5 Clinical Results in Brain Injury Trials - Another Perspective

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UHM 2015, VOL. 42, NO. 4 CLINICALRESULTSINBRAININJURYTRIALS:ANOTHER PERSPECTIVE

Copyright 2015 Undersea & Hyperbaric Medical Society, Inc.

Clinical results in brain injury trials using HBO2therapy:

Another perspective

Xavier A. Figueroa, Ph.D.1, James K. Wright, M.D.2

1 The Brain Health & Healing Foundation, Seattle, Washington U.S.

2 Swedish Medical Center-Edmonds, Wound Healing & Hyperbarics, Edmonds, Washington U.S.

CORRESPONDINGAUTHOR: Xavier Figueroa [email protected]

______________________________________________________________________________________________________________________________________________________

ABSTRACT

______________________________________________________________________________________________________________________________________________________

The current debate surrounding the use of hyperbaric oxy-

gen (HBO2) for neurological indications, specically mild

to moderate chronic traumatic brain injury (mTBI) and

post-concussion syndrome (PCS), is mired in confusion

due to the use of non-validated controls and an unfamil-

iarity by many practitioners of HBO2 therapy with the

experimental literature. In the past 40 years, the use of

an air sham (21% oxygen, 1.14-1.5 atmospheres absolute/

atm abs) in clinical and animal studies, instead of obser-

vational or crossover controls, has led to false acceptance

of the null hypothesis (declaring no effect when one is

present), due to the biological activity of these sham

controls. The recent Department of Defense/Veterans

Administration (DoD/VA) sponsored trials, previous

published reports on the use of HBO2therapy on stroke

and mTBI and preliminary reports from the HOPPS

Army trial, have helped to highlight the biological ac-

tivity of pressurized air, validate the development of a

convincing control for future studies and demonstrate

the effectiveness of a hyperbaric intervention for mTBI/

PCS. Approval of HBO2 for neurological indications,

especially for mTBI/PCS, should be granted at the federal,

state and certifying body levels as a safe and viable

treatment for recovery in the post-acute phase.

_______________________________________________________________________________________________________________________

KEYWORDS: traumatic brain injury, hyperbaric oxygen, cognitive function, TBI, HBO, HBO2,

_______________________________________________________________________________________________________________________

ABBREVIATIONS: amyloid precursor protein (APP); tissue plasminogen activator (tPA); traumatic brain injury (TBI); mild to mod-

erate traumatic brain injury (mTBI); acquired brain injury (ABI); post-traumatic stress disorder (PTSD); post-concussion syndrome

(PCS); single photon emission computed tomography (SPECT); diffusion tensor imaging (DTI); regional cerebral blood flow

(rCBF); Rivermead Post-Concussion Symptom Questionnaire (RPQ); PTSD Checklist Military Version (PCL-M); Department of

Defense (DoD); Veterans Administration (VA); standard of care (SoC); hyperbaric oxygen (HBO2); Hyperbaric Oxygen Therapy for

Persistent Post-Concussive Symptoms (HOPPS). National Institutes of Health Stroke Scale (NIHSS); activities of daily living (ADL);

evaluation of quality of life (EQ); evaluation by the EQ-5D descriptive system (EQ-5D); EQ visual analogue scale (EQ-VAS).

INTRODUCTION

The conclusions of the DoD/VA sponsored studies [1-

4] on the benets of hyperbaric oxygen (HBO2) therapy

for service members diagnosed with post-concussion

syndrome have recommended ceasing the development

of a promising therapy. The published conclusions of

the DoD/VA sponsored studies recommend the view

that there is no benet of HBO2for mild to moderate

traumatic brain injury (mTBI) and post-concussion

syndrome (PCS). The DoD/VA studies have added con-

fusion to the debate on controls for HBO2trials and have

failed to account for within-group pre- and post-treat-

ment outcomes, biasing analysis and reporting towardthe conclusion that hyperbaric oxygen is ineffective

for the treatment of symptoms of mTBI and PCS. The

assumption that pressurized air is a sham intervention

has led to erroneous conclusions of non-activity, spe-

cically when the conclusions are due to comparison

between sham and HBO2 treatment as the terminal

decision point [5]. A review of the past literature will

show that this has been a recurring problem and has

led to incorrect conclusions of non-efcacy for HBO2.


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The varied biological effects of both low- and high-

pressure delivery of pure and mixed gases are substan-

tial, with a large literature in experimental and applied

therapies. The current evidence from cell culture,

animal studies, case reports and clinical trials for stroke

and mTBI treatment is consistent with a reparative

effect of HBO2on the nervous system, including low-

pressure air treatments. Furthermore, the overall safety

of this intervention is not called into doubt. The use

of HBO2 for mTBI or PCS should be sanctioned and

given provisional approval under Centers for Medi-

care and Medicaid Services (CMS) coverage with evi-

dence guidelines, as well as for the VA and TRICARE.

Biological effects of hyperbaric oxygen

The human body is sensitive to both decreases and

increases in oxygen levels, brought about by changesin total oxygen concentration and changes in absolute

pressure. Any change in cellular oxygen concentration

will have potential effects on cellular function. Indeed,

both hypobaric and hyperbaric oxygen can induce pre-

conditioning effects that can protect myocardial and

neural tissue from damaging changes in oxygen tension

[6-11]. HBO2 preconditioning has been used in coro-

nary artery bypass graft surgery and for post-operative

recovery [12-14], reducing cognitive impairments and

neurological sequelae. The application of oxygen under

pressure has been shown to induce reparative mechan-isms in a number of injury and disease induced con-

ditions.

Understanding the mechanisms that are activated

by HBO2 is essential for applying this clinical tool

correctly. In the last 30 years numerous physiological

and cellular effects of HBO2 have been identied

and elucidated. The effects are varied, occurring

simultaneously, in many cases long-lasting and extensive

in the responses that they elicit.

