Hyperbaric Oxygen Therapy for Post Traumatic Stress Disorder - a Pragmatic, Double Blinded Randomized Trial
Phase: NA
Conditions: PTSD - Post Traumatic Stress Disorder
Sponsor: Medical Corps, Israel Defense Force

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Protocol 
Hyperbaric Oxygen Therapy for Post Traumatic Stress Disorder - 
a Pragmatic, Double Blinded Randomized Trial 
Primary Investigator and physician in charge: Dr. Carmel Kalla 
This study will be conducted at the Israeli Naval Medical Institute, Haifa. 
Box 22, Rambam Healthcare Campus, P.O. 9602, Haifa 3109601 
Name 
Degree 
Role 
Telephone 
E-mail 
Signature 
Carmel 
KALLA 
MD 
Primary Investigator, 
Head of Clinical 
Psychiatric Unit, 
IDF-MC 
058-6139999
 
carmelkalla@gmail.com  
Orly KNOLL 
MD, 
MHA 
Co-investigator, Head 
of INMI 
050-2061629
 
 
orlyrofe@gmail.com
 
Dror OFIR 
PhD 
Co-investigator,  
052-9280655
 
drorof@gmail.com 
 
Ivan GUR 
MD 
Co-investigator, 
054-2555655
 
ostyly@gmail.com 
 
Yinnon 
MATSLIAH 
MD 
Co-investigator 
052-9455428
 
ymatsliah@gmail.com 
 
 
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Abstract 
Post-traumatic stress disorder (PTSD), affecting approximately 6% of the general population 
and up to one-third of individuals exposed to combat zones and disasters, is a significant 
contributor to morbidity and mortality among IDF personnel. Hyperbaric oxygen therapy 
(HBOT), in which patients breathe oxygen at a partial pressure higher than 1 atmosphere in a 
hyperbaric chamber, has been investigated in the context of treating a wide range of 
neuropsychiatric disorders, including PTSD and mild traumatic brain injury (mTBI). Four 
controlled studies conducted in patients with mTBI, about half of whom also suffered from 
PTSD, have yielded conflicting conclusions regarding the potential efficacy of hyperbaric 
therapy. A single study involving approximately 30 patients with PTSD without mTBI 
demonstrated significant clinical improvement; however, it was characterized by several 
methodological limitations—chief among them the absence of blinding or a placebo control. 
None of the studies conducted to date have reported long-term findings (beyond one year), 
included patients with a short duration of symptoms (“early PTSD”), or included female 
participants. The proposed study aims to conduct a prospective, double-blind, controlled 
investigation of the biological effect of hyperbaric therapy in PTSD, continuously throughout the 
hyperbaric treatment course, at the end of treatment, and during a substantial follow-up period 
of two years after treatment completion. We intend to include adult participants who are capable 
of providing informed consent and who meet DSM-5 diagnostic criteria for PTSD. To maintain a 
pragmatic study with high external validity, exclusion criteria will be limited to those indicating 
risk (concrete suicidality, or a history of manic or psychotic disorder) or factors likely to impair 
treatment efficacy (incompatibility with hyperbaric chamber treatment, inability to complete the 
full treatment protocol, or pregnancy). Participants who miss a substantial number of treatments 
(five consecutively or one-third of the total treatments) will be withdrawn from the study. 
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The primary outcome measure will be the CAPS-5 questionnaire. In addition, PTSD symptom 
questionnaires, surveys assessing cognitive, executive, and affective functioning, and 
health-related quality of life will be administered. An exploratory outcome will focus on sleep 
quantity and quality and physiological monitoring using wearable devices, currently considered 
the most promising biomarker in the context of PTSD. Following enrollment and the provision of 
informed consent, balanced randomization will be performed with respect to covariates 
previously described as potential confounders (such as age, duration, and severity of 
symptoms, …). Participants will receive 60 hyperbaric treatments, five days per week, at either 
2.0 atmospheres or 2.5 atmospheres. Both the participants and the evaluating clinical staff will 
be blinded to treatment allocation. 
 
