Hyperbaric Oxygen Therapy (HBOT)

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Hyperbaric Oxygen Therapy (HBOT)
Clinical Policy Bulletins Medical Clinical Policy Bulletins
Number: 0172
P o lic y Histo r y
P o lic y
I. Aetna considers systemic hyperbaric oxygen therapy (HBOT) medically necessary for any Last Review
of the following conditions:

04/23/2020
Acute air or gas embolism Effective: 08/27/1997
Acute carbon monoxide poisoning Next
Acute cerebral edema Review: 02/11/2021
Acute peripheral arterial insufficiency (i.e., compartment syndrome) requiring

emergent surgical intervention (e.g., surgical or catheter directed embolectomy or Review
bypass surgery), with imaging documentation of embolus/thrombus (e.g., MR, History
angiogram)
Definitions
Acute traumatic peripheral ischemia (including crush injuries and suturing of severed
limbs) when loss of function, limb, or life is threatened and HBOT is used in
combination with standard therapy
Central retinal artery occlusion (CRAO), acute treatment Additio nal
Chemotherapy-induced hemorrhagic cystitis Info r matio n
Chronic refractory osteomyelitis, unresponsive to conventional medical and surgical
Clinical Policy
management, including a six- week course of parenteral antibiotics and at least one
Bulletin
surgical eradication/debridement attempt, unless contraindicated,
Notes
with photograph (with ruler) of wound plus X-ray or bone culture documenting
diagnosis. *
www.aetna.com/cpb/medical/data/100_199/0172.html 1/102
Compromised skin grafts and flaps , where hypoxia or decreased perfusion has

compromised viability acutely (not for maintenance of split thickness skin grafts or
artificial skin substitutes). Required documentation includes photograph (with ruler) of
wound, type of flap, name of surgeon performing graft or flap, whether there was
surgical exploration, and transcutaneous oxygen tension testing demonstrating
hypoxia of flap or graft (TcPO2 less than 40 mm Hg on room air). *
Cyanide poisoning (with co-existing carbon monoxide poisoning)
Decompression illness (“the bends”)
Exceptional blood loss anemia only when there is overwhelming blood loss and
transfusion is impossible because there is no suitable blood available, or religion does
not permit transfusions
Gas gangrene (Clostridial myositis and myonecrosis)
Idiopathic sudden sensorineural hearing loss (SSHL) -- SSHL greater than 30 dB
affecting greater than 3 consecutive frequencies of pure-tone thresholds when
member has failed oral and intra-tympanic steroids, and HBOT is initiated within 3
months after onset
Non-healing infected deep ulcerations (reaching tendons or bone) (Wagner grade 3 or
more-- see appendix) of the lower extremity, with photographic (with
ruler) documentation, in diabetic adults unresponsive to at least 1 month of
meticulous wound care. Standard wound care in persons with diabetic wound includes
(i) Assessment of vascular status and correction of any vascular problems in the
affected limb if possible, (ii) Optimization of nutritional status, (iii) Optimization of
glucose control, (iv) Debridement by any means to remove devitalized tissue, (v)
Maintenance of clean, moist bed of granulation tissue with appropriated moist
dressings, (vi) Appropriate off-loading, and (vii) Necessary treatment to resolve any
infection that might be present. Failure to respond to standard wound care occurs
when there are no measurable signs of healing for at least 30 consecutive days.
Wounds must be evaluated at least every 30 days during the administration of
HBOT. Continued treatment with HBOT is not considered medically necessary if
measurable signs of healing have not been demonstrated within any 30-day period of
treatment. * Note: HBOT is not considered medically necessary for superficial lesions.
Pneumatosis cystoides intestinalis
Progressive necrotizing soft tissue infections, including mixed aerobic and anaerobic
infections (Meleney's ulcer, necrotizing fasciitis), with history of inpatient treatment
including antibiotics and surgical debridement, unless contraindicated, and (where
appropriate) full thickness or split thickness skin grafts, and with photographic
documentation (with ruler) of the wound. *
Prophylactic pre- and post-treatment for members undergoing dental surgery of a
radiated jaw, where the extraction site is anticipated to be within the XRT portal, and
where HBOT is delivered according to established (Marx) protocol, with 20 HBOT

treatments prior to surgery and 10 HBOT treatments immediately after surgery
Radiation-induced hemorrhagic cystitis
Radiation necrosis (including brain radionecrosis, myoradionecrosis,
osteoradionecrosis (including jaw osteonecrosis), and other soft tissue radiation
necrosis (including breast, chest wall, head and neck, and pelvic organs (e.g. bladder
and rectum)) (typically up to 40 HBOT treatments considered medically necessary, plus
an additional 10 treatments to support tissues after surgical reconstruction (if
performed))
Radiation proctitis
II. Aetna considers the use of systemic HBOT experimental and investigational for the
following conditions (not an all inclusive list) because there is insufficient evidence in the
medical literature establishing that systemic HBOT is more effective than conventional
therapies:
Actinic skin damage

Actinomycosis and other mycoses
Acute coronary syndrome
Acute or chronic cerebrovascular insufficiency/accident (including thrombotic or
embolic stroke)
Acute renal arterial insufficiency
Acute thermal and chemical pulmonary damage, i.e., smoke inhalation (e.g., carbon
tetrachloride, hydrogen sulfide) with pulmonary insufficiency
Adhesions prevention after laparotomy
Aerobic septicemia and systemic aerobic infection
Alzheimer’s disease
Anaerobic septicemia and infection other than clostridial
Anoxic brain injury
Anti-phospholipid antibody syndrome
Arthritic diseases
Arthritis
Aseptic necrosis of the femoral head and neck
Asthma
Autism spectrum disorders
Bacterial keratitis
Bell's palsy
Bone grafts or fracture healing (e.g., nonunion fractures)
Brain tumors
Calciphylaxis (calcific uremic arteriolopathy)

Cancer
Cardiogenic shock
Central airway stenosis following lung transplantation
Cerebral palsy
Chronic bowel dysfunction after pelvic radiotherapy
Chronic pain (e.g., cluster headaches, complex regional pain syndrome/reflex
sympathetic dystrophy, fibromyalgia, migraines, myofascial pain syndrome, and
trigeminal neuralgia)
Chronic peripheral vascular insufficiency
Closed head and/or spinal cord injury
Cognitive impairment (e.g., senility, senile dementia)
Coronary artery disease
Critical limb ischemia
Cystic acne
Dental implant osseointegration
Depression
Diabetic foot ulcers that are not infected
Diabetic superficial wounds
Enterocutaneous fistula
Epithelial-to-mesenchymal transition (EMT) phenomenon in keloid tissue
Erectile dysfunction
Facial neuritis
Fat necrosis
Fibromyalgia
Frostbite
Glioblastoma
Heart disease
HIV infection
Hypospadias
Infective polyneuritis
Inflammatory bowel disease (Crohn’s disease and ulcerative colitis)
Intestinal anastomosis
Interstitial cystitis
Intra-abdominal abscess, pseudomembranous colitis (antibiotic-induced colitis)
Intra-cerebral hemorrhage
Intra-cranial abscesses
Ischemia due to lupus vasculitis
Legg-Calve Perthes disease
Lepromatous leprosy
Liver diseases (e.g., hepatic artery thrombosis, hepatic fibrosis, hepatic necrosis,
hepatitis, hepatocellular carcinoma, non-alcoholic steatohepatitis, and sepsis-induced
liver injury)
Lupus vasculitis
Lyme disease
Lymphedema
Male infertility
Melasma
Meningitis
Methicillin-resistant Staphylococcus aureus (MRSA) infections
Multiple sclerosis
Myocardial infarction
Necrotizing arachnidism
Non-compromised skin grafts and flaps
Non-diabetic cutaneous, decubitus, pressure and venous stasis ulcers
Non-vascular causes of chronic brain syndrome (e.g., Alzheimer's disease, Korsakoff's
disease, Pick's disease)
Ophthalmologic diseases (including central retinal artery occlusion, central retinal vein
occlusion, diabetic retinopathy, glaucoma, keratoendotheliosis, radiation injury to the
optic nerve, retinal detachment)
Optic neuropathy
Organ transplantation and storage
Osteonecrosis of the jaw (except where cause is radiation necrosis (i.e.,
osteoradionecrosis))
Osteoporosis
Otitis externa
Parkinson's disease
Peri-anal fistula
Post-concussive syndrome
Post-operative nipple ischemia following mastectomy
Post-organ transplantation re-vascularization
Post-radiation therapy breast pain
Post-traumatic stress disorder
Pre-operative HBOT for jaw osteomyelitis
Prevention of radiation-induced complications of the head and neck cancers
Pulmonary emphysema
Pyoderma gangrenosum
Radiation-induced cholangitis, myelitis, enteritis, sarcoma
Radiation-induced pulmonary fibrosis/injury

Radiation-induced skin necrosis
Raynaud’s syndrome
Recto-vaginal fistula
Scleroderma (systemic sclerosis)
Seizure disorders
Sickle cell anemia
Sickle cell crisis or hematuria
Skin burns (thermal)
Small bowel obstruction secondary to pelvic irradiation
Spinal dural arterio-venous fistula
Superficial and/or non-infected diabetic ulcers
Surgical wound dehiscence
Systemic inflammatory response syndrome
Tetanus
Tinnitus
Traumatic brain injury
Tumor sensitization to radiotherapy
Vesicocutaneous fistula
Xerostomia/salivary gland dysfunction.
III. Aetna considers systemic HBOT experimental and investigational for members with any of
the following contraindications to systemic HBOT, as the safety of systemic HBOT for
persons with these contraindications to HBOT has not been established:
Concurrent administration of doxorubicin, cisplatin, or disulfiram

Premature infants (birth prior to 37 weeks gestation)
Untreated pneumothorax.
IV. Aetna considers topical HBOT directly administered to the open wound, and limb-specific
hyperbaric oxygen pressurization in small limb-encasing devices experimental and
investigational because its efficacy has not been established through well-controlled
clinical trials.
V. Aetna considers prophylactic HBOT prior to mastectomy experimental and investigational

because the effectiveness of this approach has not been established.
*
Documentation Requirements: Wounds must be evaluated, with photographic documentation
with ruler, after every 15 treatments and/or at least every 30 days during administration of HBOT.
Continued treatment with HBOT is not considered medically necessary if measurable signs of
healing have not been demonstrated within any 30 day period of treatment.
Bac kgr o und

Hyperbaric oxygen therapy (HBOT) is defined as systemic treatment in which the entire patient
is placed inside a pressurized chamber and breathes 100 % oxygen under a pressure greater
than 1 atmosphere (atm). It is used to treat certain diseases and conditions that may improve
when an increased partial pressure of oxygen is present in perfused tissues.
The literature states that HBOT should not be a replacement for other standard successful
therapeutic measures. Depending on the response of the individual patient and the severity of
the original problem, treatment may range from less than 1 week to several months' duration, the
average being 2 to 4 weeks. Hyperbaric oxygen therapy for more than 2 months is usually not
necessary.
The Washington State Health Care Authority’s Technology Assessment on “Hyperbaric Oxygen
Therapy (HBOT) for Tissue Damage, Including Wound Care and Treatment of Central Nervous
System (CNS) Conditions” (2013) stated that “The available data from 13 studies provides
insufficient evidence to determine the optimal treatment frequency duration or dose for HBOT.
No studies reported on the optimal duration of treatment sessions; there were mixed results from
subgroup analysis involving 8 studies looking at frequency; and significant heterogeneity means
that we have low confidence in the available results from 5 studies that looked at dose” However,
it noted that “No difference between a longer treatment course (greater than 30 sessions) and a
shorter course (less than 30 sessions) among patients with diabetic foot ulcers or sensorineural
hearing loss; conflicting results for patients with multiple sclerosis.
Hyperbaric oxygen therapy has been shown to be an effective method for treating diabetic foot
wounds in carefully selected cases of lower extremity lesions. Although the results of multiple
retrospective studies involving a significant number of patients have consistently indicated a high
success rate in patients who had been refractory to other modes of therapy, several recent
prospective, randomized studies have only supported the adjunctive role of systemic hyperbaric
oxygen therapy in the treatment of non-healing infected deep lower extremity wounds in patients
with diabetes. Such evidence is lacking, however, for superficial diabetic wounds and non-
diabetic cutaneous, decubitus, and venous stasis ulcers.
A number of technology assessment organizations, including the Cochrane Collaboration, the

Wessex Institute, the Alberta Heritage Foundation for Medical Research, and the Agency for
Healthcare Research and Quality (AHRQ), have systematically reviewed the evidence supporting
the use of hyperbaric oxygen for each of the indications for which it has been used.
An evidence review conducted by the Alberta Heritage Foundation for Medical Research (Hailey,
2003) concluded that use of HBOT is not supported for a number of conditions, including non-
diabetic wounds, multiple sclerosis, cerebral palsy, decubitus ulcers, necrotizing arachnidism,
actinomycosis, cardiovascular conditions, Bell's palsy, cluster and migraine headaches, Legg-
Calve Perthes disease, Crohn's disease, osteoporosis, cancer, head trauma, cognitive
impairment, senile dementia, glaucoma, keratoendotheliosis, HIV infection, facial neuritis, and
nonunion of fractures.
A systematic evidence review conducted for the Agency for Healthcare Research and Quality
(AHRQ) (McDonagh et al, 2003) found insufficient evidence to support the use of HBOT in brain
injury. The assessment concluded that "The balance of benefits and harms of HBOT for brain
injury, cerebral palsy, or stroke has not been adequately studied."
Denton et al (2004) systematically reviewed the evidence regarding HBOT for radiation cystitis.
Of the 19 studies that met inclusion criteria, all the reports were case series and only 1 was a
prospective series. The authors stated that "[t]he level of evidence that these data represent is
essentially IIIC (weak evidence), apart from one prospective case series of forty patients." The
latter study (Bevers et al, 1995) was graded IIC (prospective study without calculation of sample
size and without accurate and standard definition of outcome variables).
In a Cochrane review, Bennett et al (2005) concluded that for people with acute coronary
syndrome, individual small trials suggest the addition of HBOT reduced the risk of major adverse
cardiac events, some dysrrhythmias, and reduced the time to relief from ischemic pain, but did
not reduce mortality. They noted that in view of the modest number of patients, methodological
shortcomings and poor reporting, this result should be interpreted cautiously, and an
appropriately powered trial of high methodological rigor is justified to define those patients (if any)
who can be expected to derive most benefit from HBOT. The routine application of HBOT to
these patients can not be justified from this review.
A Cochrane review (Bennett et al, 2005) assessed the evidence of effectiveness of HBOT for
long-term radiation injury to the anus and rectum. The investigators found HBOT significantly
improved chance of healing for radiation proctitis (relative risk 2.7, 95 % confidence interval
[CI]: 1.2 to 6.0). The investigators concluded that small trials suggest that HBOT is useful for
treatment of long-term radiation injury to the anus and rectum.
Absolute contraindications to HBOT include: untreated pneumothorax, concurrent administration

of disulfuram (Antabuse); concurrent administration of the antineoplastic agents doxorubicin and
cisplatinum; and administration to premature infants (due to risk of retrolental fibroplasia).
Relative contraindications to the use of HBOT include prior chest surgery, lung disease, viral
infections, recent middle ear surgery, optic neuritis, seizure disorders, high fever, congenital
spherocytosis, and claustrophobia.
Topical HBOT administered to the open wound in small limb-encasing devices is not systemic
HBOT and its efficacy has not been established due to the lack of controlled clinical trials. In
addition, in vitro evidence suggests that topical HBOT does not increase tissue oxygen tension
beyond the superficial dermis. Examples of topical HBOT devices are TOPOX portable
hyperbaric oxygen extremity and sacral chambers (Jersey City, NJ), Oxyboot and Oxyhealer
from GWR Medical, L.L.P. (Chadds Ford, PA).
The Undersea and Hyperbaric Medical Society issued the following policy statement on topical
oxygen, often referred to as “topical hyperbaric oxygen therapy” (Feldmeier et al, 2005): “1.
Topical oxygen should not be termed hyperbaric oxygen since doing so either intentionally or
unintentionally suggests that topical oxygen treatment is equivalent or even identical to
hyperbaric oxygen. Published documents reporting experience with topical oxygen should
clearly state that topical oxygen not hyperbaric oxygen is being employed. 2. Mechanisms of
action or clinical study results for hyperbaric oxygen can not and should not be co-opted to
support topical oxygen since hyperbaric oxygen therapy and topical oxygen have different routes
and probably efficiencies of entry into the wound and their physiology and biochemistry are
necessarily different. 3. The application of topical oxygen cannot be recommended outside of a
clinical trial at this time based on the volume and quality of scientific supporting evidence
available, nor does the Society recommend third party payor reimbursement. 4. Before topical
oxygen can be recommended as therapy for non-healing wounds, its application should be
subjected to the same intense scientific scrutiny to which systemic hyperbaric oxygen has been
held”.
There is insufficient evidence of the effectiveness of hyperbaric oxygen as a treatment for

autism. Rossignol (2007) stated that autism is a neurodevelopmental disorder currently affecting
as many as 1 out of 166 children in the United States. Numerous studies of autistic individuals
have revealed evidence of cerebral hypoperfusion, neuro-inflammation and gastrointestinal
inflammation, immune dysregulation, oxidative stress, relative mitochondrial dysfunction,
neurotransmitter abnormalities, impaired detoxification of toxins, dysbiosis, and impaired
production of porphyrins. Many of these findings have been correlated with core autistic
symptoms. For example, cerebral hypoperfusion in autistic children has been correlated with
repetitive, self-stimulatory and stereotypical behaviors, and impairments in communication,
sensory perception, and social interaction. Hyperbaric oxygen therapy might be able to improve
each of these problems in autistic persons. Specifically HBOT has been used with clinical
success in several cerebral hypoperfusion conditions and can compensate for decreased blood
flow by increasing the oxygen content of plasma and body tissues. Hyperbaric oxygen therapy
has been reported to possess strong anti-inflammatory properties and has been shown to
improve immune function. There is evidence that oxidative stress can be reduced with HBOT
through the upregulation of antioxidant enzymes. Hyperbaric oxygen therapy can also increase
the function and production of mitochondria and improve neurotransmitter abnormalities. In
addition, HBOT up-regulates enzymes that can help with detoxification problems specifically
found in autistic children. Dysbiosis is common in autistic children and HBOT can improve this.
Impaired production of porphyrins in autistic children might affect the production of heme, and
HBOT might help overcome the effects of this problem. Finally, HBOT has been shown to
mobilize stem cells from the bone marrow to the systemic circulation. Recent studies in
humans have shown that stem cells can enter the brain and form new neurons, astrocytes, and
microglia. It is expected that amelioration of these underlying pathophysiological problems
through the use of HBOT will lead to improvements in autistic symptoms. Several studies on the
use of HBOT in autistic children are currently underway and early results are promising.
An systematic evidence review of hyperbaric oxygen therapy for autism (Moqadem and Pineau,
2007) prepared for AETMIS, a Canadian technology assessment agency, concluded: "In light of
its assessment, AETMIS concludes that there is insuffi cient evidence to build a strong case for
the efficacy of hyperbaric oxygen therapy in the management of autistic disorders. In these
circumstances, a literature watch should be conducted to evaluate the results of the current and
future studies. In short, for the management of autism, hyperbaric oxygen therapy should, for
now, be considered an experimental treatment modality. Consequently, this treatment should be
limited to formal research projects."
Rossignol et al (2009) carried out a multi-center, randomized, double-blind, controlled study to

evaluate the effectiveness of HBOT in children with autism. A total of 62 children with autism
recruited from 6 centers, aged 2 to 7 years (mean of 4.92 +/- 1.21) were randomly assigned to
40 hourly treatments of either HBOT at 1.3 atm and 24 % oxygen ("treatment group", n = 33) or
slightly pressurized room air at 1.03 atm and 21 % oxygen ("control group", n = 29). Outcome
measures included Clinical Global Impression (CGI) scale, Aberrant Behavior Checklist (ABC),
and Autism Treatment Evaluation Checklist (ATEC). After 40 sessions, mean physician CGI
scores significantly improved in the treatment group compared to controls in overall functioning
(p = 0.0008), receptive language (p < 0.0001), social interaction (p = 0.0473), and eye contact (p
= 0.0102); 9/30 children (30 %) in the treatment group were rated as "very much improved" or
"much improved" compared to 2/26 (8 %) of controls (p = 0.0471); 24/30 (80 %) in the treatment
group improved compared to 10/26 (38 %) of controls (p = 0.0024). Mean parental CGI scores
significantly improved in the treatment group compared to controls in overall functioning (p =

