University of California - San Francisco Project Descriptions
M. Margaret Knudson, MD
University of California
San Francisco General Hospital
1001 Potrero Avenue, Ward 3A
San Francisco, CA 94110
Phone: 415 206 4623
Fax: 415 206 5950
E-mail:
pknudson@sfghsurg.ucsf.edu
Project Title: Traumatic Brain Injury: Development and Refinement of a
Swine Model to Study Traumatic Brain Injury
Project Period: 08/01/01-07/31/06
Description: Brain injury is a leading cause of death and disability
following trauma. While the primary injury to the brain produces immediate
and irreversible mechanical damage, it appears increasingly that secondary
injuries occurring from the moment of the initial traumatic insult may also
have a profound effect on outcome. Prevention of these secondary insults
will require improvement in methods of monitoring and a redefinition of
resuscitation end points. Using a large animal model to simulate the human
situation, the investigators will explore three hypothesis and attempt to
accomplish three related specific aims.
Hypothesis 1: Direct monitoring of oxygenation and of aerobic and
anaerobic metabolites in brain tissue is more sensitive and specific in
detecting regional ischemia than are traditional systemic measurements
following traumatic brain injury (TBI).
Aim: To characterize focal, regional, and systemic oxygen tension and
metabolism in brain tissue during the onset and progression of experimental
TBI.
Hypothesis 2: Hyper-oxygenation following TBI produces improved
tissue oxygenation, cerebral metabolism, and cellular outcome. Also,
hyperventilation results in a decrease in tissue oxygenation, impairs
cerebral metabolism, and worsens cellular outcome.
Aim: To determine the effects of alteration in ventilation on cerebral
metabolism and cellular outcome following TBI.
Hypothesis 3: Resuscitation and maintenance with a hypertonic
hemoglobin-based oxygen-carrying (HBOC) solution results in better tissue
oxygenation, metabolism, and cellular outcome as compared with the currently
recommended resuscitation protocol using normal saline solution.
Aim: To evaluate the effects that cerebral resuscitation with normal saline
solution and a hypertonic HBOC solution have on cerebral metabolism and
cellular outcome in a model of TBI.
To address these aims, the investigators will use the model of head injury
(controlled cortical impact) that has been successful in small animals and
apply it to swine. To measure cerebral metabolism, they will employ
calibrated polarographic micro-catheters to measure oxygen tension in the
brain tissue and a micro-dialysis technique to evaluate metabolic end
products from the interstitial tissue of the brain. These will be added to
the traditional systemic and organ-based measurements of homodynamic and
oxygen differences. To evaluate extent of injury, the investigators will use
gravimetric calibration of cerebral edema and histopathologic analysis.
Standard microscopic cross-sections will be used to identify the area of
contusion; cellular injury will be measured using histochemical techniques
including a fluorochrome (fluorjade) and the TUNEL technique to identify
dying or apoptotic cells. Several other immunohistochemical approaches are
also mentioned.
Project Title: Metabolic Monitoring: Tissue Oxygen Monitoring of the
Brain and Muscle as End-points of Resuscitation during Early Phases of
Trauma Care
Project Period: 08/01/01-07/31/06
Description: Trauma deaths occur early from hemorrhage and later from
either head injury or infectious complications. This study uses tissue
oxygen monitoring of the brain and the muscle as end-points of resuscitation
during the early phases of trauma care. Tissue oxygen values will be
compared with micro-dialysis data collected in the same tissue bed to see if
measured ischemia correlates with anaerobic metabolism. These two monitored
variables will also be compared with the values obtained with more standard
measurements, such as cerebral perfusion pressure (CPP) and base deficit.
Changes in oxygen and metabolic variables will be observed during
alterations in inspired oxygen content and finally during a randomized trial
using crystalloid solution versus an oxygen carrying solution in patients
with persistent tissue ischemia. Prevention of tissue ischemia and anaerobic
metabolism may translate to improved functional outcome from head injury and
to a decrease in the mortality and infectious complications resulting from
major thoracoabdominal trauma.
The study has several specific aims:
Aim 1: Establishes critically abnormal levels of tissue oxygen in the
brain (PbrO2) and muscle (PmO2) of injured patients.