Stem cell upregulation

In the past 10 years, reports of increased circulating

endothelial progenitor cells in mouse [21] and humans

[22] have shed light on mechanisms stimulated by

HBO2 for wound healing and angiogenesis [23]. In

humans and mice, the process of increased stem cell

release is a nitric oxide (NO) mediated process that

is triggered by HBO2. Animal models of TBI have

effectively shown that angiogenesis and neurogenesis

are increased with HBO2in the injured hemisphere and

are correlated with improvements in performance and

recovery vs. the non-HBO2-treated [24,25]. In adult

cerebral stroke models in rats, neurogenesis via stem

cell migration was seen in the cortex, and the duration

of HBO2 treatment was correlated with recovery of

function [26]. Stem cell migration has been observed

in wound healing clinical studies, ranging from diabetic

foot ulcers [27] to skin wounds [28] that are treated by

HBO2. When the injured brain of those suffering from

PCS, TBI or stroke is considered as a type of wound,

the data supporting a model of stem cell recruitment to

damaged areas of the brain [29] becomes better under-

stood.

SummaryHow stem cell migration aids in the restoration of func-

tion and symptom alleviation in mTBI is not fully un-

derstood, as there are no direct studies linking these

phenomena together in humans. Possible mechanisms

are a restoration of the vascular network in damaged

or low-ow areas of the brain and repair of dam-

ages axons. Stem cell upregulation is a direct effect

of HBO2 treatment and should be considered as a re-

parative function for acquired brain injuries. HBO2

has the untapped potential as a ready and accessible

source for stem cell recruitment in future therapies.The mechanism of action remains to be elucidated,

and further work should be done, including studies of

the effect of varied pressures or oxygen concentrations

on stem cell numbers in peripheral blood and tissues.

Modulation of inammatory responses by HBO2

One of the initial responses to a TBI is an increase in

inammation to the brain (in animal models and in

humans). HBO2 has been shown to effectively re-

duce inammatory markers in blast- and blunt force

trauma-induced TBI [30-33]. Mouse models of TBI

have shown that head injuries induce widespread in-

ammatory responses; HBO2 exposure can decrease

apoptosis, reactive neuroinammation [33] and inhib-

its microglial activation and production of pro-inam-

matory cytokines [31]. New evidence suggests that

mild to moderate TBI has a strong inammatory com-

ponent that mediates acute and long-term injury [34].


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The role of HBO2induced vasoconstriction is a well-

known effect in reducing cerebral edema [35,36]. In

clinical research with severe TBI study subjects, HBO2

reduces swelling and intracranial pressure [37,38]

as well as increasing survival. More recent work has

shown that HBO2 reduces the rate and the number

of inltrating neutrophils into injury areas [39-46].

Another effect of HBO2 is its ability to modulate the

sensation of pain. In rat models of neuropathic pain

[47-49], HBO2was able to reduce the pain sensation;

it appears to be a NO-mediated process in mice [48].

In the case of severe traumatic brain injury, inam-

matory markers have been detected months to years

after the TBI incident in humans [50]. A lower level

of inammation may be present in mTBI and PCS

sufferers [34]. The recent discovery of -amyloid

(1-42) and APP increasing after blast-induced braininjury in animal models [51], and severe brain injury

in humans [52] and the increased risk of Alzheimers

disease and cumulative traumatic encephalopathy with

a history of head trauma [53-56], point to the role of a

chronic inammatory response in mediating long-term

damage in TBI and dementia of the Alzheimers type.

Summary

Inammation is a recognized component of TBIs of all

types. HBO2 has well-established anti-inammatory

capabilities in neuroinammation, suggesting that therole of HBO2in mTBI and PCS treatment extend much

further than oxygenating tissues. Mixed approaches in

controlling inammation, such as Omega-3 polyunsatu-

rated fatty acid supplementation [57-63] may enhance

recovery and alleviate symptoms of mTBI and PCS,

with adjunct HBO2. Chronic administration of NSAIDs,

specically ibuprofen, have negative correlations with

TBI recovery in animal models [64], but inhibition of

specic inammatory mediators have reparative effects

[65-67].

Cellular repair and protection

Over 8000 known biochemical processes are dependent

on oxygen in the atmosphere to carry out metabolic

processes [68]. Changes in the concentration of oxygen

in the ambient environment, hypoxic or hyperoxic, an

increase due to an elevation in air pressure, supple-

mental oxygen administration or hyperbaric oxygen

will more than likely result in changes in cellular pro-

cesses, some of which may be profound and long lasting.

In the past few years there has been a signicant in-

crease in the scientic understanding of how oxygen

works on a cellular level. Many of these cellular pro-

cesses are signaled by reactive oxygen species (ROS)

[69-72] and others are signaled by oxygen itself [73-76].

Initial exposures to HBO2can induce DNA strand breaks

[77] and increased lipid peroxidation of cell mem-

branes [78], but cellular defenses are activated that

repair and protect from further damage [77]. Although

concerns of overproduction are warranted, most organ-

isms have a wide array of defenses to limit the over-

production of oxygen radical species [79]. Cellular

ROS activity is under tight control and is involved in

cell signaling, protein trafcking and regulation of en-

zyme, receptor, transporter and transcription factors[69]. ROS produced by HBO2 induce mitochondrial

biogenesis [80] and may play a role in cell repair

and protection from neurological injuries [81].

Additionally each organelle within the cell, including

mitochondria, has different ROS regulation character-

istics that govern the function of each organelle.

Mechanisms associated with repair processes, such as

-integrin b1 receptors mediating collagen synthesis

[69] and DNA methylation (which alters the expression

of genes in cells as they divide and differentiate) affects

gene transcription and are signaled by ROS [69]. ROShave a role in signaling histone acetylation and deacety-

lation which are also key processes of gene expression

[69] and repair processes. Hyperbaric oxygen adminis-

tration alters the ROS in the cellular environment and

its known mechanisms of action in cellular inamma-

tion, repair and apoptosis regulation are activated [82].