0.0336), receptive language (p = 0.0168), and eye contact (p = 0.0322). On the ABC, significant
improvements were observed in the treatment group in total score, irritability, stereotypy,
hyperactivity, and speech (p < 0.03 for each), but not in the control group. In the treatment group
compared to the control group, mean changes on the ABC total score and subscales were
similar except a greater number of children improved in irritability (p = 0.0311). On the ATEC,
sensory/cognitive awareness significantly improved (p = 0.0367) in the treatment group
compared to the control group. Post-hoc analysis indicated that children over age 5 and children
with lower initial autism severity had the most robust improvements. Hyperbaric treatment was
safe and well-tolerated. The authors reported that children with autism who received HBOT at
1.3 atm and 24 % oxygen for 40 hourly sessions had significant improvements in overall
functioning, receptive language, social interaction, eye contact, and sensory/cognitive
awareness compared to children who received slightly pressurized room air.
Rossignol et al (2009) concluded that "[g]iven the positive findings of this study, and the shortage
of proven treatments for individuals with autism, parents who pursue hyperbaric treatment for
their child with autism can be assured that it is a safe treatment modality at the pressure used
in this study (1.3 atm), and that it may improve certain autistic behaviors. Further studies are
needed by other investigators to confirm these findings; we are aware of several other planned or
ongoing studies of hyperbaric treatment in children with autism. However, in light of the positive
results of this study and those of several previous studies, the use of hyperbaric treatment
appears to be a promising treatment for children with autism".
The study by Rossignol et al (2009) had several major limitations. First, there were no
significant differences between the treatment and control groups for most of the primary
outcomes. In the treatment group compared to the control group, mean changes on the ABC
total score and subscales were similar except a greater number of children improved in irritability
(p = 0.0311). There were no significant differences between treatment and control groups in total
ABC score, and in the subscales for social withdrawal, stereotypy, hyperactivity, and speech.
Furthermore, analysis of changes in ATEC total score and subscale scores between the
treatment and control groups showed a significant differences between treatment and controls
only in the sensory/cognitive awareness subscale. There were no significant differences
between treatment and control groups in total score, and in the subscales for speech,
sociability, and health. In addition, while mean physician CGI scores significantly improved in
the treatment group compared to controls in overall functioning, receptive language, social
interaction, and eye contact; there were no significant differences between treatment and control
groups in the other subscales: expressive language, sleep pattern, attention span, activity level,
bowel movement pattern, self-stimulatory behavior, social awareness/alertness, play skills, self-
injurious behavior, mood, anxiety level, aggression, general health, gross motor skills, and fine
motor skills. Also, while mean parental CGI scores significantly improved in the treatment group
compared to controls in overall functioning, receptive language, and eye contact; there were no
significant differences in the treatment group compared to controls in expressive language, sleep
pattern, attention span, activity level, bowel movement pattern, self-stimulatory behavior, social
awareness/alertness, social interaction, play skills, self-injurious behavior, mood, anxiety level,
aggression, general health, gross motor skills, and fine motor skills. Moreover, while post-hoc
analysis was able to identify subgroups of subjects who demonstrated additional statistically
significant differences, these findings would need to be confirmed by a prospective study of
these subgroups.
Another important issue that was not fully addressed was the adequacy of blinding. The study
states that 6 adults were not able to reliably distinguish between the treatment and control
situation. But the usual method of testing the adequacy of blinding is to query study subjects
(children and parents) and investigators themselves to ascertain if they are able to distinguish
between treatment and control better than would be expected by chance, which was not done in
this study. The important issue is whether or not the persons who actually participated in the
study were able to distinguish between treatment and control better than would be expected by
chance, and formal tests of statistical significance are employed in this analysis.
The most critical issue that was not addressed in this study was the durability of results. These
investigators measured outcomes at study initiation and immediately upon completion of 40
HBOT sessions. However, the treatment and control groups were not followed for any
substantial period of time after the study was completed to determine whether significant
differences between treatment and control groups persisted. In other words, does HBOT result
in durable benefits, or do any improvements dissipate after completion of treatment?
It should also be noted that autism is not approved as an indication for HBOT neither by the
Undersea and Hyperbaric Medical Society nor the European Committee for Hyperbaric Medicine
(Yildiz et al, 2008). Furthermore, in a review on autism, Levy and colleagues (2009) stated that
popular biologically based treatments include anti-infectives, chelation medications,
gastrointestinal medications, HBOT, and immunoglobulins. Non-biologically based treatments
include auditory integration therapy, chiropractic therapy, cranio-sacral manipulation, interactive
metronome, and transcranial stimulation. However, few studies have addressed the safety and
effectiveness of most of these treatments.
Ghanizadeh (2012) stated that there is a controversy regarding the effectiveness of HBOT for the
treatment of autism. This investigator systematically reviewed the current evidences for treating
of autism with HBOT. According to PRISMA guidelines for a systematic review, the databases of
MEDLINE/PubMed, Google Scholar, and Randomized Controlled Trials in Hyperbaric Medicine
were electronically searched. In addition, medical subject heading terms and text words for
hyperbaric oxygen therapy and autism were used. The main inclusion criteria were published
studies that reported the original data from the trials conducted on the patients with autism and
assessed outcomes with a valid and reliable instrument. A quality assessment was also
conducted. The electronically search resulted in 18 publications. Two studies were randomized,
double-blind, controlled-clinical trials. While some uncontrolled and controlled studies
suggested that HBOT is effective for the treatment of autism, these promising effects are not
replicated. The authors concluded that sham-controlled studies with rigorous methodology are
needed to provide scientific evidence-based HBOT for autism treatment.
Folio et al (2007) described a case of frostbite to all fingers of a mountain climber, treated with
HBOT. All fingers eventually healed to full function, with only some cosmetic deformity to the tip
of the most severely affected finger. Because few cases of frostbite treated with HBOT have
been reported, these researchers hoped that such case reports will stimulate future research in
this area. It is hoped that multiple anecdotal cases may help guide future research in this area.
Sequential digital photographs were taken at various stages of healing during HBOT. They
raised the possibility of photographic techniques and standards that may facilitate planning of
therapy for frostbite with improved treatment comparisons, resulting in more consistency in the
future. For example, a graphical software application was described that allows morphing of
sequential images to demonstrate healing progress in a concise movie format. The morphing
allows concise demonstration of healing to the referring provider and patient and helps in
teaching and research on frostbite treatment outcomes.
Kiralp et al (2009) evaluated the effects of HBOT on myofascial pain syndrome (MPS). A total of
30 patients with the diagnosis of MPS were divided into HBOT (n = 20) and control groups (n =
10). Patients in the HBOT group received a total of 10 HBOT sessions in 2 weeks. Patients in
the control group received placebo treatment in a hyperbaric chamber. Pain threshold and visual
analog scale (VAS) measurements were performed immediately before and after HBOT and 3
months thereafter. Additionally, Pain Disability Index (PDI) and Short Form 12 Health Survey
(SF-12) evaluations were done before HBOT and after 3 months. Hyperbaric oxygen therapy
was well-tolerated with no complications. In the HBOT group, pain threshold significantly
increased and VAS scores significantly decreased immediately after and 3 months after HBOT.
Furthermore, PDI, Mental and Physical Health SF-12 scores improved significantly with HBOT
after 3 months compared with pre-treatment values. In the control group, pain thresholds, VAS
score, and Mental Health SF-12 scores did not change with placebo treatment; however,
significant improvement was observed in the Physical Health SF-12 test. The authors concluded
that HBOT may be a valuable alternative to other methods in the management of MPS. They
stated that these findings warrant further randomized, double-blinded and placebo-controlled
studies to evaluate the possible role of HBOT in the management of MPS.
Urade (2009) stated that bisphosphonates (BPs) are effective in the treatment of hypercalcemia
of malignancy, multiple myeloma, skeletal events associated with metastatic breast cancer and
prostate cancer, and osteoporosis. Despite these benefits, however, the emergence of BP-
related osteonecrosis of the jaws (BRONJ) becomes a growing and significant problem in a
subset of patients receiving these drugs, especially intravenous preparations. Bisphosphonate-
related osteonecrosis of the jaws has also been reported in the patients receiving oral BPs,
although the incidence is extremely low. Most of BRONJ cases occur after dental treatments
such as tooth extraction, periodontal surgery, and dental implants, and are refractory to
conventional treatment modalities such as debridement, antibiotics and HBOT. As compared to
EU and USA, the number of BRONJ case is still small in Japan, but it is exactly increasing year
by year. The ratio of the number of BRONJ in patients receiving oral BPs to that in patients
receiving intravenous BPs is higher in Japan than in EU and USA, speculating due to the
difference of time of approval. In this communication, the practical guidelines for prevention,
diagnosis and treatment of BRONJ recently released from USA and Canada were introduced.
Although no effective therapy for BRONJ has been established yet, the importance of oral
hygiene, patient education and treatments suitable for clinical stage was emphasized.
Freiberger (2009) stated that BPs suppress bone turnover by disrupting osteoclast signal
transduction, maturation, and longevity. In some patients, it has been hypothesized that
suppressed turnover can impair oral wound healing, leading to BRONJ. Hyperbaric oxygen
therapy, as an adjunct to surgery and antibiotics, might have utility in the treatment of BRONJ
because it produces reactive oxygen and nitrogen species that positively modulate the redox-
sensitive intracellular signaling molecules involved in bone turnover. The effectiveness of HBOT
in the treatment of BRONJ is currently under investigation in randomized controlled trials (RCTs)
at Duke University and the University of Minnesota, and the early results have been
encouraging. This report discussed osteoclast biology, how HBOT has the potential to augment
bone turnover by way of the signaling effects on osteoclasts, the available clinical data on HBOT
in the treatment of BRONJ, the ongoing RCTs of HBOT, and the study-associated efforts to find
biomarkers to characterize an individual's risk of developing this disease.
Vescovi and Nammour (2010) stated that BRONJ is an area of uncovered bone in the maxillo-
facial region that did not heal within 8 weeks after identification by health care provider, in a
patient who was receiving or had been exposed to BP therapy (BPT) without previous radiation
therapy to the craniofacial region. Low-grade risk of ONJ is connected with oral BPT used in the
treatment of osteopenia, osteoporosis and Paget's disease (from 0.01 % to 0.04 %) while higher-
grade risk is associated with intravenous (IV) administration in the treatment of multiple
myeloma and bone metastases (from 0.8 % to 12 %). The management of BRONJ currently is
a dilemma. No effective treatment has yet been developed and interrupting BPT does not seem
to be beneficial. Temporary suspension of BPs offers no short-term benefit, while long-term
discontinuation (if systemic conditions permit it) may be beneficial in stabilizing sites of ONJ and
reducing clinical symptoms. The use of oral anti-microbial rinses in combination with oral
systemic antibiotic therapy -- penicillin, metronidazole, quinolones, clindamycin, doxycycline,
erythromycin -- is indicated for stages I and II of Ruggiero's staging. The role of HBOT is still
unclear but some benefits of this treatment have recently been described in association with
discontinuation of BPT and conventional therapy (medical or/and surgical).
In a Cochrane review, Eskes and colleagues (2010) examined the effects of HBOT as a
treatment for acute wounds (e.g., those arising from surgery and trauma). Randomized
controlled trials comparing HBOT with other interventions or comparisons between alternative
HBOT regimens were selected. Two review authors conducted selection of trials, risk of bias
assessment, data extraction and data synthesis independently. Any disagreements were
referred to a third review author. A total fo 3 trials involving 219 subjects were included. The
studies were clinically heterogeneous, therefore a meta-analysis was inappropriate. One trial
(48 participants with burn wounds undergoing split skin grafts) compared HBOT with usual care
and reported a significantly higher complete graft survival associated with HBOT (95 % healthy
graft area risk ratio [RR] 3.50; 95 % CI: 1.35 to 9.11). A second trial (36 participants with crush
injuries) reported significantly more wounds healed with HBOT than with sham HBOT (RR 1.70;
95 % CI: 1.11 to 2.61) and fewer additional surgical procedures required with HBOT: RR 0.25; 95
% CI: 0.06 to 1.02 and significantly less tissue necrosis: RR 0.13; 95 % CI: 0.02 to 0.90). A
third trial (135 subjects undergoing flap grafting) reported no significant differences in complete
graft survival with HBOT compared with dexamethasone (RR 1.14; 95 % CI: 0.95 to 1.38) or
heparin (RR 1.21; 95 % CI: 0.99 to 1.49). Many of the pre-defined secondary outcomes of the
review, including mortality, pain scores, quality of life, patient satisfaction, activities daily living,
increase in transcutaneous oxygen pressure (TcpO(2)), amputation, length of hospital stay and
costs, were not reported. All 3 trials were at unclear or high risk of bias. The authors concluded
that there is a lack of high quality, valid research evidence regarding the effects of HBOT on
wound healing. While 2 small trials suggested that HBOT may improve the outcomes of skin
grafting and trauma, these trials were at risk of bias. They stated that further evaluation by
means of high quality RCTs is needed.
The Canadian Agency for Drugs and Technologies in Health's review on the use of HBOT for
difficult wound (Boudreau et al, 2010) identified 7 health technology assessments, 5 systematic
reviews, and 1 RCT. Overall, the authors of the identified studies found that HBOT was clinically
effective as well as cost-effective when it was used to treat patients with diabetes who have lower
extremity chronic ulcers. There was some positive evidence to suggest that HBOT was
clinically effective when it was used to treat radiation proctitis. The evidence base was
considered insufficient to promote the routine use of HBOT for non-diabetic pressure ulcers,
delayed radiation-induced injury, thermal burns, as well as skin grafts and flaps. No evidence
was identified on the use of HBOT in post-organ transplantation re-vascularization. The authors
concludd that overall, the best evidence on the use of adjunctive HBOT was associated with the
treatment of chronic diabetic wounds. The evidence that supported its use, however, was not
reliable. Although there were many recommendations on the use of HBOTas adjunctive
treatment for specific indications, there is little evidence on its clinical and economic benefits.
Gallego et al (2011) evaluated the effectiveness of HBOT as a potential treatment for patients
with hemorrhagic radio-induced cystitis (RADC). This prospective study included 38 patients, 21
men and 17 women, mean age of 66.5 years (46 to 75), who had been subjected to pelvic
radiotherapy, with the diagnosis of RADC with or without radio-induced proctitis (RADP), gross
hematuria and lower urinary tract symptoms. Hyperbaric oxygen therapy was applied in a multi-
place chamber; patients breathed pure oxygen (100 %) at 2 to 2.5 atmospheres absolute
(ATAs). Patients received an average of 31.2 sessions (10 to 48 sessions) and the median
follow-up period was 56 months (4 to 72 months). Hematuria was completely resolved in 34 of
the 38 patients. After HBOT, 6 patients required re-admission, 5 for anemic hematuria and 1 for
acute obstructive pyelonephritis. In general, patients tolerated treatment well; however, 1 patient
experienced barotrauma requiring myringotomy. The authors concluded that HBOT can be used
to satisfactorily treat RADC, leading to clinical improvements that begin during the initial
sessions in the majority of cases, and with a more than acceptable level of patient tolerance.
Shao and colleagues (2012) compared the efficacy of intravesical hyaluronic acid (HA) instillation
and HBOT in the treatment of radiation-induced hemorrhagic cystitis (HC). In total 36 patients
who underwent radiotherapy for their pelvic malignancies and subsequently suffered from HC
were randomly divided into an HA group and an HBOT group. Symptoms of hematuria,
frequency of voiding and the visual analog scale of pelvic pain (range of 0 to 10) were evaluated
before and after the treatment with follow-up of 18 months. All patients completed this study and
no obvious side effects of intravesical HA were recorded. The improvement rate showed no
statistical difference between the two groups at 6, 12 and 18 months after treatment. Decrease
of frequency was significant in both groups 6 months after treatment, but was only significant in
the HA group 12 months after therapy. The improvement in the visual analog scale remained
significant in both groups for 18 months. The authors concluded that intravesical instillation of
HA was as effective in treating radiation-induced HC as HBOT. It is well-tolerated and resulted in
a sustained decrease of bladder bleeding, pelvic pain and frequency of voiding for at least 12
months.
Parra et al (2011) assessed the efficacy of HBOT in HC cases. A retrospective analysis of

patients with HC after pelvic radiotherapy receiving HBOT at the authors' center between January
2002 and January 2010 was performed. Their protocol included 40 sessions of HBOT in a multi-
place hyperbaric chamber with 90 mins of 100 % oxygen breathing at 2.2 ATAs. Success was
evaluated in terms of total or partial stop of bladder bleeding. Telephone follow-up was updated
at the time of submission in all cases. A total of 25 patients were treated (21 males, 4 females);
the mean age was 66.7 years. Twenty men were irradiated for prostate cancer and 1 for bladder
cancer; 3 women had cervix cancer and 1 endometrial cancer. In all cases previous conservative
treatment had failed and HBOT was considered only after other measures failed. All the patients
responded to HBOT and none recurred after end of treatment at a mean follow-up of 21.2
months. There were no serious complications. The authors concluded that HBOT is a highly
effective and safe, non-invasive therapy for HC secondary to pelvic radiation; it should be
considered as first line alternative in these difficult cases.
Savva-Bordalo et al (2012) stated that late-onset HC after allogeneic hematopoietic stem cell
transplantation (HSCT) has been associated with BK virus (BKV). Anti-viral drugs are of limited
efficacy and the optimal treatment for HC has not yet been established. Hyperbaric oxygen
therapy may benefit these patients. These researchers retrospectively evaluated the
effectiveness of HBOT in 16 patients with HC after allogeneic HSCT. All 16 patients had
macroscopic hematuria and BKV infection. Patients received 100 % oxygen in a hyperbaric
chamber at 2.1 ATAs for 90 mins, 5 days per week, with a median 13 treatments (range of 4 to
84). Fifteen patients (94 %) showed complete resolution of hematuria. Median urinary DNA
BKV titers declined after HBOT (p < 0.05). Patients started on HBOT earlier after diagnosis of
HC responded sooner (p < 0.05). The authors concluded that HBOT was generally well-tolerated
and proved to be a reliable option for this difficult to manage condition.
Craighead et al (2011) reviewed the evidence regarding HBOT for late radiation tissue injury in
gynecologic malignancies. The Ovid Medline, Embase, Cochrane Library, National Guidelines
Clearinghouse, and Canadian Medical Association Infobase databases were searched to June
2009 for clinical practice guidelines, systematic reviews, randomized controlled trials, or other
relevant evidence. Studies that did not evaluate soft tissue necrosis, cystitis, proctitis, bone
necrosis, and other complications were excluded. Two randomized trials, 11 non-randomized
studies, and 5 supporting documents comprise the evidence base. In addition, information on
the harms and safety of treatment with HBOT were reported in 3 additional sources. There is
modest direct evidence and emerging indirect evidence that the use of HBOT is broadly effective
for late radiation tissue injury of the pelvis in women treated for gynecologic malignancies. The
authors concluded that based on the evidence and expert consensus opinion, HBOT is likely
effective for late radiation tissue injury of the pelvis, with demonstrated efficacy specifically for
radiation damage to the anus and rectum; the main indication for HBOT therapy in gynecologic
oncology is in the management of otherwise refractory chronic radiation injury; HBOT may
provide symptomatic benefit in certain clinical settings (e.g., cystitis, soft-tissue necrosis, and
osteonecrosis); and HBOT may reduce the complications of gynecologic surgery in patients
undergoing surgical removal of necrosis.
Also, an UpToDate review on "Cystitis in patients with cancer" (Moy, 2011) states that "
[h]yperbaric oxygen therapy appears to be effective but is limited to stable patients and those
with access to a hyperbaric chamber".
Matchett et al (2009) stated that numerous studies have demonstrated a protective effect of
HBOT in experimental ischemic brain injury, and many physiological and molecular mechanisms
of HBOT-related neuro-protection have been identified. These researchers reviewed articles
pertaining to HBOT and cerebral ischemia in the National Library of Medicine and National
Institutes of Health database, emphasizing mechanisms of HBOT-related neuro-protection.
Hyperbaric oxygen therapy has been shown to ameliorate brain injury in a variety of animal
models including focal cerebral ischemia, global cerebral ischemia, neonatal hypoxia-ischemia
and subarachnoid hemorrhage. Small human trials of HBOT in focal ischemia have not shown
benefit, although 1 trial of HBOT before cardiopulmonary bypass demonstrated improved
neuropsychological and inflammatory outcomes with hyperbaric oxygen therapy. Hyperbaric
oxygen therapy is associated with improved cerebral oxygenation, reduced blood-brain barrier
breakdown, decreased inflammation, reduced cerebral edema, decreased intracranial pressure,
reduced oxidative burden, reduced metabolic derangement, decreased apoptotic cell death and
increased neural regeneration. The authors concluded that on a molecular level, HBOT leads to
activation of ion channels, inhibition of hypoxia inducible factor-1alpha, up-regulation of Bcl-2,
inhibition of MMP-9, decreased cyclooxygenase-2 activity, decreased myeloperoxidase activity,
up-regulation of superoxide dismutase and inhibition of Nogo-A (an endogenous growth-inhibitory
factor). Ongoing research will continue to describe the mechanisms of HBOT-related neuro-
protection, and possibly expand HBOT use clinically.
Michalski et al (2011) stated that high socioeconomic burden is attributed to acute ischemic
stroke, but treatment strategies are still limited. Normobaric oxygen therapy (NBOT) and HBOT
were frequently investigated in pre-clinical studies following acute focal cerebral ischemia with
predominantly beneficial effects in different outcome measurements. Best results were achieved
in transient cerebral ischemia, starting HBOT early after artery occlusion, and by using relatively
high pressures. On molecular level, oxygen application leads to blood-brain barrier stabilization,
reduction of excito-toxic metabolites, and inhibition of inflammatory processes. Therefore, NBOT
and HBOT appear excessively hopeful in salvaging impaired brain cells during ischemic stroke.
However, harmful effects have been noted contributing to damaging properties, e.g.,
vasoconstriction and free oxygen radicals. In the clinical setting, NBOT provided positive results
in a single clinical trial, but HBOT failed to show efficacy in 3 randomized trials. To date, the
translation of numerous evidentiary experimental results into clinical implementation remains
open. Recently, oxygen became interesting as an additional therapy to neuro-protective or re-
canalization drugs to combine positive effects. The authors concluded that further preclinical
research is needed exploring interactions between NBOT, HBOT, and key factors with multi-
phasic roles in acute damaging and delayed inflammatory processes after cerebral ischemia,
e.g., matrix-metallo-proteinase's and hypoxia-inducible factor-1α.
Calciphylaxis, also referred to as calcific uremic arteriolopathy (CUA), is a syndrome associated

with end-stage renal disease, and causes necrotic skin ulcers, often leading to a fatal outcome.
Hyperbaric oxygen has been used to enhance wound healing, but its role in the treatment of
calciphylaxis is unclear. Rogers and Coates (2008) stated that CUA is a rare but important
cause of morbidity and mortality in patients with chronic kidney disease. The prevalence of CUA
is increasing in patients with renal failure, and the condition is also being recognized in non-
uremic patients. There has been increasing understanding of the molecular basis of vascular
calcification, in particular on the important role of the uremic microenvironment in the factors
implicated in the differentiation of vascular smooth muscle cells into osteoblasts. New options
for treatment of hyperphosphatemia and secondary hyperparathyroidism in patients with chronic
kidney disease have become available in the last few years and these have begun to be used in
patients with CUA. These include bisphosphonates, newer non-calcium/non-aluminum-
containing phosphate binders and case reports of use of cinacalcet. Other treatments for CUA
that are not targeted directly at calcium/phosphate homeostasis include HBOT and the
antioxidant cation chelator sodium thiosulphate. The authors concluded that clinicians
managing patients with CUA should consider a combination approach of treating deranged
calcium/phosphate with newer therapeutic agents and promoting wound healing with other older
modalities such as HBOT and sodium thiosulphate infusions. They stated that randomized
controlled trials for treatments in CUA are still lacking.
In a randomized study, Gothard et al (2010) examined effect of HBOT on arm lymphedema

following adjuvant radiotherapy for early breast cancer. A total of 58 patients with greater than or
equal to 15 % increase in arm volume after supraclavicular +/- axillary radiotherapy (axillary
surgery in 52/58 patients) were randomized in a 2:1 ratio to HBOT (n = 38) or to best standard
care (n = 20). The HBOT group breathed 100 % oxygen at 2.4 ATAs for 100 mins on 30
occasions over 6 weeks. Primary endpoint was ipsilateral limb volume expressed as a
percentage of contralateral limb volume. Secondary endpoints included fractional removal rate of
radioisotopic tracer from the arm, extracellular water content, patient self-assessments and UK
SF-36 Health Survey Questionnaire. Of 53/58 (91.4 %) patients with baseline assessments, 46
had 12-month assessments (86.8 %). Median volume of ipsilateral limb (relative to contralateral)
at baseline was 133.5 % (inter-quartile range [IQR] 126.0 to 152.3 %) in the control group, and
135.5 % (IQR 126.5 to 146.0 %) in the treatment group. Twelve months after baseline the
median (IQR) volume of the ipsilateral limb was 131.2 % (IQR 122.7 to 151.5 %) in the control
group and 133.5 % (IQR 122.3 to 144.9 %) in the treatment group. Results for the secondary
endpoints were similar between randomized groups. The authors concluded that no evidence
has been found of a beneficial effect of HBOT in the treatment of arm lymphedema following
primary surgery and adjuvant radiotherapy for early breast cancer.
Radiotherapy is generally used in the treatment of malignant tumors in the head and neck
region. It causes a hypoxic, hypocellular, and hypovascular environment that leads to injury to
surrounding normal tissue, both acute and chronic, ranging from xerostomia to
osteoradionecrosis. These side effects are debilitating and greatly influence quality of life in
these patients. Hyperbaric oxygen therapy is clinically used to prevent or treat these side
effects by enhancing oxygen pressure and thereby regeneration. Although this therapy is widely
applied, its mechanism of action is still poorly understood, and controversy exists in the
literature about its clinical use. Spiegelberg et al (2010) conducted a review on HBOT in the
management of radiation-induced injury in the head and neck. A systematic search was
performed in PubMed for experimental and clinical studies conducted regarding the use of HBOT
in previously irradiated tissue, in the period from January 1990 to June 2009. Experimental
research is scarce, and clinical studies are especially lacking in terms of RCTs. Although
discussions on the subject are ongoing, most studies suggest a beneficial role for HBOT in
previously irradiated tissue. The authors concluded that further research, both experimental and
clinical, is needed to unravel the working mechanism of HBOT and validate its clinical use.
Furthermore, in a systematic review of salivary gland hypo-function and xerostomia induced by

cancer therapies, Jensen et al (2010), on behalf of the Salivary Gland Hypo-function/Xerostomia
Section; Oral Care Study Group; Multinational Association of Supportive Care in Cancer
(MASCC)/International Society of Oral Oncology), assessed the literature for management
strategies and economic impact of salivary gland hypo-function and xerostomia induced by
cancer therapies and to determine the quality of evidence-based management
recommendations. The electronic databases of MEDLINE/PubMed and EMBASE were
searched for articles published in English since the 1989 NIH Development Consensus
Conference on the Oral Complications of Cancer Therapies until 2008 inclusive. For each article,
2 independent reviewers extracted information regarding study design, study population,
interventions, outcome measures, results, and conclusions. A total of 72 interventional studies
met the inclusion criteria. In addition, 49 intensity-modulated radiation therapy (IMRT) studies
were included as a management strategy aiming for less salivary gland damage. Management
guideline recommendations were drawn up for IMRT, amifostine, muscarinic agonist stimulation,
oral mucosal lubricants, acupuncture, and submandibular gland transfer. The authors concluded
that there is evidence that salivary gland hypo-function and xerostomia induced by cancer
therapies can be prevented or symptoms be minimized to some degree, depending on the type
of cancer treatment. Management guideline recommendations are provided for IMRT, amifostine,
muscarinic agonist stimulation, oral mucosal lubricants, acupuncture, and submandibular gland
transfer. Fields of sparse literature identified included effects of gustatory and masticatory
stimulation, specific oral mucosal lubricant formulas, submandibular gland transfer, acupuncture,
HBOT, management strategies in pediatric cancer populations, and the economic consequences
of salivary gland hypo-function and xerostomia.
Also, UpToDate reviews on "Treatment of Sjögren's syndrome" (Fox and Creamer, 2012) and
"Hyperbaric oxygen therapy" (MeChem and Manaker, 2012) do not mention the use of HBOT for
the tretment of xerostomia.
An UpToDate review on "Hyperbaric oxygen therapy" (MeChem and Manaker, 2012) does not
mention the use of HBOT for radiation-induced cholangitis.
The Cancer Care Ontario’s clinical practice guideline on “The management of head and neck
cancer in Ontario” (Gilbert et al, 2009) did not mention the use of HBOT for radiation-induced
sarcoma of the scalp. UpToDate reviews on “Treatment protocols for soft tissue and bone
sarcoma” (Brenner et al, 2012) and “Local treatment for primary soft tissue sarcoma of the
extremities and chest wall” (Delaney et al, 2012) do not mention the use of HBOT. Furthermore,
the National Comprehensive Cancer Network’s clinical practice guideline on “Soft tissue
sarcoma” (Version 3.2012) does not mention “hyperbaric oxygen therapy”.
In a Cochrane review, Bennett et al (2012a) evaluated the effects of adjunctive HBOT for
traumatic brain injury (TBI). These investigators searched CENTRAL, MEDLINE, EMBASE,
CINAHL and DORCTHIM electronic databases. They also searched the reference lists of eligible
articles, hand-searched relevant journals and contacted researchers. All searches were updated
to March 2012. Randomized studies comparing the effect of therapeutic regimens that included
HBOT with those that did not, for people with TBI were selected for analysis. Three authors
independently evaluated trial quality and extracted data. A total of 7 studies are included in this
review, involving 571 people (285 receiving HBOT and 286 in the control group). The results of 2
studies indicated the use of HBOT resulted in a statistically significant decrease in the
proportion of people with an unfavorable outcome 1 month after treatment using the Glasgow
Outcome Scale (GOS) (relative risk (RR) for unfavorable outcome with HBOT 0.74, 95 % CI: 0.61
to 0.88, p = 0.001). This 5-point scale rates the outcome from 1 (dead) to 5 (good recovery); an
'unfavorable' outcome was considered as a score of 1, 2, or 3. Pooled data from final follow-up
showed a significant reduction in the risk of dying when HBOT was used (RR 0.69, 95 % CI:
0.54 to 0.88, p = 0.003) and suggested that one would have to treat 7 patients to avoid 1 extra
death (number needed to treat (NNT) 7, 95 % CI: 4 to 22). Two trials suggested favorably lower
intra-cranial pressure in people receiving HBOT and in whom myringotomies had been
performed. The results from 1 study suggested a mean difference (MD) with myringotomy of -8.2
mmHg (95 % CI: -14.7 to -1.7 mmHg, p = 0.01). The Glasgow Coma Scale (GCS) has a total of
15 points, and 2 small trials reported a significant improvement in GCS for patients treated with
HBOT (MD 2.68 points, 95 % CI: 1.84 to 3.52, p < 0.0001), although these 2 trials showed
considerable heterogeneity (I(2) = 83 %). Two studies reported an incidence of 13 % for
significant pulmonary impairment in the HBOT group versus 0 % in the non-HBOT group (p =
0.007). In general, the studies were small and carried a significant risk of bias. None described
adequate randomization procedures or allocation concealment, and none of the patients or
treating staff was blinded to treatment. The authors concluded that in people with TBI, while the
addition of HBOT may reduce the risk of death and improve the final GCS, there is little evidence
that the survivors have a good outcome. The improvement of 2.68 points in GCS is difficult to
interpret. This scale runs from 3 (deeply comatose and unresponsive) to 15 (fully conscious),
and the clinical importance of an improvement of approximately 3 points will vary dramatically
with the starting value (e.g., an improvement from 12 to 15 would represent an important clinical
benefit, but an improvement from 3 to 6 would leave the patient with severe and highly dependent
impairment). The authors stated that the routine application of HBOT to these patients cannot
be justified from this review. Given the modest number of patients, methodological shortcomings
of included trials and poor reporting, the results should be interpreted cautiously. An
appropriately powered trial of high methodological rigor is required to define which patients, if
any, can be expected to benefit most from HBOT.
In a Cochrane review, Phillips and Jones (2013) evaluated the effectiveness of adjunctive HBOT
for malignant otitis externa. These investigators searched the Cochrane Ear, Nose and Throat
Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL);
PubMed; EMBASE; CINAHL; Web of Science; ICTRP and additional sources for published and
unpublished trials. The date of the most recent search was April 4, 2013. Randomized
controlled trials, involving adults, undergoing hyperbaric oxygen therapy in malignant otitis
externa were selected for analysis. No identified articles described RCTs of HBOT in the
treatment of malignant otitis externa. The authors concluded that no clear evidence exists to
demonstrate the effectiveness of HBOT when compared to treatment with antibiotics and/or
surgery. They found no data to compare rates of complication between the different treatment
modalities; further research is required.
Margolis et al (2013) compared the effectiveness of HBOT with other conventional therapies
administered in a wound care network for the treatment of a diabetic foot ulcer and prevention of
lower-extremity amputation. This was a longitudinal observational cohort study. To address
treatment selection bias, these investigators used propensity scores to determine the
"propensity" that an individual was selected to receive HBOT. They studied 6,259 individuals
with diabetes, adequate lower limb arterial perfusion, and foot ulcer extending through the
dermis, representing 767,060 person-days of wound care. In the propensity score-adjusted
models, individuals receiving HBOT were less likely to have healing of their foot ulcer (hazard
ratio [HR] 0.68 [95 % CI: 0.63 to 0.73]) and more likely to have an amputation (2.37 [1.84 to
3.04]). Additional analyses, including the use of an instrumental variable, were conducted to
assess the robustness of these results to unmeasured confounding. Hyperbaric oxygen therapy
was not found to improve the likelihood that a wound might heal or to decrease the likelihood of
amputation in any of these analyses. The authors concluded that the use of HBOT neither
improved the likelihood that a wound would heal nor prevented amputation in a cohort of patients
defined by Centers for Medicare and Medicaid Services eligibility criteria. They noted that the
usefulness of HBOT in the treatment of diabetic foot ulcers needs to be re-evaluated.
Limb-specific HBOT entails sealing an individual's arm or leg into an air-tight plastic container
that is sealed with pliable gaskets, and exposing the limb to pure oxygen greater than 1 atm of
pressure. Much of the research on this form of therapy has centered on chronic wounds arising
in individuals with diabetic foot ulcers. However, there is currently insufficient evidence from
RCTs to determine the effectiveness of limb-specific HBOT.
In a prospective and controlled study, Lisagors et al (2008) evaluated the feasibility of HBOT as
an efficient and safe adjunct to the standardized treatment protocol and its possible
immunomodulatory impact of 44 patients with diagnosed acute pancreatitis (AP). The course of
the disease was accompanied by systemic inflammatory response syndrome in all the patients
on admission. The impact of AP and HBOT on homeostasis, the number of performed
operations, mortality rates, the levels of 2 cytokines, intra-abdominal pressure, and side effects
caused by HBOT were evaluated. A treatment group consisted of 22 patients receiving HBOT for
3 days (twice-daily) using a mono-place chamber under pressures of 1.7 to 1.9 ATA. Patients (n
= 22) in the control group were managed in accordance with the standardized treatment
protocol. The authors found more stable homeostasis, decreased mortality rate, and the number
of operations in the HBOT group. This type of additional therapy, possibly contributed to the
decrease of intra-abdominal pressure within the first 6 days after admission. The authors
concluded that these findings suggested HBOT can affect an inflammatory response, by
decreasing the levels pro-inflammatory cytokines and increasing those of anti-inflammatory
ones.
An UpToDate review on “Hyperbaric oxygen therapy” (Mechem and Manaker, 2014) states that
“A number of potential HBO uses remain poorly validated and require more rigorous evaluation.
Future indications for HBO may be derived from its apparent modulation of ischemia-reperfusion
injury and inflammation. Preliminary animal and human studies evaluating uses in syndromes
as disparate as myocardial infarction, the systemic inflammatory response syndrome, traumatic
brain or spinal cord injury, sickle cell crisis, fibromyalgia, and acute stroke have been conducted,
with variable results. Further investigation will need to be conducted before HBO can be
endorsed for these potential indications”.
In a phase II clinical trial, Ogawa al (2012) analyzed the long-term results of radiotherapy given
immediately after HBOT with multi-agent chemotherapy in adults with high-grade gliomas.
Patients with histologically confirmed high-grade gliomas were administered radiotherapy in daily
2 Gy fractions for 5 consecutive days per week up to a total dose of 60 Gy. Each fraction was
administered immediately after HBOT, with the time interval from completion of decompression
to start of irradiation being less than 15 minutes. Chemotherapy consisting of procarbazine,
nimustine, and vincristine and was administered during and after radiotherapy. A total of 57
patients (39 patients with glioblastoma and 18 patients with Grade 3 gliomas) were enrolled from
2000 to 2006, and the median follow-up of 12 surviving patients was 62.0 months (range of 43.2
to 119.1 months). All 57 patients were able to complete a total radiotherapy dose of 60 Gy
immediately after HBOT with 1 course of concurrent chemotherapy. The median overall survival
times in all 57 patients, 39 patients with glioblastoma and 18 patients with Grade 3 gliomas,
were 20.2 months, 17.2 months, and 113.4 months, respectively. On multi-variate analysis,
histologic grade alone was a significant prognostic factor for overall survival (p < 0.001). During
treatments, no patients had neutropenic fever or intracranial hemorrhage, and no serious non-
hematologic or late toxicities were seen in any of the 57 patients. The authors concluded that
radiotherapy delivered immediately after HBOT with multi-agent chemotherapy was safe, with
virtually no late toxicities, and seemed to be effective in patients with high-grade gliomas.
Moreover, they stated that this treatment strategy seemed promising and merited further
investigation.
Furthermore, the National Comprehensive Cancer Network’s clinical practice guideline on

