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COL R. Scott Miller, M.D., FACP, FIDSA Assistant Professor of Medicine, USUHS Director, Hyperbaric Oxygen Research Program US Army Medical Materiel Development Activity Ft. Detrick , MD. Post-Concussion Syndrome Rehabilitation: Is there a Role for Hyperbaric Oxygen? 4 MAY 2012. DISCLAIMER.

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post concussion syndrome rehabilitation is there a role for hyperbaric oxygen 4 may 2012
COL R. Scott Miller, M.D., FACP, FIDSA

Assistant Professor of Medicine, USUHS

Director, Hyperbaric Oxygen Research Program

US Army Medical Materiel Development Activity

Ft. Detrick, MD

Post-Concussion Syndrome Rehabilitation: Is there a Role for Hyperbaric Oxygen? 4 MAY 2012
slide2

DISCLAIMER

  • "Opinions, interpretations, conclusions, and recommendations are those of the presenter and are not necessarily endorsed by the other members of the HBO2 research consortium, the U.S. Army Medical Materiel Development Activity, the U.S. Army Medical Research and Materiel Command, the U.S. Army or the Department of Defense ."
concussions in the military

Concussions in the Military

  • 70-80% fully recover in 3 months
  • concussions may be complicated by psychological trauma or PTSD
what is hyperbaric oxygen hbo 2
What is Hyperbaric Oxygen (HBO2)?

Intervention in which a patient breathes 100% oxygen intermittently inside a chamber that is pressurized to higher than sea level pressure

specifically to pressures of 1.4 atmospheres absolute or higher.

creates supraphysiologic O2 concentrations in blood and tissues … which FDA considers a drug

FDA Approved Indications for HBO2

Decompression Sickness - Crush Injuries

Air/Gas Embolisms - Enhanced Healing of Selected Wounds

Carbon Monoxide Poisoning and Smoke Inhalation

Intracranial Abscess - Radiation Tissue Damage

Gas Gangrene - Skin Grafts and Flaps

Necrotizing Soft Tissue Infection - Thermal Burns

Osteomyelitis, refractory - Exceptional Blood Loss

slide5

HBO2Administration

Monoplace Chamber

A hyperbaric oxygen session with

oxygen hoods in multiplace chamber

Equalizing middle ear pressure

slide6

Why HBO2?

  • HBO2 is a FDA-cleared treatment modality recommended for 14 indications
    • including carbon monoxide poisoning where acutely it works in part to reduce inflammatory responses in the brain
  • As an alternative medicine therapy, it has been evaluated for a variety of other neurologic conditions:
    • acute stroke and stroke rehabilitation
    • cerebral palsy
    • autism
    • anoxic brain injury
    • acute moderate-severe TBI
    • TBI rehabilitation
hbo 2 for chronic brain injury
1967: Holbach (Germany)

Used 1.5 atm abs for chronic stroke

1973: Holbach and Caroli (Germany) – dose selection

From 1967 to 1973, over 700 HBO2 sessions for acute brain injury

Examined cerebral glucose metabolism and acid/base balance of the brain in 102 patients that received 267 courses of HBO2

Discovered that 1.5 atm abs was optimal, 2.0 atm abs was adverse

1980: Neubauer and End (Florida)

Used 1.5 atm abs for chronic stroke, 2.0 atm abs for acute stroke

Subsequently used 1.5 atm abs for other types of chronic brain injury

1994: Harch (LSU) – open label study

Used HBOT 1.5 atm abs in chronic brain injury x 40-80 sessions.

SPECT brain imaging showed increased perfusion at selected intervals and clinical improvement noted

HBO2 for chronic brain injury
hbo 2 in subacute tbi limited animal data
HBO2 in subacute TBI – limited animal data

Mechanisms of action in subacute/chronic TBI are unknown

Limited animal data

Rat focal cortical contusion model –

intervention 30d post injury

3 groups:

untreated control

sham, normobaric air group

HBO2 1.5 ATA x 90 min, 80 sessions given twice daily

Endpoint:

Morris Water Task

Improved spatial learning/memory

Increased Blood volume - Hippocampus

Harch 2007 Brain Res 1174: 120

slide9

HBO2 for TBI

Health System Perspectives

  • HBO2: a cleared product and can be prescribed ‘off-label’
    • problem is payment/reimbursement
    • no third party payers will cover acute TBI or brain rehabilitation citing that lack of quality evidence
    • requires out-of-pocket payments
  • 2003UMHS Position Statement – insufficient data for endorsement for acute or chronic brain injury
  • 2003 AHRQ – insufficient evidence for TBI, stroke and cerebral palsy
  • 2008Cochrane Review – insufficient data for acute TBI
  • 2009VA Review – insufficient data to support use for TBI or PCS
slide10