Derangements in ROS regulation and oxidative stress

have been implicated in a variety of neurologic diseases,

including TBI [69]. In TBI, oxidative stress plays a role

in the pathology of neuronal dysfunction, while HBO2

upregulates the neuronal repair processes required to

restore function [83,84]. Furthermore, HBO2 upregu-

lates anti-apoptotic mechanisms (such as the Bcl-2

family of proteins) that protect neuronal cells from

dying [85,86] and help maintain mitochondrial function

[85,87,88]. While it is not known precisely how Bcl-2

signals cellular repair via ROS, while hypoxia-induced

ROS cause inammation and cellular degeneration and


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apoptosis, it is theorized that the changes in cellular

oxygen levels, and hence ROS (termed oxygen cy-

cling) cause a perceived hypoxia by the cell which

in turn signals repair processes in the presence of ade-

quate oxygen levels for the repair to proceed [84].

It appears that it is not the actual level of oxygen

present, but the difference in the homeostatic equilib-

rium of oxygen that is sensed and the same ROS that

are produced when the equilibrium swings too far from

the set-point. The ROS act as signaling agents, inde-

pendent of hypoxic, normoxic or hyperoxic states, but

the context of the signaling (the actual level of oxygen)

may mediate the activation of context specic mech-

anisms that interpret the ROS signaling.

Summary

HBO2-produced ROS are mitigated by the cells abilityto quench ROS overproduction. HBO2activates numer-

ous cellular mechanisms of action which are neuro-

protective and assist the injured brain to heal. The

effects are broad and protective at the cellular level,

including protection of mitochondrial potential [85,87,

88]. Furthermore, the anti-apoptotic proteins, Bcl-2 and

Bcl-xL, are upregulated in neurons in contusion models

of rats after HBO2exposure and the downstream effects

that these proteins exert to inhibit apoptosis [89].

Cellular oxygen utilization: mitochondrialregulation and idling neurons

Disruption or reduction of mitochondrial activity in

nervous tissue is a reported effect of stroke [90-92] and

TBI [93]. In the case of TBI, the deregulation of mito-

chondrial activity is complex and can lead to changes

in metabolic function [37,93-96] and changes in blood

ow [97]. HBO2 has shown the ability to restore

mitochondrial activity in animal models of TBI [80,

85,87,88,96,98,99]. In the case of blast-induced TBI,

cerebral blood ow and metabolic function were

shown to improve after HBO2in a rabbit model [30].

The hypothesis of hypometabolic neural tissue in a

penumbra or an area of idling neurons in brain in-

jury was promulgated by Dr. Neubauer [100-102], but

was considered untested, mostly due to a lack of an es-

tablished mechanism for neural tissue entering into a

state of hibernation. The evidence of neural tissue that

can be rescued is supported by recovery of function

(neurological testing, EEG or SPECT) in stroke studies

that used HBO2 to detect brain tissue that was viable

in post-acute stroke with 10-15 HBO2 treatments [103]

or even a single HBO2 treatment [104]. Another case

report of post-acute stroke patients treated with HBO2

and imaged with single photon emission computer

tomography (SPECT), reported improved neurological

function [105] and increased regional cerebral blood

ow (rCBF) in the penumbra of the affected region.

The development of diffusion tensor imaging of the

brain in concussion patients appears to validate the

presence of a penumbra of non-functional damaged

axons after injury [106]. These studies help to further

validate the improved outcomes (National Institutes

of Health Stroke Scale, NIHSS; activities of daily

living, ADL; evaluation of quality of life, EQ) of

the recent post-acute stroke recovery study usingHBO2 by Efrati, et al. [107] and buttress the case

for reactivation of hypometabolic neural tissue.

The landmark studies of Blackstone, et al. [108,109]

were the rst to provide a plausible mechanism for

idling neurons. Blackstone, et al. demonstrated the

ability to downregulate mitochondrial respiration by

simultaneously exposing mice to gaseous H2S and re-

ducing oxygen levels. Not only did the mice survive

periods of reduced oxygen tension of > 6 hour at 5%

oxygen, there was no measurable neurological or myo-

cardial damage when they were restored to normal oxy-gen levels and metabolic function [108, 109]. The exact

mechanism of neural tissue protection remains unestab-

lished, but the principle is present for future investiga-

tion. Furthermore, the discovery of a hydrogen sulde

(H2S) mechanism modulating long-term potentiation

(LTP) in neurons [110] suggests that this signaling gas

is an integral and conserved mechanism in mammals

[111-115]. From a mechanism perspective, enzymatic

systems in mammalian neural tissues produce H2S

locally and could induce a local hypometabolic state by

direct regulation of mitochondrial activity [116-120].

Summary

The hypothesis that neurons can remain viable but not

electrically active after a traumatic brain injury is sup-

ported by SPECT imaging of TBI patients in the post-

acute phase. Individuals diagnosed with a TBI pres-

ent with reduced rCBF [121,122] when compared to a


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healthy, non-injured population. Diffusion tensor im-

aging in traumatic brain injury provides an anatomic

picture of idling neurons with loss of axonal integrity

demonstrable for years after injury [123]. The effects

of axonal remyelination after chronic TBI using HBO2

saw a signicant restoration of axonal tracts and motor

improvements in rats [124]. Restoration or elevation of

rCBF is seen with HBO2 treatment of TBI study par-

ticipants [125,126] with a concomitant improvement

in cognitive function and symptom improvement in

bomb-blast-induced and study subjects (civilian and

veterans). The existence of hypometabolic neural

tissue provides a plausible mechanism for the recovery

of function seen in both clinical TBI and stroke studies

that tested HBO2 as a treatment. Although the exact

mechanisms for reactivation are not elucidated, it appears

that increases from the 5% to 21% oxygen concentrationcan have an effect on the mitochondria of hypometabolic

neural tissue, restoring them to baseline function [108,

109].

The unintended oxygen dosing trials

In the literature, a sham in HBO2 (room air at 1.1-1.4

atmospheres absolute/atm abs) has been commonly

used as a comparator against a treatment dose ( 1.5 atm

abs, 100% oxygen). Yet, the sham remains a point of

contention within the hyperbaric medical research

eld. By denition HBO2is a two component therapy:increased pressure and increased oxygen concentration.

