Download Research Manual Emergency Medicine Research Associate Program Fall 2015

Research Manual
Emergency Medicine Research Associate Program
Fall 2015
The research manual is intended to provide Emergency Medicine Student Research Associates (SRA)s with an
outline of ongoing research studies. Some of these projects were initiated by members of the EMR Program,
and some by our collaborators, including medical students, UVM and UVM Medical Center faculty and staff.
Our projects are sponsored by a variety of sources, including the College of Medicine, the National Institutes
of Health, the Department of Defense, and a biomedical equipment company. This outline should be
considered a “study guide” for the current semester.
The fundamental role of an Emergency Medicine Student Research Associate (SRA) is to screen, or identify,
patients who are eligible for research studies. This requires that the SRA interact with the treating physician
or physician’s assistant. The SRA must be thoroughly familiar with each ongoing study, so that he or she can
use information from the patient’s providers and medical record to determine if a patient should be enrolled.
Unless otherwise specified, SRAs must receive permission from the patient’s provider to approach patients for
a research protocol and should be able to answer any questions that a provider or patient may have about the
purpose, inclusion criteria, and outcome measures of any study. This manual outlines these characteristics for
all ongoing studies, as well as select papers relevant to each project. All Student Research Associates are
responsible for knowing the information presented in this manual, and this material will constitute the basis of
much of the midterm and final examinations.
This manual may be updated throughout the semester as projects are amended and as new projects
commence. The updated chapters will be made available on Blackboard as PDF files, or may be requested on
paper from the instructor. A complete, current version of this manual will always be available for download
from the class Blackboard site.
Disclaimer: The chapters in this manual should only be considered an outline of extremely detailed, lengthy
protocols. For clarifications, the reader is referred to the complete Institutional Review Board documentation
for each protocol.
Last updated: 8/27/15
8/31/15
1
1. Activation of Coagulation and Inflammation
after Trauma (ACIT)
[Formerly COAG] - #11-135
The Systems Biology of Coagulation and Trauma-Induced Coagulopathy
Principal
Kathleen Brummel-Ziedins, Ph.D. and Ken Mann, Ph.D., Department of
Investigators Biochemistry
Contact
Pam Derickson ([email protected])
Research
Question
Can a comprehensive “natural history” of coagulation be constructed
that can be used to predict which patients will develop a coagulopathy
after traumatic injury?
Study
Design
Complex systems model
Primary
Outcome
Incidence of coagulation abnormalities and total quantity of blood
product transfusions
Secondary
Outcomes
Incidence of DIC, pulmonary embolism, acute lung injury, myocardial
infarction, renal failure or other organ injury, ventilator-associated
pneumonia or other nosocomial infections, 28-day mortality, ventilatorfree days, ICU stay, hospital stay
Inclusion
Criteria

≥ 18 years old

Admitted to the FAHC
Trauma Team

Exclusion
Criteria
Have an indwelling
line placed (central,
arterial, or venous)
Vulnerable Population Eligibility
Minors
Pregnant women
Incarcerated
Cognitively impaired
Minorities
Economically or educationally disadvantaged
Seriously injured or ill
Procedures
8/31/15

< 18 years old

Existing bleeding disorder

Are taking anticoagulant
medication

Pregnant women

Incarcerated
Included
Excluded







SRA: Screening, data collection, transfer of blood from syringe to tubes
RA: Data collection, blood processing
2
Summary
Bleeding is a frequent cause of preventable death after traumatic injury. People with severe injuries are
susceptible to both bleeding and clotting disorders, known as coagulopathies, that may complicate the control
of bleeding and increase morbidity and mortality. Disruption of normal clotting mechanisms in severe
traumatic injury, contributing to the continued loss of blood, has been termed the acute coagulopathy of
traumatic shock. Moreover, the condition can subsequently develop into a hypercoagulable state (i.e., excess
clotting), which is associated with additional complications, such as blood clots, or overwhelming clotting
called disseminated intravascular coagulation (DIC). Thus, trauma induced coagulopathies comprise a
spectrum of bleeding and clotting disorders that appear to result from multiple independent but interactive
factors whose roles are difficult to elucidate and characterize using the conventional reductionist approaches
often employed in clinical research. In addition, there is no single animal model that accounts for all of the
variables involved in trauma induced coagulopathies, complicating experimental approaches to investigating
coagulopathic disease states.
The University of Vermont is collaborating with University of California, San Francisco and others in a
multicenter project entitled “Systems Biology of Coagulation and Trauma-Induced Coagulopathy”. This project
seeks to develop a comprehensive understanding of the fundamental, highly networked, molecular and
physiological processes underlying normal coagulation and the perturbations of those processes that result in
trauma-induced coagulopathies. Using systems biology approaches, the initiative will combine clinical data
with animal and computer modeling to describe a “natural history” of coagulopathy, and to create a coherent,
predictive, mathematical model that represents the progression of the disease state. The Biochemistry
Department and Emergency Medicine Research Program at the University of Vermont will help this project by
supplying blood samples and corresponding clinical data from trauma patients.
Our group will enroll trauma patients in the Fletcher Allen Emergency Department for this prospective,
observational clinical study that includes serial blood draws. The study requires a waiver for small volume
blood with the stipulation that consent is sought from the subject or the subject’s legally authorized
representative (called a “surrogate” in this study) as soon as possible. Patient blood samples are used to
perform assays studying coagulation, inflammatory mediators, protein structure and function, and gene
function. The data collected by this and other centers will be integrated into a database of the coagulation
process for modeling using systems biology approaches. The “Systems Biology of Coagulation and TraumaInduced Coagulopathy” initiative has the potential to have enormous impact on trauma and emergency
medicine, and our participation will be a great asset to the project.
(Funded by the Department of Defense)
References
Hess JR, Brohi K, Dutton RP, et al. The coagulopathy of trauma: a review of mechanisms. The Journal of trauma
2008;65:748-754.
Mann KG, Brummel K, Butenas S. What is all that thrombin for? J Thromb Haemost. 2003 Jul;1(7):1504-14.
8/31/15
3
2.a. Luoxis-Trauma - #14-537
Oxidation-Reduction Potential as a Diagnostic Biomarker
in Trauma and Sepsis
Principal
Investigator
Kalev Freeman, MD, PhD, Department of Surgery
Contact
Nate Dreyfus ([email protected])
Research
Question



