induced to be effective? The therapeutic window for
induced hypothermia should help identify critical mechanisms for neuronal
recovery. Hypothermia induced during brain injury effectively reduces
the magnitude of the injury. However, hypothermia induced after a given
injury can only interfere with those processes occurring during that time
window. Using the example of global ischemia, mild hypothermia is known
to be beneficial when initiated up to several hours after reperfusion.
Because the most severe oxidative stress, excitatory amino acid release
and energy failure occur during ischemia and the first 30-60 minutes of
reperfusion, these processes are probably not the ones targeted by cooling.
Therefore, mechanistic inquiries should focus on later events in the cascade
leading to neuronal death or survival. How long should hypothermia
be maintained? Again, the therapeutic window
for induced hypothermia can provide important clues about the mechanisms
that it affects. For global ischemia, brief hypothermia (1-2 hours) only
proved effective if it began immediately. In fact, brief hypothermia is
best if it begins to overlap the ischemic period itself. Thus, the free
radical burst, excitatory amino acid release and energy failure that occur
during that period are likely targets for brief hypothermia. Strangely,
the beneficial effects of brief hypothermia may not be permanent, and
may only delay neuronal degeneration. Prolonged hypothermia (6-36 hours)
appears to be effective even if initiated much later (up to 6 hours after
reperfusion), suggesting again that other more protracted processes are
affected. Intracellular signaling, new gene expression and protein processing
are possible target mechanisms. Importantly, the beneficial effects of
prolonged hypothermia appear to be more permanent. Understanding what
cellular processes are affected could help guide how long to maintain
hypothermia in clinical settings. Because different cellular
events occur after different types of brain injury, practical application
of hypothermia must develop an appreciation of these differences, rather
than assuming that one regimen fits all. For example, traumatic brain
injury seems to have a burst of high intensity events that progress rapidly
after the insult. However, survivable global brain ischemia appears to
initiate a smoldering cascade of cellular events leading to protracted
cell death. Therefore, rapid induction of hypothermia may prove more important
after traumatic brain injury than after cardiac arrest. Appreciation of
these different mechanisms could help interpret the different success
observed in clinical trial for different diseases. Furthermore, understanding
these cascades may help clinicians to identify which patients are most
likely to benefit from induced hypothermia. Methods of inducing hypothermia:
Endovascular catheters or external cooling devices? Dr. Mimi Yenari, Questions
regarding hypothermia in patients with stroke. Is hypothermia protective
against experimental stroke in the absence of reperfusion? What are the interactions
between hypothermia and thrombolysis? Can hypothermia help us identify other therapeutic targets for neuroprotective stroke treatment? Can hypothermia work as a part of "Cocktail" approaches with other neuroprotectants? For example, hypothermia may
be used in combination with gene therapy. Dr. Samuel Tisherman,
Questions regarding hypothermia in patients with hemorrhagic shock. A much more controversial area
of interest is the effect of mild hypothermia during hemorrhagic shock.
There is an ever increasing body of laboratory research suggesting that
mild (33-36°C.) to moderate (28-32°C.) hypothermia improves survival
from hemorrhagic shock. In some preliminary studies, this does not seem
to be related to changes in systemic cytokines or in free radical production.
The benefits seem to be more related to cardiovascular support, i.e.,
maintaining blood pressure and preventing cardiac arrest. This is even
truth if hypothermia is not initiated until the end of shock and start
of full fluid resuscitation. In contrast, retrospective
clinical studies of trauma patients have correlated hypothermia with increased
mortality. The studies are compounded by the fact that the most severely
injured patients are the ones who become hypothermic as a result of exposure,
shock, administration of cold fluids, intoxication and analgesia/anesthesia.