A sham, as established for all clinical trial interven-

tions, is a treatment or procedure that is performed as

a control and which is similar to but omits a key thera-

peutic element of the treatment or procedure under

investigation. Therefore, controlling the oxygen con-

centration (keeping oxygen at a level equivalent to 21%

at sea level) is essential to developing a sham that

controls for oxygen. To effectively create a sham for

a treatment of 100% oxygen at 1.5 atm abs would

require a breathing mixture of 14% oxygen (and the

remainder presumably nitrogen) delivered at 1.5 atm

abs. This would deliver an oxygen equivalent dose to

21% oxygen breathed at sea level (1.0 atm abs) but

would also deliver an increased dose of nitrogen which

could have biological effects. Use of pressurized air at

1.2 to 1.3 atm abs would not be a true sham treatment

for oxygen, as the subjects would be breathing a 20%-

30% increase in oxygen than that breathed at sea level.

This increase in oxygen (and also possibly the nitrogen

increase) would be expected to have cellular effects.

Pressurized air shams are not inactive. In actuality the

use of pressurized air in studies of hyperbaric oxygen

treatments constitutes a dosing trial rather than a sham.

The issue facing hyperbaric medical research boils

down to dening what constitutes a medically relevant

dose of oxygen and fully understanding the biology of

oxygen. Changes in air pressure smaller than 0.1 atm abs

have induced growth factor production and an increase

in cell division [129] in epithelial cell cultures when

compared to the control cultures. Studies of smooth

muscle cells derived from the human aorta reported

that 1.1 atm abs of room air (an increase of 0.1 atm

abs) was sufcient to increase growth rates [130,131].

Cells (as demonstrated in vitro) detect minute change inoxygen concentration (up or down) and the 20%-30%

increase in dissolved oxygen concentration in reported

shams as comparators in HBO2 trials represent a

therapeutic dose.

The cell culture data is supported by evidence from

studies of lung function and oxygenation with chronic

obstructive pulmonary disease, cystic brosis, pulmo-

nary brosis and pulmonary hypertension (thromboem-

bolic). Moving patients from cities located 800 meters

above sea level (0.91 atm abs, ~21% oxygen) to loca-

tions 400 meters below sea-level (1.05 atm abs, ~21%oxygen) improved oxygenation and lung function

[132,133]. In a presentation of pilot study data looking

at the effects of scuba diving on veterans diagnosed with

post-traumatic stress disorder (PTSD), a large reduction

(~80%) in PTSD symptoms (PCL-M) was observed

[134], with pressure ranges from 1.3 to 1.5 atm abs

with nitrox (32%-36% oxygen/68%-64% nitrogen) sus-

tained while diving. The sham in the Wolf, et al. [4]

report dissolved ~30% more oxygen into the plasma

than just breathing room air at 1.0 atm abs, inducing

a signicant change in symptoms scores (IMPACT

symptoms score and the PCL-M), which are in agree-

ment with Kaplin, et al. [134], and the HOPPS trial

[135] results, both of which reported a therapeutic

effect of breathing pressurized air.

Illustrative of the sham issues are two published

studies by Anderson, et al. [5] and Nighoghossian, et al.

[136]. Both papers were designed as double-blind


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HBO2 (1.5 atm abs, 100% oxygen) vs. air sham cere-bral stroke studies. The air sham showed an equivalent

effect when compared to HBO2 in the Anderson, et al.

study (Figure 1, left graph: Air: Nstart=19, Nend=11;

HBO2: Nstart=20, Nend=14), while Nighoghossian, et al.

reported statistically signicant results between the

sham and the HBO2 treatment, with the sham show-

ing superior improvement in two out of three measures

(Figure 1, right graph). Lower scores on the Orgogozo

and Rankin scales and higher scores on the Trouillas

scale are measures of better outcomes (N=17; both

groups; Figure 1, left graphs). In both studies it wasassumed that the shams would not be biologically

active. The authors compared HBO2 treatment to the

supposed inactive sham, resulting in an invalid

analysis. Re-examination of the pre- and post-neuro-

logical scores revealed statistically signicant differ-

ences in both groups (before vs. after treatment)

using a two-tailed T-test (=0.05, Figure 1). Had a

third comparator been included, such as a standard

of care group, the analysis and conclusions would

likely have been markedly different.

The use of an air sham requires the assumption of

inactivity of the sham [137], but with sham treatments

consistently showing better results than higher treat-

ment pressures (100% oxygen, 1.14 atm abs vs. 2.5 atm

abs; Figure 2 [left side]) the sham treatment shows

biological activity. Outcomes at 90 days involved four

stroke scales with good outcomes dened as follows:

Reanalysis of pre- and post-HBO2therapy measures of sham vs. HBO2treatment in stroke study participants. Left box:

Anderson, et al. study. Right box: Nighoghossian, et al. Columns are final mean values. Error bars are standard deviations.

__________________________________________________________________________________________________________________________________________________________

Figure 1

Pre-HBO2Post-HBO2

1.5 atm abs 1.5 atm abs

1.2 atm abs 1.5 atm abs 1.2 atm abs 1.5 atm abs 1.2 atm abs 1.5 atm abs

an NIHSS score 1; a Barthel Index score of 95 or 100;

a modied Rankin Scale score 1; and

a Glasgow Outcome Scale score of 5

(Nsham=11; NHBO2=16).

Lacking in the Rusyniak, et al. study [137] was a com-

parator for standard of care (SoC). As can be compared

in Figure 2 (right side), published results [138,139]

of non-related studies (using the same post-stroke

outcome denition criteria as Rusyniak, et al.) give

a clear indication that air shams are not inactive, and

higher pressures of oxygen are not necessarily betterfor treatment in post-acute stroke. Some of the problems

in selecting an appropriate sham or control in a hyper-

baric oxygen trial are illustrated in Table 1.