“Central nervous system cancers” (Version 1.2014) does not mention the use of HBOT as a
therapeutic option.
The Infectious Diseases Society of America’s clinical practice guideline on “The diagnosis and
treatment of diabetic foot infections” (Lipsky et al, 2012) stated that “For specifically treating
DFO [diabetic foot osteomyelitis], the developers do not currently support using adjunctive
treatments such as hyperbaric oxygen therapy …. Consider providing empiric therapy directed
against methicillin-resistant Staphylococcus aureus (MRSA) in a patient with a prior history of
MRSA infection; when the local prevalence of MRSA colonization or infection is high; or if the
infection is clinically severe”.
Also, an UpToDate review on “Treatment of invasive methicillin-resistant Staphylococcus aureus

infections in adults” (Lowy, 2014) does not mention the use of HBOT as a therapeutic option.
The European Society of Clinical Microbiology and Infectious Diseases Fungal Infection Study
Group and the European Confederation of Medical Mycology’s joint clinical guidelines on “The
diagnosis and management of mucormycosis” (Cornely et al, 2014) stated that “Hyperbaric
oxygen is supported with marginal strength only”. Furthermore, an UpToDate review on

“Hyperbaric oxygen therapy” (Mechem and Manaker, 2014) states that “HBO has been
advocated for use in other severe invasive infections such as cutaneous soft-tissue and
rhinocerebral mucormycosis (or zygomycosis) and actinomycotic brain abscesses, although
data in support of these indications are less robust”.
An UpToDate review on “Treatment of the Raynaud phenomenon resistant to initial therapy”

(Wigley, 2014) does not mention the use of HBOT as a therapeutic option.
A clinical cases summary by the University of Michigan Medical School on “Vesicocutaneous

fistula” (2000) did not mention use of HBOT. Furthermore, an UpToDate review on “Hyperbaric
oxygen therapy” (Mechem and Manaker, 2014) does not list fistula as an indication.
Central Retinal Artery Occlusion (CRAO)
A review of treatment options for retinal artery occlusion by Cugati, et al. (2013) stated that "The
proposed role for hyperbaric oxygen in CRAO is an increase the partial pressure of oxygen
delivery to ischemic tissue until spontaneous or assisted reperfusion occurs. The exact
pathogenesis is debated and the efficacy is not proven. The protocol for hyperbaric oxygen varies
in different studies, with an average of 2–2.5 atm for approximately 90 min within 8 h of onset of
CRAO.
More recently, a review by (2017) found: "Hyperbaric oxygen therapy is sometimes used in an
acute CRAO to increase the oxygen tension leading to increased concentration of soluble
oxygen in the blood, thereby increasing the relative amount of oxygen delivered to ischemic
retinal tissue. Hyperbaric oxygen therapy is used as a supportive measure until spontaneous
reperfusion of the retina occurs or other modalities are used to restore retinal perfusion. Although
there have been case series suggesting improvement in visual function following hyperbaric
oxygen therapy for CRAO, the improvement in visual function was not statistically significant
compared with patients who did not receive hyperbaric oxygen therapy. Specifically, in the study
by Menzel-Severing and colleagues [2012], most patients who did not receive hyperbaric oxygen
therapy had similar visual acuity at the 3-month follow-up visit compared with the patients who
received hyperbaric oxygen treatment."
Butler et al. ( 2008) included ischemic central retinal vein and artery occlusions among
indications for HBOT.
Murphy-Lavoie et al (2012) stated that central retinal artery occlusion (CRAO) is an uncommon
eye disorder, but one that typically produces severe and irreversible vision loss in the affected
eye. The retina has a dual blood supply, with the retinal circulation supplying the inner layers
and the choroidal circulation supplying the outer layers. In CRAO, vision loss results from cell
death in the inner retinal layers despite relative sparing of the outer layers. If supplemental
oxygen is provided, however, oxygen from the choroidal circulation may diffuse in adequate
quantity to the inner layers of the retina to maintain retinal function and restore vision. In some
patients this can be achieved with normobaric hyperoxia; in others, hyperbaric oxygen (HBO2)
may be required. The challenge is to provide the supplemental oxygen early enough after the
onset of vision loss to prevent irreversible damage to the retina. In experimental models of
complete CRAO, the ischemic time window before permanent retinal damage occurs is just over
90 minutes; in the clinical setting where occlusion may be incomplete, return of vision may be
achieved even after delays of 8 to 24 hours. In patients with a clinical picture of CRAO who
present within 24 hours of vision loss, supplemental oxygen should be started immediately at
the highest possible fraction of inspired oxygen (FiO2). If vision is not quickly restored,
emergent HBO2 should be undertaken if feasible. If the patient responds to HBO2, follow-up
treatment with supplemental oxygen should be customized to maintain retinal viability until the
obstructed retinal artery re-canalizes, which typically occurs within the first 72 hours.
Celebi et al (2016) reported on the case of a 43-year old male presented with sudden onset of
painless, blurred vision in his left eye. Dilated fundoscopic examination showed signs
consistent with the diagnosis of a combination of central retinal vein occlusion (CRVO) and cilio-
retinal artery occlusion (CLRAO). He received daily 2-hour sessions of hyperbaric oxygen
treatment (HBOT), 253 kPa for 14 days. At the end of the HBOT course, the patient's left visual
acuity had improved from 20/200 to 20/20. Dilated fundoscopic examination showed that the
intra-retinal hemorrhages in the entire retina and the retinal whitening along the course of the
CLRA seen at presentation had completely resolved. The combination of CLRAO and CRVO
comprises a discrete clinical entity. Even though there are many hypotheses concerning this
condition, it is most likely the result of elevated intraluminal pressure in the retinal capillaries due
to CRVO that exceeds the pressure in the CLRA. The authors concluded that HBOT may be an
effective treatment for CRVO-associated CLRAO.
Hwang (2016) noted that the most serious complication of filler or fat injection is blindness.
According to a recent systematic review of 98 patients of blindness provoked by filler or fat
injection, only 2 patients had the outcome of a complete recovery of vision. In the literature, only
2 papers were found in which HBOT was used in ophthalmic artery obstruction. However, no
improvement of vision was obtained in either patient. Recently, the authors treated a patient who
had central retinal vein occlusion and CLRAO with HBOT (daily 2-hour sessions at 253 kPa for
14 days), and his visual acuity returned to normal. In central retinal artery obstruction, if the
cilio-retinal artery is present, it will maintain the thickness of the retina to a variable extent.
Though the size of the cilio-retinal artery and the area it supplies varies, 36.2 % (32.1 to 40.2 %)
of people have a cilio-retinal artery. Thereafter, HBOT might be applied to patients with central
retinal artery occlusion following filler injection.
Tang et al (2016) stated that CRAO is an infarction to the retina that results in acute, frequently
severe vision loss. Long-term complications such as ocular neovascularization (ONV) can occur
and result in neovascular glaucoma and vitreous hemorrhage. Recent studies have explored
acute HBOT as a promising treatment for CRAO to improve long-term vision potential; however,
its effects on CRAO complications have not been well characterized. This study was conducted
to better characterize the effects of HBOT on complications from CRAO. These researchers
presented a unique case of ONV in an eye within 1 month after successfully completing acute
HBOT for a CRAO, highlighting the importance of routine monitoring in this unique population.
The authors concluded that HBOT remains a controversial treatment modality for CRAO, a
condition for which clinicians are still without a proven and widely accepted means of improving
vision. The NVG was treated effectively in this patient, and his current level of vision in the RE is
most likely due to the original CRAO rather than the subsequent ONV. This case underscored,
however, that patients undergoing HBOT for CRAO may need to be followed more closely for the
development of secondary CRAO complications such as ONV compared to those who have not
undergone HBOT.
Soares et al (2017) stated that CRAO is an ophthalmological emergency. Various treatment

modalities have been tried, but none have shown to alter natural history of the disease.
Hyperoxia can restore retinal oxygenation, and favorable results were obtained with HBOT.
These investigators reported 2 patients with sudden visual loss due to CRAO treated with
HBOT. Case 1: A 61-year old female, presented with CRAO in her left eye(OS). She was
submitted to 8 sessions of HBOT (2.4 atmosphere absolute (ATA)). BCVA (best corrected visual
acuity) improved from counting fingers (CF) to 1.0 and fluorescein angiography (FA) showed a
normalization. Vascular study showed a value of 8.8 % for HbA1c and ventricular extra-systoles.
Case 2: A 69-year old male presented with CRAO in his OS; 9 sessions of HBOT(2.4 ATA) were
performed; BCVA improved from CF to 0.8 and the FA was normalized. Vascular study revealed
an atheromatous carotid disease, and cardiac pathology. The authors concluded that HBOT
appeared to be beneficial on the recovery of vision following CRAO. Moreover, they noted that
the major barrier to effective treatment for CRAO is the fact that people are rarely seen acutely
and there is no consensus for treatment or guideline-based therapy; further studies with more
patients are needed to determine the value and safety of this therapy in the treatment of CRAO,
as well as the exact time window to perform HBOT. (This was a small study with 2 patients).
An UpToDate review on “Central and branch retinal artery occlusion” (Hedges, 2017) states that
“Hyperbaric oxygen therapy, to maintain oxygenation of the retina pending reperfusion, has been
used to preserve vision with mixed results in small series of patients”.
An American Academy of Ophthalmology Focal Points education module on retinal artery

occlusions (AAO, 2010) stated that "Another approach is to improve retinal oxygenation through
the use of hyperbaric oxygen. Limited studies have reported visual improvement, but it appears
unlikely that the brief periods of improved oxygenation could sustain the retina through days of
ischemia."
Anti-Phospholipid Antibody Syndrome
Lazurova and colleagues (2007) reported an episode of gastroenteritis triggered severe necrosis
of all extremities in a previously asymptomatic male. Hepatic and renal involvement were also
manifest, while the hematological picture was one of thrombotic microangiopathic hemolytic
anemia. Anti-phospholipid antibodies were negative. He responded well to a combination of
plasma exchange, anti-coagulation (heparin), parenteral steroids, and antibiotics, as well as
vasodilators (prostacycline) and HBOT, but died because of a cerebral hemorrhage. The
differential diagnosis included thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome,
or sero-negative catastrophic anti-phospholipid (Asherson's) syndrome. The dangers of
administering such a combination of therapies with anti-coagulation, as well as vasodilatation
(prostacycline) and HBOT, were highlighted by the case report.
Furthermore, an UpToDate review on “Treatment of the antiphospholipid syndrome” (Schur and

Kaplan, 2015) does not mention HBOT as a therapeutic option.
Intestinal Anastomosis
Oines et al (2014) identified pharmaceuticals for the prophylaxis of anastomotic leakage (AL).
These investigators systematically reviewed studies on anastomosis repair after colorectal
surgery. They searched PubMed and EMBASE for articles published between January 1975 and
December 2012 and included studies in English with the primary purpose of promoting healing of
anastomoses made in the colon or rectum under uncomplicated conditions. These researchers
excluded studies on adverse events from interventions, nutritional interventions or in-situ physical
supporting biomaterials. The primary outcome was biomechanical strength or AL. The authors
performed meta-analyses on therapeutic agents investigated by 3 or more independent research
groups using the same outcome. The DerSimonian-Laird method for random effects was applied
with p < 0.05. Of the 56 different therapeutic agents assessed, 7 met the inclusion criteria for
the meta-analysis. The prostacyclin analog iloprost increased the weighted mean of the early
bursting pressure of colonic anastomoses in male rats by 60 mmHg (95 % CI: 30 to 89) versus
the controls, and the immunosuppressant tacrolimus increased this value by 29 mmHg (95 %
CI: 4 to 53) versus the controls. Erythropoietin showed an enhancement of bursting pressure by
45 mmHg (95 % CI: 14 to 76). The anabolic compound growth hormone augmented the
anastomotic strength by 21 mmHg (95 % CI: 7 to 35), possibly via the up-regulation of insulin-
like growth factor-1, as this growth factor increased the bursting pressure by 61 mmHg (95 % CI:
43 to 79) via increased collagen deposition. Hyperbaric oxygen therapy increased the bursting
pressure by 24 mmHg (95 % CI: 13 to 34). Broad-spectrum matrix metalloproteinase inhibitors
increased the bursting pressure by 48 mmHg (95 % CI: 31 to 66) on post-operative days 3 to 4.
In the only human study, the AL incidence was not significantly reduced in the 103 colorectal
patients treated with aprotinin (11.7 %) compared with the 113 placebo-treated patients (9.7 %).
The authors concluded that this systematic review identified only 1 randomized clinical trial and
7 therapeutic agents from pre-clinical models that could be explored further for the prophylaxis of
AL after colorectal surgery. Moreover , they noted that although the results from animal studies
on oxygen therapy were inconsistent, HBO significantly increased BPR by 24 mmHg (95 % CI:
13 to 34, p < 0.0001) in the meta-analysis. However, the sole human study on oxygen therapy
that the authors retrieved was recently retracted by the journal that published it.
Lupus Vasculitis
Lui et al (2009) stated that large refractory vasculitic ulcers are not commonly seen in systemic
lupus erythematosus (SLE) patients. These investigators reported a case of refractory vasculitic
ulcers responding to rituximab. This treatment was initiated after treatment with high-dose
steroids and other immunosuppressants were ineffective/associated with significant side-effects.
Following treatment with rituximab, there was sustained clinical improvement and subsequent
reduction of prednisolone dose. Rituximab was well-tolerated. Concomitant methotrexate
therapy and HBOT may have aided the recovery of the patient's vasculitic ulcers. The authors
concluded that this case and anecdotal reports have illustrated the safety and effectiveness of
rituximab in the treatment of refractory SLE-related vasculitic ulcers. They stated that further
studies are needed to determine the long-term efficacy and side-effects. This was a single-case
study; and its findings were confounded by the combinational use of rituximab, methotrexate and
HBOT.
Olivieri et al (2010) noted that skin ulcers are a dangerous and uncommon complication of
vasculitis. These researchers described the case of a teenager suffering from SLE with digital
ulcer resistant to conventional therapy, treated successfully with HBOT. The application of
hyperbaric oxygen, which was used for the treatment of ischemic ulcers, is an effective and safe
therapeutic option in patients with ischemic vasculitic ulcers in combination with

immunosuppressive drugs. The authors concluded that further studies are needed to evaluate its
role as primary therapy for this group of patients.
Furthermore, an UpToDate review on “Overview of the management of vasculitis in adults”

(Merkel, 2015) does not mention HBOT as a therapeutic option.
Osteonecrosis of the Jaw
Chiu and colleagues (2010) offered recommendations of risk factors, prevention, and treatment of
oral bisphosphonate and steroid-related osteonecrosis of the jaw (BSRONJ) in Taiwan. A total of
12 patients were clinicopathologically proved to have bisphosphonate-related osteonecrosis of
the jaw (BRONJ). All of the patients were taking oral bisphosphonates and were concurrently
administered long-term steroids. Of the 12 patients, 3 patients were assigned to the 1st stage
of BRONJ; 5 patients were assigned to the 2nd stage, and 4 patients were assigned to the 3rd
stage. The patients' symptoms, localization of necrosis, presence of a fistula, and association
with possible triggering factors for onset of the lesion were recorded. The radiologic
investigations revealed osteolytic areas and scintigraphy demonstrated increased bone
metabolism. Microbiologic analysis showed pathogenic actinomycosis organisms in a majority
of patients (91.6 %). Antibiotic therapy, minor debridement surgery, and combined hyperbaric
oxygen therapy (HBOT) were useful in obtaining short-term symptomatic relief. The authors
concluded that co-morbidities of steroid use along with bisphosphonates may cause
osteonecrosis of the jaw to occur sooner, be more severe, and respond more slowly to a drug
discontinuation. The clinical disease of BSRONJ is more severe and more unpredictable to treat
than BRONJ. From the data gained from other published studies of BRONJ and the authors’
clinical experience with the series of cases of BSRONJ, they offered recommendations of risk
factors, prevention, and treatment of BSRONJ in southern Taiwan. This was a small study (n =
12) and its findings were confounded by the combinational use of antibiotics, debridement
surgery, and HBOT. Moreover, the authors stated that long-term follow-up studies are needed to
better understand treatment outcomes.
Freiberger et al (2012) examined the use of HBOT as an adjunct to surgery and antibiotics in the
treatment of BRONJ and evaluated its effects on gingival healing, pain, and quality of life. The
investigators implemented a randomized controlled trial and enrolled a sample composed of
patients with ONJ, where the predictor variable was HBOT administered at 2 ATM twice-daily for
40 treatments as an adjunct to conventional therapy of surgery and antibiotics versus
conventional therapy alone. Over the next 24 months, oral lesion size and number, pain, and
quality of life were assessed. A total of 46 patients (mean age of 66 years; 57 % women)
contributed data to the trial. There were no statistically significant differences in the distribution
of variables used to assess randomization success between the HBOT and standard treatment
groups. Seventeen of 25 HBOT-treated patients (68 %) improved versus 8 of 21 controls (38.1
%; p = 0.043, χ(2) test). Mean time to improvement was 39.7 weeks (95 % confidence interval
[CI]: 22.4 to 57.0 weeks) for HBOT-treated patients versus 67.9 weeks (95 CI: 48.4 to 87.5
weeks) for controls (p = 0.03, log-rank test). However, complete gingival healing occurred in only
14 of 25 HBOT-treated patients (52 %) versus 7 of 21 controls (33.3 %; p = 0.203, χ(2) test), and
time to healing was 59 weeks (95 % CI: 42.8 % to 75.8 %) for HBOT-treated patients versus 70
weeks (95 CI: 52.2 % to 88.36 %) for controls (p = 0.32, log-rank test). Pain decreased faster
for HBOT-treated subjects (p < 0.01, linear regression). Quality-of-life scores for physical health
(p = 0.002) and perceived health (p = 0.043) decreased at 6 months for control group but for not
the HBOT group. The authors concluded that ONJ is multi-factorial and no single treatment
modality is likely to reverse it; however, it is treatable and even advanced presentations can
improve with intensive multi-modal therapy. Clinically, HBOT appears to be a useful adjunct to
ONJ treatment, particularly for more severe cases, although this study was under-powered to
fully support this claim.
Spanou et al (2015) stated that osteonecrosis of the jaw (ONJ) is a serious side effect of
bisphosphonate use in patients with osteoporosis, Paget's disease, hypercalcemia of
malignancy, metastatic bone disease and multiple myeloma, although recently this complication
has also been reported in patients under non-bisphosphonate medication, such as denosumab
and bevacizumab. The occurrence of ONJ is higher in oncology patients treated with high-dose
iv bisphosphonates than in osteoporosis patients treated with oral bisphosphonates. Although
multiple hypotheses have been proposed, the exact pathogenic mechanism of ONJ still remains
unclear. Since treatment protocols based on randomized controlled trials (RCTs) do not exist,
these researchers critically reviewed the existing data concerning the management of
bisphosphonate-related osteonecrosis of the jaw, including the most recent data for the use of
teriparatide and hyperbaric oxygen.
On behalf of the International Task Force on Osteonecrosis of the Jaw, Khan et al (2015)
provided a systematic review of the literature from January 2003 to April 2014 pertaining to the
incidence, pathophysiology, diagnosis, and treatment of ONJ, and offered recommendations for
its management based on multi-disciplinary international consensus. ONJ is associated with
oncology-dose parenteral anti-resorptive therapy of bisphosphonates (BP) and denosumab
(Dmab). The incidence of ONJ is greatest in the oncology patient population (1 % to 15 %),
where high doses of these medications are used at frequent intervals. In the osteoporosis
patient population, the incidence of ONJ is estimated at 0.001 % to 0.01 %, marginally higher
than the incidence in the general population (less than 0.001 %). New insights into the
pathophysiology of ONJ include anti-resorptive effects of BPs and Dmab, effects of BPs on
gamma delta T-cells and on monocyte and macrophage function, as well as the role of local
bacterial infection, inflammation, and necrosis. Advances in imaging include the use of cone
beam computerized tomography assessing cortical and cancellous architecture with lower
radiation exposure, magnetic resonance imaging (MRI), bone scanning, and positron emission
tomography, although plain films often suffice. Other risk factors for ONJ include glucocorticoid
use, maxillary or mandibular bone surgery, poor oral hygiene, chronic inflammation, diabetes
mellitus, ill-fitting dentures, as well as other drugs, including antiangiogenic agents. Prevention
strategies for ONJ include elimination or stabilization of oral disease prior to initiation of anti-
resorptive agents, as well as maintenance of good oral hygiene. In those patients at high risk for
the development of ONJ, including cancer patients receiving high-dose BP or Dmab therapy,
consideration should be given to withholding anti-resorptive therapy following extensive oral
surgery until the surgical site heals with mature mucosal coverage. Management of ONJ is
based on the stage of the disease, size of the lesions, and the presence of contributing drug
therapy and comorbidity. Conservative therapy includes topical antibiotic oral rinses and
systemic antibiotic therapy. Localized surgical debridement is indicated in advanced non-
responsive disease and has been successful. Early data have suggested enhanced osseous
wound healing with teriparatide in those without contraindications for its use. Experimental
therapy includes bone marrow stem cell intralesional transplantation, low-level laser therapy,
local platelet-derived growth factor application, hyperbaric oxygen, and tissue grafting.
Post-Concussive Syndrome
Harch et al (2012) provided a preliminary report on the safety and effectiveness of 1.5 ATA HBOT
in military subjects with chronic blast-induced mild-to-moderate TBI/post-concussive syndrome
(PCS) and post-traumatic stress disorder (PTSD). A total of 16 military subjects received 40 1.5
ATA/60 min HBOT sessions in 30 days. Symptoms, physical and neurological exams, SPECT
brain imaging, and neuropsychological and psychological testing were completed before and
within 1 week after treatment. Subjects experienced reversible middle ear barotrauma (n = 5),
transient deterioration in symptoms (n = 4), and reversible bronchospasm (n = 1); 1 subject
withdrew. Post-treatment testing demonstrated significant improvement in: symptoms,
neurological exam, full-scale IQ (+14.8 points; p < 0.001), WMS IV Delayed Memory (p =
0.026), WMS-IV Working Memory (p = 0.003), Stroop Test (p < 0.001), TOVA Impulsivity (p =
0.041), TOVA Variability (p = 0.045), Grooved Pegboard (p = 0.028), PCS symptoms (Rivermead
PCSQ: p = 0.0002), PTSD symptoms (PCL-M: p < 0.001), depression (PHQ-9: p < 0.001),
anxiety (GAD-7: p = 0.007), quality of life (MPQoL: p = 0.003), and self-report of percent of
normal (p < 0.001), SPECT coefficient of variation in all white matter and some gray matter ROIs
after the first HBOT, and in 50 % of white matter ROIs after 40 HBOT sessions, and SPECT
statistical parametric mapping analysis (diffuse improvements in regional cerebral blood flow
after 1 and 40 HBOT sessions). The authors concluded that 40 1.5 ATA HBOT sessions in 1
month was safe in a military cohort with chronic blast-induced PCS and PTSD. Significant
improvements occurred in symptoms, abnormal physical exam findings, cognitive testing, and
quality-of-life measurements, with concomitant significant improvements in SPECT. This was a
small (n = 15) phase I study. The authors noted that more objective psychometric testing and
SPECT imaging were not performed to confirm the durability of the HBOT treatment effect ….
These data are preliminary and need confirmation with larger numbers of subjects or with a
stronger design such as a randomized or Bayesian study.
Boussi-Gross et al (2013) noted that TBI is the leading cause of death and disability in the US.
Approximately 70 to 90 % of the TBI cases are classified as mild, and up to 25 % of them will
not recover and suffer chronic neurocognitive impairments. The main pathology in these cases
involves diffuse brain injuries, which are hard to detect by anatomical imaging yet noticeable in
metabolic imaging. The current study tested the effectiveness of HBOT in improving brain
function and quality of life in mild TBI (mTBI) patients suffering chronic neurocognitive
impairments. The trial population included 56 mTBI patients 1 to 5 years after injury with
prolonged PCS. The HBOT effect was evaluated by means of prospective, randomized, cross-
over controlled trial: the patients were randomly assigned to treated or cross-over groups.
Patients in the treated group were evaluated at baseline and following 40 HBOT sessions;
patients in the cross-over group were evaluated 3 times: at baseline, following a 2-month control
period of no treatment, and following subsequent 2-months of 40 HBOT sessions. The HBOT
protocol included 40 treatment sessions (5 days/week), 60 minutes each, with 100 % oxygen at
1.5 ATA. "Mindstreams" was used for cognitive evaluations, quality of life (QOL) was evaluated
by the EQ-5D, and changes in brain activity were assessed by SPECT imaging. Significant
improvements were demonstrated in cognitive function and QOL in both groups following HBOT
but no significant improvement was observed following the control period. SPECT imaging
revealed elevated brain activity in good agreement with the cognitive improvements. The authors
concluded that HBOT can induce neuroplasticity leading to repair of chronically impaired brain
functions and improved quality of life in mTBI patients with prolonged PCS at late chronic stage.
The authors stated that these results call for better understanding of how to set the optimal
HBOT protocol for the specific patients and how to determine which patients benefit the most
from this treatment. The findings reported here bear the promises that HBOT can be effective in
treating other brain impairments, like easing PTSD symptoms or repairing radiation damage.
This was a small study; its findings need to be validated by well-designed studies.
Efrati and Ben-Jacob (2014) stated that TBI and stroke are the major causes of brain damage
and chronic neurological impairments. There is no agreed-upon effective metabolic intervention
for TBI and stroke patients with chronic neurological dysfunction. Clinical studies published this
year presented convincing evidence that HBOT might be the coveted neuro-therapeutic method
for brain repair. These researchers discussed the multi-faceted role of HBOT in neuro-
therapeutics, in light of recent persuasive evidence for HBOT efficacy in brain repair and the new
understanding of brain energy management and response to damage. They discussed optimal
timing of treatment, dosage, suitable candidates and promising future directions. The authors
stated that there is an urgent need for additional, larger-scale, multi-center clinical studies to
further confirm the findings and determine the most effective and personalized treatment
protocols. To guarantee effective and well-designed clinical studies, wide-scale biomedical
research is required. Such research will also provide validation of the clinical findings, crucial aid
in interpretation of the results and important clues to additional applications of HBOT.
Kraitsy et al (2014) stated that cells in the central nervous system rely almost exclusively on
aerobic metabolism. Oxygen deprivation, such as injury-associated ischemia, results in
detrimental apoptotic and necrotic cell loss. There is evidence that repetitive HBOT improves
outcomes in TBI patients. However, there are no experimental studies investigating the
mechanism of repetitive long-term HBOT treatment-associated protective effects. These
investigators analyzed the effect of long-term repetitive HBOT treatment on brain trauma-
associated cerebral modulations using the lateral fluid percussion model for rats. Trauma-
associated neurological impairment regressed significantly in the group of HBO-treated animals
within 3 weeks post-trauma. Evaluation of somatosensory-evoked potentials indicated a
possible re-myelination of neurons in the injured hemisphere following HBOT. This presumption
was confirmed by a pronounced increase in myelin basic protein isoforms, PLP expression as
well as an increase in myelin following 3 weeks of repetitive HBO treatment. The authors
concluded that these findings indicated that protective long-term HBOT effects following brain
injury is mediated by a pronounced re-myelination in the ipsilateral injured cortex as
substantiated by the associated recovery of sensorimotor function. Moreover, these researchers
stated that their results indicated that HBO treatment might augment neuronal and
neurophysiological function in damaged cerebral tissue due to re-myelination events. Their
results also indicated that these regenerative processes are based on the repetitive long-term
HBO treatment of the injured animals. However, a direct extrapolation of these promising
observations to trauma patients or patients suffering from demyelination diseases should be
regarded with caution. In order to translate these experimental observations into clinical settings
it is a pre-requisite to understand the particular cerebral conditions that allow for the HBO-
mediated induction of regenerative processes. In this standardized setting the first HBO
treatment was administered immediately following trauma during the acute phase of the cerebral
response. The perceptibility of the cerebral environment to HBO treatment during later stages of
injury induced inflammatory responses or during chronic cerebral inflammation has yet to be
shown.
In a single-center, double-blind, randomized, sham-controlled, prospective trial, Cifu et al (2014)