 
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Background 
Post Traumatic Stress Disorder 
Post Traumatic Stress Disorder is a significant public health concern.(1) Affecting over 6% of the 
general population, lifetime prevalence may be as high as 33% in high risk populations - 
including veterans, combat zone residents and areas affected by natural disasters. (2) 
Manifested clinically as significant hyperarousal, hypervigilance, intrusive thoughts and 
flashbacks, and a myriad of sleep disturbances, PTSD is an important cause of morbidity and 
mortality. (3) Comorbid affective disorders reach a prevalence of over 50%. Over 20% of 
patients with PTSD have concomitant substance use disorders. Suicidal ideation is reported in 
as many as 50% of persons struggling with PTSD. Death by suicide is at least twice as common 
in individuals with PTSD compared to matched controls. Disability and loss of income affect 
over 90% of patients. (4) Despite several well researched treatment approaches, including 
various psychotherapeutic interventions aided by pharmacotherapy and biofeedback, the 
prognosis of PTSD remains poor. (5) The economic burden of PTSD exceeds 232 billion $ 
annually in the United States alone. (6) The risk of PTSD in Israel is estimated to increase 
three- to ten-fold following the attack of October 7th, 2023.(7)  
Disruptions in frontolimbic circuits have been stipulated as important culprits in PTSD 
pathogenesis. Monoaminergic dysregulation in the infralimbic cortex is accepted to be a core 
mechanism in PTSD pathogenesis. In an animal model (8) HBO therapy restored 
hypothalamus-pituitary-adrenal axis activity in the infralimbic cortex in a rat model. Thioreduxin 
reductase has been shown to be deregulated in the hippocampus of single prolonged stress 
exposed rats.(9)  
Hyperbaric Oxygen Therapy 
Defined as the administration of breathing oxygen at partial pressures exceeding 1 atm, 
hyperbaric oxygen (HBO) therapy has been attempted in various neurological and psychiatric 
impairments.(1,10,11) Hyperoxemia, with PaO2 as high as 1800mmHg under 3.0 ATA of pure 
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O2, is the most important mechanistic path by which HBO alters physiology.(12) Hyperoxemia 
leads to hyperoxic vasoconstriction, increased tissue oxygen concentration (up to 400 mmHg) 
and decreased reactive oxygen species (ROS) formation.  Alternating between normal and 
supraphysiological PO2 has been shown to induce local transcriptional, paracrine and systemic 
changes, modulating mitochondrial and cellular function and promoting the release of hypoxia 
inducible factors (HiFs). (1)  
While generally safe, potential complications can be divided into those originating in pressure 
shifts, and those attributed to increased PO2. As a consequence of Boyle’s law, changing the 
pressure gradient on a confined gas will result in a proportional change in  its volume. Thus, gas 
pockets that are not fully ventilated may experience volume shifts during the inherent pressure 
shifts in the hyperbaric chamber. This will result in considerable shear forces, often resulting in 
tissue damage, also known as barotrauma. Ear barotrauma is most often reported, at the rate of 
1-5%. Sinus barotrauma is reported at 0.5-0.6%, with no serious cases of lung barotrauma or air 
embolization reported in any of the currently available elective HBO therapy literature.(1,13) The 
increased PO2 may result in CNS oxygen toxicity (COT), often manifested as myoclonus, visual 
or other focal neurological impairments, and seizures. Reported incidence associated with 
elective HBO therapy is estimated below 0.5:10,000 treatments. All of these potential adverse 
events are fully reversible.(12)  
HBO Therapy for PTSD 
The majority of prospectively randomized studies were conducted in subjects with mild 
traumatic brain injury (mTBI), in whom PTSD was reported in 30-60% of cases. (1) A recent 
pooled estimate of 4 RCTs (11,14) (15) (16) totaling 252 patients found no significant effect of 
HBO therapy compared with sham (PCL Md of 0.61, 95% CI [−7.75, 8.96], p = 0.38). (1)  The 
only trial reporting outcomes over 1 month after HBO therapy termination (14) reported no 
significant difference between the HBO therapy and the sham control groups at six months 
(PCL Md 4.1, 95%C.I.[-11.9, 3.7], p=0.29). This is in stark contrast with the significant 
improvement observed at the end of the 60 consecutive HBO therapy sessions (PCL Md of 
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12.3, 95%C.I.[-21.4,-3.1], p=0.01). At 12 months, PCL scores were actually worse in both 
groups (mean PCL 5.8 (±11.8) higher than baseline in the HBO therapy and 5.8 (±13.3) in the 
sham control, p=0.99). Longer (2 and 3 years post treatment termination) follow up was 
conducted in a small subgroup (40% and 14% of the original cohort, respectively). In another 
study focused on patients with fibromyalgia and childhood sexual assault,  somatization, anxiety 
and depression levels reduced by 50% following 60 daily treatments compared to no change in 
controls receiving psychotherapy alone.(10) 
To our knowledge, only one RCT thus far focused on PTSD patients with no mTBI. (17) Of 35 
patients allocated 1:1 to 60 daily HBO therapy sessions at 2.0 ATA for 90 minutes each, 14/18 
completed the HBO therapy (three removed due to problems equalizing, one opted out after 20 
sessions) and 15/17 completed follow up of no sham control. While Clinician-Administered 
PTSD Scale (CAPS-5) scores were similar at baseline (46.6±11.5 vs 49.5±10.7), a significant 
reduction was observed after 12 weeks of therapy (28.5±17.4 vs 51.5±8.4, group by time 
ANOVA F=30.6, p<0.001). Significant improvements were also demonstrated in BSI and BDI 
scores (F = 5.72, p = 0.024 and F = 7.65, p = 0.01). Twenty two (78.6%) of the original 28 
patients completing HBO therapy in this study were re-evaluated a median of 704 (±230) days 
after treatment termination. Mean CAPS-5 scores were unchanged compared to those obtained 
immediately after treatment (26.6±14.4 vs 28.6±16.7, p = 0.745) and both were significantly 
lower than pretreatment scores (47.5±13.1, p<0.001) (18). 
A safety concern unique to PTSD is the potential to aggravate symptomatology during 
treatment. Observational data collected during the above mentioned study (19) suggests 
surfacing of new trauma related memories is not uncommon, occurring in 35.7% of patients 
after 30.5±13.2 treatments on average. No increased risk of  suicide ideation or behaviour was 
recorded in this study.  
 