Summary

Pressurized air is not inactive, and comparison between

different pressure regimes suggest that a dose response

to neuronal healing is present with different levels of

oxygen concentration and pressure. The 2.5-atm abs

(at 100% oxygen) treatments appear to have very little

effect when compared to standard of care (Figure 2),

but mild pressurization (1.14 atm abs, 100% oxygen)

appears to have an equivalent clinical response as tPA

therapy for stroke and a superior response than 2.5 atm

abs It is no surprise that subsequent DoD/VA spon-

sored reports [1,2] used a different control group: An

oxygen sham that controlled for oxygen concentration

(10.5% O2 at 2.0 atm abs=21% oxygen equivalent).

neurologic

score

Anderson, et al. Orgogozo RankinTrouillas


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339X.A. Figueroa, J.K. Wright

Graph of pre- and post-HBO2therapy measures of sham (1.14 atm abs, 100% oxygen) vs. 2.5 atm abs in stroke study

participants (left graph) Columns are the end mean values. Standard of care for stroke and of tPA intervention (right graph).

__________________________________________________________________________________________________________________________________________________________

Figure 2

1.14 atm abs

2.5 atm abs

___________________________________________________________________________________________________________________________________________________________

Table 1

type of control purported effect advantage(s) disadvantage(s) potential error as control___________________________________________________________________________________________________________________________________________________________

pressurized air at no oxygen effect allows for pressure effect increased concentration ignores cellular effects of

1.2-1.5 atm abs in experimental subjects of oxygen and nitrogen increased oxygen and nitrogen

have biological effects concentration___________________________________________________________________________________________________________________________________________________________

no treatment none allows for monitoring subjects may experience enrolling in a study may have

observation at rare subjects with minimal Hawthorne effect a treatment effect intervals placebo or Hawthorne effect___________________________________________________________________________________________________________________________________________________________

pressurization with mixed none for oxygen control oxygen concentration pressure effects, regular participation in study

gas to give room air at room air (1 atm abs) increased nitrogen protocol, increased nitrogen

(1 atm abs) equivalent equivalent effects, placebo and concentration may have an

oxygen concentration Hawthorne effects effect___________________________________________________________________________________________________________________________________________________________

delay in treatment/ none during delay all participants can be subjects may improve subjects may change for

crossover study offered HBO2therapy or deteriorate during better or worse during delay

delay, placebo and and differ from treatment

Hawthorne effects may group

be operational during delay___________________________________________________________________________________________________________________________________________________________

historical controls none allows for monitoring the data may be insufficient

untreated course of the and too varied for

disease adequate comparison,

no possibility of measuring

placebo or Hawthorne

effects___________________________________________________________________________________________________________________________________________________________

standard of care healing through allows comparison with standard of care may not excludes intervention, placebo

supportive therapy historical data and comparison actually be therapeutic and Hawthorne effects

or accepted standard with new treatments

therapy___________________________________________________________________________________________________________________________________________________________

Comparison of different controls used in HBO2clinical trials for TBI/PCS and PTSD.

p=0.11 p=0.02 p=0.01 p=0.04

percentagepfparticipants

with

goodoutcomemeasures

Barthel Modified Glasgow NIHHS Barthel Modified NIHHS

Index Rankin Outcome Index Rankin


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Reinterpreting the DoD/VA results

The single DoD/VA sponsored clinical trial by Cifu,

et al. was a three-arm design [1,2] and reported on

one group of Marines (N=61). Study participant were

randomized into three different treatments groups

(2.0 atm abs: 10.5% oxygen, 75% oxygen and 100%

oxygen), with participants and researchers blinded to

treatment. The participants were given the exact same

pressure (2.0 atm abs) but given different oxygen mix-

tures to simulate different treatments: 21% oxygen;

1.5 atm abs at 100% oxygen; 2.0 atm abs at 100% oxy-

gen. The two primary measures they looked at were

the Rivermead Post-Concussion Questionnaire (RPQ)

and the PTSD Checklist Military Version (PCL-M).

In each of the articles by Cifu, et al. [1,2], the con-

clusions were that there was no effect from HBO2,

partially contradicting the reported results from the

Wolf, et al. study [4]. The Wolf, et al. study reports a

statistically signicant effect with hyperbaric air (1.3

atm abs, 21% oxygen). The effects were large in the

Wolf, et al. publication (41% difference between pre-

and post-testing on the RPQ, Figure 3), but they were

not reported as signicant in the aggregate scores,

although nine symptoms showed signicant differenc-

es in the sham treatment group (Figure 3). The PCL-

M scores are also very close in overall effect between

pre- and post-treatment: 16% improvement in the Wolf

__________________________________________________________________________________________________________________________________________________________

Figure 3

Pre-HBO2Post-HBO2

Wolf, et al.

Meansymptoms

core

Cifu, et al. Harch, et al.

sham

2.4atm

sham

2.4atm

10.5

%

75%

100%

10.5

%

75%

100%

1.4atm

1.5atm

RPQ PTSD RPQ PTSD RPQ PTSD

Cross-study analysis of results from the Rivermead Post-Concussion Questionnaire (RPQ) and the PTSD Checklist-Military Version

(PCL-M). Wolf: Nsham=24, NHBO2=24; Cifu: N10.5%= 21, N75%= 18, N100%=21; Harch: N=16. *= p 0.05; ?=unreported value of P.

study and 14% in the Cifu study. The Cifu, et al. studies

conclude that the results were clinically non-signicant,

but the aggregate PCL-M scores were statistically sig-

nicant, just like in the Wolf, et al. study (see Figure 3).

The lack of change in the RPQ and PCL-M scores

in the sham and 1.5 atm abs equivalent groups for

the Cifu study could be due to insufcient number

of study participants, the use of paper and pencil vs.

computerized testing (time variations in response times

are subject to analysis in computer tests), subject

selection (all Marines were in a Warrior Transition

Unit) or other external factors associated with study

location. The Wolf, et al. study had six and three more

study participants per group, respectively (N=24 for

both the sham and 2.4 atm abs groups) than the Cifu

study (N=18 for the 75% oxygen and N=21 for the

100% group). Given how close the results were be-

tween both studies, the addition of six and three more

study participants by the Wolf, et al. study could ex-

plain the difference seen between both articles. The Cifu

et al. studies [1,2] also appears to have been under-

powered, a point they acknowledge in their publication.