examined the effects of HBOT on persistent post-concussion symptoms in 60 military service
members with at least 1 combat-related mild TBI. Over a 10-week period, subjects received a
series of 40, once-daily, hyperbaric chamber compressions at 2.0 ATA. During each session,
subjects breathed 1 of 3 pre-assigned oxygen fractions (10.5 %, 75 %, or 100 %) for 60 minutes,
resulting in an oxygen exposure equivalent to breathing surface air, 100 % oxygen at 1.5 ATA, or
100 % oxygen at 2.0 ATA, respectively. Individual, subscale and total item responses on the
Rivermead Postconcussion Symptom Questionnaire and individual and total Posttraumatic
Disorder Checklist-Military Version were measured just prior to intervention and immediately
post-intervention. Between-group testing of pre- and post-intervention means revealed no
significant differences on individual or total scores on the Posttraumatic Disorder Checklist-
Military Version or Rivermead Postconcussion Symptom Questionnaire, demonstrating a
successful randomization and no significant main effect for HBOT at 1.5 or 2.0 ATA equivalent
compared with the sham compression. Within-group testing of pre- and post-intervention means
revealed significant differences on several individual items for each group and difference in the
Posttraumatic Disorder Checklist-Military Version total score for the 2.0 ATA HBOT group. The
primary analyses of between group differences found no evidence of effectiveness for HBOT. The
scattered within group differences were threatened by type 2 errors and could be explained by
non-specific effects. The authors concluded that this study demonstrated that HBOT at either
1.5 or 2.0 ATA equivalent had no effect on post-concussion symptoms after mild TBI when
compared with sham compression.
In a randomized, multi-center, double-blind, sham-controlled clinical trial, Miller et al (2015)

compared the safety of and estimated the effectiveness for symptomatic outcomes from
standard PCS care alone, care supplemented with HBO, or a sham procedure. A total of 72
military service members with ongoing symptoms at least 4 months after mild TBI enrolled at
military hospitals in Colorado, North Carolina, California, and Georgia between April 26, 2011,
and August 24, 2012 were included in this study. Assessments occurred before randomization,
at the mid-point, and within 1 month after completing the interventions. Routine PCS care was
provided in specialized clinics. In addition, participants were randomized 1:1:1 to 40 HBO
sessions administered at 1.5 (ATA, 40 sham sessions consisting of room air at 1.2 ATA, or no
supplemental chamber procedures. The Rivermead Post-Concussion Symptoms Questionnaire
(RPQ) served as the primary outcome measure. A change score of at least 2 points on the
RPQ-3 subscale (range of 0 to 12) was defined as clinically significant. Change scores from
baseline were calculated for the RPQ-3 and for the total RPQ. Secondary measures included
additional patient-reported outcomes and automated neuropsychometric testing. On average,
participants had sustained 3 lifetime mild TBIs; the most recent occurred 23 months before
enrollment. No differences were observed between groups for improvement of at least 2 points
on the RPQ-3 subscale (25 % in the no intervention group, 52 % in the HBO group, and 33 % in
the sham group; p = 0.24). Compared with the no intervention group (mean change score, 0.5;
95 % CI: -4.8 to 5.8; p = 0.91), both groups undergoing supplemental chamber procedures
showed improvement in symptoms on the RPQ (mean change score, 5.4; 95 % CI: -0.5 to 11.3;
p = 0.008 in the HBO group and 7.0; 95 % CI: 1.0 to 12.9; p = 0.02 in the sham group). No
difference between the HBO group and the sham group was observed (p = 0.70). Chamber
sessions were well-tolerated. The authors concluded that among service members with
persistent PCS, HBO showed no benefits over sham compressions. Both intervention groups
demonstrated improved outcomes compared with PCS care alone. They stated that this finding
suggested that the observed improvements were not oxygen-mediated but may reflect non-
specific improvements related to placebo effects.
Central Airway Stenosis Following Lung Transplantation
Kraft and colleagues (2016) stated that central airway stenosis (CAS) after lung transplantation
has been attributed in part to chronic airway ischemia; however, little is known about the time
course or significance of large airway hypoxia early after transplantation. These researchers
evaluated large airway oxygenation and hypoxic gene expression during the 1st month following
lung transplantation and their relation to airway complications. Subjects who received lung
transplantation underwent endobronchial tissue oximetry of native and donor bronchi at 0, 3, and
30 days after transplantation (n = 11) and/or endobronchial biopsies (n = 14) at 30 days for real-
time polymerase chain reaction (PCR) of hypoxia-inducible genes. Patients were monitored for
6 months for the development of transplant-related complications. Compared with native
endobronchial tissues, donor tissue oxygen saturations (Sto2) were reduced in the upper lobes
(74.1 ± 1.8 % versus 68.8 ± 1.7 %; p < 0.05) and lower lobes (75.6 ± 1.6 % versus 71.5 ± 1.8 %;
p = 0.065) at 30 days post-transplantation. Donor upper lobe and subcarina Sto2 levels were
also lower than the main carina (difference of -3.9 ± 1.5 and -4.8 ± 2.1, respectively; p < 0.05) at
30 days. Up-regulation of hypoxia-inducible genes VEGFA, FLT1, VEGFC, HMOX1, and TIE2
was significant in donor airways relative to native airways (all p < 0.05); VEGFA, KDR, and
HMOX1 were associated with prolonged respiratory failure, prolonged hospitalization, extensive
airway necrosis, and CAS (p < 0.05). The authors concluded that these findings implicated
donor bronchial hypoxia as a driving factor for post-transplantation airway complications;
strategies to improve airway oxygenation, such as bronchial artery re-anastomosis and HBOT
merit clinical investigation.
In a pilot study, Mahmood and associates (2016) examined if HBOT could be safely
administered to lung transplant patients with extensive necrotic airway plaques. These
researchers also assessed any effects of HBOT on the incidence and severity of CAS. Patients
with extensive necrotic airway plaques within 1 to 2 months after lung transplantation were
treated with HBOT along with standard care. These patients were compared with a
contemporaneous reference group with similar plaques who did not receive HBOT. A total of 10
patients received HBOT for 18.5 (IQR 11 to 20) sessions, starting at 40.5 (IQR 34 to 54) days
after transplantation; HBOT was well-tolerated. Incidence of CAS was similar between HBOT-
treated patients and reference patients (70 % versus 87 %, respectively; p = 0.34), but fewer
stents were needed in HBOT patients (10 % versus 56 %, respectively; p = 0.03). The authors
concluded that this pilot study was the first to demonstrate HBOT safety in patients who develop
necrotic airway plaques after lung transplantation. They stated that HBOT may reduce the need
for airway stent placement in patients with CAS. These preliminary findings need to be validated
by well-designed studies.
Chemotherapy-Induced Hemorrhagic Cystitis
Davis et al (2011) stated that cyclophosphamide-induced hemorrhagic cystitis (CHC) is an