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Mild Traumatic Brain Injury 
Mild traumatic brain injury (mTBI) is often defined as the occurrence of neurological symptoms 
(including a brief loss of consciousness) following a trauma to the head, without significantly 
prolonged decrease in consciousness (Glasgow Coma Scale of 13-15) or amnesia (if present, 
shorter than 24 hours). (11) A major concern in military medicine, mTBI is a complication of up 
to 30% of battlefield injuries. (20) Co-occurrence with PTSD is common: as many as 10-20% of 
veterans with PTSD have mTBI, and up to 50% of those suffering from mTBI develop PTSD. 
Phenotypically similar to PTSD, mTBI can be complicated by prolonged post-concussion 
symptoms, including headaches, cognitive impairments, affective disorders and sleep 
disturbances. (21) A recent meta-analysis of participant level data from four studies (totaling 254 
patients) reported a significant improvement in verbal memory (CVLT-II Md of 3.8; 95% CI [1.0, 
6.7], p=0.01), a marginally significant improvement in the PTSD checklist score (Md -2.7 points, 
95% CI [-5.8, 0.4], p=0.09), and a trend towards improvement in the Rivermead Postconcussion 
Symptoms Score (Md -2.3, 95% CI [-5.6, 1.0], p=0.18). (21) 
Well described in the treatment of mTBI, animal studies demonstrated HBO therapy to improve 
tissue oxygenation, induce stem cell proliferation and decrease inflammation. (22) Case series 
in humans have demonstrated improved cerebral blood flow and decreased markers of CNS 
inflammation. (4)  
Limitations of current knowledge 
Isolating the true biological effect of HBO on PTSD has been the cornerstone of the scientific 
controversy surrounding the role of HBO therapy in psychiatry. Namely, neutralizing participation 
and placebo effects on the one hand, while providing no increased pressure or PO2 on the 
other, has been the main limitation of studies conducted thus far. Sham protocols that involve 
hyperbaric air exposure result in increased PO2 (albeit usually <1.0 atm).(14,15) In a single 
study using hypoxic (10.5% O2) nitrox at 2.0 ATA,(16) there was still exposure to increased 
ambient pressure. Thus, proponents of HBO explain the lack of effect observed in these studies 
to be the result of unjustified exposure to hyperbaric conditions in the control group.(23)  
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Conversely, the effect reported in studies opting to avoid any hyperbaric chamber-setting 
exposure in the control group could be easily attributed to participation and placebo effects. (1) 
In this approach, neither participants nor observers can be reasonably blinded. Beyond these 
effects, the behavioral modifications inherent to the intervention (but not the passive control) 
group - i.e. attending daily treatments, the strong and intense interpersonal interaction during 
2-3 hours of treatment (with other patients and the chamber attendant) daily, completing 
questionnaires and assessments, etc - may have a direct effect on PTSD symptoms. Finally, the 
selection of patients proving to be able to complete a full HBO course (typically 40-60 daily 
encounters), not applied in the control group, can be an important source of bias when gauging 
the effect of HBO in passively controlled PTSD studies. These concerns are further supported 
by the only RCT examining both sham (1.2 ATA of air) and no hyperbaric intervention controls in 
patients with mTBI: improvement was similar in both the HBO and sham groups, both superior 
to the no hyperbaric intervention group.(15)​
Beyond these cardinal concerns, previous studies have been very restrictive in including 
relatively healthy, chronic (>1-4 years duration), and overwhelmingly male patients. There have 
been no head to head comparison of different treatment protocols and HBO dosing thus far.  
Goals  
Our primary goal is to examine the effect of HBO therapy dose on PTSD symptoms.  
Specific Secondary Aims 
●​
Assessing the long-term effects of HBO in PTSD 
●​
Examining the effect modification of mTBI on the therapeutic effect of HBO in PTSD 
●​
Describing in detail trends in PTSD symptoms throughout the treatment period (as 
opposed to before and after assessments only), thus assessing the optimal duration of therapy.  
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Study Hypotheses 
●​
Symptoms of PTSD will reach peak improvement following 40-60 HBO treatments 
compared to sham pressurized controls 
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 This improvement will wane over the coarse of the ensuing 2 years of follow up, with the 
mean difference of PTSD measurements (e.g. CAPS-5 scores) decreasing. 
●​
The improvement will be more significant in patients with a shorter duration of symptoms 
●​
The improvement will be more significant in patients suffering from concomitant mTBI 
●​
The improvement will reach a plateau after about 40 treatments 
Materials and Methods 
Study Design 
This is a double blinded, prospectively randomized, controlled, pragmatic study. The pragmatic 
design allowing for a myriad of additional therapy approaches, and in particular - stepping up or 
down pharmaco- and psycho- therapy during the trial, as well as widely applicable inclusion and 
exclusion criteria, aims to answer previous concerns raised of the external validity of 
contemporary clinical HBO research. (20)  
Population and Setting 
Patients referred by the Combat Reactions Unit or the Rehabilitation Division at the Ministry of 
Defense for hyperbaric treatment evaluation at the Israeli Naval Medicine Institute (INMI) from 
September 1st, 2024, until December 31st, 2027, will be considered for this study. A dedicated 
advertisement will be placed at military treatment centers, as outlined in Appendix B and form 
10 adjacent to this protocol. Only potential participants calling the investigator at their own 
discretion will be approached. After completing a fitness for hyperbaric chamber evaluation and 
provided inclusion and exclusion criteria are met, patients will be offered to participate in the 
study. An investigator that is not part of the treating medical team will offer an in-depth 
explanation of the existing knowledge, possible side effects and the right to refuse participation 
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before and at any moment during the study. Reasonable time (at least 12 hours) will be given 
for pondering and additional questions, before signing an informed consent. The investigator 
providing explanations and requesting informed consent will not be a member of the treatment 
team and will not wear any attributes of rank or insignia during the entire explanation and 
informed consent process.  
Inclusion Criteria  
●​
Age over 18 years and up to 80 years 
●​
Ability to understand the researcher's explanation and give informed consent.  
●​
Of any sex or gender (unlike previous studies, a significant effort will be made to include 
women in this study) 
●​
A diagnosis of PTSD according to DSM-5 criteria with a severity that warrants discharge 
from military service.  
Exclusion Criteria 
●​
The lack of ability to attend 120 daily (5 times/week) treatments at the INMI 
●​
Current or past psychotic disorder 
●​
Evidence of active suicidal ideation 
●​
Evidence of past or present manic disorder 
●​
Difficulty equalizing pressures, including pulmonary emphysema, significant sinusoidal 
obstruction, eustachian tube dysfunction, or an pneumothorax that is not drained.  
●​
Known or suspected pregnancy.   
Primary Outcome 
●​
The change in the Clinician-Administered PTSD Scale (CAPS)-5 score at the end of the 
treatment series compared to the baseline score 
 
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Secondary Outcomes 
●​
The change in the CAPS-5 score two years after inclusion in the study relative to the 
baseline score 
●​
Changes in the Beck's Depression Inventory (BDI) score 
●​
Changes in the score of the Pittsburgh Sleep Quality Questionnaire (PSQ) 
●​
Changes in the State Trait Anxiety questionnaire score  
●​
Changes in the post-traumatic disorder score in the CAPS-5 continuously over time 
●​
Changes in the Basic Symptoms Inventory (BSI) 
●​
Changes in Executive Function Questionnaire (BRIEF-A) 
Exploratory Outcomes 
●​
Sleep continuity index 
●​
Average blood pressure while awake and asleep over 24 hours 
●​
Psychomotor Vigilance Test (PVT) 
Research Site 
This research will be conducted at the Israeli Naval Medicine Institute (INMI), Israeli Navy, 
Haifa.  
Study Duration 
Enrollment over two years (1.9.2024-31.12.2027), follow-up for another two years, data 
analysis, processing and publication for up to one year. A total of five years.   
Equipment and Materials 
The treatment will be carried out in a HAUX STARMED  multi-place pressure chamber (by 
HAUX LIFESUPPORT SYSTEMS, Cuxhaven, Germany) containing three sections (12+2+6 
places, respectively). Ambulatory blood pressure measurement will be performed by an 
ambulatory blood pressure monitor (ABPM) model F11 (by SUNTECH). Measurement of sleep 
continuity and physiological monitoring will be performed using a combined pulse-oxymetry and 
accelerometry wearable device such as the Oura ring (Oulu. Finland). 
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Detailed Research Plan 
Week (-3) to 0:​
PRE ENROLLMENT 
●​
Review of the electronic healthcare registry (EHR) by the primary investigator 
●​
Eligibility check (inclusion and exclusion criteria) 
●​
A designated investigator will approach the patient by phone and offer a general 
description of the study procedure and duration, as well as clearly stating the voluntary nature of 
the study and the ability to refuse or withdraw consent at any point 
●​
Office visit #1, during which a detailed explanation of the study procedure, the ⅓ 
probability of sham treatments necessitating a further 60 therapeutic sessions, and potential 
side effects (including barotrauma and CNS oxygen toxicity) will be offered. In addition a 
pressure-chamber fitness test (including full medical history, physical examination and otoscopy 
during valsalva) will be completed.  
●​
The patient will be offered at least 12 hours before signing informed consent, during 
which time a full copy of the informed consent, as well as a telephone number of the explaining 
investigator (with an invitation to ask any further questions) 
●​
Obtaining a written and signed informed consent by an investigator that is not a part of 
the treatment team 
●​
Childhood Trauma Questionnaire (STQ) 
●​
Structured Clinical Interview for DSM-5 (SCID) 
●​
A roll in (baseline) physiological monitoring (including ABPM and sleep monitoring) 
week 0:​
​
randomization 
●​
Randomization at a ratio of 1:1 (2.0ATA:2.5ATA). The randomization will be performed using 
the Frane algorithm (24,25) For random allocation, covariate adaptive randomization (CARAT) 
will be used in the R software,(26) taking into account covariates that have previously been 
associated with the likelihood of improvement in post-traumatic stress disorder,(1) including:  
○​
Duration of symptoms 
○​
Age 
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Severity of baseline functioning (baseline CAPS-5 score) 
○​
The presence of additional psychiatric morbidity, including the use of addictive 
substances 
○​
Presence of mTBI 
○​
The baseline index of the primary and secondary outcome questionnaires (CAPS-5, BDI, 
PSQ, STA, PCL-5, BSI, BRIEF-A) 
○​
Potential competing therapies, including the following:  
 
