Hyperbaric Oxygen Therapy (HBOT)

Number: 0172

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

Policy

Scope of Policy

This Clinical Policy Bulletin addresses hyperbaric oxygen therapy.

Medical Necessity

Aetna considers systemic hyperbaric oxygen therapy (HBOT) medically necessary for any of the following conditions (with usual medically necessary number of sessions (dives) in parentheses):
1. Acute air or gas embolism (up to 10 sessions);
2. Acute carbon monoxide poisoning (up to 5 sessions or clinical plateau);
3. Acute peripheral arterial insufficiency (i.e., compartment syndrome) requiring emergent surgical intervention (e.g., surgical or catheter directed embolectomy or bypass surgery), with imaging documentation of embolus/thrombus (e.g., MR, angiogram) (three treatments in the first 24 hours then twice daily until tissue at risk subsides);
4. 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 (twice a day up to 7 days or 14 sessions);
5. Central retinal artery occlusion (CRAO), acute treatment (treat twice daily until clinical plateau plus three days; usual medically necessary duration is up to 10 days);
6. Chronic refractory osteomyelitis, unresponsive to conventional medical and surgical management, including a six- week course of parenteral antibiotics and at least one surgical eradication/debridement attempt, unless contraindicated, with photograph (with ruler) of wound plus X-ray or bone culture documenting diagnosis; 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 (up to 40 sessions); Footnote1*
7. 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); Footnote2** 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; (twice daily up to 20 sessions); Footnote1*
8. Cyanide poisoning (only with co-existing carbon monoxide poisoning) (up to 5 sessions or clinical plateau);
9. Decompression sickness ("the bends") (to clinical plateau; up to 10 sessions);
10. Gas gangrene (Clostridial myositis and myonecrosis) (three times in the first 24 hours, then twice daily for up to 5 days);
11. 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 (up to 20 sessions);
12. 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:
  1. Standard wound care in persons with diabetic wound includes:
    1. Assessment of vascular status and correction of any vascular problems in the affected limb if possible,
    2. Optimization of nutritional status,
    3. Optimization of glucose control,
    4. Debridement by any means to remove devitalized tissue,
    5. Maintenance of clean, moist bed of granulation tissue with appropriated moist dressings,
    6. Appropriate off-loading, and
    7. Necessary treatment to resolve any infection that might be present;
  2. 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 (usual duration up to 40 daily sessions; for HBOT to continue, must show progress in healing; no more than 60 sessions are considered medically necessary) Footnote1* Note: HBOT is not considered medically necessary for superficial lesions;
13. Pneumatosis cystoides intestinalis (daily 2.5 hour treatments for up to 3 days);
14. 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; 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 (twice daily until stabilization occurs; usual duration up to 30 sessions); Footnote1*
15. Prophylaxis and treatment of radiation necrosis of the of mandible in 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;
16. Radiation-induced hemorrhagic cystitis (daily 90-minute treatments, up to 40 sessions);
17. 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));
18. Radiation proctitis (up to 45 sessions).
19. Severe 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 (three or four times a day until there is replacement of red blood cells by regeneration or transfusion);
Footnote1*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.

Footnote2**Transcutaneous oxygen pressure (TcPO2) measures the partial pressure of oxygen diffusing through the skin. Tissue oxygen tensions below 30-40 mmHg are considered suboptimal for wound healing and control of infection (Clarke, 1997).