uncommon, but well-recognized condition caused by a metabolite, acrolein, which is toxic to the
urothelium. Based on similarities in the histopathology of radiation- and chemotherapy-induced
HC, benefit from HBOT has been proposed. Hyperbaric oxygen therapy produces an increased
oxygen partial pressure diffusion gradient between the circulation and surrounding tissues, which
enhances neutrophil function and fibroblast and macrophage migration into damaged hypoxic
soft tissue, promoting collagen formation, fibroblast growth, angiogenesis and white-cell bacterial
killing. There are only isolated case reports of HBOT for CHC, in the literature, thus, these
investigators reviewed the New Zealand experience with HBOT in CHC. The case records of all
patients with CHC referred to the 3 hyperbaric medicine units in New Zealand between 2000 and
2007 were reviewed retrospectively. A total of 6 patients, with life-threatening hemorrhage at the
time of referral for HBOT weeks or months after initial presentation with CHC, were identified.
Cessation of bleeding occurred in all 6 patients after 14 to 40 HBOT, without complications. All
patients remained clear of hematuria at 11 to 36 months follow-up. The authors recommended
the use of HBOT in the management of intractable cyclophosphamide-induced HC as an
effective and low-risk therapy.
Payne and colleagues (2013) reviewed the published data on predisposing risk factors for cancer
treatment-induced HC and the evidence for the different preventive and therapeutic measures that
have been used in order to help clinicians optimally define and manage this potentially serious
condition. Despite recognition that HC can be a significant complication of cancer treatment,
there is currently a lack of United Kingdom-led guidelines available on how it should optimally be
defined and managed. A systematic literature review was undertaken to evaluate the evidence
for preventative measures and therapeutic options in the management of cancer treatment-
induced HC. There is a wide range of reported incidence due to several factors including
variability in study design and quality, the type of causal agent, the grading of bleeding, and
discrepancies in definition criteria. The most frequently reported causal factors are radiotherapy
to the pelvic area, where HC has been reported in up to 20 % of patients, and treatment with
cyclophosphamide and bacillus Calmette-Guerin, where the incidence has been reported as up
to 30 %. Mesna (2-mercaptoethane sodium sulphonate), hyper-hydration and bladder irrigation
have been the most frequently used prophylactic measures to prevent treatment-related cystitis,
but are not always effective. Cranberry juice is widely cited as a preventative measure and
sodium pentosanpolysulphate as a treatment, although the evidence for both is very limited. The
best evidence exists for intra-vesical hyaluronic acid as an effective preventative and active
treatment, and for HBO as an equally effective therapeutic option. Moreover, the authors noted
that the lack of robust data and variability in treatment strategies used highlighted the need for
further research, as well as best practice guidance and consensus on the management of HC.
Degener et al (2015) stated that radiotherapy and cyclophosphamide-induced HC are rare but
severe complications occurring in 3 to 6 % of patients; and HBOT has been demonstrated to be
an effective treatment for hematuria not responding to conventional management. Only very few
data exist for long-term follow-up after HBOT. These researchers retrospectively reviewed 15
patients referred for HBOT for CHC; HBOT was performed for 130 mins/day at a pressure of 2.4
atmospheres. They evaluated patient demographics, type of radio- and chemo-therapy and
characteristics of hematuria. The effect of HBOT was defined as complete or partial resolution of
hematuria according to the RTOG/EORTC grade and Gray score. A total of 15 patients (12 after
radiotherapy, 2 after chemotherapy and 1 patient with a combination of both) were treated with a
median of 34 HBOT sessions. Radiotherapy patients received primary, adjuvant, salvage and
HDR radiotherapy (60 to 78 Gy) for prostate, colon or cervical cancer. The patient with
combination therapy and both of the chemotherapy patients were treated with
cyclophosphamide. First episodes of hematuria occurred at a median of 48 months after
completion of initial therapy. The first HBOT was performed at a median of 11 months after the
1st episode of hematuria. After a median of a 68-month follow-up after HBOT, 80 % experienced
a complete resolution and 2 patients suffered a singular new minor hematuria (p < 0.00001). A
salvage-cystectomy was necessary in 1 patient. No adverse effects (AEs) were documented.
The authors concluded that their experience indicated that HBOT is a safe and effective
therapeutic option for treatment-resistant radiogenic and chemotherapy-induced HC. Moreover,
they stated that for a better evaluation, prospective clinical trials are needed
An eMedicine review on “Hemorrhagic Cystitis Treatment & Management” (Basler, 2015) stated
that “Hyperbaric oxygen therapy is an alternative in patients with refractory hemorrhagic cystitis.
This treatment is better for radiation-induced hemorrhagic cystitis than for cyclophosphamide-
induced hemorrhagic cystitis. Treatment involves 100 % oxygenation at 2 ATA for 90 minutes 5
times weekly. On average, 40 sessions are given. Contraindications include active cancer,
active viral infection, pneumothorax, treatment with doxorubicin or cisplatin, and ear
reconstruction".
Furthermore, an UpToDate review on “Cystitis in patients with cancer” (Moy, 2016) states that
“Treatment of hemorrhagic cystitis -- The use of hyperbaric oxygen was initially described in
patients with radiation-induced HC . Most of these patients had severe inflammation requiring
transfusion of RBC, but they were hemodynamically stable enough to be confined to a
hyperbaric chamber under the supervision of a registered nurse without the direct presence of a
clinician. All but 1 patient had failed prior therapy. The oxygen tension was raised slowly to 2
atmospheres. Each session was 2 hours, and 60 sessions were planned with a cystoscopic
examination after 30 treatments. Twelve of 13 patients experienced durable cessation of HC.
The single failure demonstrated full-thickness bladder necrosis at the time of cystectomy.
Similar favorable results were reported in 4 more contemporary series in which complete
resolution or marked improvement in symptoms of HC was seen in 65 to 81 % of patients,
respectively, with a regimen of 100 % oxygen at 2 to 2.5 atmospheres for 90 to 120 minutes
during 20 to 40 sessions. In 2 of the studies, outcomes appeared better when patients were
treated earlier in the course of disease (i.e., within 6 months of hematuria onset). Cystoscopies
done at resolution of HC demonstrated resolution of the underlying pathology and return to
normal bladder mucosa and function. There were no side effects of hyperbaric oxygen in these
reports. In the third report, the most common side effect of hyperbaric oxygen therapy was
otalgia, seen in 33 % of the patients, which resolved after placement of tympanostomy tubes.
Hyperbaric oxygen therapy appears to be effective but is limited to stable patients and those
with access to a hyperbaric chamber”.
Chronic Bowel Dysfunction After Pelvic Radiotherapy
In a randomized, double-blind, sham-controlled phase III clinical trial (HOT2), Glover and
colleagues (2016) evaluated results for the clinical benefits of HBOT in patients with chronic
bowel dysfunction after radiotherapy for pelvic malignancies. Patients (greater than or equal to
18 years) with chronic gastro-intestinal (GI) symptoms for 12 months or more after radiotherapy
and which persisted despite at least 3 months of optimal medical therapy and no evidence of
cancer recurrence. Participants were stratified by participating hyperbaric center and randomly
assigned (2:1) by a computer-generated list (block size 9 or 12) to receive treatment with HBOT
or sham. Participants in the active treatment group breathed 100 % oxygen at 2.4 ATA and the
control group breathed 21 % oxygen at 1.3 ATA; both treatment groups received 90-min air
pressure exposures once-daily for 5 days per week for a total of 8 weeks (total of 40
exposures). Staff at the participating hyperbaric medicine facilities knew the allocated
treatment, but patients, clinicians, nurse practitioners, and other health-care professionals
associated with patients' care were masked to treatment allocation. Primary end-points were
changes in the bowel component of the modified Inflammatory Bowel Disease Questionnaire
(IBDQ) score and the IBDQ rectal bleeding score 12 months after start of treatment relative to
baseline. The primary outcome was analyzed in a modified intention-to-treat population,
excluding patients who did not provide IBDQ scores within a pre-determined time-frame. All
patients have completed 12 months of follow-up and the final analysis was complete. Between
August 14, 2009, and October 23, 2012, a total of 84 participants were randomly assigned: 55 to
HBOT and 29 to sham control; 75 (89 %) participants received 40 pressure exposures, all
participants returned the IBDQ at baseline, 75 (89 %) participants returned the IBDQ at 2 weeks
post-treatment, and 79 (94 %) participants returned the IBDQ at 12 months post-start of
treatment. Patients were excluded from analyses of co-primary end-points if they had missing
IBDQ scores for intestinal function or rectal bleeding at baseline or at 12 months. In an analysis
of 46 participants in the active treatment group and 23 participants in the control group, these
researchers found no significant differences in the change of IBDQ bowel component score
(median change from baseline to 12 months of 4 (IQR -3 to 11) in the treatment group versus 4
(-6 to 9) in the sham group; Mann-Whitney U score 0.67, p = 0.50). In an analysis of 29
participants in the active treatment group and 11 participants in the sham group with rectal
bleeding at baseline, these investigators also found no significant differences in the change of
IBDQ rectal bleeding score (median change from baseline to 12 months of 3 [1 to 3] in the
treatment group versus 1 [1 to 2] in the sham group; U score 1.69, p = 0·092). Common AEs in
both groups were eye refractive changes (3 [11 %] of 28 patients in the control group versus 16
[30 %] of 53 patients in the treatment group), increased fatigue (3 [11 %] versus 2 [4 %]), and
ear pain (6 [21 %] versus 15 [28 %]); 8 serious AEs were reported in 8 patients: 2 were reported
in 2 patients in the control group (tonsillitis requiring surgery [grade 3]; recurrent cancer of the
vulva [grade 4]) and 6 serious AEs were reported in 6 patients in the treatment group (malignant
spinal cord compression requiring surgery [grade 3]; malignant paraortic lymph node involvement
requiring surgery [grade 3]; recurrence of vomiting and dehydration [grade 3]; diarrhea and fever
associated with Campylobacter infection [grade 3]; recurrence of abdominal pain, bloating,
diarrhea, and urinary tract infection [grade 3]; aneurysm [grade 4]), none of which was deemed
treatment-related. The authors concluded that they found no evidence that patients with
radiation-induced chronic GI symptoms, including those patients with rectal bleeding, benefit
from HBOT. They stated that these findings contrast with evidence used to justify current
practices, and more level 1 evidence is urgently needed.
In a Cochrane review, van de Wetering and associates (2016) evaluated the safety and the
effectiveness of non-surgical interventions for managing late radiation proctopathy. These
investigators searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 11,
2015); Medline (Ovid); Embase (Ovid); CANCERCD; Science Citation Index; and CINAHL from
inception to November 2015. They included RCTs comparing non-surgical interventions for the
management of late radiation proctopathy in people with cancer who have undergone pelvic
radiotherapy for cancer. Primary outcomes considered were: episodes of bowel activity,
bleeding, pain, tenesmus, urgency, and sphincter dysfunction. Study selection, “risk of bias”
assessment, and data extraction were performed in duplicate, and any disagreements were
resolved by involving a 3rd review author. The authors identified 1,221 unique references and 16
studies including 993 participants who met inclusion criteria. One study found through the last
update was moved to the “Studies awaiting classification” section. They did not pool outcomes
for a meta-analysis due to variation in study characteristics and end-points across included
studies. Since radiation proctopathy is a condition with various symptoms or combinations of
symptoms, the studies were heterogeneous in their intended effect. Some studies investigated
treatments targeted at bleeding only (group 1), some investigated treatments targeted at a
combination of anorectal symptoms, but not a single treatment (group 2). The 3rd group focused
on the treatment of the collection of symptoms referred to as pelvic radiation disease. In order to
enable some comparison of this heterogeneous collection of studies, these researchers
described the effects in these 3 groups separately. A total of 9 studies assessed treatments for
rectal bleeding and were unclear or at high risk of bias. The only treatments that made a
significant difference on primary outcomes were argon plasma coagulation (APC) followed by
oral sucralfate versus APC with placebo (endoscopic score 6 to 9 in favor of APC with placebo,
RR 2.26, 95 % CI: 1.12 to 4.55; 1 study, 122 participants, low- to moderate-quality evidence);
formalin dab treatment (4 %) versus sucralfate steroid retention enema (symptom score after
treatment graded by the Radiation Proctopathy System Assessments Scale (RPSAS) and
sigmoidoscopic score in favor of formalin (p = 0.001, effect not quantified, 1 study, 102
participants, very low- to low-quality evidence), and colonic irrigation plus ciprofloxacin and
metronidazole versus formalin application (4 %) (bleeding (p = 0.007, effect not quantified),
urgency (p = 0.0004, effect not quantified), and diarrhea (p = 0.007, effect not quantified) in favor
of colonic irrigation (1 study, 50 participants, low-quality evidence); 3 studies, of unclear and high
risk of bias, assessed treatments targeted at something very localized but not a single
pathology. These investigators identified no significant differences on our primary outcomes.
They graded all studies as very low-quality evidence due to unclear risk of bias and very serious
imprecision; 4 studies, of unclear and high risk of bias, assessed treatments targeted at more
than 1 symptom yet confined to the anorectal region. Studies that demonstrated an effect on
symptoms included: gastroenterologist-led algorithm-based treatment versus usual care
(detailed self-help booklet) (significant difference in favor of gastroenterologist-led algorithm-
based treatment on change in Inflammatory Bowel Disease Questionnaire-Bowel (IBDQ-B) score
at 6 months, MD 5.47, 95 % CI: 1.14 to 9.81) and nurse-led algorithm-based treatment versus
usual care (significant difference in favor of the nurse-led algorithm-based treatment on change in
IBDQ-B score at 6 months, MD 4.12, 95 % CI: 0.04 to 8.19) (1 study, 218 participants, low-
quality evidence); HBOT (at 2.0 ATA) versus placebo (improvement of Subjective, Objective,
Management, Analytic - Late Effects of Normal Tissue (SOMA-LENT) score in favor of HBOT (p
= 0.0019) (1 study, 150 participants, moderate-quality evidence, retinol palmitate versus placebo
(improvement in RPSAS in favor of retinol palmitate, p = 0.01) (1 study, 19 participants, low-
quality evidence) and integrated Chinese traditional plus Western medicine versus Western
medicine (grade 0 to 1 radio-proctopathy after treatment in favor of integrated Chinese traditional
medicine, RR 2.55, 95 % CI: 1.30 to 5.02) (1 study, 58 participants, low-quality evidence). The
level of evidence for the majority of outcomes was down-graded using GRADE to low or very low,
mainly due to imprecision and study limitations. The authors concluded that although some
interventions for late radiation proctopathy look promising (including rectal sucralfate,
metronidazole added to an anti-inflammatory regimen, and HBOT), single small studies provided
limited evidence. Furthermore, outcomes important to people with cancer, including QOL and
long-term effects, were not well-recorded. They stated that the episodic and variable nature of
late radiation proctopathy requires large, multi-center RCTs to establish whether treatments are
effective. They stated that future studies should address the possibility of associated injury to
other GI, urinary, or sexual organs, known as pelvic radiation disease.
Chronic Pain
Sutherland and associates (2016) reviewed clinical studies suggesting that HBOT may be useful
in treating chronic pain syndromes, including chronic headache, fibromyalgia, complex regional
pain syndrome, and trigeminal neuralgia. These researchers performed a comprehensive search
through Medline, Embase, Scopus, and Web of Science for studies relating to HBOT and pain
using the following keywords: hyperbaric oxygen therapy or hyperbaric oxygen treatment
(HBOT), nociceptive pain, inflammatory pain, neuropathic pain, HBOT and pain, HBOT and
headache, HBOT and fibromyalgia, HBOT and complex regional pain syndrome, and HBOT and
trigeminal neuralgia. A total of 25 studies examining the role of HBOT in animal models of pain
and human clinical trials were found and reviewed for this narrative review. The authors
concluded that HBOT has been shown to reduce pain using animal models. They stated that
early clinical research indicated HBOT may also be useful in modulating human pain; however,
further studies are needed to examine if HBOT is safe and effective in treating chronic pain
conditions.
Improvement of Free Flap Survival
Teoh and colleagues (2005) estimated the cumulative survival rates (CSRs) of implants placed in
reconstructed mandibles and identified prognostic factors that may influence implant survival.
The charts of 24 patients (10 males, 14 females) who had undergone mandibular resection and
reconstruction with fibula free-flaps treated with implant-supported prostheses from April 1986
through December 2001 were reviewed. Information on demographics, surgical characteristics,
treatment modalities, dentition, implant parameters, prostheses, and HBOT was gathered.
Kaplan-Meier survival estimates were generated for the 100 implants that satisfied the inclusion
criteria. Multi-variate Cox proportional hazards regression models accounting for correlated
implants within subjects were developed to identify prognostic factors for implant survival. A total
of 19 implants had been placed in native mandible (3 in irradiated bone) and 81 in fibula bone
flap; 6 implants failed during the follow-up period (mean of 51.7 months). The 5- and 10-year
CSRs were 97.0 % and 79.9 %, respectively. In the univariate analysis, variables associated
with implant survival were age, gender, chemotherapy, radiation therapy, HBOT, irradiated bone,
implant diameter, xerostomia, trismus, opposing dentition, and type of prosthesis. At 5 years,
the CSR of implants in patients with HBOT was 86.7 %; HBOT was statistically associated with
an increased risk for implant failure (p = 0.005, HR = 19.79, 95 % CI: 2.42 to 161.71). The CSR
was lower when implants were placed in a previously irradiated mandible. The authors
concluded that there is still a lack of reliable clinical evidence to support the effectiveness of
HBOT in these patients. They stated that a high survival rate was demonstrated for implants
placed in fibula free-flap reconstructed mandibles. The finding that HBOT was a risk factor can
probably be attributed to the small sample size; further study is needed in this patient
population.
Shaw et al (2005) noted that advances in the management of oral malignancy have resulted in
significant improvements in survival and functional outcome. Ablation of oral tissues and
radiotherapy render many patients unable to wear conventional prostheses, and these patients
were, thus, candidates for oral rehabilitation with osseo-integrated implants. These researchers
presented outcomes and complications of such treatment over a 14-year period in a single unit.
Data were collected for 81 consecutive patients, most of whom had received microvascular free
flap reconstruction after surgical ablation of oral squamous cell carcinoma; 386 implants were
placed after a delay of 12 months after surgery; 65 % of implants were placed in the anterior
mandible. Radiotherapy was used in 47 % of the patients, and HBOT was routinely used in
irradiated subjects during the latter half of the series. Retrospective analysis of implants and
prostheses was made by use of case notes, radiographs, and a computerized database. Data
were presented for 364 of the 386 implants in 77 of the 81 patients after a median follow-up of 4
years; 265 (73 %) of the implants were in function supporting prostheses, 56 (15 %) had been
lost, and 43 (12 %) were present but not loaded (i.e., "sleepers"). Implant loss seemed patient-
specific and was also correlated with host bone type; 13 % of patients in whom implants were
placed in the mandible lost at least 1 implant, and the equivalent values for the maxilla was 40
%; 36 % of patients in whom implants were placed in bone graft or flap lost at least 1 implant.
The effects of implant manufacture, dimensions, radiotherapy, and HBOT did not reach statistical
significance in this series. Cases of a second primary malignancy were noteworthy; however,
the impact of recurrence was minimized by the delay between resection and rehabilitation. Of
the 42 fixed and 29 removable prostheses fitted, 12 (17 %) failed. The authors concluded that
implants placed in mandible were reliable, but failure rates in vascularized bone graft and maxilla
were higher. Radiotherapy did not seem to prejudice implant survival, and HBOT had no
demonstrable benefit in this series.
Friedman et al (2006) noted that HBOT has been advocated, both as an adjunctive or primary
form of treatment, for a variety of disorders, including gas gangrene, osteo-radionecrosis, and
carbon monoxide poisoning. It has also been used to improve ischemic wounds before skin
grafting and to support ischemic flaps. These investigators analyzed the available literature that
examined the use of HBOT for composite grafts, skin grafts, random flaps, distant flaps, and free
flaps. An appraisal of the level of evidence for each of these uses of HBOT was offered.
Although there are a significant amount of animal data supporting the application of HBOT for
grafts and flaps, there is very little clinical information other than case reports and series to
sustain its choice over other modalities of therapy. The authors concluded that multi-center
prospective clinical studies are needed comparing HBOT to other mechanical or pharmacologic
interventions to improve wound healing for grafting or to support flap survival.
Schoen et al (2007) noted that surgical treatment of malignancies in the oral cavity and
subsequent radiotherapy often result in an anatomic and physiological oral condition unfavorable
for prosthodontic rehabilitation. These researchers evaluated the effect of HBOT on treatment
outcome (condition of peri-implant tissues, implant survival, oral functioning and quality of life) of
prosthodontic rehabilitation with implant-retained lower dentures in radiated head and neck
cancer patients 6 weeks and 1 year after placing the new dentures. The treatment outcome was
assessed in a group of 26 head neck cancer patients who were subjected to radiotherapy after
tumor surgery. Standardized questionnaires were completed and clinical and radiographic
assessments were performed. After randomization, endosseous Branemark implants were
placed in the anterior part of the mandible either under antibiotic prophylaxis (13 patients) or
under antibiotic prophylaxis combined with pre- and post-surgery HBOT (13 patients). In the
HBOT and non-HBOT group, 8 implants (implant survival 85.2 %) and 3 implants (implant survival
93.9 %) were lost, respectively. Peri-implant tissues had a healthy appearance in both groups.
Osteo-radionecrosis developed in 1 patient in the HBOT group. All patients functioned well with
their implant-retained lower denture. The quality of life related to oral functioning and denture
satisfaction were improved to a comparable extent in the HBOT and non-HBOT group. The
authors concluded that implant-retained lower dentures can improve the quality of life related to
oral functioning and denture satisfaction in head and neck cancer patients; adjuvant HBOT could
not be shown to enhance implant survival in radiated mandibular jaw bone.
Zhou et al (2014) stated that in China, HBOT has been widely applied in the treatment of
ischemia/hypoxia related diseases including decompression sickness, carbon monoxide
poisoning, diabetic foot ulcer and others. Wounds after skin grafts are an indication for HBOT in
the Chinese Guideline for Hyperbaric Oxygen Therapy. These investigators retrospectively
reviewed the available studies on the application of HBOT in the management of skin flaps. The
mechanisms underlying the therapeutic effects of HBOT were summarized, and therapeutic
aspects in the HBOT of skin flaps in China were also described. Finally, some important issues
influencing the therapeutic effectiveness and further systemic reviews were proposed. The
authors concluded that their findings may help to improve the quality of future studies in this field
and to more rationally apply HBOT in patients receiving skin grafting procedures.
Nolen et al (2014) stated that HBOT induces native tissue oxygenation. The hypothesis was
patients with mandibular osteoradionecrosis (ORN) and a history of HBOT would have less free
flap reconstruction complications than patients without HBT. These researchers conducted a
multi-site retrospective review involving radical debridement and free flap reconstruction for ORN
between January 1, 1995 and June 30, 2011. Patients were stratified based on receiving prior
HBOT or not; 39 of 89 patients (43.8 %) had HBOT whereas 50 of 89 (56.2 %) did not. The
HBOT group had significantly less patients with diabetes. There was no statistical difference in
overall complication in patients between groups (p = 0.5478). However, there was marginal
significance of increased infections in the patients with a history of HBOT (p = 0.0545). The
authors concluded that although no significant differences in free flap reconstruction complication
rates were observed between these 2 patient cohorts, there was marginal significance of
increased infections in the patients with a history of HBT. They stated that a prospective multi-
institutional randomized study examining issues of infection would address issues inherent in
this retrospective study.
Furthermore, an UpToDate review on “Hyperbaric oxygen therapy” (Mechem and Manaker, 2016)
does not mention improvement of free flap survival as an indication of HBOT.
Male Infertility
Metelev et al (2015) examined the potential of HBOT for reduction of sperm DNA fragmentation
level and reactive oxygen species (ROS) in semen. This study included 90 men with idiopathic
infertility. Patients of the treatment group (n = 60) underwent HBOT before in-vitro fertilization
(IVF) procedure. In the control group (n = 30) IVF was carried out without a prior course of
HBOT. Sperm DNA fragmentation analysis was carried out using the TUNEL assay, the level of
ROS in the ejaculate was measured by chemiluminescence. Hyperbaric oxygen therapy
resulted in a significant decrease in the mean level of sperm DNA fragmentation from 33.2 ± 7.5
to 11.9 ± 5.9 %, and the median ROS in sperm from 0.89 to 0.39 mV/s (p < 0.05). In the control
group these changes were not statistically significant. Pregnancy after IVF occurred in 63.3 %
(38/60) of sexual partners of the treatment group men and in 36.7 % (11/30) of the control group
(p < 0.05). The authors concluded that the high efficiency of HBOT in overcoming the AEs of
oxidative stress on sperm parameters suggested that this approach is a promising method for
the treatment of men with idiopathic infertility.
Post-Traumatic Stress Disorder
Eve and colleagues (2016) noted that TBI describes the presence of physical damage to the
brain as a consequence of an insult and frequently possesses psychological and neurological
symptoms depending on the severity of the injury. The recent increased military presence of US
troops in Iraq and Afghanistan has coincided with greater use of improvised exploding devices,
resulting in many returning soldiers suffering from some degree of TBI. A bi-phasic response is
observed which is first directly injury-related, and second due to hypoxia, increased oxidative
stress, and inflammation. A proportion of the returning soldiers also suffer from post-traumatic
stress disorder (PTSD), and in some cases, this may be a consequence of TBI. Effective
treatments are still being identified, and a possible therapeutic candidate is HBOT. Some
clinical trials have been performed that suggested benefits with regard to survival and disease
severity of TBI and/or PTSD, while several other studies did not see any improvement compared
to a possibly poorly controlled sham. Hyperbaric oxygen therapy has been shown to reduce
apoptosis, up-regulate growth factors, promote anti-oxidant levels, and inhibit inflammatory
cytokines in animal models, and hence, it is likely that HBOT could be advantageous in treating
at least the secondary phase of TBI and PTSD. There is some evidence of a putative
prophylactic or pre-conditioning benefit of HBOT exposure in animal models of brain injury, and
the optimal time frame for treatment is yet to be determined. The authors concluded that HBOT
has potential side effects such as acute cerebral toxicity and more reactive oxygen species with
long-term use, and therefore, optimizing exposure duration to maximize the reward and decrease
the detrimental effects of HBOT is needed..
Radiation-Induced Pulmonary Fibrosis/Injury
Cancer Care Ontario’s evidence-based care advice report on “Hyperbaric Oxygen Therapy for the
Treatment and Prevention of Radionecrosis and Other Radiation-Induced Injuries in Cancer
Patients” (2013) did not mention radiation induced pulmonary fibrosis/ injury as an indication of
HBOT.
Also, the Undersea and Hyperbaric Medical Society’s review on “Delayed Radiation Injury (Soft
Tissue and Bony Necrosis)” (2016) does not mention HBOT as a therapeutic option for radiation-
induced pulmonary fibrosis/injury.
Furthermore, an UpToDate review on “Radiation induced lung injury” (Merrill, 2016) does not
mention HBOT as a therapeutic option; and an UpToDate review on “Hyperbaric oxygen therapy”
(Mechem and Manaker, 2016) does not mention radiation-induced pulmonary fibrosis/injury as
an indication of HBOT.
Spinal Dural Arterio-Venous Fistula
Chen and colleagues (2016) noted that spinal dural arterio-venous fistula (SDAVF) is a common
type of spinal vascular malformation. Surgical obliteration of the fistula can cure SDAVF
anatomically, but the functional outcome is unsatisfactory. In a prospective, observational,
cohort study, these researchers evaluated the effect of HBOT on the functional recovery of post-
operative SDAVF patients. Patients were divided into control and HBOT groups. Patients in
control group received conventional treatment, whereas those in the HBOT group received
conventional treatment plus HBOT (2.0 atmospheric pressure absolute, 14 days). Follow-up was
done at 1, 3, 6, 12, and 24 months after surgery for evaluation, including symptoms. To evaluate
the effectiveness of HBOT on SDAVF patients, these investigators compared the post-operative
MRI and neurological outcomes of each group with respect to modified Aminoff-Lougue scale
and modified Denis Pain and Numbness Scale (mDPNS). From September 1, 2013 to January
31, 2014, a total of 33 SDAVF patients (27 male) treated by microsurgery were included in this
study; 16 patients were in the HBOT group and 17 patients were in the control group. At 24
months follow-up, the improvement of mDPNS for the HBOT group was significantly larger than
those of the control group (2.25 versus 0.88; p = 0.005). In the HBOT group, the average length
of hyper-signal in MRI T2 image decrease at 3 months after surgery was 3.25 compared with
2.29 in the control group (p = 0.009). No major AEs were reported for all 16 patients who received
HBOT. The authors concluded that these findings suggested that HBOT is safe and effective
treatment to relieve lower body pain and numbness for post-operative SDAVF patients. These
preliminary findings need to be validated by well-designed studies.
Traumatic Brain Injury
In a systematic review, Crawford and associates (2017) examined the efficacy of HBOT for
traumatic brain injury (TBI) to make evidence-based recommendations for its application and
future research. These investigators performed a comprehensive search to identify studies
through 2014. Methodological quality was assessed and synthesis and interpretation of relevant
data was performed. A total of 12 randomized trials were included. All mild TBI studies
demonstrated minimal bias and no statistically significant differences between HBOT and sham
arms. Statistically significant improvement occurred over time within both groups. Moderate-to-
severe TBI studies were of mixed quality, with majority of results favoring HBOT compared with
"standard care". The placebo analysis conducted was limited by lack of details. The authors
concluded that for mild TBI, results indicated HBOT was no better than sham treatment.
Improvements within both HBOT and sham groups cannot be ignored. For acute treatment of
moderate-to-severe TBI, although methodology appeared flawed across some studies, because
of the complexity of brain injury, HBOT may be beneficial as a relatively safe adjunctive therapy if
feasible. They stated that further research should be considered to resolve the controversy
surrounding this field, but only if methodological flaws are avoided and bias minimized.
Daly and colleagues (2018) noted that there has been no major advancement in a quarter of a
century for the treatment of acute severe TBI. These investigators summarized 40 years of
clinical and pre-clinical research on the treatment of acute TBI with HBOT in the context of an
impending National Institute of Neurologic Disorders and Stroke (NINDS)-funded, multi-center,
randomized, adaptive phase-II clinical trial -- the Hyperbaric Oxygen Brain Injury Treatment
(HOBIT) trial. A total of 30 studies (8 clinical and 22 pre-clinical) that administered HBOT within
30 days of a TBI were identified from PubMed searches. The pre-clinical studies consistently
reported positive treatment effects across a variety of outcome measures with almost no safety
concerns, thus providing strong proof-of-concept evidence for treating severe TBI in the acute
setting. Of the 8 clinical studies reviewed, 4 were based on the senior author's investigation of
HBOT as a treatment for acute severe TBI. These studies provided evidence that HBOT
significantly improved physiologic measures without causing cerebral or pulmonary toxicity and
can potentially improve clinical outcome. These results were consistent across the other 4
reviewed clinical studies, thus providing preliminary clinical data supporting the HOBIT trial. The
authors concluded that this comprehensive review demonstrated that HBOT has the potential to
be the first significant treatment in the acute phase of severe TBI.
Prevention of Radiation-Induced Complications of the Head and Neck Cancers
Ravi and colleagues (2017) stated that radiation therapy for the treatment of head and neck
cancer can injure normal tissues and have devastating side effects. Hyperbaric oxygen therapy
is known to reduce the severity of radiation-induced injury by promoting wound healing. These
researchers identified the various benefits of HBOT in patients who have undergone radiation for
head and neck cancer. An electronic database search was carried out to identify relevant
articles and selected articles were reviewed in detail. The quality of evidence for each benefit,
including preserving salivary gland function, preventing osteonecrosis, dental implant success,
and overall QoL, was evaluated. Evidence showed that HBOT was effective in improving
subjective symptoms of xerostomia, swallowing, speech and overall QoL. There was no
conclusive evidence to show that HBOT improved implant survival, prevented osteonecrosis, or
improved salivary gland function.
Treatment of Bacterial Keratitis
Dakhil and colleagues (2017) stated that no RCTs are available in the literature that discusses
the effect of HBOT in bacterial keratitis. Chong et al (2007) reported a 30-year old woman with
culture-proven soft contact lens associated Pseudomonas keratitis who was getting
progressively worse despite topical, oral, and intravenous antibiotics. On her 3rd day, HBOT
was started for 90 mins daily in addition to her antibiotics therapy; 24 hours later, her vision
improved from counting fingers to 6/24; HBOT continued to complete a course of 3 days.
Patient discharged with the vision of 6/9. The authors concluded that further studies into the
therapeutic effect of HBOT as adjunctive therapy to antibiotics are needed to prove its clinical
efficacy and to determine the safe dose to avoid ocular and systematic complications.
Treatment of Intra-Cerebral Hemorrhage
Cui and associates (2017) noted that HBOT for treatment of intra-cerebral hemorrhage (ICH)
remains controversial, in either animal or clinical studies. These researchers conducted a
systematic review and meta-analysis on studies describing the efficacy of HBOT in animal
models of ICH. Studies were identified by searching mainstream databases through November
2015. The efficacy of HBOT in animal models of ICH was assessed by changes in the brain
water content (BWC), neurobehavioral outcome (NO) or both. Subgroup analyses were
performed according to different design characteristics. A total of 15 studies met inclusion
criteria; HBOT reduced the BWC (-0.982, 95 % CI: -1.148 to -0.817; p < 0.01; 57 comparisons),
and improved NO (-0.767, 95 % CI: -1.376 to -0.159; p < 0.01; 8 comparisons); HBOT was most
effective in reducing BWC when given 72 hours after ICH for a 4- to 5-day consecutive treatment
at the chamber pressure of 3.0 atmosphere absolute. Efficacy was higher with phenobarbital
anesthesia, the blood infusion model and in rabbits. The authors concluded that although HBOT
was found to be effective in experimental ICH, additional confirmation is needed due to possible
publication bias, poor study quality and the limited number of studies conducting clinical trials.
Treatment of Radiation-Induced Skin Necrosis
Borab and colleagues (2017) noted that 1.2 million cancer patients receive radiation therapy in
the United States every year. Late radiation tissue injury occurs in an estimated 5 to 15 % of
these patients. Tissue injury can include skin necrosis, which can lead to chronic non-healing
wounds. Despite many treatments available to help heal skin necrosis such as HBOT, no
clinical guidelines exist and evidence is lacking. These researchers identified and summarized
studies published to-date to evaluate the effectiveness of HBOT for the treatment of radiation-
induced skin necrosis. Adhering to PRISMA guidelines, a systematic review of currently
published articles was performed, evaluating the use of HBOT to treat skin necrosis. A total of 8
articles were identified, including 1 observational cohort, 5 case series, and 2 case reports. The
articles described changes in symptoms and alteration in wound healing of radiation-induced
skin necrosis after treatment with HBOT. The authors concluded that HBOT is a safe
intervention with promising outcomes; however, additional evidence is needed to recommend its
application as a relevant therapy in the treatment of radiation-induced skin necrosis.
Treatment of Scleroderma (Systemic Sclerosis)
Moran (2014) noted that digital ulcers are difficult to heal, increasing the chance of infection,
gangrene, amputation and limited functional use of hands. They are a complication in
scleroderma or systematic sclerosis (SSc) and occur in approximately 50 % of patients. This
was a systematic review of the evidence supporting the use of non-pharmaceutical therapeutic
modalities and their effectiveness to facilitate the healing of chronic digital ulcers in patients with
scleroderma. The author carried out a comprehensive review of computerized databases from
2000 to 2013: PubMed/Medline, CINAHL, Pedro, OT Seeker, OT Search, OVID, and Proquest as
well as manual review of other resources using the following search terms scleroderma or
systemic sclerosis and/or digital ulcers, specific modalities (low level laser therapy, electrical
stimulation, intermittent compression, ultrasound, vitamin E, myofascial release, wound
dressings, iontophoresis, negative pressure therapy, and exercise), chronic wounds, and wound
care. English language studies, from 2000 to January 2013, which used therapeutic modalities
to facilitate healing of digital ulcers and use healing of the digital ulcer as an outcome measure
were reviewed. Of the 403 identified articles, only 11 studies addressed non-pharmaceutical
treatment modalities to facilitate healing for digital ulcers. Exercise had no direct effect on
healing ulcers. The following studies were positive but have limitations in design and sample
size: HBOT (n = 2), negative pressure therapy (n = 1), intermittent compression (n = 27) and
acoustic pressure wound healing (n = 1). Vitamin E gel showed a significant difference
compared to a control group (n = 27). Iontophoresis studies have shown that the modality
increases blood flow but the results in 5 different studies are mixed and the application and
intensity were inconsistent. The author concluded that no one modality was proven to be the
most effective; larger efficacy studies on treating digital ulcers are needed in order to develop
appropriate care guidelines to improve outcomes, promote function and lower health-care costs.
Furthermore, an UpToDate review on “Overview of the treatment and prognosis of systemic

sclerosis (scleroderma) in adults” (Denton, 2017) does not mention HBOT as a therapeutic
option.
Treatment of Post-Operative Nipple Ischemia Following Mastectomy
Shuck and colleagues (2017) stated that nipple preservation provides superior aesthetic results
as well as patient satisfaction in patients treated with both therapeutic and prophylactic
mastectomy. Post-operative nipple ischemia and necrosis presents a unique clinical challenge
that may be treated with hyperbaric oxygen therapy (HBOT) or conservative measures alone.
To-date, the efficacy of HBOT on post-operative nipple ischemia has yet to be evaluated. These
researchers carried out a retrospective review of patients treated with either HBOT or
conservative management. Post-operative photographs were evaluated using a novel imaging
data pathway to in both groups to determine rates of healing. Although patients treated with
HBOT experienced rates of healing nearly twice those of patients treated with conservative
measures alone, no statistical significance was found between groups in this series. The
authors concluded that no significance difference was found between groups treated with HBOT
or conservative management in this series. They stated that further large scale, multi-center
studies are needed to further determine clinical utility and cost-effectiveness of HBOT for nipple
ischemia following nipple sparing mastectomy (NSM) and implant based reconstruction.
Treatment of Sudden Sensorineural Hearing Loss
On behalf of the American Academy of Otolaryngology-Head and Neck Surgery, Stachler and
colleagues (2012) stated that sudden hearing loss (SHL) is a frightening symptom that often
prompts an urgent or emergent visit to a physician. These investigators provided an evidence-
based guideline for the diagnosis, management, and follow-up of patients who present with SHL.
The guideline primarily focused on sudden sensorineural hearing loss (SSNHL) in adult patients
(aged 18 and older). Prompt recognition and management of SSNHL may improve hearing
recovery and patient quality of life (QOL). Sudden sensorineural hearing loss affects 5 to 20 per
100,000 population, with about 4,000 new cases per year in the United States. This guideline
was intended for all clinicians who diagnose or manage adult patients who present with SHL.
The panel recognized that patients enter the health care system with SHL as a non-specific,
primary complaint. Therefore, the initial recommendations of the guideline deal with efficiently
distinguishing SSNHL from other causes of SHL at the time of presentation. By focusing on
opportunities for quality improvement, the guideline should improve diagnostic accuracy, facilitate
prompt intervention, decrease variations in management, reduce unnecessary tests and imaging
procedures, and improve hearing and rehabilitative outcomes for affected patients.
The panel made strong recommendations that clinicians should do the following:
Distinguish sensorineural hearing loss from conductive hearing loss in a patient presenting
with SHL
Educate patients with idiopathic sudden sensorineural hearing loss (ISSNHL) about the
natural history of the condition, the benefits and risks of medical interventions, and the
limitations of existing evidence regarding efficacy
Counsel patients with incomplete recovery of hearing about the possible benefits of
amplification and hearing-assistive technology and other supportive measures
The panel made recommendations that clinicians should do the following:
Assess patients with presumptive SSNHL for bilateral SHL, recurrent episodes of SHL, or
focal neurologic findings
Diagnose presumptive ISSNHL if audiometry confirms a 30-dB hearing loss at 3

consecutive frequencies and an underlying condition cannot be identified by history and
physical examination
Evaluate patients with ISSNHL for retro-cochlear pathology by obtaining magnetic
resonance imaging (MRI), auditory brainstem response, or audiometric follow-up
Offer intra-tympanic steroid perfusion when patients have incomplete recovery from
ISSNHL after failure of initial management
Obtain follow-up audiometric evaluation within 6 months of diagnosis for patients with
ISSNHL
The panel offered as options that clinicians may offer:
Corticosteroids as initial therapy to patients with ISSNHL