Another factor at play is the relatively high pressures

used by the DoD/VA sponsored studies [1,2,4]. Global-

ly, a consensus is building for the use of lower pressure

treatments, ideally 1.5 atm abs or lower, for central

nervous system injuries. For the DoD/VA sponsored


9/19



studies [1,2,4], the HBO2 intervention doses were

at or above 2.0 atm abs in pressure. The lower sham

treatment [4] was much closer to the ideal pressure

that proponents of HBO2normally use for neurological

treatments [125,126,140,141].

The improvements measured for RPQ and PCL-M

outcomes in the Wolf and Cifu studies are in agreement

with another published report by Harch, et al. [126].

Harch, et al. reported on the treatment of 16 Marines

with bomb-blast-induced mild TBIs (mTBI) and pro-

duced results that were in agreement with the DoD/VA

sponsored study results [1,2,4], if not their conclusions

(Figure 3). The conclusion of Cifu, et al. that HBO2 is

ineffective on mTBI is not supported by the data they

acquired. All three studies measured statistically signi-

cant improvements in the PCL-M scores [1,3,126] and

are in agreement with previously published outcomes

[142] in case reports of HBO2 reducing PTSD symp-

toms. The overall trend between the published studies

using HBO2 as an intervention on chronic mTBI/PCS

favors a clinically positive outcome with HBO2 treat-

ment across a variety of measures. Adding to this dis-

cussion is a presentation of an Army study, HOPPS

[135] (Clinicaltrials.gov, NCT01306968). The HOPPS

study (Hyperbaric Oxygen Therapy for Persistent Post-

Concussive Symptoms) saw a statistically and clinically

__________________________________________________________________________________________________________________________________________________________

Figure 4

SoC N = 23

1.5 atm N = 24

sham N = 25

SoC

1.5atm

sham

SoC

1.5atm

sham

SoC 1.5 atm sham

Result of HOPPS study. (Left side) RPQ and PCL-M (PTSD) results compared to standard of care (SoC), 1.5 atm abs

(100% oxygen) and sham (1.3 atm abs, 21% oxygen). PTSD scores that exceed 8 points (*C) are considered clinically significant.

(Right side) The results of the health survey (SF36) of HOPPS study.

RPQ PTSD

signicant improvement six months post-treatment

in the Rivermead Symptoms Questionnaire (RPQ;

p< 0.05) and PCL-M scores (*C; >8 point improvement;

Figure 4). Six-month post treatment measures (using

the Short Form Health Survey [143]) revealed that im-

provements were greater than standard of care (SoC),

but it also saw a graded improvement between sham

and HBO2 treatments. The sham produced results

equivalent to or better than the 1.5 atm abs treatments.

HOPPS has a one-year follow-up to perform and other

measures, such as cognitive, neurological and psycho-

motor outcomes remain to be reported, but based on

previous clinical experience with TBI and PCS sufferers

we expect the one-year follow-up results to retain

their signicance.

Relevant to our discussion regarding the use of

HBO2for neurological injuries is the necessity to ensure

that studies use a well-controlled population of study

subjects. The Churchill, et al. study [144] tested a

mixed population of acquired brain injury study subjects

(ABI; stroke, anoxia and trauma) and saw a mix of posi-

tive and inconclusive results. The TBI population was

skewed toward the severe TBI category (21/27), with

six study subjects in the mild-to-moderate TBI category

(Figure 4, top graph). Illustrative of the difculties in

testing a heterogeneous ABI population are the Wechsler

Short Form Health Survey (SF36)HOPPS

pointimprovement

fromb

aseline

unfavorable

favorable

14

12

10

8

6

4

2

0

20

15

10

5

0

-5

-10

-15


10/19


X.A. Figueroa, J.K. Wright342

Abbreviated Scale of Intelligence (WASI: Figure 5,

bottom graph) scores. Although the WASI reported

signicant improvements in aggregate, when broken

down by groups (TBI, stroke and anoxia), only theTBI and stroke showed statistically signicant changes

(Figure 4, bottom graphs). The anoxia group saw no

statistically signicant improvements using the WASI.

Further testing via other parameters produced results

that were, at best, difcult to interpret. Although there

is a temptation to conclude that HYBOBI (hyper-

baric oxygen therapy in chronic stable brain injury;

NCT00830453) is another publication pointing to the

failure of HBO2 for treating neurological conditions,

we would agree with the authors concluding remarks:

Many clinical trials incorporate patient reported

outcomes, but future studies should use a standard-

ized brain injury symptom questionnaire that has

been robustly validated in the population of interest

[underline is ours]. Unfortunately, such a measure,

validated across all brain injury etiologies and

severities, was not available for this study.

Dening the population that will be treated and grading

the injury level are important steps in assessing and

validating the effectiveness of a therapy.

Summary

The DoD/VA sponsored studies [1,2,4] reached conclu-

sions that were technically correct, but failed to recog-

nize the clinical relevance in the pre- and post-treatment

values; one study [4] relied on the difference between

treatment groups and a questionable sham intervention

to reach a questionable conclusion. Published case

reports and clinical studies that have utilized HBO2as

an intervention in mild to moderate TBI and PCS have

shown consistent positive results [125,126,141,145,

146]. The conclusions of the DoD/VA sponsored tri-

als received the widest media coverage [147], giv-

ing the impression to the public and general medicine

that HBO2 was ineffective for the treatment of mTBI/

PCS. In reality, the DoD/VA study results provid-

ed a boon to HBO2 clinical research at many levels.

__________________________________________________________________________________________________________________________________________________________

Figure 5

Graphical representation of HYBOBI results. Top graph, distribution of acquired brain injuries.

Bottom graphs, WASI intelligence scores divided by injury type. P-values are pre- and post-HBO 2analysis at six months.