Do oxidative-reduction potentials (ORPs) distinguish TBI patients from nonhead injured controls?
Do elevated ORP levels in head injury patients predict severe injury?
Do elevated ORP levels correlate with post-concussive symptoms in patients
with mild TBI?
Study
Design
Evaluation of performance characteristics of a diagnostic test
Primary
Outcomes
Severe TBI, defined as: CT scan positive for blood; neurosurgical intervention; or
admission to ICU or neuro observation unit.
Secondary
Outcomes
ImPACT scores on cognitive function and post-concussion severity score
Inclusion
Criteria



18 - 80 years of age
TBI group: head injury
requiring CT scan for
evaluation
Control group:
orthopedic trauma
without head injury
Exclusion
Criteria
Vulnerable Population Eligibility
Minors
Pregnant women
Incarcerated
Cognitively impaired
Minorities
Economically or educationally disadvantaged
Seriously injured or ill
Procedures
8/31/15




History of disabling TBI
Non-English speaking
Dementia or active psychiatric
disorder
Active autoimmune condition,
infection or fever
Included
Excluded







SRA: Screening, data collection, transfer of blood from syringe to tubes
RA: Data collection, blood processing
4
Summary
The biological basis of neuronal damage and recovery following traumatic brain injury (TBI) is not
completely understood. Oxidative stress secondary to tissue ischemia reperfusion injury and systemic
inflammatory responses may play a role. In animal models, elevated levels of reactive oxygen species (ROS)
have been demonstrated after traumatic brain injury in neuronal tissue 1-3. Altered redox balance reduces
nitric oxide bioavailability and impairs vascular endothelial reactivity4-6. Cerebrovascular dysfunction
ultimately contributes to cerebral edema and poor recovery after a traumatic brain injury leading to cognitive
deficits.
Oxidative stress after trauma is counteracted by physiological production of antioxidants. Since
measuring multiple biochemical parameters (total antioxidants, lipid peroxidation, free radical production,
protein oxidation, and enzyme activity) is impractical for the clinical setting, the overall redox balance may be
assessed using the oxidation-reduction potential (ORP) with a point of care device. In preliminary studies this
method has provided an integrated measure of the balance between total oxidants and total reductants in
plasma7. This project seeks to measure ORP in patients with TBI as an index of oxidative stress, and to
determine if oxidative stress correlates with injury severity or clinical recovery.
While disorders of other organ systems can often be detected through rapid, serum-based biomarkers,
further research is needed to establish definitive neurochemical markers for brain injury 8. In particular, there
are no prognostic biomarkers that can categorize TBI patients by degree of risk for disease progress and
inform clinicians about the natural history of the injury. Clinicians treating patients after relatively mild TBIs,
who present after a loss of consciousness or period of altered cognitive function, must make several decisions
that could be aided by validated biomarkers of injury. For example, the clinician needs to determine if the
patient needs transport to the emergency department for evaluation or if neuroimaging is warranted. It would
also be valuable to predict if a patient is likely to recover completely or develop persistent post-concussive
symptoms. We hypothesize that a normal ORP measurement in the context of a normal Glasgow Coma Scale
(GCS) score will serve as a prognostic biomarker to rule out acute intracranial lesions or need for neurosurgical
intervention.
(Funded by Luoxis)
References
1.
2.
3.
4.
5.
6.
7.
8.
8/31/15
Awasthi D, Church DF, Torbati D, Carey ME, Pryor WA. Oxidative stress following traumatic brain injury in rats.
Surgical neurology. Jun 1997;47(6):575-581; discussion 581-572.
Bayir H, Tyurin VA, Tyurina YY, et al. Selective early cardiolipin peroxidation after traumatic brain injury: an
oxidative lipidomics analysis. Annals of neurology. Aug 2007;62(2):154-169.
Tyurin VA, Tyurina YY, Borisenko GG, et al. Oxidative stress following traumatic brain injury in rats: quantitation
of biomarkers and detection of free radical intermediates. Journal of neurochemistry. Nov 2000;75(5):21782189.
Osler T, Glance L, Buzas JS, Mukamel D, Wagner J, Dick A. A trauma mortality prediction model based on the
anatomic injury scale. Annals of surgery. Jun 2008;247(6):1041-1048.
Kojda G, Harrison D. Interactions between NO and reactive oxygen species: pathophysiological importance in
atherosclerosis, hypertension, diabetes and heart failure. Cardiovascular research. Aug 15 1999;43(3):562-571.
Vasquez-Vivar J. Tetrahydrobiopterin, superoxide, and vascular dysfunction. Free radical biology & medicine. Oct
15 2009;47(8):1108-1119.
Rael LT, Bar-Or R, Mains CW, Slone DS, Levy AS, Bar-Or D. Plasma oxidation-reduction potential and protein
oxidation in traumatic brain injury. Journal of neurotrauma. Aug 2009;26(8):1203-1211.
Zetterberg H, Smith DH, Blennow K. Biomarkers of mild traumatic brain injury in cerebrospinal fluid and blood.
Nat Rev Neurol. Apr 2013;9(4):201-210.
5
2b. Luoxis-Sepsis - #14-537
Oxidation-Reduction Potential as a Diagnostic Biomarker
in Trauma and Sepsis
Principal
Investigator
Kalev Freeman, MD, PhD, Department of Surgery
Contact
Nate Dreyfus ([email protected])