Hyperbaric oxygen therapy (HBOT) within 3 months of diagnosis of ISSNHL
The panel made a recommendation against:
Clinicians routinely prescribing anti-virals, thrombolytics, vasodilators, vasoactive

substances, or anti-oxidants to patients with ISSNHL
The panel made strong recommendations against:
Clinicians ordering computerized tomography (CT) of the head/brain in the initial

evaluation of a patient with presumptive SSNHL; and obtaining routine laboratory tests in
patients with ISSNHL
In a Cochrane review, Bennett and associates (2012) evaluated the benefits and harms of HBOT
for treating ISSHL and/or tinnitus. These investigators searched the Cochrane Ear, Nose and
Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials
(CENTRAL); PubMed; Embase; Database of Randomized Trials in Hyperbaric Medicine
(DORCTHIM); CINAHL; Web of Science; BIOSIS Previews; Cambridge Scientific Abstracts;
ICTRP and additional sources for published and unpublished trials. The date of the most recent
search was May 2, 2012, following previous searches in 2009, 2007 and 2004. Randomized
studies comparing the effect on ISSHL and tinnitus of HBOT and alternative therapies were
selected for analysis; 3 authors evaluated the quality of trials using the “Risk of bias” tool and
extracted data from the included trials. A total of 7 trials contributed to this review (392
participants) . The studies were small and of generally poor quality. Pooled data from 2 trials did
not show any significant improvement in the chance of a 50 % increase in hearing threshold on
pure-tone average with HBOT (risk ratio (RR) with HBOT 1.53, 95 % confidence interval (CI): 0.85
to 2.78, p = 0.16), but did show a significantly increased chance of a 25 % increase in pure-tone
average (RR 1.39, 95 % CI: 1.05 to 1.84, p = 0.02). There was a 22 % greater chance of
improvement with HBOT, and the number needed to treat (NNT) to achieve 1 extra good outcome
was 5 (95 % CI: 3 to 20). There was also an absolute improvement in average pure-tone
audiometric threshold following HBOT (mean difference (MD) 15.6 dB greater with HBOT, 95 %
CI: 1.5 to 29.8, p = 0.03). The significance of any improvement in tinnitus could not be
assessed. There were no significant improvements in hearing or tinnitus reported for chronic
presentation (6 months) of ISSHL and/or tinnitus. The authors concluded that for people with
acute ISSHL, the application of HBOT significantly improved hearing, but the clinical significance
remains unclear. These researchers could not evaluate the effect of HBOT on tinnitus by pooled
analysis. In view of the modest number of patients, methodological shortcomings and poor
reporting, this result should be interpreted cautiously. An appropriately powered trial is justified
to define those patients (if any) who can be expected to derive most benefit from HBOT. There is
no evidence of a beneficial effect of HBOT on chronic ISSHL or tinnitus and the authors did not
recommend the use of HBOT for this purpose.
van der Veen and co-workers (2014) studied the clinical question -- What is the effect of HBOT
on hearing thresholds in patients who suffered a recent acute acoustic trauma? After screening
for eligible titles and abstracts and extracting duplicates, a total of 6 original research papers
were found. The general methodology of the studies was weak and the differences between
these studies were too profound to pool the data, especially because of heterogeneity in
adjuvant therapies, follow-up, and treatment protocol. The mean dB of hearing recovery in these
studies ranged from 17 to 47 dB in the groups treated with HBOT versus 5 to 46 dB in the
groups who did not receive HBOT. The authors concluded that the effect of HBOT on hearing
thresholds in patients with hearing loss caused by a recent acute acoustic trauma remains
unclear. They stated that a well-designed randomized controlled trial (RCT) with enough power
is needed to answer this clinical question.
Lawrence and Thevasagayam (2015) noted that SSNHL is considered an otological emergency.
It may present as an isolated condition or be the presenting feature of a systemic disease
process; ISSNHL is diagnosed when an underlying cause or condition cannot be identified.
These investigators reviewed the current literature on SSNHL and proposed a treatment
algorithm based on the highest quality evidence. An evidence-based literature review using
Medline (search terms “sudden sensorineural hearing loss” and “acute sensorineural hearing
loss”).
Baseline Investigations:
All patients should be assessed with a thorough history and examination. This should
include a pure tone audiogram (PTA) where possible. Baseline and targeted laboratory
tests should be carried out to diagnose specific conditions
Imaging:
MRI should be carried out in all cases of ISSNHL. If MRI imaging is contraindicated, either
CT or auditory brainstem response (ABR) testing should be performed
Medical Management:
If a specific cause for a SSNHL is found, the patient should be managed accordingly. If
idiopathic in nature, patients may be offered a course of oral steroid. If systemic steroids
are contraindicated and/or there is no improvement with initial oral therapy, intra-
tympanic steroids (IT) as either primary or salvage therapy may be considered
Further Management:
There is no evidence to support the routine use of anti-viral therapy. The cost, limited
availability and lack of strong evidence for HBOT make it impractical at present. Due to the
variability in the vasodilator and vasoactive agents used, there is insufficient evidence to
support the routine use of these agents. Consideration should be given to both
temporary and permanent hearing amplification when required.
The authors concluded that SSNHL is an important condition that can have a significant impact
on QOL. Some patients respond spontaneously without intervention; however, evidence
indicated that certain interventions such as corticosteroid treatment may improve outcomes.
They stated that further high-quality research is needed.
Alimoglu and Inci (2016) examined the efficacy of HBOT as a salvage treatment after
unsuccessful oral corticosteroid therapy in patients with for SSHL. Case notes of patients who
were followed-up because of ISSHL between 2005 and 2011 in a tertiary care center were
examined retrospectively. Audiograms from before and after HBOT were examined in terms of
mean gains in pure tone average and at 0.25, 0.5, 1, 2, 4 and 8 kHz. In addition, recovery
according to Siegel's criteria was noted. Mean gain in pure tone average was 10.55 ± 13.56 dB.
Mean gains at 0.25, 0.5, 1, 2, 4 and 8 kHz were 16.66 ± 18.43 dB, 16.94 ± 19.93 dB, 12.63 ±
16.71 dB, 7.36 ± 15.28 dB, 5.27 ± 11.58 dB and 2.91 ± 12.44 dB, respectively; 3 patients had
complete recovery, 1 had partial recovery, 5 had slight recovery and 25 had no improvement. The
authors concluded that HBOT utilized as a salvage therapy after failed corticosteroid therapy
may be beneficial in some patients; studies with more patients are needed.
Van Der Wal et al (2016) noted that SSHL in divers may be caused by either inner-ear
barotrauma or inner-ear decompression sickness. There is no consensus on the best
therapeutic option. These researchers evaluated the therapeutic value of HBOT for SSHL in
divers. A literature review and 3 cases of divers with SSHL treated with HBOT were presented;
HBOT resulted in hearing improvement in 80 % of patients: 39 % had hearing improvement and
41 % had full recovery. The authors concluded that HBOT improved hearing in divers with SSHL.
Hosokawa et al (2017) evaluated the outcomes of and prognostic factors for ISSNHL treated with
adjuvant HBOT. These researchers performed a retrospective review of clinical data for 167
patients with ISSNHL who failed to respond to systemic steroids and were treated by adjuvant
HBOT at Shizuoka Saiseikai General Hospital. They analyzed the clinical outcomes, the
averaged 5-frequency hearing level after systemic steroids, patient age, the interval between
post-steroids and pre-HBOT, vertigo as a complication, the presence of diabetes mellitus,
smoking history, and hypertension. Overall, after HBOT, complete recovery occurred in 16 (9.6
%) of the patients, with definite improvement in 16 (9.6 %) and slight improvement in 45 (26.9
%). The overall rate of hearing improvement was higher in the study group (77/167 cases, 46.1
%) than in the control group (52/160 cases, 32.5 %; p = 0.021). The authors concluded that if
performed appropriately (early), HBOT should be able to improve hearing in many cases
unresponsive to initial therapy.
Chin et al (2017) evaluated the hearing gain efficacy from adjunctive HBOT in patients with
ISSHL. These researchers performed a retrospective analysis of chart reviews on patients with
ISSHL between January 2013 through December 2015. All patients were referred to the authors
from their ENT Department for adjunctive HBOT. The results were assessed through PTA data
change (hearing gain), both before and after HBOT. Age, gender, affected ear side, HBOT
sessions, both before and after HBOT PTA were all recorded. A total of 93 patients with ISSHL
were included in the study . The average hearing gain in this study was 17.9 dB (p = 0.001),
where a total of 46 (49.46 %) patients showed an improvement (hearing gain ≥ ?? dB) in
response to HBOT (p = 0.002). Patients with the poorest initial severity of hearing loss who
displayed a greater degree of hearing improvement after HBOT were male and in the 40- to 59-
year-old age group. The authors concluded that this study found that adjunctive HBOT was
effective for patients with ISSHL. The total average hearing gain was recorded to be 17.9 dB.
Xie and colleagues (2018) evaluate possible prognostic factors of ISSNHL treated with adjuvant
HBOT using uni-variate and multi-variate analyses. From January 2008 to October 2016, records
of 178 ISSNHL patients treated with auxiliary HBOT were reviewed to assess hearing recovery
and evaluate associated prognostic factors (gender, age, localization, initial hearing threshold,
presence of tinnitus, vertigo, ear fullness, hypertension, diabetes, onset of HBOT, number of
HBOT, and audiogram), by using uni-variate and multi-variate analyses. The overall recovery rate
was 37.1 %, including complete recovery (19.7 %) and partial recovery (17.4 %). According to
multi-variate analysis, later onset of HBOT and higher initial hearing threshold were associated
with a poor prognosis in ISSNHL patients treated with HBOT. The authors concluded that HBOT
is a safe and beneficial adjuvant therapy for ISSNHL patients; 20 sessions of HBOT is possibly
enough to show its therapeutic effect. Earlier HBOT onset and lower initial hearing threshold is
associated with favorable hearing recovery.
Furthermore, an UpToDate review on “Sudden sensorineural hearing loss” (Weber, 2018) states
that “Many therapies have been evaluated, with studies hindered by varying definitions of
recovery and small sample sizes. Some effectiveness has been suggested for … A systematic
review concluded that hyperbaric oxygen therapy may be of some benefit when administered
early in the course of SSNHL, although the clinical significance of the benefit was unclear and
the underlying studies had methodologic shortcomings. In one institution, patients seen
between 2002 and 2009 were treated with intravenous glucocorticoids and hyperbaric oxygen,
and those seen between 2009 and 2011 were treated with systemic plus IT glucocorticoids;
patients who received IT steroids were more likely to recover hearing”.
Ulcerative Colitis
Dulai et al (2014) stated that although there is experience using HBOT in Crohn's disease and
ulcerative colitis, the safety and overall effectiveness of HBOT in inflammatory bowel disease
(IBD) is unknown. These researchers quantified the safety and effectiveness of HBOT for
Crohn's disease (CD) and ulcerative colitis (UC). The rate of adverse events with HBOT for IBD
was compared to the expected rate of adverse events with HBOT. MEDLINE, EMBASE,
Cochrane Collaboration and Web of Knowledge were systematically searched using the
PRISMA standards for systematic reviews. A total of 17 studies involving 613 patients (286 CD,
327 UC) were included. The overall response rate was 86 % (85 % CD, 88 % UC). The overall
response rate for perineal CD was 88 % (18/40 complete healing, 17/40 partial healing). Of the
40 UC patients with endoscopic follow-up reported, the overall response rate to HBOT was 100
%. During the 8,924 treatments, there were a total of 9 adverse events, 6 of which were
serious. The rate of adverse events with HBOT in IBD is lower than that seen when utilizing
HBOT for other indications (p < 0.01). The risk of bias across studies was high. The authors
concluded that HBOT is a relatively safe and potentially effective treatment option for IBD
patients. Moreover, they stated that to understand the true benefit of HBOT in IBD, well-
controlled, blinded, randomized trials are needed for both CD and UC.
In a phase-IIA, multi-center, randomized, double-blind, sham-controlled, pilot trial, Dulai and

colleagues (2018) examined the therapeutic potential of HBOT as an adjunct to steroids for UC
flares requiring hospitalization. The study was terminated early due to poor recruitment with 18
of the planned 70 patients enrolled. In this trial, UC patients hospitalized for moderate-severe
flares (Mayo score greater than or equal to 6, endoscopic sub-score greater than or equal to 2)
were block randomized to steroids + daily HBOT (n = 10) or steroids + daily sham hyperbaric air
(n = 8). Patients were blinded to study assignment, and evaluations were performed by a blinded
gastroenterologist. Primary outcome was the clinical remission rate at study day 5 (partial
Mayo score less than or equal to 2 with no sub-score greater than 1). Key secondary outcomes
were: clinical response (reduction in partial Mayo score greater than or equal to 2, rectal
bleeding sub-score of 0 to 1) and progression to 2nd-line therapy (colectomy or biologic therapy)
during the hospitalization. A significantly higher proportion of HBOT-treated patients achieved
clinical remission at study day 5 and 10 (50 % versus 0 %, p = 0.04). HBOT-treated patients
less often required progression to 2nd-line therapy during the hospitalization (10 % versus 63 %,
p = 0.04). The proportion requiring in-hospital colectomy specifically as 2nd-line therapy for
medically refractory UC was lower in the HBOT group compared to sham (0 % versus 38 %, p =
0.07); there were no serious AEs. The authors concluded that in this small, proof-of-concept,
phase-IIA clinical trial, the use of HBOT as an adjunctive therapy to steroids for UC patients
hospitalized for moderate-severe flares resulted in higher rates of clinical remission, and a
reduction in rates of progression to 2nd-line therapy during the hospitalization. Moreover, these
researchers stated that larger well-powered trials are needed to provide definitive evidence of
therapeutic benefit.
Jairath (2018) noted that 25 % of patients with UC will develop a severe acute exacerbation of
disease during their lifetime. Despite high dose corticosteroids, 50 % of these patients will fail
subsequent medical rescue therapy, and 50 % will require colectomy within 5 years. Dulai and
colleagues reported the results of a double-blind, sham-controlled, proof-of-concept phase-IIA
clinical trial, which demonstrated that administration of short-term HBOT at the point of
presentation with severe UC was able to rapidly induce short-term remission and avoided the
need for urgent 2nd-line medical rescue therapy. The author concluded that further dose-finding
studies are underway.
Soft Tissue Radionecrosis
Buboltz and Cooper (2018) noted that “Common sites of soft tissue radionecrosis treated with
hyperbaric oxygen therapy are head and neck, breast or chest wall, pelvic organs such as
bladder and rectum, but any organ or tissue that was in the radiation field can be damaged, and
thus treatable with hyperbaric oxygen therapy”.
Also, An UpToDate review on “Clinical manifestations, prevention, and treatment of radiation-

induced fibrosis” (Weiss, 2018) states that “Hyperbaric oxygen has been evaluated as a
treatment for late toxicities, including radiation-induced fibrosis, in multiple studies investigating
the benefit for patients treated in the head and neck, breast, and pelvic area in particular”.
Adhesions Prevention after Laparotomy
In a pilot study, Bento and colleagues (2018) evaluated the effects of HBO on prevention of
adhesions in the abdominal cavity after laparotomy. A total of 54 rats underwent laparotomy;
stitches were made in the 4 quadrant parietal peritoneum and abdominal cavity closure.
Animals were divided into 3 groups: 1 -- control; 2 -- subjected to high pressures and
oxygenation; and 3 -- subjected to 100 % HBO. The animals in groups 2 and 3 were daily
submitted to HBO chamber after surgery. On the 7th day another laparotomy, registration of
procedure, assessment of adhesions and biopsies of the peritoneum were held. Professionals
analyzed the videos and the biopsies. Peritoneal cavity adhesions occurred in animals of 3
groups with no difference between them. In Group 3, the adhesions presented more fragile and
vascular proliferation more pronounced, and there was no difference in comparison with the 1st
and 2nd groups. However, there was no significant difference in the evaluation of these
parameters between the animals in groups 1 and 2. The authors concluded that post-operative
HBO in rats submitted to laparotomy did not alter the frequency, but reduced the density of
adhesions in the peritoneal cavity and promoted vascular proliferation. The change in
atmospheric pressure alone had no influence on the results.
Epithelial-to-Mesenchymal Transition (EMT) Phenomenon in Keloid Tissue
Zhang and colleagues (2018) stated that HBOT has been widely used in the clinical setting. In
this study, HBOT was evaluated for its ability to ameliorate the epithelial-to-mesenchymal
transition (EMT) phenomenon in keloid tissue. Keloid patients were randomly divided into 2
groups: keloid patients (K group, 9 patients) and keloid patients receiving HBOT (O group, 9
patients). A 3rd group with normal skin (S group, 9 patients) was established for control. Before
HBOT and surgery, a laser Doppler flowmeter was used to measure the keloid blood supply of
patients in the O group. Hematoxylin and eosin (H&E) staining was used to observe
morphology. E-cadherin, ZO-1, vimentin, fibronectin, vascular endothelial growth factor (VEGF),
and hypoxia inducible factor (HIF)-1α were measured by immunofluorescence staining and
Western blot analysis. Real-time quantitative PCR (RT-qPCR) was used to evaluate the mRNA
expression level of these factors as well. In the O group, keloid blood perfusion was significantly
reduced after patients received HBOT. Compared with the K group, lower expression levels of
vimentin, vibronectin, VEGF, and HIF-1α were observed in the O group, whereas the expression
of E-cadherin and ZO-1 was significantly higher. The mRNA expression of E-cadherin and ZO-1
was also increased after HBOT. The authors concluded that the expression levels of factors
related to the EMT phenomenon were significantly reversed in keloid patients after they received
HBOT, indicating that HBOT may be an effective therapy against the EMT phenomenon in keloid
patients. Furthermore, these researchers stated that the effect of HBOT on the EMT
phenomenon in other body parts and in patients of different ages requires further study.
Erectile Dysfunction
In a prospective, clinical trial, Sahin and colleagues (2018) evaluated the effects of HBOT on
erectile function in patients who had no cavernosal or urethral injury by using International Index
of Erectile Function (IIEF) questionnaire. The male patients who were treated by HBOT for
several diseases between July 2017 and September 2017 were examined. All patients filled the
IIEF questionnaire form before the 1st day and after the last day of HBOT and a questionnaire
including demographic characteristics and medical history. The effects of demographic
characteristics and risk factors on erectile function were evaluated, and the IIEF domain scores
of patients in 1st day and last day of HBOT were compared. A total of 50 patients were included
in the study between July 2017 and September 2017 and the mean age was 59.38 ± 13.77. The
mean post-HBOT IIEF-EF score of patients was significantly higher than the mean pre-HBOT
IIEF-EF score of patients (15.74 ± 10.52 versus 19.50 ± 10.91; p < 0.001). The mean post-
HBOT IIEF scores of other domains including intercourse satisfaction, orgasmic function, sexual
desire, and overall satisfaction were also significantly higher than pre-HBOT scores. The authors
concluded that HBOT may be a good alternative treatment or adjunctive treatment for erectile
dysfunction (ED). These findings need to be validated by well-designed studies.
Furthermore, an UpToDate review on “Treatment of male sexual dysfunction” (Khera and

Cunningham, 2018) does not mention HBOT as a therapeutic option.
Implant Osseointegration
Shah and associates (2017) stated that the significantly higher implant failure rates in maxilla-
facial patients, undergoing radiotherapy, might be caused by the long-term effects of reduced
vascularization compromising the implantation site. An extensive pre-clinical animal literature
and a multitude of clinical reports suggested the use of HBOT as it can improve the tissue
vascularity. Hence, it may increase the implant survival rate by enhancing osseointegration
process in such patients. In a systematic review, these investigators examined the effectiveness
of HBOT on dental implant survival rate in irradiated maxilla-facial patients who require
prosthodontic rehabilitation. An electronic search without time restrictions was undertaken in
April 2016 using databases: PubMed, Google Scholar, and the Cochrane Oral Health Group
Trials Register. They also tried to contact the manufacturers and researchers in the field for
necessary details. Clinical human studies, on irradiated maxilla-facial dental implant patients,
including RCTs, prospective controlled trials, retrospective studies, and preliminary reports were
included in the study. Data collection was performed by 2 of the authors' independently. The
titles and abstracts of all reports were screened for the study design and type of reported
intervention; all the duplicates were removed. The data search yielded 62 titles, out of which 14
articles were selected for the study by the article filtration criteria: Title/abstract/full text. Data
which were extracted by 2 authors with any disagreement were resolved by the 3rd author, and a
meta-analysis was done using binary random-effect model. The results show decreased implant
failure rate in HBO group (9.21 %) compared to non-HBO group (22.44 %). The potential
limitations of this study were amount of radiation doses used, period lasting from radiotherapy to
the placement of the implants, and follow-up period that varied for every subject of the included
study, which could affect the treatment outcome. Although there were many sensitive articles
published about HBO, including a number of review papers, RCTs are still lacking. These
researchers noted that according to above statistical analysis, results showed that preventive
HBOT could reduce the risk of implant failures in irradiated patients, may be due to improved
vascularity which led to reduced risk of radiation-induced damages to tissue, and thus, HBO can
be the effective treatment protocol, while planning for the implant treatment in irradiated maxilla-
facial patients. Still, some important factors, other than irradiation, that affected the implant
survival rate in irradiated bone were type of implant, surgical procedures used, time interval
between radiotherapy and implant placement, and radiation dose, which were not included in the
meta-analysis, due to insufficient data. The authors concluded that further investigation is
needed to specify above-mentioned various reasons of failures and various factors affecting the
success and failure rates of dental implants in irradiated maxilla-facial patients.
There is a definite need for more RCTs to ascertain the effectiveness of HBO in irradiated
maxillofacial dental implant patients. These trials ought to be of a high quality and reported as
recommended by the consort statement (www.consort-statement.org/). Each clinical center may
have limited numbers of patients and it is likely that multi-centered trials will be needed. Only
with that clinicians will receive the evidence they need for their study and make the best
treatment decisions possible.
Altug and co-workers (2018) examined if HBO has a favorable effect on implant osseointegration
in diabetic rabbits. An experimental diabetes model was induced in 32 New Zealand rabbits
through IV injection of alloxan. After the state of diabetes had been confirmed, 1 dental implant
was placed in the metaphysical region of each animal's tibia. After the implants' placements,
the animals were divided into 2 groups; half of the animals received HBO, while the other group
did not receive HBO and served as the control group. The animals were euthanized at the 4th
and 8th weeks; osseointegration of the implants were compared by histomorphometry and
resonance frequency analysis (RFA). The Bone Implant Contact (BIC) values were significantly
higher in the HBO group than in the control group at the 4th week. There was no difference in
the BIC values between the groups at the 8th week. There was no significant difference in the
RFA scores between the groups both at the 4th and 8th weeks after the operation. The authors
concluded that histomorphometry findings suggested that HBO had positive effect on implant
osseointegration in the early healing period in diabetic rabbits. However, implant stability was
not affected by HBO. The authors concluded that HBO favorably affected implant
osseointegration of diabetic rabbits in the early healing period. This effect could be determined
at histological level. However, the corresponding improvements on osseointegration were not
enough to increase the implants’ mechanical stability. Thus, despite the positive findings
observed in this study, the effects of the HBO on implant osseointegration may still be
considered debatable and more studies should be performed to evaluate effectiveness of HBO as
an adjunctive treatment method for patients with diabetes mellitus, who would undergo dental
implant treatment.
The authors stated that 1 drawback of this study was that they did not include non-diabetic
subjects in it. Including such a group would make the comparison between diabetic and non-
diabetic subjects possible. Previous studies, which evaluated effects of HBO on irradiated
bones, also included non-irradiated limbs and mostly demonstrated that HBO favorably affects
implant osseointegration in non-irradiated bones. Based on the results of these studies, these
investigators accepted that HBO enhanced implant osseointegration of healthy animals.
Juan and colleagues (2018) examined the impact of HBO on the healing of bone tissues around
implants using an animal model. A total of 32 beagle dogs were selected and randomly divided
into the HBO group and the blank group. The dogs in the HBO group were subjected to 90 mins
of HBO therapy; X-ray, cone-beam computerized tomography imaging, implant stability quotient
(ISQ) values, histological observation, quantitative analysis of bone histomorphometry, and
hematoxylin-eosin (HE) and Masson staining were evaluated. In this study, at 4 weeks after the
surgery, the mean ISQ value in the HBO group was higher than that in the blank group, and the
difference was statistically significant (p < 0.05). At week 4 and 8, the mean values of bone
ingrowth fraction (BIC %) and the percentage of bone area (BA %) in the HBO group were both
higher than those of the blank group. Decalcified paraffin sections were stained with HE and
Masson staining showed that the bone tissue around the implant in the HBO group had more
osteoblasts than control group, and many irregular marrow cavities and Haversian bone plates
were observed in the new bone tissue. The authors concluded that the findings of this study
showed that after implantation, early osteogenesis was better in the HBO group than in the
blank group.
Liver Disease
Sun and colleagues (2018) noted that HBOT is an efficient therapeutic option to improve
progress of lots of diseases especially hypoxia-related injuries, and has been clinically
established as a wide-used therapy for patients with carbon monoxide poisoning, decompression
sickness, arterial gas embolism, problematic wound, and so on. In the liver, most studies
positively evaluated HBOT as a potential therapeutic option for liver transplantation, acute liver
injury, non-alcoholic steatohepatitis, fibrosis and cancer, especially for hepatic artery
thrombosis. This might mainly attribute to the anti-oxidation and anti-inflammation of HBOT.
However, some controversies exist, possibly due to hyperbaric oxygen toxicity. The authors
summarized the current understandings of the role of HBOT in liver diseases and hepatic
regeneration; they stated that future understanding of HBOT in clinical trials and its in-depth
mechanisms may contribute to the development of this novel adjuvant strategy for clinical
therapy of liver diseases.
Optic Neuropathy
Di Censo and associates (2016) stated that non-arteritic anterior ischemic optic neuropathy
(NAION) is one of the most widespread visually disabling diseases in the middle-aged and
elderly population. It typically presents as acute painless unilateral vision loss in patients over
50 years of age. The fellow eye of NAION patients is often sequentially affected. Involvement of
the 2nd eye occurs within 3 years in approximately 45 % to 50 % of patients. Currently there is
no generally accepted treatment for NAION but a number of medical and surgical therapies have
been proposed. This was a case of non-contemporary bilateral NAION in a 66-year old woman
treated with HBOT after ineffective systemic corticosteroid therapy; visual acuity (VA), visual
evoked potentials (VEP) findings, perimetric examination results and angiographic images were
recorded and analyzed before and after HBOT. The authors concluded that after several months
from the optic nerve vascular injury, VA, VEP values, perimetric examination results and
angiographic images revealed a very important recovery. These results maintained stable during
the follow-up at about 9 months. They stated that HBOT has been revealed to be a safe and
effective adjunctive therapy, even after many months post-injury. These researchers stated that
while this case is promising, double-blind RCTs are needed to prove the efficacy of HBOT in the
treatment of NAION.
Hsieh and colleagues (2018) noted that direct traumatic optic neuropathy (TON) is a devastating
condition and clinical challenge; its adequate treatment remains controversial. Hyperbaric
oxygen therapy has been proposed as an adjunctive treatment for eye disease but has rarely
been used in optic neuropathy. This case-report entailed a 57-year old woman who had direct
TON and brain injury after contusion injury. After receiving delayed HBOT, her VA got better --
from hand motion to 6/60 -- along with improvement of visual field and color vision. She was
treated at 2.5 ATM absolute for 100 mins, 5 times a week, for a total of 61 sessions. This case
highlighted that HBOT may be beneficial as an alternative treatment for direct TON, particularly
when combined with brain injury. The authors concluded that although this entity is promising,
further RCTs are needed to clarify the effectiveness of HBOT in the treatment of direct TON.
Small Bowel Obstruction Secondary to Pelvic Irradiation
Fukami et al (2014) stated that HBOT is a controversial treatment for adhesive post-operative
small bowel obstruction (SBO), with only a few small studies reported. These researchers
evaluated the clinical value of HBOT in the treatment of adhesive post-operative SBO. Between
April 2006 and March 2012, all patients with adhesive post-operative SBO were treated using
either decompression therapy or HBOT. Patients undergoing HBOT were treated once-daily at a
pressure of 2.0 atmospheres absolute and received 100 % oxygen. Patients showing no clinical
and radiological improvement with HBOT were converted to decompression therapy by means of
a long tube. Medical records were reviewed and outcomes analyzed. A total of 305 patients
were treated, of whom 142 underwent tube decompression therapy during the 1st 3 years and
the remaining 163 had HBOT during the last 3 years. The median number of HBOT was 3 (range
of 1 to 7). A total of 143 patients (87.7 %) were treated successfully with HBOT without long-
tube decompression. HBOT was associated with earlier resumption of oral intake (mean 4.7
versus 6.5 days; p = 0.001) and a shorter hospital stay (mean 10.3 versus 14.1 days; p =
0.001). The rate of operation was 7.4 % in the HBOT group and 14.8 % in group treated by
decompression alone (P = 0.037). the authors concluded that in this study, HBOT was safe for
the treatment of adhesive post-operative SBO. It reduced the need for surgery and time to
recovery as well as the hospital stay.
Tamura et al (2018) stated that pneumatosis cystoides intestinalis (PCI) is a rare disease
characterized by multiple gas-filled cysts in the intestinal wall and is associated with various co-
morbidities. These investigators reported a case of intractable paralytic ileus caused by primary
PCI. A 73-year old man visited the authors’ hospital complaining of abdominal pain and
vomiting. He had been hospitalized twice for intestinal obstruction in the past 2 months. Based
on his history of appendectomy, mechanical bowel obstruction caused by adhesion was
diagnosed, and the patient underwent surgery. However, laparotomy revealed small bowel
dilatation despite the absence of obstruction or stenosis. Multiple nodules were found in the wall
of the dilated bowel loops. The dilated jejunum was excised. Histological examination revealed
that the nodules were small gas-filled cysts, suggesting PCI. These investigators made a
diagnosis of ileus with underlying PCI and managed the patient conservatively. A large amount
of naso-gastric tube drainage continued for a long period post-operatively. The patient underwent
re-laparotomy 35 days after the 1st operation. The upper jejunum was markedly dilated,
although no mechanical stenosis was found. The atonic, dilated jejunum was excised and the
ileal stump was anastomosed to the duodenum in a double-tract fashion. The patient underwent
HBOT because the ileus persisted post-operatively. His condition gradually improved and he
was discharged 53 days after the 2nd operation. The authors concluded that non-operative
treatment is recommended for primary PCI of unknown etiology. Surgeons should be mindful of
the possibility of primary PCI when considering surgical intervention for patients with bowel
obstruction.
Furthermore, an UpToDate review on “Overview of management of mechanical small bowel