One prospective study comparing a more rapid rewarming technique (continuous
arteriovenous rewarming) with standard rewarming procedures showed some
physiologic benefits of more rapid rewarming, but no overall survival
benefit. Unfortunately, this study did not compare totally equivalent
groups of patients. More importantly, no studies have explored the effects
of controlled, resuscitative mild hypothermia in this patient population. In trauma patients, one of
the main concerns regarding hypothermia is coagulopathy. There is some
data, mostly in vitro, suggesting that clinically important coagulation
changes do not occur above 34°C. In a trauma patient with significant
tissue trauma, massive blood loss, shock, and massive transfusions, it
is difficult to determine the direct effects of temperature. Also, novel
hemostatic agents may make these issues less important. Only a prospective, randomized
clinical trial, with precise control of temperature and prevention of
shivering and sympathetic response, will be able to clearly answer these
questions. Collaborations
This panel was asked to lead
a discussion on: What are the best models of collaborative research efforts in hypothermia? Is it valuable and feasible to develop consensus methodologies for effectiveness and safety endpoints, patient management strategies, data fields and timepoints? Do we need a consortium, a registry, a consensus conference, or something else? Is it best to create multi?center efforts de novo for each study, or would it be valuable to have an ongoing hypothermia research network? Is it realistic to expect centers to be able to perform hypothermia research across several disease states, or are centers too dependent on individual investigators with a specialized interest to make crossover feasible? How should funding of collaborative efforts be obtained? Public Resource or Corporate
Commodity? The costs of medical research
have increased to levels that even the wealthiest universities can no
longer afford. Private industry, driven by the public's appetite for innovation,
has begun to assume the lion's share of those costs, and a formidable
share of control. The boundaries between new science and applicable technologies,
and hence between knowledge as a good and knowledge as a commodity, have
become blurred. Some argue that the marriage of academic research with
private funding will be repented because the incompatibility of commercial
and scientific goals is so profound, that control over virtually all research
into human health should be restored to academia. Others, particularly
those working in technologically intensive fields, argue that public funds
cannot do the job. How Can These Efforts be Orchestrated? Most members of the research
community agree that partnerships with industry are essential to propel
research but must be managed with care. An increasing number of trials
are being conducted by private industry, either alone or in partnership
with other funding bodies. There is an alleged hierarchy of trial credibility
ranging from purely investigator?driven and national research body funded
trials to in?house industry trials. A pragmatic interaction between investigators
and industry may help to raise the standards overall. Issues concerning
quality and independence of the investigators have raised levels of concern
among physicians. Particular concern has been expressed about conflict
of interest in trial interpretation and the writing of guidelines. Standards
concerning the relationship between companies and investigators are being
established. In order to protect patients' rights and to honor society's
need for unimpeded scientific inquiry and dissemination of results, recognized
leadership associated with a national organization is needed to promote
unequivocal standards and monitor ethical behavior in this research. What Are The Gains of Collaboration? To effectively address theses
matters, an academic alliance committed to the pursuit of therapeutic
hypothermia in design and conduct of research projects and clinical trials
is imperative. Such an alliance of opinion leaders in research, clinical
practice and industry may perhaps best support therapeutic hypothermia
as an emerging therapeutic concept. A consortium in conjunction with national
or international organizations can promote and monitor ethical behavior
in research and set unequivocal standards to protect the rights of patients
involved and to honor society's need for unimpeded scientific inquiry
and dissemination of results. What are the Goals of a
Consortium? There are a number of trial
networks that may serve as models for such a collaborative partnership.
A therapeutic hypothermia research network may in the beginning be established
as a multidisciplinary consortium of research consultants and members
of various medical subspecialties affiliated with national or international
organizations. It should primarily be build around a clinical trial to
align centers and demonstrate authenticity. At a later stage, competency,
knowledge, and clinical expertise of the membership may be contributed
to industry and philanthropy across a spectrum of initiatives, including
clinical trial preparation and review, registries, surveys, systematic
reviews, and writing guidelines. The success of the consortium will be
determined by the amount of inquiries and the size membership. Primary
source of funding should be client sponsorship agreements rather than
membership fees. |