Research
Question

Do elevated ORP levels distinguish patients with sepsis or systemic
inflammatory response syndrome (SIRS) from patients without infection?
Do OPR levels return to normal after recovery from infection?
Study
Design
Evaluation of performance characteristics of a diagnostic test
Primary
Outcome
In-hospital mortality
Secondary
Outcomes
ICU days, ventilator-free days and APACHE II scores
Inclusion
Criteria


>18 years of age
At least two of the
following SIRS criteria:
 Fever >38.0 or
hypothermia <36.0
 Heart rate >90
 Respirations >20
 White cell count
>12 X 109/L or <4 X
109/L
Exclusion
Criteria
Vulnerable Population Eligibility
Minors
Pregnant women
Incarcerated
Cognitively impaired
Minorities
Economically or educationally disadvantaged
Seriously injured or ill
Procedures
8/31/15


< 18 years
Non-English speaking
Included
Excluded







SRA: Screening, data collection
RA: Data collection
6
Summary
Oxidative stress after trauma is counteracted by physiological production of antioxidants. Since
measuring multiple biochemical parameters (total antioxidants, lipid peroxidation, free radical production,
protein oxidation, and enzyme activity) is impractical for the clinical setting, the overall redox balance may be
assessed using the oxidation-reduction potential (ORP) with a point of care device. In preliminary studies this
method has provided an integrated measure of the balance between total oxidants and total reductants in
plasma1,2. This project seeks to measure ORP in patients with sepsis as an index of oxidative stress, and to
determine if oxidative stress correlates with mortality or illness severity.
Oxidative stress may be a potential biomarker for severe infection or sepsis. There is evidence that the
innate response to infection can be influenced by the cellular redox state3. In addition, it has also been
established that reactive oxidative species contributes to organ failure in septic patients 4. We hypothesize that
an elevated ORP measurement will serve as a biomarker in septic patients.
(Funded by Luoxis)
References
1.
2.
3.
4.
8/31/15
Rael LT, Bar-Or R, Mains CW, Slone DS, Levy AS, Bar-Or D. Plasma oxidation-reduction potential and protein
oxidation in traumatic brain injury. Journal of neurotrauma. Aug 2009;26(8):1203-1211.
Rael LT, Bar-Or R, Salottolo K, et al. Injury severity and serum amyloid A correlate with plasma oxidationreduction potential in multi-trauma patients: a retrospective analysis. Scandinavian journal of trauma,
resuscitation and emergency medicine. 2009;17:57.
Kolls JK. Oxidative stress in sepsis: a redox redux. The Journal of Clinical Investigation. 2006;116(4):860-863.
Galley HF. Oxidative stress and mitochondrial dysfunction in sepsis. British Journal of Anaesthesia. July 1, 2011
2011;107(1):57-64.
7
2c. Luoxis-Mild TBI - #14-537
Oxidation-Reduction Potential as a Diagnostic Biomarker in Mild TBI
Principal
Investigator
Kalev Freeman, MD, PhD, Department of Surgery
Contact
Nate Dreyfus ([email protected])
Research
Question


Do oxidative-reduction potentials (ORPs) distinguish TBI patients
from non-head injured controls?
Do elevated ORP levels correlated with post-concussive symptoms
in patients with mild TBI?
Study
Design
Evaluation of performance characteristics of a diagnostic test
Primary
Outcome
ORP levels in those with mild, isolated TBI at time of injury and 3-4 weeks
later
ImPACT scores on cognitive function and post-concussion severity score
3-4 weeks following injury
ImPACT scores on cognitive function and post-concussion severity score
Secondary
Outcomes
Inclusion
Criteria

≥18 years of age and have
an isolated head injury
not requiring UVM MC
Trauma and Burn Service
 Must report 2 or more of
the following concussive
symptoms:
 Loss of consciousness
 Blurred vision or “seeing
stars”
 Confusion
 Dizziness or vertigo
Vulnerable Population Eligibility
Minors
Pregnant women
Incarcerated
Cognitively impaired
Minorities
Economically or educationally disadvantaged
Seriously injured or ill
Procedures
8/31/15
Exclusion
Criteria




≤18 years of age
Non-English speaking
History of disabling TBI
Dementia or active
psychiatric disorder
Included
Excluded