obstruction in adults” (Bordeianou and Yeh, 2018) does not mention HBOT as a therapeutic
option.
Tumor Sensitization to Radiotherapy
Bennett and colleagues (2018) stated that cancer is a common disease and radiotherapy is one
well-established treatment for some solid tumors; and HBOT may improve the ability of
radiotherapy to kill hypoxic cancer cells, so the administration of radiotherapy while breathing
HBO may result in a reduction in mortality and recurrence. In a Cochrane review, these
investigators evaluated the benefits and harms of administering radiotherapy for the treatment of
malignant tumors while breathing HBO. In September 2017, these investigators searched the
Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Library Issue 8, 2017,
Medline, Embase, and the Database of Randomized Trials in Hyperbaric Medicine using the
same strategies used in 2011 and 2015, and examined the reference lists of included articles.
Randomized and quasi-randomized studies comparing the outcome of malignant tumors
following radiation therapy while breathing HBO versus air or an alternative sensitizing agent.
Three review authors independently evaluated the quality of and extracted data from the included
trials. They included 19 trials in this review (2,286 participants: 1,103 allocated to HBOT and
1,153 to control). For head and neck cancer, there was an overall reduction in the risk of dying
at both 1 year and 5 years after therapy (RR 0.83, 95 % CI: 0.70 to 0.98, number needed to treat
for an additional beneficial outcome (NNTB) = 11 and RR 0.82, 95 % CI: 0.69 to 0.98, high-
quality evidence), and some evidence of improved local tumor control immediately following
irradiation (RR with HBOT 0.58, 95 % CI: 0.39 to 0.85, moderate-quality evidence due to
imprecision). There was a lower incidence of local recurrence of tumor when using HBOT at
both 1 and 5 years (RR at 1 year 0.66, 95 % CI: 0.56 to 0.78, high-quality evidence; RR at 5
years 0.77, 95 % CI: 0.62 to 0.95, moderate-quality evidence due to inconsistency between
trials). There was also some evidence with regard to the chance of metastasis at 5 years (RR
with HBOT 0.45 95 % CI: 0.09 to 2.30, single trial moderate quality evidence imprecision). No
trials reported a QOL assessment. Any benefits come at the cost of an increased risk of severe
local radiation reactions with HBOT (severe radiation reaction RR 2.64, 95 % CI: 1.65 to 4.23,
high-quality evidence). However, the available evidence failed to clearly demonstrate an
increased risk of seizures from acute oxygen toxicity (RR 4.3, 95 % CI: 0.47 to 39.6, moderate-
quality evidence). For carcinoma of the uterine cervix, there was no clear benefit in terms of
mortality at either 1 year or 5 years (RR with HBOT at 1 year 0.88, 95 % CI: 0.69 to 1.11, high-
quality evidence; RR at 5 years 0.95, 95 % CI: 0.80 to 1.14, moderate-quality evidence due to
inconsistency between trials). Similarly, there was no clear evidence of a benefit of HBOT in the
reported rate of local recurrence (RR with HBOT at 1 year 0.82, 95 % CI 0.63 to 1.06, high-
quality evidence; RR at 5 years 0.85, 95 % CI: 0.65 to 1.13, moderate-quality evidence due to
inconsistency between trials). These researchers also found no clear evidence for any effect of
HBOT on the rate of development of metastases at both 2 years and 5 years (2 years RR with
HBOT 1.05, 95 % CI: 0.84 to 1.31, high quality evidence; 5 years RR 0.79, 95 % CI: 0.50 to
1.26, moderate-quality evidence due to inconsistency). There were, however, increased adverse
effects with HBOT. The risk of a severe radiation injury at the time of treatment with HBOT was
2.05, 95 % CI: 1.22 to 3.46, high-quality evidence. No trials reported any failure of local tumor
control, QOL assessments, or the risk of seizures during treatment. With regard to the
treatment of urinary bladder cancer, there was no clear evidence of a benefit in terms of mortality
from HBOT at 1 year (RR 0.97, 95 % CI: 0.74 to 1.27, high-quality evidence), nor any benefit in
the risk of developing metastases at 2 years (RR 2.0, 95 % CI: 0.58 to 6.91, moderate-quality
evidence due to imprecision). No trial reported on failure of local control, local recurrence, QOL,
or adverse effects. When all cancer types were combined, there was evidence for an increased
risk of severe radiation tissue injury during the course of radiotherapy with HBOT (RR 2.35, 95 %
CI: 1.66 to 3.33, high-quality evidence) and of oxygen toxic seizures during treatment (RR with
HBOT 6.76, 96 % CI: 1.16 to 39.31, moderate-quality evidence due to imprecision). The authors
concluded that they found evidence that HBOT improved local tumor control, mortality, and local
tumor recurrence for cancers of the head and neck. These benefits may only occur with unusual
fractionation schemes; HBOT was associated with severe tissue radiation injury. These
researchers stated that given the methodological and reporting inadequacies of the included
studies, thee findings demanded a cautious interpretation; more research is needed for head and
neck cancer, but is probably not justified for uterine cervical or bladder cancer. There is little
evidence available concerning malignancies at other anatomical sites.
Wu and co-workers (2018) noted that hypoxia is a fundamental hallmark of solid tumors and
helps contribute to chemotherapy resistance; HBOT could overcome tumor hypoxia and promote
chemotherapy anti-tumor efficacy; however, the simultaneous administration of some
conventional chemotherapies, including doxorubicin (DOX), with HBO is considered an absolute

contraindication. In this study, DOX-loaded liposome (Doxil) is co-administered with HBO to
examine the safety and efficacy of this combination treatment. By overcoming tumor hypoxia,
HBO not only improved Doxil tumor penetration by decreasing the collagen deposition but also
sensitized tumor cells to Doxil. As a result, the combination treatment synergistically inhibited
H22 tumor growth, with a tumor inhibition rate of 91.5 %. The authors concluded that the
combination of HBO with Doxil showed neither extra side effects nor promotion of tumor
metastasis. These findings revealed that the combination of HBO with Doxil is a safe and
effective treatment modality. They stated that since both therapies are approved by FDA and
routinely applied in widespread clinics and practices, the combination of HBO with Doxil is a
promising new modality for cancer chemotherapy and could easily be translated to clinical trials
for patients with hypoxic solid tumors.
Coronary Artery Disease
Li and colleagues (2019) improves myocardial function and reduces clinical restenosis in
coronary arteries. In a retrospective study, these researchers examined if HBOT could improve
vascular endothelial dysfunction in patients undergoing coronary stent implantation. This trial
included 115 patients undergoing coronary stent implantation. Patients receiving HBOT were
included in the HBOT group (n = 55) and those without HBOT were included as controls (n =
60). The levels of brachial artery endothelial-dependent flow-mediated dilation (FMD),
endothelial-independent nitrate-mediated dilatation (NMD), nitric oxide (NO), endothelin-1(ET-1),
calcitonin gene-related peptide (CGRP) and high-sensitivity C-reactive protein (hs-CRP) were
used to evaluate vascular endothelial function. There were no significant differences with regard
to the above parameters at baseline in either group (p > 0.05). In both the HBOT and control
groups the levels of FMD, NO and CGRP after treatment were significantly higher than those
before treatment (p < 0.05). The levels of hs-CRP and ET-1 after treatment were significantly
lower than those before treatment (p < 0.05). After treatment, the levels of FMD, NO and CGRP
in the HBOT group were significantly higher than those of the control group (p < 0.05), whereas
the hs-CRP and ET-1 levels were significantly lower than those of the control group (p < 0.05).
The authors concluded that using HBOT as an adjunct treatment in patients undergoing coronary
stent implantation may significantly improve vascular endothelial function; HBOT may have the
potential to alter the course of coronary artery disease in the future. These researchers stated
that further randomized, multi-center, prospective studies are needed.
Critical Limb Ischemia
Nakamura and colleagues (2019) stated that HBOT promotes wound healing in patients with
ischemic disease; however, HBO-induced changes in skin peripheral circulation have not been
evaluated in clinical practice. These investigators examined these changes in patients with
critical limb ischemia (CLI), with a focus on the angiosome of crural blood vessels with blood flow
improved by endovascular therapy (EVT). A total of 6 patients with CLI and ulcers who were
treated with HBO after EVT (7 limbs; 1 patient had ulcers in the bilateral limbs) and 3 healthy
subjects (6 limbs) were enrolled; HBOT was performed at 2 ATA under 100 % oxygen for 90
mins per session. Skin perfusion pressure (SPP) was measured in the dorsum and sole of the
foot 1 hour before (pre-SPP) and after (post-SPP) HBOT. Change in SPP (ΔSPP) was
calculated as post-SPP minus pre-SPP; SPP measurement regions were divided into those that
did (direct region) and did not (indirect region) correspond to the vascular angiosome in which
angiography findings of the crus were improved after EVT; i.e., when the anterior tibial artery was
effectively treated with EVT, the dorsum was the direct region and the sole was the indirect
region, and vice-versa when the posterior tibial artery was treated. In the direct, indirect, and
healthy subject groups, the ΔSPPs were 20.5 ± 8.7 (p = 0.002), -6.4 ± 10.9, and -15.1 ± 18.1 (p
= 0.014), respectively; that of the direct group was significantly greater than that of the other
groups. The authors concluded that these findings suggested that short-term improvement of
the peripheral circulation by HBOT was significant in patients with successful re-vascularization.
These preliminary findings need to be validated by well-designed studies.
Interstitial Cystitis Associated with Fibromyalgia
Bosco and colleagues (2019) noted that interstitial cystitis (IC) is a debilitating disorder of the
bladder, with a multi-factorial and poorly understood origin dealing with micro-circulation repeated
damages. Fibromyalgia (FM) is a persistent disorder whose etiology is not completely
explained, and its theorized alteration of pain processing can compromise the QOL. Both these
conditions have a high incidence of conventional therapeutic failure, but recent literature
suggested a significant beneficial response to HBOT. These researchers examined the effects
of HBOT on QOL, symptoms, urodynamic parameters, and cystoscopic examination of patients
suffering from both IC and FM. They structured an observational clinical trial design with
repeated measures (questionnaires, urodynamic test, and cystoscopy) conducted before and 6
months after a therapeutic protocol with HBOT for patients suffering from both IC and FM.
Subjects were exposed to breathing 100 % oxygen at 2 ATA in a multi-place pressure chamber
for 90 mins using an oronasal mask. Subjects undertook a cycle of 20 sessions for 5 days per
week, and a 2nd cycle of 20 sessions after 1 week of suspension. A total of 12 patients
completed the protocol. Changes after HBOT were not significant, except for hydrodistension
tolerance (mean pre-treatment: 409.2 ml; mean post-treatment: 489.2 ml; p < 0.05). A
regression of petechiae and Hunner's ulcers was also noted 6 months after the completion of
HBOT. The authors concluded that this study showed no improvement of symptoms, QOL, and
urodynamic parameters, except for hydrodistension, and a slight improvement in cystoscopic

pattern. However, to-date, these investigators could not demonstrate the significance of overall
results to justify the use of HBOT alone in patients with IC and FM. This observation suggested
that additional studies are needed to better understand if HBOT could treat this subset of
patients.
Hypospadias
Bush and Snodgrass (2019) stated that increased complications following failed hypospadias
repairs suggested that impaired wound healing is a contributing factor. These researchers used
peri-operative HBOT to promote wound healing determined by graft take in staged tubularized
autograft re-operations using oral graft; HBOT was recommended for patients with 3 or more
failed hypospadias repairs, comprising 20 pre-operative and 10 post-operative sessions. All
patients underwent re-operative staged tubularized autograft repair using oral mucosa. Graft
lengths and widths were measured at grafting and again at the 2nd stage, from which graft area
was calculated. The primary outcomes were percent graft contracture and graft failure, defined
as contracture 50 % or greater. Patients who received HBOT were compared to other patients
who underwent re-operative staged tubularized autograft who did not receive HBOT. Among 57
patients 32 received HBOT and 25 did not as they had fewer than 3 prior repairs, or were not
able to receive treatment due to insurance issues or lack of local availability. Grafts were
healthier in those receiving HBOT, with significantly less percent area contracture (9 % versus 26
%, p = 0.04) and graft failure (6 % versus 28 %, p = 0.03) compared to those not receiving
HBOT, although treated patients had significantly more prior failed hypospadias repairs. The
authors concluded that HBOT improved graft take in hypospadias re-operations. This
observation also called attention to wound healing as another variable to consider in hypospadias
surgery.
This was a relatively small (n = 32 in the HBOT group) with no follow-up data. These
researchers stated that limitations of this trial included potential variability in treatments from the
protocol that they recommended. Families did not always recall the exact number of dives their
child received. Moreover, they stated that this trial focused on graft healing, not urethroplasty
complications. Thus, the impact, if any, of HBOT on complications remained to be determine in
a larger series with additional follow-up.
Furthermore, an UpToDate review on “Hypospadias: Management and outcome” (Baskin, 2019)

does not mention HBOT as a management option.
Peri-Anal Fistula
Lansdorp and colleagues (2019) noted that peri-anal fistulizing Crohn's disease (pCD) has a
significant impact on patients' health and QOL. Current therapeutic options have a relatively low
success rate and a high recurrence risk. Positive effects of HBOT have been indicated in animal
studies as well as in small case series. This is a non-randomized, controlled, pilot study. A
total of 20 patients with pCD who have been refractory to standard therapy for at least 6 months
will be included. Patients with a seton and stable treatment regimen will be included. Patients
with anal strictures, recto-vaginal fistulas, stoma or deep ulceration of the rectum will be
excluded. Patients who are eligible but refuse HBOT will be asked to serve as controls.
Patients in the HBOT group will be treated with 40 sessions of HBOT at 243 to 253 kPa, with the
seton being removed after 30 sessions. Co-primary end-points are changes in the perianal
disease activity index and MRI-scores. Secondary outcomes are fistula drainage assessment,
laboratory findings and patient-reported outcomes. Assessment will be carried out at baseline,
16 weeks, 34 weeks and 60 weeks after finishing HBOT. The objective of this study is to
examine the feasibility and therapeutic effect of HBOT on pCD. The 1-year follow-up should
provide information on the effect durability. A comparison between patients treated with HBOT
and patients who continue to receive standard care will be made. The risk of bias will be limited
by using clearly defined inclusion and exclusion criteria, baseline characteristics and
consecutive recruitment of patients through an out-patient fistula clinic.
Prophylactic HBOT Prior to Mastectomy
Murphy and colleagues (2017) noted that for patients who have an ipsilateral breast cancer
recurrence following prior breast-conserving surgery (BCS) and radiation, total mastectomy
generally is recommended. However, little is known about the suitability and outcomes of nipple-
sparing mastectomy (NSM) with immediate breast reconstruction for the treatment of recurrent
breast cancer, prompting this investigation. From 1,008 patients scheduled for NSM for breast
cancer treatment at the authors’ institution between January 2009 and June 2016, these
researchers identified all patients who underwent surgery for ipsilateral recurrent breast cancer.
They analyzed patient, tumor, and treatment variables, nipple preservation rates, and cancer
outcomes. A total of 21 patients with ipsilateral recurrent disease were scheduled for NSM with
immediate breast reconstruction, of whom 19 had received prior whole breast radiation; 2
patients (10 %) underwent intra-operative conversion to skin-sparing mastectomy for atypia or
ductal carcinoma in-situ (DCIS) in the central nipple ducts. Post-operative complications
requiring intervention occurred in 2 patients: focal flap necrosis requiring debridement in 1 patient
and seroma aspiration in another; 3 patients received planned (pre- and/or post-operative)
HBOT. After 14.6 months median follow-up (range of 3 to 48.5 months), all 19 patients retained
their native nipple-areolar complex and were disease-free. The authors concluded that NSM may
be performed in carefully selected patients with recurrent breast cancer, despite prior ipsilateral
surgery and radiation, with successful preservation of the nipple-areolar complex and an
acceptably low complication rate. These researchers stated that these data suggested no
short-term adverse effect of NSM on oncologic outcomes.|
Rajpal and associates (2019) stated that mastectomy skin flap necrosis represents a significant
complication of breast reconstructive procedures and is reported to occur in 30 % to 52 % of
patients undergoing breast reconstruction. Early identification of ischemia and early initiation of
HBOT could mitigate the effects of ischemia and rescue otherwise non-viable breast flap tissue.
These researchers retrospectively examined the outcomes of HBOT therapy in 8 breasts with
compromised mastectomy skin flaps between September 2015 and January 2017. Indocyanine
green angiography (ICGA) was used to assess perfusion intra-operatively and post-HBOT
administration; 7 patients were referred for HBOT within 24 hours of mastectomy; 1 patient failed
to improve despite starting HBOT within 24 hours. All other patients manifested successful
healing of their mastectomy skin flaps with acceptable cosmesis after 10 HBOT treatments.
The mean relative perfusion of the at-risk area was 13.8 % (± 3.7 %) pre-HBOT and 101.6 % (±
37.3 %) post-HBOT. The average area at-risk pre-HBOT was 17.1 cm2 and reduced to zero
post-HBOT. Relative perfusion values after HBOT were found to be 6.8 (± 3.4) times greater than
those measured prior to HBOT. The authors concluded that a short course of HBOT may be
sufficient to successfully rescue at risk post-mastectomy breast flaps; ICGA was a useful
adjunct for evaluating post-mastectomy breast flap perfusion before and after HBOT therapy.
Furthermore, an UpToDate review on “Overview of breast reconstruction” (Nahabedian, 2019)

does not mention HBOT as a management tool.
Appendix
Table: Wagner Grading System
Grade 0:Intact skin
Grade 1:Superficial diabetic ulcer
Grade 2:Ulcer extensionInvolves ligam ent, tendon, joint capsule or fascia; no abscess or
osteom yelitis
Grade 3:Deep ulcer with abscess, infectious tendonitis, or osteom yelitis
Grade 4:Gangrene to portion of forefoot
Grade 5:Extensive gangrene of foot
Source: Wagner, 1987.
Requirements for documentation of Grade 3 Wagner lesion: For documentation of presence of