HBO2 for PCS

What MHS/TRICARE is Looking For

  • Evidence of a nationally accepted practice (32 CFR 199.2)
  • Reliable evidence
    • well-controlled trials of clinically meaningful endpoints, published in peer-reviewed literature
    • published formal technology assessments
    • published reports of national medical associations (i.e. UHMS)
    • published national medical policy organizations (i.e. AHRQ)
    • published reports of national expert opinions organizations (i.e. IOM)
  • NOT anecdotes and case series
slide11

Obtaining the Evidence

FDA Perspectives

  • U.S. Army Office of the Surgeon General holds the IND #104,678 for testing HBO2 for post-concussion syndrome
  • FDA considers hyperbaric oxygen a ‘combination product’
    • supraphysiologic levels of oxygen (drug) delivered in a Class II medical device (hyperbaric chamber)
  • Requirements for New Device Application (PMA)
    • safety collection sufficient in size
    • 2 randomized, double blind pivotal trials
dod va hbo 2 research program
DoD/VA HBO2 Research Program

USAFSAM Pilot Study (n=50)

We must know these before we start pivotal trial:

- sham method validated

- dose selection of HBO2

- outcome measure

validated to detect change

after intervention

- establish range of placebo

effect to determine

sample size

VA/VCU/USN Dose Ranging Study (n=60)

IND Filed

Type C meeting

End Phase II

De Novo/ 510K

HOPPS IND Pilot Study (n=96)

TMA & UHMS Submission

Outcome Validation Project

Mechanisms of Action Study (BIMA) (n=60)

Chambers Installation at 4 MTFs

Outcomes in Normals Study (n=75)

MultiModal Rehab Effectiveness RCT? (n=100)

DSMB

DSMB

DSMB

DSMB

Multicenter Pivotal Trial? (n=300+)

Jan ‘11

Jul’11

Jan ‘12

Jul ‘12

Jan ‘13

Jul ‘13

Jan ‘14

Jul ‘14

Jan ‘15

slide13

HBO2 for PCS

Efficacy Claims being Evaluated

  • Hyperbaric oxygen is being explored for the restorative treatment of post concussion syndrome
    • Relief of symptoms
      • post concussion symptom severity
      • post traumatic stress disorder symptom severity in individuals with co-morbid PTSD and PCS
    • Improved cognitive functioning
    • Improvement in quality of life for individuals with
      • post concussion syndrome (PCS)
    • Enhancement of other rehabilitation strategies?
dod va hbo 2 mtbi research program goals

To estimate in pilot studies if HBO2 shows benefit above sham control

To estimate placebo effect on outcome measures

May impact further research funding

To develop grade 1 evidence from randomized, sham- controlled trials that demonstrate if HBO2 is safe and effective for treatment of post concussion syndrome

If effective and safe:

to seek the endorsement of UHMS and TRICARE/VA for treatment of post-concussion syndrome

Ultimately submit the data to the FDA for treatment of symptoms and neurocognitive improvement in PCS

DoD/VA HBO2mTBI Research Program Goals
post concussion syndrome

Post-Concussion Syndrome

Lack of a standardized case definition

  • Using DSM-IV-TR definition
  • History of concussion (mTBI) - a closed head injury with:
    • Loss of consciousness for 0-30 minutes – OR
    • Alteration of consciousness for a moment up to 24 hours - OR
    • Traumatic amnesia lasting no longer than 1 day
    • AND
  • At least 3 symptoms starting or worsening after mTBIAND lasting at least 3 months:
    • Headaches - Seizures
    • Dizziness/balance problems - Difficulty with memory or solving problems
    • Blurred vision - Managing stress or emotional upset
    • Fatigue or sleep problems - Controlling your temper/irritability
    • Ringing in your ears
co morbidities associated with pcs
Co-Morbidities Associated with PCS

Chronic Pain

n=277

81.5%

PTSD

n=232

68.2%

10.3%

16.5%

2.9%

42.1%

12.6%

6.8%

5.3%

PCS

n=227

66.8%

  • 8% of PCS is an isolated finding

Lew, et al. 2009. Prevalence of Chronic Pain, Posttraumatic Stress Disorder, and Persistent Postconcussive Symptoms in OIF/OEF Veterans: Polytrauma Clinical Triad, Journal of Rehabilitative Research and Development, Vol. 46: 697-702.

slide17

Treatment of Post Concussion

Syndrome

  • No proven restorative therapy, other than time
  • Avoidance of recurrent concussion
  • Skills for coping with disability
  • Drugs for individual symptom relief