SRA: Screening, data collection, enrollment
RA: Data collection, enrollment
8
Summary
Brain trauma delivers complex physiological, emotional, and cognitive insult with the potential for persistent
negative effects. Even mild TBI increases the risk for post-concussive symptoms, PTSD, and physical health problems.
TBI often results in persistent pain, impairment of cognitive function, and may also disrupt the normal neuroregulation
of the cardiovascular system.
The biological basis of neuronal damage and recovery following traumatic brain injury (TBI) is not completely
understood. Oxidative stress, secondary to tissue ischemia reperfusion injury and systemic inflammatory responses, may
play a role. In animal models, elevated levels of reactive oxygen species (ROS) have been demonstrated after traumatic
brain injury in neuronal tissue1-3. Altered redox balance reduces nitric oxide bioavailability and impairs vascular
endothelial reactivity4-6. Cerebrovascular dysfunction ultimately contributes to cerebral edema and poor recovery after a
traumatic brain injury leading to cognitive deficits.
Oxidative stress after trauma is counteracted by physiological production of antioxidants. Since measuring
multiple biochemical parameters (total antioxidants, lipid peroxidation, free radical production, protein oxidation, and
enzyme activity) is impractical for the clinical setting, the overall redox balance may be assessed using the oxidationreduction potential (ORP) with a point of care device. In preliminary studies this method has provided an integrated
measure of the balance between total oxidants and total reductants in plasma 7,8.
Clinicians treating patients after relatively mild TBIs, who present after a loss of consciousness or period of
altered cognitive function, must make several decisions that could be aided by validated biomarkers of injury. For
example, the clinician needs to determine if the patient needs transport to the emergency department for evaluation or
if neuroimaging is warranted. It would also be valuable to predict if a patient is likely to recover completely or develop
persistent post-concussive symptoms.
This project seeks to measure ORP in patients with TBI as an index of oxidative stress and to determine if
oxidative stress correlates with injury severity. Additionally, we will seek to determine whether ORP levels will correlate
with performance on neurocognitive testing and delays in recovery in patients with mild TBI. We will determine
cognitive outcomes and post-concussive symptoms using the computerized ImPACT test battery.
(Funded by Luoxis)
References
1.
Awasthi D, Church DF, Torbati D, Carey ME, Pryor WA. Oxidative stress following traumatic brain injury in rats.
Surgical neurology. Jun 1997;47(6):575-581; discussion 581-572.
2.
Bayir H, Tyurin VA, Tyurina YY, et al. Selective early cardiolipin peroxidation after traumatic brain injury: an
oxidative lipidomics analysis. Annals of neurology. Aug 2007;62(2):154-169.
3.
Tyurin VA, Tyurina YY, Borisenko GG, et al. Oxidative stress following traumatic brain injury in rats: quantitation
of biomarkers and detection of free radical intermediates. Journal of neurochemistry. Nov 2000;75(5):21782189.
4.
Osler T, Glance L, Buzas JS, Mukamel D, Wagner J, Dick A. A trauma mortality prediction model based on the
anatomic injury scale. Annals of surgery. Jun 2008;247(6):1041-1048.
5.
Kojda G, Harrison D. Interactions between NO and reactive oxygen species: pathophysiological importance in
atherosclerosis, hypertension, diabetes and heart failure. Cardiovascular research. Aug 15 1999;43(3):562-571.
6.
Vasquez-Vivar J. Tetrahydrobiopterin, superoxide, and vascular dysfunction. Free radical biology & medicine. Oct
15 2009;47(8):1108-1119.
7.
Rael LT, Bar-Or R, Mains CW, Slone DS, Levy AS, Bar-Or D. Plasma oxidation-reduction potential and protein
oxidation in traumatic brain injury. Journal of neurotrauma. Aug 2009;26(8):1203-1211.
8.
Rael LT, Bar-Or R, Salottolo K, et al. Injury severity and serum amyloid A correlate with plasma oxidationreduction potential in multi-trauma patients: a retrospective analysis. Scandinavian journal of trauma,
resuscitation and emergency medicine. 2009;17:57.
8/31/15
9
3. PATH-C - # 14-162
Post-Arrest Therapeutic Hypothermia with a Cooling Collar
Principal
Investigator
Dan Wolfson, MD, Department of Surgery
Contact
Mike O’Keefe ([email protected])
Research
Question
Primary:
What is the effectiveness of the Excel Cryo Cooling Collar for inducing therapeutic
hypothermia (TH) in the EMS setting?
How quickly does the collar drop tympanic temp?
Secondary objectives are to report:
– Ease of use
– When collar not applied, why
– Patient outcome at admission and at discharge
Study
Design
Survey (observational longitudinal study)
Primary
Outcome
Temperature rate of change
Secondary
Outcomes
Time to achieve a 0.8-3.0°C reduction in temperature
Time to reach and maintain subject temperature of 32°-34°C
Techniques employed to initiate/maintain induced mild hypothermia
Complications with the Excel Cryo device or other methods of induction
Ease of use of Excel Cryo Cooling Collar in the VT EMS setting
Inclusion
Criteria



≥ 18 years old
Sustained cardiac arrest
Regained pulse but
without regaining
consciousness
Exclusion
Criteria
Vulnerable Population Eligibility
Minors
Pregnant women
Incarcerated
Cognitively impaired
Minorities
Economically or educationally disadvantaged
Seriously injured or ill
Procedures
8/31/15