PTSD specific 
therapy 
Collected (and balanced) parameters 
Conversational 
therapy 
Primary approach (CBT, psychodynamic, 
mixed), frequency (N of sessions/month) 
Pharmaco - 
therapy 
Drug class (SSRI, SNRI, TCA, Cannabinoids, 
Hallucinogens, Other), daily dose, duration of 
therapy 
Experimental 
therapy  
E.g. vagal stimulation (date, proceedure 
preformed) 
 
Week 1-12:​ Daily hyperbaric treatment (five treatments per week) 
●​
HBO 10 = 2.0ATA Treatment group: compression to 2.0 ATA for up to fifteen minutes, 
breathing pure oxygen for 45 minutes, breathing air for 5 minutes, breathing pure oxygen for 45 
minutes, decompression with a safety stop for 20 minutes. The choice of 2.0 ATA peak PO2 was 
made in view of previously raised theoretical concerns of cerebral hypoxic vasoconstriction at 
higher PO2s,(23) and the fact this was the peak pressure chosen in the only PTSD oriented 
RCT thus far.(17) 
●​
HBO 15 = 2.5ATA Treatment group: compression to 2.0 ATA for up to fifteen minutes, 
breathing pure oxygen for 45 minutes, breathing air for 5 minutes, breathing pure oxygen for 45 
minutes, decompression with a safety stop for 20 minutes.  
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Weekly measurement: asking each patient “are you in a treatment group?”, “what 
pressure do you think you have reached?”, as well as physiological (ABPM and sleep) 
monitoring 
●​
Bi-weekly measurement (every ten treatments): CAPS-5, BDI, PSQ, STA 
●​
Measurement at the beginning and end of the period only: BRIEF-A, EQ-5D 
Week 26:​
Long-term outcome 1 
For all participants: the main and secondary outcome questionnaires (CAPS-5, BDI, PSQ, STA, 
PCL-5, BSI, BRIEF-A), Physiological monitoring (ABPM and sleep), full medication history, PVT, 
PrePulse Inhibition test. 
Week 52: ​
Long-term outcome 2 
For all participants: the main and secondary outcome questionnaires (CAPS-5, BDI, PSQ, STA, 
PCL-5, BSI, BRIEF-A), Physiological monitoring (ABPM and sleep), full medication history, PVT, 
PrePulse Inhibition test. 
Week 78:​
Long-term outcome 3 
For all participants: the main and secondary outcome questionnaires (CAPS-5, BDI, PSQ, STA, 
PCL-5, BSI, BRIEF-A), Physiological monitoring (ABPM and sleep), full medication history, PVT, 
PrePulse Inhibition test. 
Week 104:​ Long-term outcome 4 and study completion 
For all participants: the main and secondary outcome questionnaires (CAPS-5, BDI, PSQ, STA, 
PCL-5, BSI, BRIEF-A), Physiological monitoring (ABPM and sleep), full medication history, PVT, 
PrePulse Inhibition test.  
Removal Criteria (any of the following): 
●​
As per the subject’s request, at any point, for any (or no) reason whatsoever.  
●​
Loss of more than five consecutive treatments for any reason 
●​
Loss of more than 20 cumulative treatments for any reason 
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CNS oxygen toxicity 
 