WechslerAbbreviated

Scale

ofIntelligence

numberofstudy

participants

Pre-HBO2

Post-HBO2


11/19


X.A. Figueroa, J.K. Wright 343

The missing placebo

The placebo effect is a well-recognized component of

medical treatment, sometimes superseding the effects

of the actual treatment [148-152]. Controls are an es-

sential component of clinical trials, but sometimes the

use of specic controls (a sham or placebo) is just not

feasible or too costly to set up (especially with HBO2).

Placebos are not always used (cancer studies compare

new drugs or procedures against standard of care) and

comparing pre- and post-treatment measures (including

crossover designs), although not deemed the most

stringent, are acceptable and valuable in medicine

[153]. As we have discussed above, the use of a non-

validated sham (pressurized air) in many of the previ-

ous HBO2 studies have clouded the debate regarding

HBO2 effects and efcacy for neurological injuries.

The assumption of a placebo effect with studies thatused pressurized air as a sham control is awed. Using

a comparator that has biological activity equal to the

treatment group is not a sham or a placebo: It is a bad

study design.

Although poorly controlled, some useful results can

be extracted from existing studies. An example is

the magnitude of the placebo effect in HBO2 studies.

Unreported in the discussions of the Cifu, et al. publi-

cations [1,2] was the lack of any measurable placebo

or Hawthorne effect in the 2.0 atm abs, 10.5% oxygen

group (the 21% oxygen equivalent; Figure 3). TheCifu, et al. study demonstrated that being in the pres-

ence of a hyperbaric chamber and sensing an increase

in pressure did not induce a placebo effect in their

21% oxygen equivalent sham group (Figure 3). The

increased attention by the study technician and doctors

did not produce a Hawthorne effect on the study par-

ticipants. On the contrary:

...we found that the sham and the 1.5 ATA

equivalent groups demonstrated nonsignicant

[underline is ours] ... (worsening) in their raw

total RPQ scores... (P.18) [2]

The 2.0 atm abs, 10.5% oxygen group did not produce

any statistically signicant changes in the RPQ or

PTSD scores (placebo or nocebo) from baseline

measures, as would be expected when simulating a

21% oxygen equivalent.

In lieu of this analysis, a serious reconsideration of

the published literature must occur. Previous studies that

have a crossover design, that compare pre- and post-

treatment measures and have avoided the sham assump-

tion (using compressed air at 1.14-1.5 atm abs) should

be given equal consideration when analyzed side by

side with the sham or placebo controlled studies. The

assumption that pressurized air has negligible or no

biological activity is refuted by cell culture, animal

studies and clinical reports. The requirement for a sham

control is an important component for clinical trials,

but the absolute requirement for a sham should be

tempered by the results of previous trials, the realiza-

tion that pressurized air is biologically active and the

inclusion of other controls (such as standard of care).

Taken as a whole, these results support the idea that we

are witnessing a real and powerful neurological repair/

reactivation mechanism for mTBI with oxygen, even

under low positive-pressure room air.

Summary

The result from the rst DoD/VA study [4] must be

viewed as an early entry in the arena of low-pressure

therapy results, as the sham group is not a true sham.

The results from the other DoD/VA sponsored stud-

ies [1,2], highlight the lack of a measurable placebo/

Hawthorne effect and the ability of HBO2 to improve

PTSD symptoms in blast-induced PCS. The HOPPS

study [135] supports the results of the Wolf, et al. study

[4] and the other published HBO2outcome for TBI/PCS[125,126,141,145,146]. Pressurized air (1.3 stm abs,

21% oxygen) can produce a treatment response that

improves measured outcomes in TBI/PCS and PTSD

symptoms and is superior to standard of care for

TBI/PCS [135].

The urgency of now

A large fraction of the current epidemic of active duty

U.S. military suicides (22+ service members a day take

their lives, 44 attempt suicide) [154] is possibly due to

misdiagnosing the military TBI population with PTSD

or failing to appropriately diagnose other mental health

conditions [155]. In the civilian population as well, the

issue of misdiagnosis of TBI as PTSD is similar to that

for the U.S. military [156]. The DoD and VA have spent

at least $9.2 billion since 2010 [157] treating PTSD

but have been unable to stem the epidemic of suicide

and mental illness in veterans. Drug interventions are


12/19

344



inadequate, and studies continue to nd that pharmaco-

logical interventions are not effective in treating the

symptoms of TBI or PTSD [158-160]. Many cases of

veteran suicide have been linked to prescribed medi-

cation [161,162].

Currently, the debate regarding the utility of HBO2for

treating mTBI, PCS or PTSD is mired in controversy. At

the heart of this controversy is a simple question:

Does it work?

Based on information from case reports and phase I

studies HBO2 does work as a therapy for mTBI/PCS

and PTSD as they are currently diagnosed. None of

the prescribed therapies for mTBI or PCS for service

members (or civilians) has undergone a phase III RCT.

Currently, the best that medicine and therapy can offer

is the chance for a new normal, a term that is utilized

in rehabilitation to inform those with a brain injury that

they have to live with lower expectations and abilities.

For individuals who are living with a chronic brain

injury and surviving the symptoms, being told that they

need to adapt to reduced abilities can be a demoralizing

diagnosis. The literature in English for mTBI, PCS and

PTSD case reports and clinical trials has the weight of

evidence in favor of HBO2 having a reparative

effect (Table 2).

Realistically, not all patients will benet from HBO2.

Yet, is it worthwhile to consider HBO2 as a therapy

for mTBI/PCS if it can improve the lives of 10%, 25%

or 50% of affected individuals? Would a new new

normal that is, 25%-50% better than the old new

normal be worth the effort? At what point will the

general medical community draw the line for the

potential treatment of more than 5 million Americans?

The fundamental questions that should be asked by

physicians are the following:

1. Who are the most likely candidates to benet

from HBO2?

2. What are the minimum treatments that can elicit

a clinically relevant improvement?