< 18 years old
Arrest caused by trauma
Not already hypothermic
Included
Excluded







SRA: Screening, data collection, enrollment
RA: Data collection, enrollment
10
Summary
Induced mild hypothermia is an accepted part of the care for post-resuscitation patients in the emergency
department (ED) and intensive care unit setting.1 The application of induced mild hypothermia in the prehospital setting has been a topic of debate. One study showed no benefit in neurologic outcome with pre-ED
induced hypothermia, but other studies have yielded different results.2 The Excel Cryo Cooling System is a
non-invasive cervical collar that provides cooling to the carotid arteries, the main blood supply to the brain,
and allows for the rapid initiation and stabilization of cerebral cooling.
Current initiation and maintenance of induced mild hypothermia involves surface cooling and/or intravenous
infusion of cold saline. Surface cooling with ice packs can cause skin irritation and is a time-consuming
application with variable results. Chemical ice packs are also one time use and can lead to adverse skin
reactions and are of variable efficacy. Cold saline is hard to store because it requires a refrigeration device,
which is not always available, requires pre-hospital providers to first establish IV access which is often
challenging in post-arrest patients, can be associated with volume overload or electrolyte abnormalities, and
has been shown to be ineffective for induced mild hypothermia maintenance.
The Excel Cryo Cooling System is a logical choice for the pre-hospital care of the post-arrest patient as it can be
applied rapidly by any level of provider (EMR/EMT/AEMT/Paramedic), quickly initiates selective cerebral
cooling, and can be maintained over long transport times. While the collar stabilizes the neck, the cooling
element targets the main arterial blood flow to the brain, increasing the rate of counter-current heat
exchange away from the brain. The device also includes a hinged door so access to the neck or cooling
element, should it be necessary, does not necessitate removal of the device and cooling can be continued
indefinitely.
Vermont Emergency Medical Services protocols state that for adult comatose survivors of cardiac arrest with a
pulse and patent airway, the initial temperature will be measured and recorded. If the patient remains
comatose, induced mild hypothermia measures will be followed using the Excel Cryo Cooling System. It is
common practice to use multiple methods to induce mild hypothermia. The addition of axilla and groin cooling
packs or the administration of chilled intravenous fluid will be dependent on the qualifications and judgment
of the emergency medical personnel at the scene.
The design of the clinical portion of this study is purely observational. EMS staff will take measurements of
tympanic temperature in increments of 5 minutes in the field. Temperature measurements in the ED will occur
in 5 minute intervals and are purely observational. When induced mild hypothermia management has been
transferred to the Arctic Sun system, the Excel Cryo Cooling Collar has been removed and the target
temperature for induced mild hypothermia (< 34° C) has been reached, the subject’s involvement in the study
will cease. The head of the EMS crew and the attending physician in the emergency department will answer a
questionnaire pertaining to the application of induced mild hypothermia and cooling collar ease of use.
(Funded by UVM Department of Surgery with support from Cryothermic Systems)
References
1. Xiao G, Guo Q, Shu M, et al. Safety profile and outcome of mild thypothermia in patients following cardiac
arrest: systematic review and meta-analysis. Emergency medicine journal : EMJ 2013;30:91-100.
2. Bernard SA, Smith K, Cameron P, et al. Induction of therapeutic hypothermia by paramedics after
resuscitation from out-of-hospital ventricular fibrillation cardiac arrest: a randomized controlled trial.
Circulation 2010;122:737-42.
8/31/15
11
4. TEM-C - # 14-150
Temperature Evaluation by MRI-Thermometry
with PRF during Cervical Cooling
Principal
Investigator
Dan Wolfson, MD, Department of Surgery
Contact
Eric Curran ([email protected])
Research
Question
Primary: Investigate the MRI thermometry rate-of-cooling of the brain
in subjects wearing the Excel Cryo Cooling Collar.
Secondary:
Document the time to induced mild hypothermia threshold
Evaluate the relationship between the rate-of-cooling of the brain
measured by MRI and by tympanic temperature
Study
Design
Self-controlled trial
Primary
Outcome
Rate of cooling
Secondary
Outcomes
Time to drop subject temperature 0.8-3.0°C
Time to induced mild hypothermia threshold (34ºC)
Relationship between MRI temperature of brain and externally measured
temperature (tympanic)
Inclusion
Criteria


>18 years of age
No MRI risk factors
Exclusion
Criteria








8/31/15
<18 or > 60 years of age
Any known medical problems that
limit activity or decrease blood
flow
Taking any medications (except
for certain common ones)
Oral medications that inhibit the
body’s ability to respond to cold
History of cardiac condition in a
family member < 40 years
Inability to fit in the MRI scanner
(BMI > 30 kg/m2)
MRI risk factors
Vital signs outside of acceptable
ranges
12
Vulnerable Population Eligibility
Minors
Pregnant women
Incarcerated
Cognitively impaired
Minorities
Economically or educationally disadvantaged
Seriously injured or ill
Procedures
Included
Excluded







SRA: None – subjects are healthy volunteers, NOT ED patients
RA: None
Summary
Induced mild hypothermia is an accepted part of the care for post-resuscitation patients in the emergency
department (ED) and intensive care unit setting.1 The application of induced mild hypothermia in the prehospital setting has been a topic of debate. One study showed no benefit in neurologic outcome with pre-ED
induced hypothermia, but other studies have yielded different results.2 The Excel Cryo Cooling System is a
non-invasive cervical collar that provides cooling to the carotid arteries, the main blood supply to the brain,
and allows for the rapid initiation and stabilization of cerebral cooling.
In the emergency medicine setting tympanic temperature is the primary means of obtaining a temperature.
However, it is debated whether tympanic temperature is a good proxy for brain temperature. 3, 4 Healthy
subjects will be recruited for an MRI study of the cooling effects of the Excel Cryo Cooling System (MRI
compatible). Controls will be healthy volunteers recruited from advertisements. They will be asked to undergo
an MRI while wearing the Excel Cryo Cooling Collar and will have their temperature measured throughout the
cooling phase until induced mild hypothermia has been attained (this will take approximately 45 minutes).
Once subject temperature drops 0.8-3.0°C they will be monitored for an additional 15 minutes to check for
the maintenance of cooling and to verify if they reach the induced mild hypothermia range of 32-34°C.
Subjects will also undergo a second MRI while wearing the non-functioning Excel Cryo Cooling Collar to obtain
a baseline MRI image. MRI thermometry provides a more precise measure of temperature rate-of-change in
targeted tissues, compared to tympanic temperature, which is beneficial when studying the induction of
induced mild hypothermia.
(Funded by UVM Department of Surgery with support from Cryothermic Systems)
References
1. Xiao G, Guo Q, Shu M, et al. Safety profile and outcome of mild thypothermia in patients following cardiac
arrest: systematic review and meta-analysis. Emergency medicine journal : EMJ 2013;30:91-100.
2. Bernard SA, Smith K, Cameron P, et al. Induction of therapeutic hypothermia by paramedics after
resuscitation from out-of-hospital ventricular fibrillation cardiac arrest: a randomized controlled trial.
Circulation 2010;122:737-42.
3. Hasper D, Nee J, Schefold JC, Krueger A, Storm C. Tympanic temperature during therapeutic hypothermia.
Emergency medicine journal : EMJ 2011;28:483-5.
4. Mooney MR, Unger BT, Boland LL, et al. Therapeutic hypothermia after out-of-hospital cardiac arrest:
evaluation of a regional system to increase access to cooling. Circulation 2011;124:206-14.
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5. CHF Study # 14-421
Urine studies (sodium, potassium, creatinine and osmolality) as an early predictor of loop
diuretic response for acute decompensated congestive heart failure with fluid overload
Principal
Investigator
Richard Solomon, MD, Department of Medicine
Contact
Medicine: Sherrie Khadanga, MD ([email protected])
EMRAP: Pam Derickson ([email protected])
Research
Question
Primary: Can urine studies (osmolarity, Na, Cr, K) obtained at 0, 2, and 6 hours
post loop diuretic dose predict diuretic efficacy as measured by conventional
methods (UOP, weight change, PE)?
Secondary: Do patients with optimal urine studies following initial loop diuretics
have a shorter hospital stay, decreased readmission rates, lower change in
serum creatinine, heart failure symptom questionnaire, and decreased
complications?
Study
Design
Observational longitudinal study
Primary
Outcome
Urine output, weight change, physical exam findings
Secondary
Outcomes
Length of hospital stay, frequency of readmission, change in serum creatinine,
heart failure symptom questionnaire score, and complications
Inclusion
Criteria