abscess, medical record should note the presence of some fluid release during the course of a
surgical debridement or incision. For documentation of osteomyelitis, X-rays or culture are
required. For infectious tendonitis, clinical observation (rubor, calor, discharge) with photographic
documentation or culture is required.
CPT Codes / HCPCS Codes / ICD-10 Codes
Information in the [brackets] below has been added for clarification purposes. Codes requiring a
7th character are represented by "+":
Code Code Description
CPT codes covered if selection criteria are met:
99183 Physician attendance and supervision of hyperbaric oxygen therapy, per session
Other CPT codes related to the CPB:
19301 - 19307 Mastectom y
HCPCS codes covered if selection criteria are met:
G0277 Hyperbaric oxygen under pressure, full body cham ber, per 30 m inute interval
HCPCS codes not covered for indications listed in the CPB:
A4575 Topical hyperbaric oxygen cham ber, disposable
E0446 Topical oxygen delivery system , not otherwise specified, includes all supplies
and accessories
Other HCPCS codes related to the CPB:
J9000 Injection, doxorubicin HCl, 10 m g
J9060 Injection, cisplatin, powder or solution, 10 m g
Q2050 Injection, doxorubicin hydrochloride, liposom al, not otherwise specified, 10 m g
ICD-10 codes covered if selection criteria are met:
A41.4 Septicem ia due to anaerobes [progressive necrotizing soft tissue anaerobic
infections]
A48.0 Gas gangrene [Clostridial m yositis and m yonecrosis]
D50.0 Iron deficiency anem ia secondary to blood loss (chronic) [overwhelm ing and
transfusion is im possible because there is no suitable blood available or
religion does not perm it]
D62 Acute posthem orrhagic anem ia [overwhelm ing and transfusion is im possible
because there is no suitable blood available or religion does not perm it]
E10.51 - E10.59 Diabetes m ellitus with circulatory com plications [non-healing infected deep
E11.51 - E11.59 ulcerations (reaching tendons or bone) of the lower extrem ity unresponsive to at
least 1 m onth of m eticulous wound care, including aggressive debridem ent,
m axim al antibiotic therapy, tight glycem ic control, and appropriate treatm ent of
arterial insufficiency, including revascularization if necessary]
E10.618 - E10.638 Diabetes m ellitus with other specified com plications [non-healing infected deep
E10.649 - E10.69 ulcerations (reaching tendons or bone) Wagner grade 3 of the lower extrem ity]
E11.618 - E11.638
E11.649 - E11.69
G93.6 Cerebral edem a [acute]
H34.10 - H34.13 Central retinal artery occlusion
H90.3 Sensorineural hearing loss, bilateral
H91.20 - H91.23 Sudden idiopathic hearing loss [idiopathic when HBOT is initiated within 3
m onths after onset]
I70.201 - I70.92 Atherosclerosis of native arteries and bypass graft(s) of the extrem ities
[non-healing infected deep ulcerations (reaching tendons or bone) of the lower
extrem ity unresponsive to at least 1 m onth of m eticulous wound care, including
aggressive debridem ent, m axim al antibiotic therapy, tight glycem ic control, and
appropriate treatm ent of arterial insufficiency, including revascularization if
necessary]
I72.1 - I72.4 Other aneurysm of extrem ities
I73.00 - I73.1 Other peripheral vascular disease [acute peripheral arterial insufficiency]
I73.81 - I73.9 Other specified peripheral vascular diseases [acute peripheral arterial
I79.8 insufficiency]
I74.2 - I74.3 Arterial em bolism of the extrem ities [acute peripheral arterial insufficiency]
I74.5 Arterial em bolism and throm bosis of the iliac artery [acute peripheral arterial
insufficiency]
I83.001 - I83.029 Varicose veins of lower extrem ities with ulcer [non-healing infected deep
ulcerations (reaching tendons or bone) of the lower extrem ity unresponsive to at
least 1 m onth of m eticulous wound care, including aggressive debridem ent,
m axim al antibiotic therapy, tight glycem ic control, and appropriate treatm ent of
arterial insufficiency, including revascularization if necessary]
I83.201 - I83.229 Varicose veins of lower extrem ities with both ulcer and inflam m ation
[non-healing infected deep ulcerations (reaching tendons or bone) of the lower
extrem ity unresponsive to at least 1 m onth of m eticulous wound care, including
necessary]
I87.2 Venous insufficiency (chronic) (peripheral) [venous stasis ulcer - non-healing
infected deep ulcerations (reaching tendons or bone) of the lower extrem ity
unresponsive to at least 1 m onth of m eticulous wound care, including
necessary]
L97.101 - L97.929 Non-pressure chronic ulcer of lower lim b [diabetic ulcers] [non-healing infected
deep ulcerations (reaching tendons or bone) Wagner grade 3 of the lower
extrem ity]
M27.8 Other specified diseases of jaw [prophylactic pre- and post-treatm ent for
m em bers undergoing dental surgery of a radiated jaw]
M72.6 Necrotizing fasciitis
M86.60 - M86.69 Chronic osteom yelitis [unresponsive to conventional m edical and surgical
M86.8x0 - M86.8x9 m anagem ent]
M87.08 Idiopathic aseptic necrosis of bone, other site [jaw]
N30.41 Irradiation cystitis with hem aturia
N30.91 Cystitis, unspecified with hem aturia [chem otherapy-induced hem orrhagic
cystitis]
O88.011 - O88.019 Obstetric air em bolism in pregnancy
S07.0xx+ - Crushing injuries [when loss of function, lim b, or life is threatened and HBOT is
S07.9xx+ used in com bination with standard therapy]
S17.0xx+ -
S17.9xx+
S28.0xx+
S38.001+ -
S38.1xx+
S47.1xx+ -
S47.9xx+
S57.00x+ -
S57.82x+
S67.00x+ -
S67.92x+
S77.00x+ -
S77.22x+
S87.00x+ -
S87.82x+
S97.00x+ -
S97.82x+
S35.511+ - Injury to the iliac artery [acute peripheral ischem ia when loss of function, lim b, or
S35.513+ life is threatened and HBOT is used in com bination with standard therapy]
S45.001+ - Injury to axillary artery [acute peripheral ischem ia when loss of function, lim b, or
S48.011+ - Traum atic am putation thum b, finger(s), arm and hand [when loss of function or
S58.011+ -
S58.929+
S68.011+ -
S68.729+
S45.301+ - Injury to other specified blood vessels of upper extrem ity [acute peripheral
S45.399+ ischem ia when loss of function, lim b, or life is threatened and HBOT is used in
S45.801+ - com bination with standard therapy]
S45.899+
S55.201+ -
S55.299+
S55.801+ -
S55.899+
S65.801+ -
S65.899+
S65.201+ - Injury to palm ar artery [acute peripheral ischem ia when loss of function, lim b, or
S65.301+ -
S65.399+
S75.001+ - Injury of fem oral artery [acute peripheral ischem ia when loss of function, lim b, or
S75.801+ - Injury to other specified blood vessels of lower extrem ity [acute peripheral
S75.899+ ischem ia when loss of function, lim b, or life is threatened and HBOT is used in
S85.801+ - com bination with standard therapy]
S85.899+
S95.801+ -
S95.899+
S78.011+ - Traum atic am putation toe(s), foot, leg(s) [when loss of function or life is
S78.929+ threatened and HBOT is used in com bination with standard therapy]
S88.011+ -
S88.929+
S98.011+ -
S98.929+
S85.001+ - Injury to popliteal artery [acute peripheral ischem ia when loss of function, lim b,
S85.099+ or life is threatened and HBOT is used in com bination with standard therapy]
S85.131+ - Injury to anterior tibial artery [acute peripheral ischem ia when loss of function,
S85.159+ lim b, or life is threatened and HBOT is used in com bination with standard
therapy]
S85.161+ - Injury to posterior tibial artery [acute peripheral ischem ia when loss of function,
S85.189+ lim b, or life is threatened and HBOT is used in com bination with standard
therapy]
T57.3x1+ - Toxic effect of hydrogen cyanide [with co-existing carbon m onoxide poisoning]
T57.3x4+
T58.01x+ - Toxic effect of carbon m onoxide [acute]
T58.94x+
T65.0x1+ - Toxic effect of cyanides [with co-existing carbon m onoxide poisoning]
T65.0x4+
T66.xxxA - Radiation sickness, unspecified
T66.xxxS
T70.3xx+ Caisson disease [decom pression illness]
T79.0xx+ Air em bolism (traum atic) [acute]
T79.a0x+ - Traum atic com partm ent syndrom e
T79.a9x+
T81.40xA - Infection following a procedure [reaching tendons or bone of the lower extrem ity
T81.49xS unresponsive to at least 1 m onth of m eticulous wound care, including
necessary]
T81.89x+ Other com plications of procedures, not elsewhere classified (reaching tendons
or bone) of the lower extrem ity unresponsive to at least 1 m onth of m eticulous
wound care, including aggressive debridem ent, m axim al antibiotic therapy, tight
glycem ic control, and appropriate treatm ent of arterial insufficiency, including
revascularization if necessary]
T85.693+ Other m echanical com plication of artificial skin graft and decellularized
alloderm is [com prom ised skin grafts and flaps]
T85.79x+ Infection and inflam m atory reaction due to other internal prosthetic devices,
im plants and grafts [com prom ised skin grafts and flaps]
T85.810+ Other specified com plications of internal prosthetic devices, im plants and grafts,
-T85.898+ not elsewhere classified [com prom ised skin grafts and flaps]
T86.820 - T86.829 Com plications of skin graft (allograft) (autograft) [com prom ised skin grafts and
flaps]
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
A02.21 Salm onella m eningitis
A04.71 - A04.72 Enterocolitis due to Clostridium difficile [intra-abdom inal abscess,
pseudom em branous colitis (antibiotic-induced colitis)]
A17.0 Tuberculous m eningitis
A27.81 Aseptic m eningitis in leptospirosis
A30.5 Leprom atous leprosy
A35 Other tetanus
A39.0 Meningococcal m eningitis
A40.0 - A41.3 Sepsis [except sepsis due to anaerobes]
A41.50 - A41.9
A42.0 - A42.2 Actinom ycotic infections
A42.81 - A42.9
A43.0 - A43.9
B47.0 - B47.9
L08.1
A49.02 Methicillin resistant Staphylococcus aureus infection, unspecified site
A50.41 Late congenital syphilitic m eningitis
A51.41 Secondary syphilitic m eningitis
A52.13 Late syphilitic m eningitis
A54.81 Gonococcal m eningitis
A69.20 - A69.9 Lym e disease
B15.0 - B19.9 Viral hepatitis
B20 Hum an im m unodeficiency virus [HIV] disease
B35.0 - B47.0 Mycoses
B48.0 - B49
C00.0 - C43.9 Malignant neoplasm [cancer]
C44.0 - C75.9
C76.0 - C86.6
C88.4 - C94.32
C94.80 - C96.4
C96.6 - C96.9
C71.0 - C71.9 Malignant neoplasm of brain [glioblastom a]
D00.00 - D09.9 In situ neoplasm s [cancer]
D57.00 - D57.819 Hb-SS disease with crisis [sickle cell crisis]
D68.61 Antiphospholipid syndrom e
D68.62 Lupus anticoagulant syndrom e
E11.311 - E11.39 Type 2 diabetes m ellitus with ophthalm ic com plications
E83.2 Disorders of zinc m etabolism
E83.59 Other disorders of calcium m etabolism [calciphylaxis (calcific urem ic
arteriolopathy)]
F01.50 - F01.51 Dem entias [cognitive im pairm ent]
F03.90 - F03.91
F05
F06.8 Other persistent m ental disorders due to conditions classified elsewhere
[dem entia NOS] [cognitive im pairm ent]
F07.0 Personality change due to known physiological condition [cognitive im pairm ent]
F07.81 Postconcussional syndrom e
F07.89 Other personality and behavioral disorders due to known physiological condition
[cognitive im pairm ent]
F32.0 - F33.9 Depression
F43.10 - F43.12 Post-traum atic stress disorder
F80.0 - F89 Pervasive and specific developm ental disorders
F84.0 Autistic disorder
G00.0 - G03.1 Meningitis- bacterial, due to other organism s, and of unspecified cause
G03.8 - G03.9
G04.2
G06.0 Intracranial abscess and granulom a
G20 Parkinson's disease
G21.11 - G21.19 Other drug-induced secondary parkinsonism
G30.0 - G31.2 Alzheim er's disease and other degenerative diseases of nervous system
G31.83 - G31.9 [cognitive im pairm ent]
G91.0 - G91.2
G93.7, G94
G35 Multiple sclerosis
G37.1 - G37.3 Acute transverse m yelitis in dem yelinating diseases of central nervous system
G37.8 - G37.9 [radiation induced]
G40.001 - G40.919 Epilepsy and recurrent seizures
G43.001 - G43.919 Migraine
G44.001 - G44.029 Cluster headaches
G45.0 - G45.1 Transient cerebral ischem ic attacks and related syndrom es [acute or chronic
G45.8 - G45.9 cerebrovascular insufficiency]
I67.8
G45.4 Other specified cerebrovascular diseases [acute or chronic cerebrovascular
insufficiency/accident including throm botic or em bolic stroke]
G51.0 Bell's palsy
G51.8 Other disorders of facial nerve [facial neuritis]
G61.0 Guillain-Barre syndrom e
G80.0 - G80.9 Cerebral palsy
G89.21 - G89.3 Chronic pain, not elsewhere classified
G89.4 Chronic pain syndrom e
G90.50 - G90.59 Com plex regional pain syndrom e I (CRPSI)
G93.1 Anoxic brain dam age, not elsewhere classified
H00.011 - H57.9 Diseases of the eye and adnexa
H60.00 - H60.93 Otitis externa
H93.11 - H93.19 Tinnitus
I20.0, I21.01 - Ischem ic heart diseases
I22.9, I21.A1 -
121.A9, I24.0 -
I24.9, I25.2
I26.01 - I52 Heart disease
I61.0 - I61.9 Nontraum atic intracerebral hem orrhage
I63.00 - I66.9 Cerebral infarction and occlusion and throm bosis of precerebral and cerebral
arteries, not resulting in cerebral infarction [acute or chronic cerebrovascular
insufficiency/accident including throm botic or em bolic stroke]
I67.1 - I67.2 Other cerebrovascular diseases [acute or chronic cerebrovascular
I67.4 - I67.9 insufficiency/accident including throm botic or em bolic stroke]
I69.910 - I69.919 Cognitive deficits following unspecified cerebrovascular disease
I73.00 - I73.01 Raynaud's syndrom e
I74.8 Arterial em bolism and throm bosis of other arteries [hepatic]
I77.0 Arteriovenous fistula, acquired [spinal dural]
I77.6 Arteritis, unspecified [Lupus vasculitis]
I89.0, I97.2 Lym phedem a
J43.0 - J43.9 Em physem a
J44.0 - J44.9 Other chronic obstructive pulm onary disease [bronchitis with em physem a]
J45.20 - J45.998 Asthm a
J68.0 - J68.9 Respiratory conditions due to inhalation of chem icals, gases, fum es and vapors
[Acute therm al and chem ical pulm onary dam age, i.e., sm oke inhalation (e.g.,
carbon tetrachloride, hydrogen sulfide) with pulm onary insufficiency]
J70.0 - J70.9 Respiratory conditions due to other external agents [Acute therm al and chem ical
pulm onary dam age, i.e., sm oke inhalation (e.g., carbon tetrachloride, hydrogen
sulfide) with pulm onary insufficiency]
J84.10 Pulm onary fibrosis, unspecified [radiation induced]
J98.09 Other diseases of bronchus, not elsewhere classified [central airway stenosis
following lung transplantation]
K11.7 - K11.9 Disturbances and diseases of salivary glands
K50.00 - K50.919 Crohn's disease [regional enteritis]
K51.00 - K51.919 Ulcerative colitis
K52.0 Gastroenteritis and colitis due to radiation
K56.690 - K56.699 Other intestinal obstruction [sm all bowel obstruction]
K60.3 Anal fistula
K63.2 Fistula of intestine [enterocutaneous fistulae]
K63.89 Other specified diseases of intestine [intestinal anastom osis]
K65.1 Peritoneal abscess [intra-abdom inal]
K70.0 - K77 Diseases of liver
K72.00 - K72.01 Acute and subacute hepatic failure
K76.2
K73.0 - K73.9 Chronic hepatitis, NEC
K83.01 - K83.09 Cholangitis [radiation-induced hem orrhagic]
L08.0, L08.81 - Other local infections and disorders of the skin and subcutaneous tissue [except
L08.9 Meleney's ulcer] [infection other than clostridial]
L88, L98.0
L55.0 - L55.9 Contact derm atitis and other eczem a due to solar radiation [actinic skin
L56.0 - L56.9 dam age]
L57.0 - L57.1
L57.5 - L57.9
L59.0 - L59.9 Other disorders of skin and subcutaneous tissue related to radiation
[radiation-induced skin necrosis]
L70.0 Acne vulgaris [cystic]
L81.1 Chloasm a [m elasm a]
L91.0 Hypertrophic scar [epithelial-to-m esenchym al transition (EMT) phenom enon in
keloid tissue]
M00.00 - M12.19 Arthropathies
M12.50 - M19.93
M27.61 Endosseous dental im plant failure
M32.0 - M32.9 System ic lupus erythem atosus (SLE) [ischem ia due to lupus vasculitis]
M34.0 - M34.2 System ic sclerosis [scleroderm a]
M48.50x+ - Pathologic fracture [fracture healing]
M48.58x+
M80.00x+ -
M80.88x+
M84.40x+ -
M84.48x+
M62.20 - M62.28 Nontraum atic ischem ic infarction of m uscle [critical lim b ischem ia]
M79.10 - M79.18 Myalgia [m yofascial pain syndrom e]
M79.7 Fibrom yalgia
M81.0 - M81.8 Osteoporosis without current pathological fracture
M86.8X8 Other osteom yelitis, other site [pre-operative HBOT for jaw]
M86.9 Osteom yelitis, unspecified [pre-operative HBOT for jaw]
M87.059 Idiopathic aseptic necrosis of unspecified fem ur [head and neck]
M87.08 Idiopathic aseptic necrosis of bone, other site [jaw]
M91.10 - M91.12 Juvenile osteochondrosis of head of fem ur [Legg-Calve-Perthes]
N30.10 - N30.11 Interstitial cystitis (chronic)
N30.40 Irradiation cystitis without hem aturia
N32.2 Vesical fistula, not elsewhere classified
N46.0 - N46.9 Male infertility
N52.0 - N52.9 Male erectile dysfunction
N64.4 Mastodynia [post-radiation therapy]
N82.4 Other fem ale intestinal-genital tract fistulae [rectovaginal fistula]
O90.0 Disruption of cesarean delivery wound
P25.0 - P25.8 Interstitial em physem a and related conditions originating in the perinatal period
Q15.0 Congenital glaucom a
Q54.0 - Q54.9 Hypospadias
Q82.0 Hereditary lym phedem a [legs]
R31.0 - R31.9 Hem aturia
R41.4 Neurologic neglect syndrom e [cognitive im pairm ent]
R41.81 Age-related cognitive decline
R41.82 Altered m ental status [cognitive im pairm ent]
R56.00 - R56.9 Convulsions, not elsewhere classified
R57.0 Cardiogenic shock
R65.10 - R65.11 System ic inflam m atory response syndrom e (SIRS) of non-infectious origin
S04.011+ - Injury of optic nerve and pathways [ophthalm ologic diseases (including diabetic
S04.049+ retinopathy, retinal detachm ent, central retinal artery occlusion, radiation injury to
the optic nerve, glaucom a, keratoendotheliosis)]
S06.0x0+ - Intracranial injury [cognitive im pairm ent] [not covered for traum atic brain injury]
S06.9x9+
S09.8xx+ - Specified and unspecified head injury [cognitive im pairm ent] [closed head injury]
S09.90x+
S14.101+ - Other and unspecified injury of cervical, thoracic, lum bar and sacral spinal cord
S14.139+
S14.151+ -
S14.159+
S24.101+ -
S24.139+
S24.151+ -
S24.159+
S34.101+ -
S34.139+
T20.00x+ - Burns and corrosions of head, face, neck, trunk, upper lim b, wrist and hand,
T25.799+ lower lim b, and m ultiple and unspecified body regions [skin, therm al]
T30.0 - T30.4
T33.011+ - Frostbite [face, hand, foot, and other and unspecified sites]
T34.99x+
T53.0x1+ - Toxic effects of other gases, fum es, or vapors [other than carbon m onoxide]
T53.0x4+ [Acute therm al and chem ical pulm onary dam age, i.e., sm oke inhalation (e.g.,
T53.5x1+ - carbon tetrachloride, hydrogen sulfide) with pulm onary insufficiency]
T53.5x4+
T59.0x1+ -
T59.1x4+
T59.3x1+ - T59.6x4
T63.001+ - Toxic effect of contact with venom ous anim als and plants [necrotizing
T63.94x+ arachnidism ]
T81.30x+ - Disruption of wound [dehiscence of operation wound]
T81.33x+
T84.010+ - Mechanical com plication of internal orthopedic devices, im plants and grafts
T84.498+ [bone grafts]
T84.60x+ - Infection and inflam m atory reaction due to internal fixation devices and other
T84.7xx+ internal orthopedic prosthetic devices, im plants and grafts [bone grafts]
Z40.01 Encounter for prophylactic rem oval of breast
Z48.21 - Z48.298 Encounter for aftercare following organ transplant [post organ transplant
revascularization]
Z76.82 Awaiting organ transplant status [organ transplant or storage]
Z94.0 - Z94.9 Transplanted organ and tissue status, and presence of cardiac and vascular
Z95.2 - Z95.4 im plants and grafts and other functional im plants and other devices [organ
Z95.811 - Z95.812 transplant or storage]
Z95.820 - Z95.828
Z96.0 - Z96.1
Z96.3, Z96.5 -
Z97.16
Numerous Aftercare for healing fracture [Codes not listed due to expanded specificity]
options
Numerous Fractures, including m alunion and nonunion [Codes not listed due to expanded
options specificity]
Numerous Intracranial injury, sequela [Codes not listed due to expanded specificity]
options
ICD-10 codes contraindicated for this CPB:
A28.1, A60.00 - Viral infections and diseases
A99
B00.0 - B19.9
B25.0 - B34.9
B97.0 - B97.89
L44.4
A48.1, B44.9 Diseases of the respiratory system [lung disease including J93.0 - J93.9
J00 - J99 untreated pneum othorax]
M34.81, R09.1
D58.0 Hereditary spherocytosis [congenital]
P07.00 - P07.32 Disorders of newborn related to short gestation and low birth weight, not
elsewhere classified [prem ature infants (birth prior to 37 weeks)]
R50.9 Fever [high]
The abo ve po lic y is based o n the fo llo wing r efer enc es:
1. Agence d'Evaluation des Technologies et des Modes d'Intervention en Sante (AETMIS).
Hyperbaric oxygen therapy in Quebec. AETMIS 2000-3 RE. Montreal, QC: AETMIS; 2000.
2. Agency for Health Care Policy and Research (AHCPR). Treatment of pressure ulcers.
Clinical Guideline Number 15. AHCPR Publication No. 95-0652. Bethesda, MD: AHCPR;
December 1994.
3. Alimoglu Y, Inci E. Is hyperbaric oxygen therapy a salvage treatment option for sudden
sensorineural hearing loss? J Laryngol Otol. 2016;130(10):943-947.
4. Alternative Therapy Evaluation Committee for the Insurance Corporation of British
Columbia. A review of the scientific evidence on the treatment of traumatic brain injuries
and strokes with hyperbaric oxygen. Brain Inj. 2003;17(3):225-236.
5. Altug HA, Tatli U, Coskun AT, et al. Effects of hyperbaric oxygen treatment on implant
osseointegration in experimental diabetes mellitus. J Appl Oral Sci. 2018;26:e20180083.
6. Ball CM. Hyperbaric oxygen therapy for multiple sclerosis. STEER: Succint and Timely
Evaluated Evidence Reviews. Bazian Ltd., eds. London, UK: Wessex Institute for Health
Research and Development, University of Southampton; 2002;2(6).
7. Bartek J Jr, Jakola AS, Skyrman S, et al. Hyperbaric oxygen therapy in spontaneous brain
abscess patients: A population-based comparative cohort study. Acta Neurochir (Wien).
2016;158(7):1259-1267.
8. Baskin LS. Hypospadias: Management and outcome. UpToDate Inc., Waltham, MA. Last
reviewed October 2019.
9. Bennett M, Feldmeier J, Smee R, Milross C. Hyperbaric oxygenation for tumour
sensitisation to radiotherapy. Cochrane Database Syst Rev. 2005;(4):CD005007.pub2.
10. Bennett M, Heard R. Hyperbaric oxygen therapy for multiple sclerosis.
Cochrane Database Syst Rev. 2004(1):CD003057.
11. Bennett M, Jepson N, Lehm P. Hyperbaric oxygen therapy for acute coronary syndrome.
Cochrane Database Syst Rev. 2005;(2):CD004818.
12. Bennett M, Best TM, Babul S, Taunton J. Hyperbaric oxygen therapy for delayed onset
muscle soreness and closed soft tissue injury. Cochrane Database Syst Rev. 2005;(4):
CD004713.
13. Bennett MH, Feldmeier J, Hampson N, et al. Hyperbaric oxygen therapy for late radiation
tissue injury. Cochrane Database Syst Rev. 2005;(3):CD005005.
14. Bennett MH, Feldmeier J, Smee R, Milross C. Hyperbaric oxygenation for tumour
sensitisation to radiotherapy. Cochrane Database Syst Rev. 2018;4:CD005007.
15. Bennett MH, French C, Schnabel A, et al. Normobaric and hyperbaric oxygen therapy for
migraine and cluster headache. Cochrane Database Syst Rev. 2008;(3):CD005219.
16. Bennett MH, Kertesz T, Perleth M, et al. Hyperbaric oxygen for idiopathic sudden
sensorineural hearing loss and tinnitus. Cochrane Database Syst Rev. 2012c;10:CD004739.
17. Bennett MH, Kertesz T, Yeung P. Hyperbaric oxygen for idiopathic sudden sensorineural
hearing loss and tinnitus. Cochrane Database Syst Rev. 2007;(1):CD004739.
18. Bennett MH, Lehm JP, Jepson N. Hyperbaric oxygen therapy for acute coronary
syndrome. Cochrane Database Syst Rev. 2011;(8):CD004818.
19. Bennett MH, Lehm JP, Mitchell SJ, Wasiak J. Recompression and adjunctive therapy for
decompression illness. Cochrane Database Syst Rev. 2007;(2):CD005277.
20. Bennett MH, Stanford R, Turner R. Hyperbaric oxygen therapy for promoting fracture
healing and treating fracture non-union. Cochrane Database Syst Rev. 2005;(1):CD004712.
21. Bennett MH, Stanford RE, Turner R. Hyperbaric oxygen therapy for promoting fracture
healing and treating fracture non-union. Cochrane Database Syst Rev.
2012b;11:CD004712.
22. Bennett MH, Trytko B, Jonker B. Hyperbaric oxygen therapy for the adjunctive treatment
of traumatic brain injury. Cochrane Database Syst Rev. 2004;(4):CD004609.
23. Bennett MH, Trytko B, Jonker B. Hyperbaric oxygen therapy for the adjunctive treatment
of traumatic brain injury. Cochrane Database Syst Rev. 2012a;12:CD004609.
24. Bennett MH, Wasiak J, Schnabel A, et al. Hyperbaric oxygen therapy for acute ischaemic
stroke. Cochrane Database Syst Rev. 2005;(3): CD004954.
25. Bento SV, Nunes TA, Araújo ID, et al. Hyperbaric oxygenation on adhesions prevention
after laparotomy in rats. Acta Cir Bras. 2018;33(9):824-833.
26. Bevers RF, Bakker DJ, Kurth KH. Hyperbaric oxygen treatment for haemorrhagic radiation
cystitis. Lancet. 1995;346(8978):803-805.
27. Bisset F. Hyperbaric oxygen therapy in people with necrotising fasciitis or Fournier's
gangrene. STEER: Succint and Timely Evaluated Evidence Reviews. Bazian Ltd., eds.
London, UK: Wessex Institute for Health Research and Development, University of
Southampton; 2002;2(14).
28. Borab Z, Mirmanesh MD, Gantz M, et al. Systematic review of hyperbaric oxygen therapy
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Clinical Policy Bulletins Medical Clinical Policy Bulletins

of the following conditions:

Acute air or gas embolism Effective: 08/27/1997

Acute carbon monoxide poisoning Next

Acute cerebral edema Review: 02/11/2021

Acute peripheral arterial insuﬃciency (i.e., compartment syndrome) requiring

bypass surgery), with imaging documentation of embolus/thrombus (e.g., MR, History

Compromised skin grafts and ﬂaps , where hypoxia or decreased perfusion has

where HBOT is delivered according to established (Marx) protocol, with 20 HBOT

Actinic skin damage

Calciphylaxis (calciﬁc uremic arteriolopathy)

Radiation-induced pulmonary ﬁbrosis/injury

Concurrent administration of doxorubicin, cisplatin, or disulﬁram

V. Aetna considers prophylactic HBOT prior to mastectomy experimental and investigational

Bac kgr o und

A number of technology assessment organizations, including the Cochrane Collaboration, the

Absolute contraindications to HBOT include: untreated pneumothorax, concurrent administration

There is insufficient evidence of the effectiveness of hyperbaric oxygen as a treatment for

Rossignol et al (2009) carried out a multi-center, randomized, double-blind, controlled study to

significantly improved in the treatment group compared to controls in overall functioning (p =

Parra et al (2011) assessed the efficacy of HBOT in HC cases. A retrospective analysis of

Calciphylaxis, also referred to as calcific uremic arteriolopathy (CUA), is a syndrome associated

In a randomized study, Gothard et al (2010) examined effect of HBOT on arm lymphedema

Furthermore, in a systematic review of salivary gland hypo-function and xerostomia induced by

Furthermore, the National Comprehensive Cancer Network’s clinical practice guideline on

Also, an UpToDate review on “Treatment of invasive methicillin-resistant Staphylococcus aureus

oxygen is supported with marginal strength only”. Furthermore, an UpToDate review on

An UpToDate review on “Treatment of the Raynaud phenomenon resistant to initial therapy”

A clinical cases summary by the University of Michigan Medical School on “Vesicocutaneous

Central Retinal Artery Occlusion (CRAO)

Soares et al (2017) stated that CRAO is an ophthalmological emergency. Various treatment

An American Academy of Ophthalmology Focal Points education module on retinal artery

Anti-Phospholipid Antibody Syndrome

Furthermore, an UpToDate review on “Treatment of the antiphospholipid syndrome” (Schur and

therapeutic option in patients with ischemic vasculitic ulcers in combination with

Furthermore, an UpToDate review on “Overview of the management of vasculitis in adults”

Osteonecrosis of the Jaw

In a single-center, double-blind, randomized, sham-controlled, prospective trial, Cifu et al (2014)

In a randomized, multi-center, double-blind, sham-controlled clinical trial, Miller et al (2015)

Central Airway Stenosis Following Lung Transplantation

Chemotherapy-Induced Hemorrhagic Cystitis

Davis et al (2011) stated that cyclophosphamide-induced hemorrhagic cystitis (CHC) is an

Chronic Bowel Dysfunction After Pelvic Radiotherapy

Improvement of Free Flap Survival

Post-Traumatic Stress Disorder

Radiation-Induced Pulmonary Fibrosis/Injury

Spinal Dural Arterio-Venous Fistula

Traumatic Brain Injury

Prevention of Radiation-Induced Complications of the Head and Neck Cancers

Treatment of Bacterial Keratitis

Treatment of Intra-Cerebral Hemorrhage

Treatment of Radiation-Induced Skin Necrosis

Treatment of Scleroderma (Systemic Sclerosis)

Furthermore, an UpToDate review on “Overview of the treatment and prognosis of systemic

Treatment of Post-Operative Nipple Ischemia Following Mastectomy

Treatment of Sudden Sensorineural Hearing Loss

The panel made recommendations that clinicians should do the following:

Diagnose presumptive ISSNHL if audiometry conﬁrms a 30-dB hearing loss at 3

The panel offered as options that clinicians may offer:

Corticosteroids as initial therapy to patients with ISSNHL

The panel made a recommendation against: