Post-Concussion Syndrome Rehabilitation

Report
USAMMDA - Developing Quality Medical Products for U.S. Forces
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
[email protected]
UNCLASSIFIED
1
USAMMDA - Developing Quality Medical Products for U.S. Forces
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 ."
[email protected]
UNCLASSIFIED
2
USAMMDA - Developing Quality Medical Products for U.S. Forces
Concussions in the Military
• 70-80%
fully recover in 3 months
• concussions may be complicated by psychological trauma or
PTSD
[email protected]
UNCLASSIFIED
3
USAMMDA - Developing Quality Medical Products for U.S. Forces
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
Air/Gas Embolisms
Carbon Monoxide Poisoning and Smoke Inhalation
Intracranial Abscess
Gas Gangrene
Necrotizing Soft Tissue Infection
Osteomyelitis, refractory
[email protected]
UNCLASSIFIED
- Crush Injuries
- Enhanced Healing of Selected Wounds
- Radiation Tissue Damage
- Skin Grafts and Flaps
- Thermal Burns
- Exceptional Blood Loss
4
USAMMDA - Developing Quality Medical Products for U.S. Forces
HBO2 Administration
Monoplace Chamber
A hyperbaric oxygen session with
oxygen hoods in multiplace chamber
Equalizing
middle ear
pressure
[email protected]
UNCLASSIFIED
5
USAMMDA - Developing Quality Medical Products for U.S. Forces
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
[email protected]
UNCLASSIFIED
6
USAMMDA - Developing Quality Medical Products for U.S. Forces
HBO2 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
[email protected]
UNCLASSIFIED
7
USAMMDA - Developing Quality Medical Products for U.S. Forces
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
[email protected]
UNCLASSIFIED
8
USAMMDA - Developing Quality Medical Products for U.S. Forces
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
• 2003 UMHS Position Statement – insufficient data for endorsement
for acute or chronic brain injury
• 2003 AHRQ – insufficient evidence for TBI, stroke and cerebral
palsy
• 2008 Cochrane Review – insufficient data for acute TBI
• 2009 VA Review – insufficient data to support use for TBI or PCS
[email protected]
UNCLASSIFIED
9
USAMMDA - Developing Quality Medical Products for U.S. Forces
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
[email protected]
UNCLASSIFIED
10
USAMMDA - Developing Quality Medical Products for U.S. Forces
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
[email protected]
UNCLASSIFIED
11
USAMMDA - Developing Quality Medical Products for U.S. Forces
DoD/VA HBO2 Research Program
USAFSAM Pilot
Study (n=50)
We must know these before we
start pivotal trial:
VA/VCU/USN Dose Ranging Study (n=60)
IND
Filed
Type C
meeting
End
Phase II
HOPPS IND Pilot Study
(n=96)
TMA & UHMS
Submission
Outcome Validation Project
- sham method validated
- dose selection of HBO2
- outcome measure
validated to detect change
after intervention
- establish range of placebo
effect to determine
sample size
De Novo/
510K
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
[email protected]
Jan ‘12
Jul ‘12
Jan ‘13
UNCLASSIFIED
Jul ‘13
Jan ‘14
Jul ‘14
Jan ‘15
13
USAMMDA - Developing Quality Medical Products for U.S. Forces
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
[email protected]
of other rehabilitation strategies?
UNCLASSIFIED
14
USAMMDA - Developing Quality Medical Products for U.S. Forces
DoD/VA HBO2 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
[email protected]
UNCLASSIFIED
15
USAMMDA - Developing Quality Medical Products for U.S. Forces
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 mTBI AND lasting at least 3 months:
–
–
–
–
–
Headaches
Dizziness/balance problems
Blurred vision
Fatigue or sleep problems
Ringing in your ears
[email protected]
- Seizures
- Difficulty with memory or solving problems
- Managing stress or emotional upset
- Controlling your temper/irritability
UNCLASSIFIED
16
USAMMDA - Developing Quality Medical Products for U.S. Forces
Co-Morbidities Associated with PCS
Chronic
Pain
n=277
81.5%
10.3%
16.5%
2.9%
PTSD
n=232
68.2%
42.1%
• 8% of PCS is an isolated
finding
12.6%
6.8%
5.3%
PCS
n=227
66.8%
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.
[email protected]
UNCLASSIFIED
17
USAMMDA - Developing Quality Medical Products for U.S. Forces
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
[email protected]
UNCLASSIFIED
18
USAMMDA - Developing Quality Medical Products for U.S. Forces
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
[email protected]
UNCLASSIFIED
19
USAMMDA - Developing Quality Medical Products for U.S. Forces
Evidence for HBO2 for PCS/PTSD
• Our wounded warriors deserve the best evidencebased 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
[email protected]
UNCLASSIFIED
20
USAMMDA - Developing Quality Medical Products for U.S. Forces
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.
[email protected]
UNCLASSIFIED
21
USAMMDA - Developing Quality Medical Products for U.S. Forces
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
Interactions with Caring
Staff/ Placebo Effects
HBO2
Treatment
• 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
• effective placebo response –
[email protected]
antidepressants 30-50%
anxiolytics 30-50%
PTSD treatment 38.5%
UNCLASSIFIED
22
USAMMDA - Developing Quality Medical Products for U.S. Forces
• 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
[email protected]
Walsh BT et al, JAMA 2002; 287: 1840-7
UNCLASSIFIED
23
USAMMDA - Developing Quality Medical Products for U.S. Forces
Challenge:
Systemically Measuring 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
[email protected]
UNCLASSIFIED
24
USAMMDA - Developing Quality Medical Products for U.S. Forces
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 evidencebased decision-making
[email protected]
UNCLASSIFIED
25
USAMMDA - Developing Quality Medical Products for U.S. Forces
MHS Partnerships and
Info for Wounded Warriors
USAF Study
USAFSAM
Wilford Hall Medical Center
Hyperion Inc.
Navy/VA Study
NOMI Pensacola
Virginia Commonwealth University
McGuire Richmond VAMC
Upcoming Studies
NICoE
Madigan AMC
Many new academic partners
•
•
MRMC Multicenter Study
USAMMDA
Walter Reed Army Institute of Research
Evans Army Community Hosp/10th SF 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
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
[email protected]
UNCLASSIFIED
26
USAMMDA - Developing Quality Medical Products for U.S. Forces
Questions
[email protected]
UNCLASSIFIED
27

похожие документы