>18 years of age
ED diagnosis of:
 “CHF”
 “acute on chronic
systolic heart
failure” or
 “acute on chronic
diastolic heart
failure”
Exclusion
Criteria
Vulnerable Population Eligibility
Minors
Pregnant women
Incarcerated
Cognitively impaired
Minorities
Economically or educationally disadvantaged
Seriously injured or ill
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



<18 years of age
End-stage renal disease
Chronic kidney disease stage 4
New onset heart failure
Included
Excluded







14
Procedures
SRA: Screening, data collection
RA: Data collection, enrollment
Summary
There are more than 1 million hospitalizations for acute decompensated heart failure (ADHF) annually which
accounts for more than $34 billion of United States health care expenditure, and the majority of these
hospitalizations are due to fluid overload (1). The current standard of therapy for fluid overload consists of
loop diuretics along with fluid status monitoring using urine output (UOP), physical exam (PE), and weight to
guide the proceeding dose and/or type of diuretic for continued therapy. An inherent flaw in our current
standard of therapy is a delay of up to 24 hours in obtaining feedback (UOP, weight, and PE) on diuretic
efficiency, which may lead to a longer hospital stay, and potentially increase risk to the patient. To complicate
things further, PE is user specific and it has been shown that there is no correlation between either weight loss
or net fluid loss and symptom relief (3). Clear and efficient guidelines to direct diuretic selection and dose are
lacking. We believe that if we could correlate urine studies [sodium (Na), potassium (K), creatinine (Cr), and
osmolarity (osm)] with diuretic efficiency, we may be able to determine when a class of diuretic (e.g., loop
diuretic) has achieved its potential maximum effect, and when further escalation of doses is futile. Defining
and implementing an algorithmic approached guided by readily available objective biomarkers would lead to
altering diuretic regimens sooner. This may lead to more efficient diuresis, resulting in shortened hospital stay,
decreased morbidity associated with longer hospitalizations, and decreased overall cost.
We propose that urine Na concentration less than 20 mEq/L will predict inefficient diuretic therapy and
prolonged hospital stay. In addition, loop diuretics decrease the osmolarity of the renal medulla. A clear
correlation in changes of medulla osmolarity achieved by loop diuretics and volume of diuresis and Na loss in
response to this group of medications has been shown (2). Since heart failure patients are in high anti diuretic
hormone (ADH) state, low urine osmolarity is a reliable marker for low medulla osmolarity. This results in
renin production, thus triggering the renin-angiotensin-aldosterone-system (RAAS) (6). Measuring urine
potassium (K) will provide information on the activity of the RAAS.
We plan to analyze efficiency of loop diuretics in patients with ADHF by obtaining urine studies (Na, K, Cr, osm)
at 0, 2 and 6 hours after initial ED dose of loop diuretic followed by data collection of UOP, weight change,
creatinine change, duration of hospitalization, and readmission rates. If a correlation is found between urine
studies (low urinary Na and high urinary osmolarity) and diuretic efficacy (as judged by UOP, weight change,
serum creatinine and sodium change, duration of hospitalization, heart failure symptom questionnaire, and
readmission rates), this could lead to urine-indices-guided diuretic therapy which could establish new
guidelines in diuretic therapy use for ADHF with fluid overload.
(Funded by UVM Department of Medicine)
References
1.
2.
3.
4.
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Thomas M. O’Brien, MD, Santosh Menon, MD, et al. Algorithm-based Assessment of target weight removal in acute
decompensated heart failure. Congest Heart failure 2012; vol 18: No. 1
Kim N, Cheema-Dhadli, et al. Non-natriuretic doses of furosemide: potential use for decreasing the workload of the renal outer
medulla with minimal magnesium wasting in the rat. Nephron Physiology 2012; 122(1-2):7-12
Robb D. Kociol, MD et al. Markers of decongestion, Dyspnea Relief, and Clinical Outcomes Among Patients Hospitalized with
Acute Heart Failure. Circ Heart Fail 2013; 240-245.
David E. Golan et al. Principles of Pharmacology. The pathophysiologic Basis of Drug Therapy. Third Edition; 345-346.
15
6. MAAT-P Study # 15-099
Mobile Assessment After Trauma- Pilot (MAAT-P)
Principal
Investigator
Matthew Price, Ph.D., Department of Psychology
Contact
Psychology: Matthew Price, Ph.D., ([email protected])
EMRAP: Nate Dreyfus ([email protected])
Research
Question
Primary: Evaluate the variation in mental health symptoms that occur in trauma
victims post-discharge. It is hypothesized that patients repeatedly exposed to
trauma cues and experience consistently high levels of pain will be most likely to
develop mental health disorders including posttraumatic stress disorder,
depression, and related issues.
Secondary: Determine the primary concerns of trauma patients in the days and
weeks post-discharge. These concerns will help guide post-acute care.
Study Design Observational longitudinal study using ecological momentary assessment (EMA)
Primary
Outcome
Mental health diagnoses at 1-month and 3-month post discharge.
Secondary
Outcomes
Injury related disability
Inclusion
Criteria



>18 years of age
Meets the criterion A
of a DSM 5 PTSD
diagnosis
Landline or mobile
phone
Exclusion
Criteria
Vulnerable Population Eligibility
Minors
Pregnant women
Incarcerated
Cognitively impaired
Minorities
Economically or educationally disadvantaged
Seriously injured or ill
Procedures
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
<18 years of age
Included
Excluded







SRA: Screening, data collection
RA: Data collection, enrollment
16
Summary
One third of patients admitted to the hospital for a traumatic injury develops a psychiatric condition, the most
common being posttraumatic stress disorder (PTSD) and depression. Substance abuse is also common in this
population, but in most cases predates the injury (i.e., is not a result of the injury) (O’Donnell, Bryant,
Creamer, & Carty, 2008). Many emergency departments across the US now implement a well-established
screening and referral mechanism for substance using patients (Bernstein & Boudreaux, 2007). However,
similar screening and referral mechanisms are not in place for PTSD and depression despite traumatic injury
patients being at very high risk for these disorders (O’Donnell et al., 2008). As a result, the majority of patients
who develop PTSD or depression will not receive any mental health follow-up post-discharge despite the
availability of simple screening tools and effective treatments. Research has shown that only 2/3 of individuals
who develop post-traumatic injury mental health conditions do not receive treatment with ethnic minorities
being half as likely to access such services (Bryant et al., 2010). Patients who do not receive appropriate
treatment for PTSD and depression have poorer physical and mental recovery from the injury, take longer to
resume employment, have a lower quality of life, and place increased burden on the healthcare system
(Haagsma et al., 2012). Estimates have shown that patients with untreated PTSD cost healthcare systems 50%
more than those who receive care for their symptoms. Fletcher Allen Health Care has the only level 1 Trauma
Center in Vermont that is certified by the American College of Surgeons.
A key challenge in connecting patients to mental health care after an injury is successful identification of
those who are in need of treatment. Nearly all patients who present to a trauma center for treatment have
significant emotional distress. Longitudinal studies have shown that this initial reaction is a poor predictor of
chronic PTSD and depression (O’Donnell et al., 2008). It is therefore inappropriate to simply refer all patients
with significant emotional distress to follow-up mental health care. It is similarly inappropriate and costly to
apply a universal approach to treatment where all patients with traumatic injuries receive comprehensive
mental health services (Litz & Gray, 2004). A targeted approach for high-risk patients is essential (Draper &
Ghiglieri, 2011). The majority of trauma injury patients will not require formal mental health treatment and
will demonstrate resilience or recovery without intervention. Prior work has suggested that patients who
continue to demonstrate symptoms within 2 to 4 weeks after the injury are unlikely to recover without
comprehensive mental health treatment (Bryant et al., 2010). Proper identification of patients who will need
mental health treatment therefore requires a symptom tracking system that monitors patients’ symptoms
over a short period post-discharge, a process referred to as watchful waiting (Tarrier et al., 1999). Watchful
waiting will be a key component of our proposed program to ensure that patients at low risk for PTSD and
depression are not receiving unnecessary services and that those at high risk are connected to effective
treatment.
The majority of trauma centers in the United States, including FAHC, do not currently assess risk for PTSD
and depression after a traumatic injury. There are several potential reasons for the lack of such services. First,
follow up mental health care falls outside the scope of practice for acute care services. Trauma surgery
primarily consults with mental health for cases in which immediate intervention is required because the
patient is (1) suicidal, (2) displays psychotic symptoms, or (3) is in a life threatening situation due to substances
(e.g. overdose or alcohol detoxification). Second, for traditional face-to-face or telephone-based symptom
tracking mechanisms, substantial infrastructure is required to conduct repeated follow up assessments. Such
resources, including case managers and tracking systems, are not typically available in trauma centers. Clinical
trials that have integrated mental health care into an acute medical setting have found the approach to be
unsustainable without external funding. One such trial reported that case managers spent approximately 60
hours per patient in the year following the injury. Third, repeated follow up telephone conversations and inperson appointments with medical staff for mental health care can prove burdensome to patients. Patients
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17
may be increasingly unwilling to engage in repeated phone calls with case managers about their mental
health, an initial low area of concern, in the immediate aftermath of a trauma. Alternative strategies that do
not place such burden on patients and medical centers are needed to identify patients at risk for mental
health disorders after injury.
Unfortunately, the lack of assessment strategies translates to fragmented follow up care for trauma injury
patients. A recent review of two years of outpatient records from the National Crime Victims Center (NCVC), a
specialty clinic for mental health treatment following trauma, revealed that none of the approximately
patients treated by local hospitals received evaluation or treatment within 3 months of their injury.
References
Bernstein, E., & Boudreaux, E. D. (2007). An evidence based alcohol screening, brief intervention and referral
to treatment (SBIRT) curriculum for emergency department (ED) providers improves skills and
utilization. Substance Abuse : Official Publication of the Association for Medical Education and Research
in Substance Abuse, 28(4). Retrieved from http://works.bepress.com/edwin_boudreaux/19
Bryant, R. A., O’Donnell, M. L., Creamer, M., McFarlane, A. C., Clark, C. R., & Silove, D. (2010). The Psychiatric
Sequelae of Traumatic Injury. American Journal of Psychiatry, 167(3), 312–320.
doi:10.1176/appi.ajp.2009.09050617
Draper, C., & Ghiglieri, M. (2011). Post-traumatic stress disorder. Computer based stepped care: Practical
applications to clinical problems. In Stepped care and e-health (pp. 77–97). Springer.
Haagsma, J. A., Polinder, S., Olff, M., Toet, H., Bonsel, G. J., & Beeck, E. F. van. (2012). Posttraumatic stress
symptoms and health-related quality of life: a two year follow up study of injury treated at the
emergency department. BMC Psychiatry, 12(1), 1. doi:10.1186/1471-244X-12-1
Gray, M. J., Litz, B. T., Hsu, J. L., & Lombardo, T. W. (2004). Psychometric properties of the life events
checklist. Assessment, 11(4), 330-341.
O'Donnell, M. L., Bryant, R. A., Creamer, M., & Carty, J. (2008). Mental health following traumatic injury:
toward a health system model of early psychological intervention. Clinical Psychology Review, 28(3),
387-406.
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7. Biomarkers in Uncontrolled Asthma- Poorly
Controlled Asthma Component #14-393
Screening patients in the ED for asthmatics using certain medications
Principal
Investigator
Anne Dixon, M.A., B.M., B.Ch., Pulmonary Disease and Critical Care Medicine
Contact
Pam Derickson ([email protected])
Research
Question


How do asthma medications (specficially Advair, Symbicort, and Dulera) affect
asthma symptoms?
What effects do these medications have on circulating factors in one’s blood
and nasal epithelial tissue?
Study
Design
Pilot screening study to investigate how asthma medications control
symptoms
Primary
Outcomes
Incidence of circulating IgE, TARC, and ST2 and of biomarkers in blood and nasal
epithelial brushings when using the asthma medications Advair, Symbicort, and
Dulera
Secondary
Outcomes
Analysis of various assay formats for detection of IgE, TARC, and ST2
Inclusion
Criteria



15 - 70 years of age
Self-report of
physician diagnosis of
asthma
Are prescribed Advair,
Symbicort, or Dulera
(viewable on a
patient’s medical
record) and have a
diagnosis of asthma
Exclusion
Criteria







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Use of systemic steroids for more
than 48 hours within the last 4
weeks
Use of omalizumab within last year
Other significant disease that in
the opinion of the investigator
would interfere with the study
(including cystic fibrosis, diabetes
mellitus, immunodeficiency
disorder, chronic lung disease
other than asthma)
Inability to perform required
testing
Smoking within the last 6 months
Greater than 20 pack year smoking
history
Pregnancy
19
Vulnerable Population Eligibility
Minors
Pregnant women
Incarcerated
Cognitively impaired
Minorities
Economically or educationally disadvantaged
Procedures
Included
 (Ages 15+)
Excluded





SRA: Screening for asthma exacerbation using PRISM
RA: Approaching patients here for asthma exacerbation, providing them
with informed consent documents (don’t have to sign)
Summary
Asthma is one of the most common chronic illnesses afflicting children and adults in the United States.
Despite an ongoing massive global research effort, few new treatments have emerged for the treatment of
asthma in the last two decades. The standard form of treatment for patients with moderate to severe asthma
remains combination therapy with inhaled corticosteroids and long acting beta agonists. Patients that do not
respond to moderate to high dose inhaled corticosteroids combined with long acting bronchodilators present
a particularly difficult patient population. One of the major barriers to developing new treatments is the lack
of accurate biomarkers of disease activity in patients. The goal of this research plan is to evaluate the
sensitivity, range, and performance of candidate biomarker assays, and to assess their suitability for use in
clinical studies of asthma patients with moderate to severe disease and who are either controlled,
uncontrolled, or partially controlled with their current treatment regimen.
In clinical studies, cytokine-targeted therapeutics have shown modulation of serum biomarkers,
including IgE, TARC, and ST2. We propose to examine various assay formats for detection of these and other
markers in serum and plasma samples from moderate to severe asthmatics. The goals of this study are to
determine if circulating levels of the marker are related to asthma exacerbations. Additionally, biomarkers in
blood, nasal epithelial brushings of asthmatics will be analyzed as a measure of anti-inflammatory
pharmacodynamics activity. Gene expression signatures can be examined in RNA prepared from whole blood
cells, enriched T cells, circulating monocytes, sputum cells, or nasal epithelial cells. The goal of this arm of the
study is to identify possible changes in gene expression that may correlate with asthma exacerbations. These
variables will be measured at an exacerbation visit and recovery visit (3-6 weeks after exacerbation visit).
References
1. Al-Alwan A, Bates JHT, Chapman D, Kaminsky DA, DeSarno MJ, Irvin CG, Dixon AE. The non-allergic asthma
of obesity: a matter of distal lung compliance. Am J Respir Crit Care Med. 2014 Jun;189(12):1494-502
2. Dixon AE, Suratt BT. Active Lifestyle: The Next "Smoking Cessation"? Am J Respir Crit Care Med. 2014
May;189(10):1155-6.
3. Kapadia SG, Wei C, Bartlett SG, Lang JE, Wise RA, Dixon AE. Obesity and depression contribute
independently to the poor asthma control of obesity. Resp Med. 2014 - accepted for publication
4. Sideleva O, Dixon AE. The many faces of asthma in obesity. J Cell Biochem. 2014 Mar;115(3):421-6.
5. Sideleva O, Suratt BT, Black K, Tharp WG, Pratley RE, Forgione P, Dienz O, Irvin CG, Dixon AE. Obesity and
Asthma: an inflammatory disease of adipose tissue not the airway, American Journal of Respiratory and
Critical Care Medicine 2012; 186(7): 598-605.
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