Crosby return on hold as concussion symptoms continue

Reuters – Wed, Dec 28, 2011

slide18

Treatment of Post Concussion Syndrome

  • Cognitive Rehabilitation – IOM Report Oct 2011
    • 88 non-coordinated, mostly single-site studies using:
      • non-standardized interventions; and
      • non-standardized outcome measures
    • limited evidence of benefit for post concussion syndrome (single study)
    • recommended continuing use until more evidence
slide19

Evidence for HBO2 for PCS/PTSD

  • Our wounded warriors deserve the best evidence-based medical care that is available
    • onus on MHS to evaluate off-label uses of traditional and alternative therapies when a treatment gap exists
  • Despite lots of hype and lobbying efforts, HBO2 remains a promising but unproven therapy for PCS
claims of efficacy in case reports case series in mtbi in warriors

Claims of Efficacy in Case Reports &Case Series in mTBI in Warriors

Anecdotal case reports (2009): Harch and Wright

SOCOM experience

Harch et al reported a case series of 15 warriors with

PCS/PTSD in J Neurotrauma Dec 2011

Veterans 1-4 years post mild TBI with chronic symptoms exposed to HBO2 1.5 ATA x 40 days with twice daily dive sessions

Assessment pre and immediately post treatment;

Up to 51% improvement in self-reported anxiety and depression sx

Self-reported ‘improved to normal’:

cognition (50 67%); emotional (3261%); physical (4766%)

Marked improvement in self-reported sleep

~ 10 % improvement in memory and neurocognitive tests

Most retained symptomatic improvement at 6 months.

slide21

Challenge:

Understanding the Placebo Response

Month stay in New Orleans

  • PCS symptoms, like all psychologic
  • & self-reported outcomes, are
  • markedly prone to
  • placebo/Hawthorne effects
  • RCT control group needed
    • placebo effects are pharmacologic
    • without understanding placebo effects, no claims of HBO2 efficacy can be confirmed
  • Khan 2002: half of all trials of antidepressants later FDA approved showed no benefit over placebo
    • effectiveplacebo response – antidepressants 30-50%
    • anxiolytics 30-50%
      • PTSD treatment 38.5%

Interactions with Caring Staff/ Placebo Effects

HBO2 Treatment

slide22

Meta-analysis of placebo-controlled 75 depression trials from 1981-2000

  • Successful outcome defined as 50% reduction in Hamilton depression scale
  • Overall 30% of placebo recipients met the 50% improvement threshold
  • Individual studies showed up 51% of placebo recipients met a 50% symptom improvement score
  • Placebo drift: effects are more pronounced in recent studies

Walsh BT et al, JAMA 2002; 287: 1840-7

slide23

Challenge:

SystemicallyMeasuring Improvement

  • As no current therapies exist for post-concussion syndrome, there are no validated outcome measures
  • Goal to validate outcome measures as scaffold for future clinical trials
    • Post-concussion symptoms questionnaire
      • Neurobehavioral Symptom Inventory (NSI)
        • - Must address confounds of co-morbidities
    • Global Outcome Score
    • Possibly, a battery of neurocognitive tests
summary state of the science
Summary: State of the Science

Despite a series of anecdotes and lobbying efforts for the hyperbaric industry, there remains no definitive medical evidence that HBO2 has a therapeutic role in the relief of symptoms or brain dysfunction for warriors with post-concussion syndrome/mild TBI or PTSD.

DoD leadership has partnered with the VA and academia to develop a coordinated research program to collect the data to allow evidence-based decision-making

mhs partnerships and info for wounded warriors
MHS Partnerships and Info for Wounded Warriors

ClinTrials.gov – registry of all clinical trials

HBO2 Information Hotline is available

Warriors can call 1-877-445-3199 to get information about any HBO2 research trial

Info on ongoing DoD and civilian studies

USAF Study

USAFSAM

Wilford Hall Medical Center

Hyperion Inc.

MRMC Multicenter Study

USAMMDA

Walter Reed Army Institute of Research

Evans Army Community Hosp/10thSF Group

Naval Hospital Camp Lejeune

Naval Hospital Camp Pendleton

Eisenhower Army Medical Center

LDS Hospital/Intermountain Healthcare

Denver VAMC/Center of Mental Illness Research

Henry M. Jackson Foundation

EmpiriStat Inc.

OxyHeal Health Group

Navy/VA Study

NOMI Pensacola

Virginia Commonwealth University

McGuire Richmond VAMC

Upcoming Studies

NICoE

Madigan AMC

Many new academic partners