Prespecified Subgroup Analysis 
Expansive inclusion criteria and a pragmatic research design are our guiding principles, as we 
believe this approach to result in externally valid and clinically impactful results. At the same 
time, a separate analysis of the following a priori defined subgroups will expand our 
understanding of the effect of hyperbaric oxygen in specific subtypes of PTSD: 
Duration of Symptoms: There is much evidence, both in animal models and in observational 
studies in humans, regarding the substantial difference in neuropathophysiology in young stroke 
patients versus patients with chronic PTSD. The definitions in the literature are not consistent, 
but similar to several previous studies we will define the subgroup of early PTSD as patients 
who started hyperbaric treatment less than a year from the onset of symptoms, and chronic 
PTSD as the duration of symptoms over 4 years before the start of hyperbaric treatment.  
Mild Traumatic Brain Injury (mTBI): Previous studies have shown significant improvement in 
traumatic brain injury symptoms under hyperbaric therapy. In view of this evidence, we 
anticipate that a possible therapeutic effect of hyperbaric oxygen will be increased in patients 
with concomitant TBI.  
Statistical Analysis 
Standard descriptive statistics will be used to summarize population characteristics. Comparing 
pre and post treatment values, as well as between groups (2.0ATA vs. 2.5ATA, subgroups) we will 
use a chi-square test for categorical variables, Mann-Witney U test for nonparametric variables 
and student's unpaired t-test for normally distributed continuous variables. Tukey’s correction 
was applied when applicable to adjust for multiple comparisons. Categorical variables will be 
described using proportions and percentages, non-parametric variables with median and 
interquartile range (IQR) and normally distributed continuous variables as mean with standard 
deviation (SD). A 2-sided Pv<0.05 will be considered statistically significant for all tests. A mixed 
model for repeated measures will be constructed for the primary, as well as every of the 
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secondary and exploratory outcomes. Included will be covariates found to significantly predict 
the outcome at question in a univariate analysis. All calculations will be performed using R 
version 4.4.1.  
Sample Size and Power 
Based on previously published data, we estimate the primary outcome (CAPS-5 score) to have 
a standard deviation of around 12 points. In view of previously published results and our 
hypothesis as detailed above, we will not assume homoscedasticity. Given the lowest effect 
reported thus far in a positive study was a mean difference of 12 CAPS-5 points,(18) and in line 
with the accepted definition utilized in most previous studies,(18) we will define a clinically 
significant imrovement at >10 CAPS-5 points. Aiming to maintain a power of at least 80% to 
detect such a difference at an alpha of <0.05 and a 1:1 allocation our minimal estimated sample 
size is 38 participants in the intervention group and 19 participants in the control group. Allowing 
for the previously reported 70% participation and an additional ~20% attrition rate, numbers that 
are consistent with our own experience (e.g. treating acute acoustic trauma), we will need to 
approach at least 102 patients during the study period. A  full monte carlo based code for these 
calculations is provided in Appendix A. (17) 
Data Handling 
All data collection will be carried out solely by the investigators outlined below. A designated 
clinical research form (CRF) using microsoft excel will be created to handle all data collected. All 
identified data will be saved on a designated unclassified (בלמ”ס) password protected computed. 
Access will be restricted to the abovementioned investigators. The CRF will be encrypted by a 
128 bit RAS protocol. Removing all identifiers (including dates - to be replaced by time intervals, 
names, addresses, ID, military ID and phone numbers) and coding the information will be 
performed by Mj. Dror Ofir, PhD, who’ll be keeping the coding key. Handling coded information 
will be performed on a separate, unclassified, password protected and designated computer, 
access to which will be restricted to investigators handling data analysis as detailed below.  
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Data Visualization 
We expect the following key metrics to be collected. Tables hereby presented are a rough, 
preliminary estimate of the data we strive to collect.   
Table 1 - Basic Cohort Characteristics 
Variable 
Intervention 
N=2x 
Control 
N=x 
P-value 
Age (Mean, SD) 
Females (N, %) 
Background Medical History (N, %) 
   Asthma 
   Allergic rhinitis 
   Smoking 
   Hypertension 
   Dyslipidemia 
   Siezures 
Chronic Medication (N, %) 
   Antihypertensives 
   Lipid Lowering Drugs 
   GLP-1 or glucose lowering  
   Anticonvulsants 
 
 
 
Psychiatric History 
   Duration of PTSD Symptoms (median, IQR) 
   Known Comorbidity (N,%) 
      Substance use  
      Affective dis.  
      Personality dis. 
      Family history of psychosis  
 
 
 
Baseline Questionaires (median, IQR) 
CAPS-5 
STQ 
SCID 
BDI 
PSQ 
STA 
PCL-5 
BSI 
BRIEF-A 
 
 
 
Baseline Physiology (mean, SD) 
   Sleep duration 
   Mean daytime, sleeping and overall BP 
   Daytime, sleeping and overall HRV 
 
 
 
 
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Table 2 - Primary Outcome 
 
Sampling 
TIme 
Bas
elin
e 
14 
day
s 
28 
day
s 
42 
day
s 
56 
day
s 
70 
day
s 
84 
day
s 
6 
mon
ths 
12 
mon
ths 
18 
mon
ths 
24 
mon
ths 
Unadju
sted 
MLM 
MMLM 
Intervention 
Group 
CAPS-5 
(median, 
IQR) 
 
 
 
 
 
 
 
 
 
 
 
p-value 
P- 
value 
Control 
Group 
CAPS-5 
(median, 
IQR) 
 
 
 
 
 
 
 
 
 
 
 
p-value 
P- 
value 
 
Scientific Importance and Clinical Significance 
While HBO proponents point towards reported trends of PTSD symptoms amelioration under 
HBO therapy, (23) skeptics underline the limitations of scarce prospectively randomized studies 
(a total of 30 patients thus far), narrow selection (chronic PTSD, often excluding females and 
mTBI) and the lack of appropriate placebo control. Empirically, thus far the role of HBO in the 
treatment of PTSD has not been sufficiently validated. A recent meta-analysis of HBO therapy in 
PTSD deemed the conduction of a well designed (sham) control in a prospectively randomized 
trial to be the most important milestone in the clarification of this question.(21)   
We believe the following additional considerations to further justify the ethical importance and 
scientific novelty of this proposed study: 
●​ Thus far, females have been excluded, or at the very least neglegably represented 
in all research examining HBO for PTSD. Our study aims to include as many 
women as possible.  
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●​ Our understanding of the long term effect of HBO is extremely limited (thus far we 
have data of only 40 patients)(27). This is the first study, to our knowledge, a-priory 
designed to include a long term follow up.  
●​ We hope physiological metrics collected, and in particularly - sleep data, will help 
to further elucidate effects remaining obscure when relying solely on self reported, 
questionnaire based outcomes.  
●​ Our pragmatic design aims to include the great majority of PTSD patients, 
including those with a relatively short duration of symptoms (the absolute majority 
of patients described thus far have been suffering from PTSD for many years prior 
to inclusion). Studying potential interventions in this physiologically distinct 
subgroup is imperative in view of the national disaster befallen upon our nation on 
with the tragic events of October 2023.  
Ethical Considerations 
We identify a few important caveats when considering the potential risks of this study: 
●​ Central Oxygen Toxicity (COT) - manifested as visual and neurological changes, 
and rarely - seizures. This condition is rare (point incidence of 1:10,000 
treatments)(1) and completely treatable with the discontinuation of hyperbaric 
oxygen. A recent study found no evidence of long term sequelae in patients with 
documented COT.  In view of the very low risk and lack of any evidence of long 
term harm, we believe the risk of COT to be justifiable.  
●​ Barotrauma - the combined risk or around 5% is pertaining to minor injuries, fully 
cured spontaneously within 2-3 days of pressure changes abstinence. Available 
evidence(13), as well as our combined experience of over 40 years, has no 
documented evidence of serious barotrauma occurring in the highly monitored and 
controlled setting of HBO therapy.  
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●​ Memory resurfacing - the only available study examining potential psychiatric side 
effects (19) suggests trends towards increased memory resurfacing, without any 
signals of increased suicidal ideation or intent. We take these potential, albeit yet 
to be substantiated, concerns very seriously, and intend to have a dedicated 
hotline directly to the board certified psychiatrist (and the PI) should the patient, 
their next of keen or the treatment team have any concerns. Notwithstanding these 
concerns, we believe the benefits of clarifying the true effect of a potential 
treatment outweigh these risks.  
Funding 
This work will be partially supported by the Israeli Ministry of Defence, the Division of Veteran 
Rehabilitation, grant nu 2024-0189 (totallin 150,000 NIS, of which 130,000 NIS are allocated for 
perishables (e.g. breathing gasses, breathing masks and tubing) and 20,000 NIS are reserved 
for statistical analysis and publication expenses).  
Access and Delegation of Responsibility 
 
Name 
Allowed Roles and Access 
Duration 
Signature 
PI’s Signature 
Carme
l Kalla 
Approaching potential 
recruits, providing 
explanations, questionnaire 
administration,  
Physiological monitoring, 
Raw CRF 
1.9.2024-
31.8.2027 
 
 
Orly 
Knoll 
Approaching potential 
recruits, providing 
explanations, fitness to dive 
examination, HBO 
administration. 
CRF completion,  
1.9.2024-
31.8.2027 
 
 
Dror 
Ofir 
obtaining informed consent, 
Physiological monitoring, 
full access to the CRF and 
the coded information.  
1.9.2024-
31.8.2027 
 
 
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Ivan 
Gur 
Approaching potential 
recruits, providing 
explanations, fitness to dive 
examination, Physiological 
monitoring, HBO 
administration, CRF 
completion, Coded data 
and Statistical analysis  
1.9.2024-
31.8.2027 
 
 
Yinnon 
Matzlia
ch 
Approaching potential 
recruits, providing 
explanations, fitness to dive 
examination, HBO 
administration. 
CRF completion,  
 
 
 
Limitations 
Challenges, potential technical issues and biases. The research requires coordination with busy 
participants who are not always free. At the same time, the importance of the post-traumatic 
disorder and the lack of other good treatments justify in our view an excessive investment in the 
recruitment and retention of research subjects with an important potential therapeutic method 
such as hyperbaric therapy.   
 
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Appendix A - sample size simulation 
set.seed(123)  # For reproducibility 
 
# Parameters 
effect_size <- 10   # Difference in means 
std_dev <- 12         # Standard deviation 
power <- 0.8        # Desired power 
alpha <- 0.05       # Significance level 
 
# Simulation Function 
calculate_power <- function(n) { 
  p_values <- replicate(10000, { 
    group1 <- rnorm(n*2, mean = 0, sd = std_dev) 
    group2 <- rnorm(n, mean = effect_size, sd = std_dev) 
    t.test(group1, group2)$p.value 
  }) 
  mean(p_values < alpha)  
} 
 
# Find Sample Size 
n <- 10  # Initial guess 
while (calculate_power(n) < power) { 
  n <- n + 1 
} 
 
cat("Required sample size per group:", n) 
 
n/0.70/0.80
 
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Appendix B - Recruitment Add: 
 
​
For a medical study involving volunteers suffering from PTSD (a 
condition also known in Hebrew as “combat stress reaction”):  
Volunteers are needed for a study titled: “Hyperbaric Oxygen Therapy for 
Post Traumatic Stress Disorder - a Pragmatic, Double Blinded Randomized 
Trial.”  
The study will take place at: The Institute of Marine Medicine.  
Address: 8 HaAliya HaShniya St., Haifa (Haifa Naval Base, Bat Galim, 
opposite to Rambam Medical Center). 
A medical study is being conducted on the topic: The effect of hyperbaric 
chamber treatment on PTSD.  
Study description: Volunteers who are interested in participating in the study 
will receive a detailed explanation from a designated researcher, undergo an 
evaluation for suitability for hyperbaric chamber treatment, and complete a 
series of assessments (including questionnaires and measurements of heart 
rate and blood pressure). Participants will then be randomly assigned to 
receive either hyperbaric chamber treatment or placebo (sham) treatment, 
without the participants or the research staff being aware of the assignment. 
Participants will then be asked to attend a series of 60 treatments (five 
treatments per week for 12 weeks). Participants assigned to the placebo 
group will be able to complete the full course of 60 treatments after the 
study concludes. During the treatment period, weekly assessments will be 
conducted (including questionnaires, heart rate measurements, and blood 
pressure measurements). 
Those interested in participating are invited to contact 054-255-5655 at any 
time. 
 
 
 
 
 
 
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