Aim 2: Compare PbrO2 and PmO2 values with levels of aerobic/anaerobic
metabolites collected from these same tissue beds.
Aim 3: Correlate PbrO2 and levels of ischemic metabolites with other
currently available diagnostic measures used in head-injured patients,
including intracranial pressure (ICP), mean arterial blood pressure (MAP),
CPP, jugular venous oxygen saturation (SjO2), computerized tomography (CT)
findings, neurological examinations, and clinical outcomes from TBI.
Aim 4: Correlate PmO2 and levels of ischemic metabolites with base
deficit measurements, standard physiologic variables, infectious
complications, and outcomes in critically injured patients.
Aim 5: Describe the changes in PbrO2 and PmO2 that occur with changes
in inspired oxygen in critically injured patients and to determine whether
improving PbrO2 and PmO2 improves outcome.
Aim 6: Compare the effects of two resuscitation solutions—standard
crystalloid and hemoglobin-based oxygen carrying solution (HBOC)—on PbrO2
and PmO2 levels and tissue metabolic measurements.
Project Title: Pediatric Post-traumatic Stress Disorder (PTSD):
Identification and Treatment of PTSD Symptoms Resulting from Traumatic
Injuries
Project Period: 08/01/01-07/31/06
Description: This project will clarify the relationship between
childhood PTSD and future impairment in social, academic, and psychological
functioning. The research evaluates a novel treatment intervention for
childhood PTSD that combines the Chapman Art Therapy Treatment Intervention
(ART) with Eye Movement Desensitization and Reprocessing (EMDR). Researchers
hypothesize that this combination could be an effective tool for reducing
PTSD symptoms for hospitalized children and for large numbers of children
requiring immediate treatment following natural disasters, school shootings,
and other catastrophic events.
Researchers have several aims for the project:
Aim 2: Determine the effectiveness of a brief psychological
intervention, administered at 1 month after a child's injury, in reducing
the number and severity of PTSD symptoms.
Aim 3: Examine the influence of child-specific factors on the
development, duration and severity of PTSD symptoms following an index
trauma event.
Aim 4: Examine the influence of parental and familial factors on the
development, duration, and severity of PTSD symptoms in pediatric trauma
patients.
Aim 5: Examine the effect of PTSD on a child's overall social,
academic, and familial functioning.
This is a prospective, randomized cohort study of children ages 7 to 17 who
are hospitalized for physical trauma. Participants will be enrolled during
the index trauma admission. One month after injury, they will be tested for
PTSD symptoms using the UCLA PTSD Reaction Index (PTSD-RI). Parents will
assess their child's level of stress and answer interview questions about
their own stress and about the family environment. Children with moderate to
severe PTSD symptoms will be randomized to receive either a new intervention
that combines ART with EMDR techniques or no intervention. Those randomized
to receive the intervention will be treated in two successive weekly
sessions. The discrepancy between parental assessment of child stress and
the child's assessment will be calculated. Children and parents will be
followed at 3 months, 6 months and 12 months post-injury to measure
longitudinal development or resolution of symptoms.
There are several primary outcome measures: rate of significant PTSD
symptoms at 1 month; the effect of treatment on rates of resolution of
significant PTSD; change in PTSD-RI scores from 1 month (pre-intervention)
to each follow up; and parent-child discrepancies. The Department of
Psychiatry at Children’s Hospital, Oakland (CHO) will be the site for
initial and follow-up interviews and the intervention.
Project Title: Biomechanics of Vertebral Fractures for Repetitive Loads:
Study of Fatigue Life of Elderly Vertebral Trabecular Bone
Project Period: 08/01/01-07/31/06
Description: The overall goal of this project is to establish the
concept that, after moderate or minor isolated overloads, fatigue failure of
human vertebral bone can occur at repetitive cyclic load levels that would
otherwise not cause failure. Three hypotheses will be tested: (1) that the
fatigue life of elderly trabecular bone cores is reduced by the intensity
level of an isolated overload; (2) that the fatigue life is reduced more for
older and/or less dense bone than for younger, denser bone; and (3) that
fatigue life of a whole vertebral body is reduced after a single overload.
The aims for the project include the following: