Experimental Interventions for Brain Injury

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Experimental Interventions for Brain Injury

• Sue Churchill, NP
• Hyperbaric Medicine
• LDS Hospital

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Experimental vs. Accepted Practices

• Evidence-based practice guidelines
• Definition integration of clinical expertise,
  patient values, and the best evidence into the
  decision-making process for patient care.
• Medical literature search with rules for
  evidence in evaluating literature

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Best Evidence

• Gold standard peer-reviewed publications of
  randomized, controlled, double-blind trials
• absence of evidence does not equal evidence
  absence
• Brain Injury Association website best practices
  www.biausa.org
• www.ahrq.gov/clinic/epcix.htm
• www.hsl.unc.edu/services/tutorials/ebm.index.htm

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Objectives

• Present examples of medical interventions for
  traumatic brain injury that have not yet met
  criteria to be accepted as standards of care

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Neuroprotective or Regenerative Interventions

• Decompression Craniectomy
• Hypothermia
• Nanotechnology
• Pharmaceuticals
• Stem Cell Therapy
• Electrical Implants
• Hyperbaric Oxygen

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Traumatic Brain Injury

• Primary
• Immediate damage caused at the time of impact
• Unavoidable
• Secondary
• Damage that occurs as a consequence of primary
  injury within hours, days, or months after the
  injury at the cellular/molecular level
• Potentially avoidable

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Cascade of Events

• Injury
• Glutamine release
• ? intracellular calcium
• Activation of ion channels
• Triggering intracellular protolytic processes
• Blood-brain barrier leakage
• Brain edema
• ? blood flow
• ? intracranial pressure
• Ischemia/cell death

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Late Changes

• Scarring
• Environment that inhibits axon growth and repair
  of injured tissue
• Resulting in chronic debility, disability, or
  death

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Ischemic PenumbraTraumatic Penumbra
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Decompression Craniectomy

• Acute phase intervention
• ? intracranial pressure is the leading cause of
  death/poor outcome
• Craniectomy surgical removal of cranium to
  decompress the brain (remove pressure)
• Initially described 100 years ago by Theodor Emil
  Kocher (1901)

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Decompression Craniectomy Scientific Evidence

• No prospective randomized controlled trials in
  humans
• Not included in TBI guidelines as a primary
  therapeutic option for TBI
• Time-sensitive if to be beneficial (lt12-24 hours)
• Best used before pathological ICP
• Risks infection, further trauma
• Plesnila N. Decompression craniectomy after
  traumatic brain injury recent experimental
  results. Prog Brain Res. 2007161393-400.

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Clinically-Induced Hypothermia

• Neuroprotective
• First recognized in 1950s
• Used for ischemic and non-ischemic brain hypoxia,
  TBI, anoxia after cardiac arrest
• Busato, et al. 1987

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Mechanisms of Neuroprotection

• ? brain metabolic rate
• Blocks excitotoxic mechanism
• Calcium antagonist
• Modulates inflammatory response
• ? edema, ? ICP
• Modulates apoptosis (programmed cell death)
• Sahuquillo J, Vilalta A. Cooling the injured
  brain how does moderate hypothermia influence
  the pathophysiology of traumatic brain injury.
  Curr Pharm Des. 200713(22)2310-22.

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NABISH I

• National Acute Brain Injury Hypothermia Trial
  (1990s)
• 16-65 y/o with TBI
• Multicenter
• Cooled within 6 hours of injury for 48 hours
• Stopped early (392/500 enrolled)
• Clifton GL, et al. Lack of effect of induction
  of hypothermia after acute brain injury. N Engl J
  Med. 2001 Feb 22344(8)556-63.

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NABISH I

• Primary outcome 6-month neuro outcome
• No benefit, some did worse with hypothermia than
  control
• Flaws
• Multicenter variability
• Some patients presented to the ED hypothermic,
  and if control were warmed

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NABISH II

• Currently underway (started 2002), multicenter
  trial, non-randomized
• Severe TBI at scene (GCS 3-8)
• 16-45 y/o
• Cool within 2 hours of injury
• 33º for 48 hours, then gradually warmed

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Pediatric Study

• Hypothermia for severe TBI in children
• 12 centers, over the next 5 years
• Waived consent (time sensitive)
• All children up to 16 y/o
• Hypothermia within 6 hours
• http//www.clinicaltrials.gov/ct/show/NCT00282269

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Induction of Hypothermia

• Patient maximally oxygenated on ventilator
• Paralyzed to prevent shivering
• Sedated for comfort
• Cooled with fans, ice packs, cooling blanket,
  cold IV fluids
• Constant temperature monitoring with indwelling
  Foley catheter
• No stimulation

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Risks of Hypothermia

• Sepsis
• Cardiac arrhythmias
• Coagulopathy
• Electrolyte disturbances
• Rebound cerebral edema with warming
• Seppelt I. Hypothermia does not improve outcome
  from traumatic brain injury. Crit Care Resusc.
  2005 Sep7(3)233-7.

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Hypothermia Scientific Evidence

• Hypothermia not standard of care for TBI
• No evidence yet it improves outcome in TBI
• Is accepted standard of care in cardiac arrest
• Studies continue because
• Cooling techniques are changing
• Hypothermia and drugs may be more beneficial
• Mechanistically, it makes sense
• Ramani R. Hypothermia for brain protection and
  resuscitation. Curr Opin Anaesthesiol. 2006
  Oct19(5)487-91.

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Nanotechnology

• Neuronanomedicine a new science

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Nanotechnology

• Definition technology that is built from single
  atoms and depends on individual atoms for
  function
• Nanomaterial is lt100 nanometers (1 nanometer is 1
  millionth of a a millimeter)
• Single human hair is 80,000 nanometers

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Current Examples

• Drugs like antidepressants, tranquilizers,
  lithium
• Eliminate the blood-brain barrier as an obstacle
  to delivering therapeutic interventions

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Applications of Nanotechnology

• Using nanoparticles to provide a structure for
  regeneration of tissue
• Drug attached to nanoparticles to maximize
  targeted delivery and minimize systemic side
  effects
• To advance non-invasive procedures and diagnostic
  imaging capability
• Ellis-Behnke RG, Teather LA, Schneider GE, So
  KF. Using nanotechnology to design potential
  therapies for CNS regeneration. Curr Pharm Des.
  200713(24)2519-28.

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Nanotechnology Risks

• ? delivery of therapeutic or toxic products
  across blood-brain barrier ? toxicity
• Toxicity of nanoparticles themselves (causing
  plaques which can be harmful)
• Likely more risks that are unknown to us

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Neuroprotective Pharmaceuticals

• Estrogen and progesterone have known
  neuroprotective properties
• Animal studies using progesterone
• Mechanism of effect may be
• Acute antioxidant properties
• Anti-apoptotic activity
• Cell membrane stabilization
• Wright DW, et al. ProTECT a randomized clinical
  trial of progesterone for acute traumatic brain
  injury. Ann Emerg Med. 2007 Apr49(4)391-402,
  402.e1-2.

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ProTECT RCT

• Randomized clinical trial of progesterone for
  acute TBI (double-blind, placebo-controlled )
• 100 adult trauma patients, arrival lt11 hours from
  injury, moderate to severe TBI
• Proxy consent, IV progesterone or placebo
• Neurological outcome _at_30 days
• No serious adverse events attributed to
  progesterone
• Poor outcomes in both groups with severe TBI
• Possibly some benefit with progesterone in
  moderate TBI

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Stem Cell Therapy/ Transplantation

• CNS has limited capability to regenerate
• Stem cells can produce tissue, potentially to
  cure disease
• Controversy over which cells are best and most
  ethically acceptable
• Steindler DA. Stem cells, regenerative medicine,
  and animal models of disease. ILAR J.
  200748(4)323-38.

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Types of Stem Cells

• Embryonic/fetal neuronal stem cells
• Origin of all cells
• Difficult to get (sources aborted fetuses,
  non-used embryos, fertility clinics, cord blood)
• Ethically controversial
• Stromal cells
• Able to differentiate into multiple tissues
• Reseeding the lawn

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Stem Cells

• Process harvest cells culture freeze or use
  cells
• No evidence of cell rejection
• May be cytokines or chemotractants act as
  mediators
• Opydo-Chanek M. Bone marrow stromal cells in
  traumatic brain injury (TBI) therapy true
  perspective or false hope? Acta Neurobiol Exp
  (Wars). 200767(2)187-95.

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Administering Stem Cells

• Animal work (mice)
• Implant cells in brain which migrate to regions
  of brain and differentiate to new specialized
  cells
• Cuts from nervous system turn into nerve cells or
  glial cells
• Next step try process in monkeys ? humans
• In rats, IV injection to sites of injury
• Describe improved outcome
• Found timing of injection to injury important
  (within 24 hours, not after 7 days)

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Stem Cell Summary

• Predominantly pre-clinical studies
• Future studies
• Interval of injection/transplantation
• Quantity of cells
• How stem cells know to differentiate?
• Effects of trophic factors
• Risks of procedure (cancer)
• Picinich SC, et al. The therapeutic potential of
  mesenchymal stem cells. Cell- tissue-based
  therapy. Expert Opin Biol Ther. 2007
  Jul7(7)965-73.

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Brain Plasticity

• Ability of the brain to be formed or molded
• Brain adapts to deficits and injury
• The interventions utilized in the chronic phase
  rely on this concept

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Implanted Devices

• Single case report out of Weill Cornell Medical
  College in New York
• Patient in minimally conscious state improved (?
  alert) with electrical stimulation of a specific
  brain region with implanted electrodes

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Case Report

• 38 y/o M, minimally conscious for 6 years
  post-TBI
• Electrical stimulus to central thalamus
• Was able to chew food, speak, purposeful hand
  gestures
• Had an improvement in arousal system

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Visual Restoration Therapy

• Home-based tx, expand visual fields of hemianopic
  patients w/repetitive stimulation of border zone
  adjacent to blind field
• 6 subjects, 1 month therapy
• fMRI before and after
• First to demonstrate enhance visual processing in
  brain activity in response to visual
  field-specific training
• Marshall RS, et al. Brain activity associated
  with stimulation therapy of the visual borderzone
  in hemianopic stroke patients. Neurorehabil
  Neural Repair. 2007 Aug 15

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Hyperbaric Oxygen Therapy (HBO2)

• Definition Inhalation of 100 oxygen while
  pressured to greater than 1.4 atm abs
• (sea level 1 atm abs).

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Hyperbaric Oxygen Physiology

• Bubble volume reduction
• ? Blood/tissue PO2
• Gas washout (eg N2, CO)
• Vasoconstriction
• Neovascularization
• ? Growth factor receptors
• ? WBC oxidative killing
• Modulation ischemia/reperfusion

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HBO2 Indications

• Carbon monoxide poisoning
• Radiation tissue damage (osteoradionecrosis)
• Osteomyelitis (refractory)
• Skin grafts and flaps (compromised)
• Clostridial myonecrosis (gas gangrene)
• Problem ischemic wounds

UHMS 2003
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HBO2 Indications

• Crush injury/traumatic ischemia
• Decompression sickness
• Gas embolism
• Intracranial abscess
• Thermal burns
• Exceptional blood loss (anemia)

UHMS 2003
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Risks of Hyperbaric Oxygen

• Toxicity
• Seizures (1/3,000 1/5,000)
• Pulmonary O2 toxicity (rare)
• Middle ear and pulmonary barotrauma (lt5)
• Claustrophobia
• Flash pulmonary edema
• Heart failure
• Myopia

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AHRQ Tech Assessment

• Findings 1 RCT for TBI
• HBO2 might decrease mortality or duration of coma
  in severe TBI, but ? chance of poor functional
  outcome
• Second study, no difference in HBO2 group
• Agency for Healthcare Research Quality (AHRQ)
  Evidence Report (Tech Assessment 85)
  www.ahrq.gov/clinic/epcsums/hypoxsum.htm

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AHRQ Tech Assessment

• Conclusions
• Due to design or small sample size, do not
  establish a clear, consistent relationship
  between physiological changes after HBO2 sessions

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Neubauer, et al. Harch, et al. (1992-2004)

• Extrapolated HBO2 mechanisms ini wound healing to
  HBO2 in brain injury
• Proponents of HBO2 for chronic TBI, used low-dose
  HBO2 and SPECT brain to monitor changes
• Major weakness of their work
• Subjective outcome
• No clear treatment protocols
• No peer-review of work
• Not accepted as best evidence to support HBO2 as
  a standard of care

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Harch, et al. 2007

• Attempt to develop an animal model of aspects of
  the human case series, to experimentally examine
  efficacy of HBO2 in recovery after chronic brain
  injury
• Replication of pilot study with greater
  scientific rigor (statistical power and stronger
  experimental design)
• Harch PG, Kriedt C, Van Meter KW, Sutherland RJ.
  Hyperbaric oxygen therapy improves spatial
  learning and memory in a rat model of chronic
  traumatic brain injury. Brain Res. 2007 Oct
  121174120-9.

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Animal Study

• 64 rats
• Control group sham tx
• Treated group HBO2 80 tx, BID, 7 days per week,
  1.5 ATA 90 minutes
• Outcome measures learning location of platform
  in a pool, SPECT scan pre/post
• Results HBO2 group improved cognitive function
  with ? vascular density in hippocampus
• IN RATS!

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HBO2 in Chronic Stable Brain Injury

• LDS Hospital, feasibility study
• Eligibility gt 1 year from stroke, traumatic, or
  anoxic brain injury, gt 18 years old
• Outcomes Neuropsych testing, neurology, speech,
  PT
• Protocol
• Pre-HBO2 outcome testing
• 60 HBO2 sessions, 60 minutes daily, 1.5 ATA
• Post-HBO2 outcome testing
• 6-Month Post-HBO2 outcome testing

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MRI HBO2 in Chronic Stable Brain Injury

• 20 subjects
• Pre- and post-HBO2 fMRI with DTI SPECT scan
• SPECT single photon emission computed
  tomography
• Measure of blood flow to normal and impaired
  brain tissue
• fMRI functional magnetic resonance imaging
  (axial sequences for auditory, visual, and motor
  function)

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MRI HBO2 in Chronic Stable Brain Injury

• DTI diffusion tensor imaging (3-dimensional
  images of brain fiber tracks)

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Status of Project

• No data analysis yet
• Anticipate enrollment completed in 1 year, study
  finished in 1 ½ years
• May lead to a multi-center trial

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Summary

• Most of this research is still early
• Hard to extrapolate from animal studies to human
  response without human trials
• More information is needed to alter the standard
  of care in traumatic brain injury