_____________________________________________________________________________________________________________________________________

Table 2

authors year Dx symptoms neurocog pre-/post- between type of # of sham HBO2 HBO2 # of time since tests HBO2 tests design arms press. press. dives subj. injury

A75% O2 100% O2 totalB10.5% O2

C(Med Air)_____________________________________________________________________________________________________________________________________

Eovaldi, et al. 2005 PTSD yes N/A N/A N/A pre- to post- 1 N/A 2.4 atm 7 1 4 days_____________________________________________________________________________________________________________________________________ Hardy, et al. 2007 mTBI yes yes yes N/A pre- to post- 1 N/A 2 atm 20/60 1 12 mos.

_____________________________________________________________________________________________________________________________________ Lin, et al. 2008 SoCno N/A N/A SoCno yes RCT w/ 2 N/A 1.5 atm 22/22

/yes /yes SoC grp. (44)_____________________________________________________________________________________________________________________________________ Wright et al. 2009 mTBI yes yes yes N/A pre- to post- 1 N/A 1.5 atm 40 2 8 mos.

_____________________________________________________________________________________________________________________________________ Harch et al. 2009 mTBI yes yes yes N/A pre- to post- 1 N/A 1.5 atm 40 1

_____________________________________________________________________________________________________________________________________ Harch et al. 2009 mTBI yes yes yes N/A pre- to post- 1 N/A 1.5 atm 40 12 ~ 2 yrs.

_____________________________________________________________________________________________________________________________________ Stoller et al. 2011 mTBI yes yes yes N/A pre- to post- 1 N/A 1.5 atm 40 3 3 mos./20 yrs.

_____________________________________________________________________________________________________________________________________ HOPPS 2012 PCS SoCno/ N/A SoCno/ SoCyes/ RCT w/sham 3 C1.5 atm 1.5 atm 40 23/24 ~ 2 yrs.

Ayes/yes Ayes/yes Ano/no /SoC /25 (72)_____________________________________________________________________________________________________________________________________ Wolf et al. 2012 PCS *no *no *no *no RCT w/ 2 C1.3 atm 2.4 atm 30 24/24 3-71 mos.

sham (48)

_____________________________________________________________________________________________________________________________________ Boussi- 2013 mTBI yes/no yes/no yes/no yes//no crossover 2 N.A 1.5 atm 40 32/24 ~34.6 mos./

Gross, et al. //yes //yes //yes //24 (56) ~31.7 mos._____________________________________________________________________________________________________________________________________ Cifu et al.+ 2013 PCS Bno/Ano/ Bno/Ano/ Bno/Ano/ Bno/Ano/ RCT w/ 3 B2 atm/ 2 atm 40 B21/A18 ~8.5 mos.

Walker et al. no* no* no* no sham A2 atm/ /21 (60)_____________________________________________________________________________________________________________________________________

Filled light-grey cells are for reports of positive outcomes with HBO2. Dark-grey cells are for outcome with no discernible change.

SoC = standard of care. Starred outcomes (*) for Symptoms, Neurocog Tests, Pre-/Post-HBO2and Between Groups are for stud-

ies that concluded no significant result, but statistical analysis contradicts conclusion with results that are statistically significant

between pre- and post-testing within groups.


13/19

345



3. What combination of treatments can produce

the maximum improvement?

Ideally, a set of RCTs with true shams and standard of

care comparators will settle this long-standing issue.

But we are far from the ideal. People with an mTBI or

PCS need treatment now. Given the published super-

iority of HBO2over the standard of care (in a military

and civilian population), HBO2 should be covered

or given provisional approval. If, in the future, the

medical community can replicate the presumptive

placebo effect induced by HBO2 chambers and fa-

cilities, this can become the standard of care.

The contradictory outcomes from published HBO2

studies have muddied the waters and added to the con-

fusion of clinically relevant results. Replication of

results remains difcult to accomplish with the ob-

stacles of cost, ill-dened controls and non-standardassessment scales. HBO2is not a eld known for deep

research pockets, industrial/academic collaboration or

a dedicated budget from the Federal government for

research. Clinical trials in diffuse neurological injuries

are attempts at placing parameters on complex medical

cases with varied history of injury, genetic background,

nutritional variations, socioeconomic factors and previ-

ous attempts at medical intervention. There is no single

standard for testing recovery in a general TBI popula-

tion, the ideal measure of efcacy being the return to a

productive life for the study subjects and the long-termcessation of brain injury sequelae. For the majority of

HBO2 studies approximations vs. replications of the

trials are par for the course. Variations are to be

expected with the current low number of subjects

recruited in U.S., Israeli, Taiwanese and Chinese

HBO2studies on TBI recovery.

The Wolf, et al. [4], Cifu, et al. [1,2] and Army [143]

results have added to the growing database of effects

that HBO2 has on neurological injuries. These are ac-

complishments that should be roundly applauded and

commended. We do, however, disagree with the con-

clusions reached by the authors and their interpretation

of their results. We urge the UHMS Committee to grant

preliminary approval for the use of HBO2 in the treat-

ment of chronic mild to moderate TBI/PCS. Given the

history of using non-validated shams and the emerging

data comparing HBO2 to standard of care, HBO2has a

superior outcome in phase I studies. The clinical reality

is stark: currently there are no treatments that can im-

prove symptom and cognitive performance for chronic

mild to moderate TBI or PCS, especially one year or

longer from the time of injury. HBO2 is safe, with few

side effects, has durable treatment outcomes, has avail-ability in many metropolitan centers and is managed

by both hospital-based and independent clinics. The

evidence for improving long-term symptoms (includ-

ing PTSD symptoms) and cognitive performance is

substantial in this regard. Approval of HBO2 on a

tentative basis would allow for the collection of

results in a large patient population, and we recom-

mend this be done. Even if some of the improvement

seen could be attributed to placebo or Hawthorne

effects, it is still durable and should be considered

treatment. No other intervention can offer these resultsor this degree of hope for the mTBI/PCS patient. HBO2

should be part of the approved treatment armamen-

tarium, along with other appropriate and proven thera-

pies, for mild to moderate TBI and PCS in civilian,

active-duty and veteran populations.

Conict of interest

The authors report no conict of interest with this

submission. n


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