Experimental and Investigational
1. 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:
  1. Actinic skin damage
  2. Actinomycosis and other mycoses
  3. Acute cerebral edema
  4. Acute coronary syndrome
  5. Acute or chronic cerebrovascular insufficiency/accident (including thrombotic or embolic stroke)
  6. Acute renal arterial insufficiency
  7. Acute thermal and chemical pulmonary damage, i.e., smoke inhalation (e.g., carbon tetrachloride, hydrogen sulfide) with pulmonary insufficiency
  8. Adhesions prevention after laparotomy
  9. Aerobic septicemia and systemic aerobic infection
  10. Alzheimer’s disease
  11. Anaerobic septicemia and infection other than clostridial
  12. Anoxic brain injury
  13. Anti-phospholipid antibody syndrome
  14. Arthritic diseases
  15. Arthritis
  16. Asthma
  17. Autism spectrum disorders
  18. Avascular necrosis (including aseptic necrosis of the femoral head and neck)
  19. Bacterial keratitis
  20. Bell's palsy
  21. Bone grafts or fracture healing (e.g., nonunion fractures) / bone reconstruction
  22. Brain tumors
  23. Calciphylaxis (calcific uremic arteriolopathy)
  24. Cancer
  25. Cardiogenic shock
  26. Central airway stenosis following lung transplantation
  27. Cerebral palsy
  28. Chemotherapy induced hemorrhagic cystitis
  29. Chronic bowel dysfunction after pelvic radiotherapy
  30. Chronic pain (e.g., cluster headaches, complex regional pain syndrome/reflex sympathetic dystrophy, fibromyalgia, migraines, myofascial pain syndrome, and trigeminal neuralgia)
  31. Chronic peripheral vascular insufficiency
  32. Closed head and/or spinal cord injury
  33. Cognitive impairment (e.g., senility, senile dementia)
  34. Coronary artery disease
  35. COVID-19
  36. Critical limb ischemia
  37. Cystic acne
  38. Dental implant osseointegration
  39. Depression
  40. Diabetic foot ulcers that are not infected
  41. Diabetic superficial wounds
  42. Enterocutaneous fistula
  43. Epithelial-to-mesenchymal transition (EMT) phenomenon in keloid tissue
  44. Erectile dysfunction
  45. Facial neuritis
  46. Fat necrosis
  47. Fibromyalgia
  48. Frostbite
  49. Glioblastoma
  50. Heart disease
  51. HIV infection
  52. Hypospadias
  53. Infective polyneuritis
  54. Inflammatory bowel disease (Crohn’s disease and ulcerative colitis)
  55. Intestinal anastomosis
  56. Interstitial cystitis
  57. Intra-abdominal abscess, pseudomembranous colitis (antibiotic-induced colitis)
  58. Intra-cerebral hemorrhage
  59. Intra-cranial abscesses
  60. Ischemia due to lupus vasculitis
  61. Legg-Calve Perthes disease
  62. Lepromatous leprosy
  63. Livedo reticularis
  64. Liver diseases (e.g., hepatic artery thrombosis, hepatic fibrosis, hepatic necrosis, hepatitis, hepatocellular carcinoma, non-alcoholic steatohepatitis, and sepsis-induced liver injury)
  65. Lupus vasculitis
  66. Lyme disease
  67. Lymphedema
  68. Male infertility
  69. Melasma
  70. Meningitis
  71. Methicillin-resistant Staphylococcus aureus (MRSA) infections
  72. Multiple sclerosis
  73. Myocardial infarction
  74. Necrotizing arachnidism
  75. Noise-induced sensorineural hearing loss
  76. Non-compromised skin grafts and flaps
  77. Non-diabetic cutaneous, decubitus, pressure and venous stasis ulcers
  78. Non-vascular causes of chronic brain syndrome (e.g., Alzheimer's disease, Korsakoff's disease, Pick's disease)
  79. Ophthalmologic diseases (including central retinal vein occlusion, diabetic retinopathy, glaucoma, keratoendotheliosis, radiation injury to the optic nerve, retinal detachment)
  80. Optic neuritis
  81. Optic neuropathy
  82. Organ transplantation and storage
  83. Osteonecrosis of the jaw (except where cause is radiation necrosis (i.e., osteoradionecrosis))
  84. Osteoporosis
  85. Otitis externa
  86. Parkinson's disease
  87. Peri-anal fistula
  88. Post-concussive syndrome
  89. Post-operative nipple ischemia following mastectomy
  90. Post-organ transplantation re-vascularization
  91. Post-radiation therapy breast pain
  92. Post-traumatic stress disorder
  93. Pre-operative HBOT for jaw osteomyelitis
  94. Prevention of avascular necrosis
  95. Prevention of radiation-induced complications of the head and neck cancers
  96. Pulmonary emphysema
  97. Pyoderma gangrenosum
  98. Radiation-induced cholangitis, myelitis, enteritis, sarcoma
  99. Radiation-induced gastro-intestinal complications (e.g., diarrhea, pain and rectal bleeding)
  100. Radiation-induced pulmonary fibrosis/injury
  101. Radiation-induced skin necrosis
  102. Raynaud’s syndrome
  103. Recto-vaginal fistula
  104. Scleroderma (systemic sclerosis)
  105. Seizure disorders
  106. Sickle cell anemia
  107. Sickle cell crisis or hematuria
  108. Skin burns (thermal)
  109. Small bowel obstruction secondary to pelvic irradiation
  110. Spinal dural arterio-venous fistula
  111. Superficial and/or non-infected diabetic ulcers
  112. Surgical wound dehiscence
  113. Systemic inflammatory response syndrome
  114. Tetanus
  115. Tinnitus
  116. Traumatic brain injury
  117. Tumor sensitization to radiotherapy
  118. Vesicocutaneous fistula
  119. Xerostomia/salivary gland dysfunction.
2. Aetna considers systemic HBOT experimental and investigational and not medically necessary 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:
  1. Concurrent administration of doxorubicin, cisplatin, or disulfiram
  2. Premature infants (birth prior to 37 weeks gestation)
  3. Untreated pneumothorax.
3. 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.
4. Aetna considers prophylactic HBOT prior to mastectomy experimental and investigational because the effectiveness of this approach has not been established.
5. Aetna considers preventive HBOT experimental and investigational for improvement of surgical outcome (other than indications listed as medically necessary above) because the effectiveness of this approach has not been established.
6. Aetna considers vaporous hyperoxia therapy (VHT) for non-healing diabetic foot wounds experimental and investigational because the effectiveness of this approach has not been established.

Table:
CPT Codes / HCPCS Codes / ICD-10 Codes
Code	Code Description
CPT codes covered if selection criteria are met:
99183	Physician attendance and supervision of hyperbaric oxygen therapy, per session
CPT codes not covered for indications listed in the CPB:
Vaporous hyperoxia therapy (VHT) -no specific code
Other CPT codes related to the CPB:
19301 - 19307	Mastectomy
HCPCS codes covered if selection criteria are met:
G0277	Hyperbaric oxygen under pressure, full body chamber, per 30 minute interval
HCPCS codes not covered for indications listed in the CPB:
A4575	Topical hyperbaric oxygen chamber, 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 mg
J9060	Injection, cisplatin, powder or solution, 10 mg
Q2050	Injection, doxorubicin hydrochloride, liposomal, not otherwise specified, 10 mg
ICD-10 codes covered if selection criteria are met:
A41.4	Septicemia due to anaerobes [progressive necrotizing soft tissue anaerobic infections]
A48.0	Gas gangrene [Clostridial myositis and myonecrosis]
D50.0	Iron deficiency anemia secondary to blood loss (chronic) [overwhelming and transfusion is impossible because there is no suitable blood available or religion does not permit]
D62	Acute posthemorrhagic anemia [overwhelming and transfusion is impossible because there is no suitable blood available or religion does not permit]
E10.51 - E10.59 E11.51 - E11.59	Diabetes mellitus with circulatory complications [non-healing infected deep ulcerations (reaching tendons or bone) of the lower extremity unresponsive to at least 1 month of meticulous wound care, including aggressive debridement, maximal antibiotic therapy, tight glycemic control, and appropriate treatment of arterial insufficiency, including revascularization if necessary]
E10.618 - E10.638 E10.649 - E10.69 E11.618 - E11.638 E11.649 - E11.69	Diabetes mellitus with other specified complications [non-healing infected deep ulcerations (reaching tendons or bone) Wagner grade 3 of the lower extremity]
H34.10 - H34.13	Central retinal artery occlusion
H90.3	Sensorineural hearing loss, bilateral [not covered for noise-induced sensorineural hearing loss]
H91.20 - H91.23	Sudden idiopathic hearing loss [idiopathic when HBOT is initiated within 3 months after onset]
I70.201 - I70.92	Atherosclerosis of native arteries and bypass graft(s) of the extremities [non-healing infected deep ulcerations (reaching tendons or bone) of the lower extremity unresponsive to at least 1 month of meticulous wound care, including aggressive debridement, maximal antibiotic therapy, tight glycemic control, and appropriate treatment of arterial insufficiency, including revascularization if necessary]
I72.1 - I72.4	Other aneurysm of extremities
I73.1 - I73.9	Other peripheral vascular disease [acute peripheral arterial insufficiency]
I74.2 - I74.3	Arterial embolism of the extremities [acute peripheral arterial insufficiency]
I74.5	Arterial embolism and thrombosis of the iliac artery [acute peripheral arterial insufficiency]
I79.8	Other disorders of arteries, arterioles and capillaries in diseases classified elsewhere [acute peripheral arterial insufficiency]
I83.001 - I83.029	Varicose veins of lower extremities with ulcer [non-healing infected deep ulcerations (reaching tendons or bone) of the lower extremity unresponsive to at least 1 month of meticulous wound care, including aggressive debridement, maximal antibiotic therapy, tight glycemic control, and appropriate treatment of arterial insufficiency, including revascularization if necessary]
I83.201 - I83.229	Varicose veins of lower extremities with both ulcer and inflammation [non-healing infected deep ulcerations (reaching tendons or bone) of the lower extremity unresponsive to at least 1 month of meticulous wound care, including aggressive debridement, maximal antibiotic therapy, tight glycemic control, and appropriate treatment of arterial insufficiency, including revascularization if necessary]
I96	Gangrene not elsewhere classified [Meleney's ulcer]
K62.7	Radiation proctitis
L97.101 - L97.929	Non-pressure chronic ulcer of lower limb [diabetic ulcers] [non-healing infected deep ulcerations (reaching tendons or bone) Wagner grade 3 of the lower extremity]
M27.8	Other specified diseases of jaw [prophylactic pre- and post-treatment for members undergoing dental surgery of a radiated jaw]
M72.6	Necrotizing fasciitis
M86.30 - M86.9	Chronic osteomyelitis [not covered pre-operative for jaw]
N30.41	Irradiation cystitis with hematuria
O88.011 - O88.019	Obstetric air embolism in pregnancy
S07.0xx+ - S07.9xx+ 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+	Crushing injuries [when loss of function, limb, or life is threatened and HBOT is used in combination with standard therapy]
S35.511+ - S35.513+	Injury to the iliac artery [acute peripheral ischemia when loss of function, limb, or life is threatened and HBOT is used in combination with standard therapy]
S45.001+ - S45.099+	Injury to axillary artery [acute peripheral ischemia when loss of function, limb, or life is threatened and HBOT is used in combination with standard therapy]
S45.101A - S45.109S	Injury of brachial artery [acute peripheral ischemia when loss of function, limb, or life is threatened and HBOT is used in combination with standard therapy]
S48.011+ - S48.929+ S58.011+ - S58.929+ S68.011+ - S68.729+	Traumatic amputation thumb, finger(s), arm and hand [when loss of function or life is threatened and HBOT is used in combination with standard therapy]
S45.301+ - S45.399+ S45.801+ - S45.899+ S55.201+ - S55.299+ S55.801+ - S55.899+ S65.801+ - S65.899+	Injury to other specified blood vessels of upper extremity [acute peripheral ischemia when loss of function, limb, or life is threatened and HBOT is used in combination with standard therapy]
S65.001A - S65.099S	Injury of ulnar artery at wrist and hand level [acute peripheral ischemia when loss of function, limb, or life is threatened and HBOT is used in combination with standard therapy]
S65.101A - S65.199S	Injury of radial artery at wrist and hand level [acute peripheral ischemia when loss of function, limb, or life is threatened and HBOT is used in combination with standard therapy]
S65.201+ - S65.299+ S65.301+ - S65.399+	Injury to palmar artery [acute peripheral ischemia when loss of function, limb, or life is threatened and HBOT is used in combination with standard therapy]
S75.001+ - S75.099+	Injury of femoral artery [acute peripheral ischemia when loss of function, limb, or life is threatened and HBOT is used in combination with standard therapy]
S75.801+ - S75.899+ S85.801+ - S85.899+ S95.801+ - S95.899+	Injury to other specified blood vessels of lower extremity [acute peripheral ischemia when loss of function, limb, or life is threatened and HBOT is used in combination with standard therapy]
S78.011+ - S78.929+ S88.011+ - S88.929+ S98.011+ - S98.929+	Traumatic amputation toe(s), foot, leg(s) [when loss of function or life is threatened and HBOT is used in combination with standard therapy]
S85.001+ - S85.099+	Injury to popliteal artery [acute peripheral ischemia when loss of function, limb, or life is threatened and HBOT is used in combination with standard therapy]
S85.131+ - S85.159+	Injury to anterior tibial artery [acute peripheral ischemia when loss of function, limb, or life is threatened and HBOT is used in combination with standard therapy]
S85.161+ - S85.189+	Injury to posterior tibial artery [acute peripheral ischemia when loss of function, limb, or life is threatened and HBOT is used in combination with standard therapy]
S85.201A - S85.299S	Injury of peroneal artery [acute peripheral ischemia when loss of function, limb, or life is threatened and HBOT is used in combination with standard therapy]
T57.3x1+ - T57.3x4+	Toxic effect of hydrogen cyanide [with co-existing carbon monoxide poisoning]
T58.01x+ - T58.94x+	Toxic effect of carbon monoxide [acute]
T65.0x1+ - T65.0x4+	Toxic effect of cyanides [with co-existing carbon monoxide poisoning]
T66.xxxA - T66.xxxS	Radiation sickness, unspecified [radiation necrosis]
T70.3xx+	Caisson disease [decompression illness]
T79.0xx+	Air embolism (traumatic) [acute]
T79.a0x+ - T79.a9x+	Traumatic compartment syndrome
T81.40xA - T81.49xS	Infection following a procedure [reaching tendons or bone of the lower extremity unresponsive to at least 1 month of meticulous wound care, including aggressive debridement, maximal antibiotic therapy, tight glycemic control, and appropriate treatment of arterial insufficiency, including revascularization if necessary]
T81.89x+	Other complications of procedures, not elsewhere classified (reaching tendons or bone) of the lower extremity unresponsive to at least 1 month of meticulous wound care, including aggressive debridement, maximal antibiotic therapy, tight glycemic control, and appropriate treatment of arterial insufficiency, including revascularization if necessary]
T85.693+	Other mechanical complication of artificial skin graft and decellularized allodermis [compromised skin grafts and flaps]
T85.79x+	Infection and inflammatory reaction due to other internal prosthetic devices, implants and grafts [compromised skin grafts and flaps]
T85.810+ -T85.898+	Other specified complications of internal prosthetic devices, implants and grafts, not elsewhere classified [compromised skin grafts and flaps]
T86.820 - T86.829	Complications of skin graft (allograft) (autograft) [compromised skin grafts and flaps]
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
A02.21	Salmonella meningitis
A04.71 - A04.72	Enterocolitis due to Clostridium difficile [intra-abdominal abscess, pseudomembranous colitis (antibiotic-induced colitis)]
A17.0	Tuberculous meningitis
A27.81	Aseptic meningitis in leptospirosis
A30.5	Lepromatous leprosy
A35	Other tetanus
A39.0	Meningococcal meningitis
A40.0 - A41.3 A41.50 - A41.9	Sepsis [except sepsis due to anaerobes]
A42.0 - A42.2 A42.81 - A42.9 A43.0 - A43.9 B47.0 - B47.9 L08.1	Actinomycotic infections
A49.02	Methicillin resistant Staphylococcus aureus infection, unspecified site
A50.41	Late congenital syphilitic meningitis
A51.41	Secondary syphilitic meningitis
A52.13	Late syphilitic meningitis
A54.81	Gonococcal meningitis
A69.20 - A69.9	Lyme disease
B15.0 - B19.9	Viral hepatitis
B20	Human immunodeficiency virus [HIV] disease
B35.0 - B47.0 B48.0 - B49	Mycoses
C00.0 - C43.9 C44.0 - C75.9 C76.0 - C86.6 C88.4 - C94.32 C94.80 - C96.4 C96.6 - C96.9	Malignant neoplasm [cancer]
C71.0 - C71.9	Malignant neoplasm of brain [glioblastoma]
D00.00 - D09.9	In situ neoplasms [cancer]
D57.00 - D57.819	Hb-SS disease with crisis [sickle cell crisis]
D68.61	Antiphospholipid syndrome
D68.62	Lupus anticoagulant syndrome
E11.311 - E11.39	Type 2 diabetes mellitus with ophthalmic complications
E83.2	Disorders of zinc metabolism
E83.59	Other disorders of calcium metabolism [calciphylaxis (calcific uremic arteriolopathy)]
F01.50 - F01.C4 F03.90 - F03.C4 F05	Dementias [cognitive impairment]
F06.8	Other persistent mental disorders due to conditions classified elsewhere [dementia NOS] [cognitive impairment]
F07.0	Personality change due to known physiological condition [cognitive impairment]
F07.81	Postconcussional syndrome
F07.89	Other personality and behavioral disorders due to known physiological condition [cognitive impairment]
F32.0 - F33.9	Depression
F43.10 - F43.12	Post-traumatic stress disorder
F80.0 - F89	Pervasive and specific developmental disorders
F84.0	Autistic disorder
G00.0 - G03.1 G03.8 - G03.9 G04.2	Meningitis- bacterial, due to other organisms, and of unspecified cause
G06.0	Intracranial abscess and granuloma
G20	Parkinson's disease
G21.11 - G21.19	Other drug-induced secondary parkinsonism
G30.0 - G31.2 G31.83 - G31.9 G91.0 - G91.2 G93.7, G94	Alzheimer's disease and other degenerative diseases of nervous system [cognitive impairment]
G35	Multiple sclerosis
G37.1 - G37.3 G37.8 - G37.9	Acute transverse myelitis in demyelinating diseases of central nervous system [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 G45.8 - G45.9 I67.8	Transient cerebral ischemic attacks and related syndromes [acute or chronic cerebrovascular insufficiency]
G45.4	Other specified cerebrovascular diseases [acute or chronic cerebrovascular insufficiency/accident including thrombotic or embolic stroke]
G51.0	Bell's palsy
G51.8	Other disorders of facial nerve [facial neuritis]
G61.0	Guillain-Barre syndrome
G80.0 - G80.9	Cerebral palsy
G89.21 - G89.3	Chronic pain, not elsewhere classified
G89.4	Chronic pain syndrome
G90.50 - G90.59	Complex regional pain syndrome I (CRPSI)
G93.1	Anoxic brain damage, not elsewhere classified
G93.6	Cerebral edema [acute]
H00.011 - H34.03, H34.211 - H59.89	Diseases of the eye and adnexa [except central retinal artery occlusion]
H60.00 - H60.93	Otitis externa
H83.3X1 - H83.3X9	Noise effects on inner ear [noise-induced sensorineural hearing loss]
H90.41 - H90.42	Sensorineural hearing loss, unilateral with unrestricted hearing on the contralateral side [noise-induced sensorineural hearing loss]
H90.5	Unspecified sensorineural hearing loss [noise-induced sensorineural hearing loss]
H93.11 - H93.19	Tinnitus
I20.0, I21.01 - I22.9, I21.A1 - 121.A9, I24.0 - I24.9, I25.2	Ischemic heart diseases
I26.01 - I52	Heart disease
I61.0 - I61.9	Nontraumatic intracerebral hemorrhage
I63.00 - I66.9	Cerebral infarction and occlusion and thrombosis of precerebral and cerebral arteries, not resulting in cerebral infarction [acute or chronic cerebrovascular insufficiency/accident including thrombotic or embolic stroke]
I67.1 - I67.2 I67.4 - I67.9	Other cerebrovascular diseases [acute or chronic cerebrovascular insufficiency/accident including thrombotic or embolic stroke]
I69.910 - I69.919	Cognitive deficits following unspecified cerebrovascular disease
I73.00 - I73.01	Raynaud's syndrome
I74.8	Arterial embolism and thrombosis of other arteries [hepatic]
I77.0	Arteriovenous fistula, acquired [spinal dural]
I77.6	Arteritis, unspecified [Lupus vasculitis]
I89.0, I97.2	Lymphedema
J43.0 - J43.9	Emphysema
J44.0 - J44.9	Other chronic obstructive pulmonary disease [bronchitis with emphysema]
J45.20 - J45.998	Asthma
J68.0 - J68.9	Respiratory conditions due to inhalation of chemicals, gases, fumes and vapors [Acute thermal and chemical pulmonary damage, i.e., smoke inhalation (e.g., carbon tetrachloride, hydrogen sulfide) with pulmonary insufficiency]
J70.0 - J70.9	Respiratory conditions due to other external agents [Acute thermal and chemical pulmonary damage, i.e., smoke inhalation (e.g., carbon tetrachloride, hydrogen sulfide) with pulmonary insufficiency]
J84.10	Pulmonary 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 [Radiation-induced gastrointestinal complications]
K56.690 - K56.699	Other intestinal obstruction [small bowel obstruction]
K60.3	Anal fistula
K63.2	Fistula of intestine [enterocutaneous fistulae]
K63.89	Other specified diseases of intestine [intestinal anastomosis]
K65.1	Peritoneal abscess [intra-abdominal]
K70.0 - K77	Diseases of liver
K72.00 - K72.01 K76.2	Acute and subacute hepatic failure
K73.0 - K73.9	Chronic hepatitis, NEC
K83.01 - K83.09	Cholangitis [radiation-induced hemorrhagic]
L08.0, L08.81 - L08.9 L88, L98.0	Other local infections and disorders of the skin and subcutaneous tissue [except Meleney's ulcer] [infection other than clostridial]
L55.0 - L55.9 L56.0 - L56.9 L57.0 - L57.1 L57.5 - L57.9	Contact dermatitis and other eczema due to solar radiation [actinic skin damage]
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	Chloasma [melasma]
L91.0	Hypertrophic scar [epithelial-to-mesenchymal transition (EMT) phenomenon in keloid tissue]
M00.00 - M12.19 M12.50 - M19.93	Arthropathies
M27.61	Endosseous dental implant failure
M32.0 - M32.9	Systemic lupus erythematosus (SLE) [ischemia due to lupus vasculitis]
M34.0 - M34.2	Systemic sclerosis [scleroderma]
M48.50x+ - M48.58x+ M80.00x+ - M80.88x+ M84.40x+ - M84.48x+	Pathologic fracture [fracture healing]
M62.20 - M62.28	Nontraumatic ischemic infarction of muscle [critical limb ischemia]
M79.10 - M79.18	Myalgia [myofascial pain syndrome]
M79.7	Fibromyalgia
M81.0 - M81.8	Osteoporosis without current pathological fracture
M87.00 - M87.9	Idiopathic aseptic necrosis of bone
M91.10 - M91.12	Juvenile osteochondrosis of head of femur [Legg-Calve-Perthes]
N30.10 - N30.11	Interstitial cystitis (chronic)
N30.81	Other cystitis with hematuria [Chemotherapy-induced hemorrhagic cystitis]
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 female intestinal-genital tract fistulae [rectovaginal fistula]
O90.0	Disruption of cesarean delivery wound
P25.0 - P25.8	Interstitial emphysema and related conditions originating in the perinatal period
Q15.0	Congenital glaucoma
Q54.0 - Q54.9	Hypospadias
Q82.0	Hereditary lymphedema [legs]
R23.1	Pallor [Livedo reticularis]
R31.0 - R31.9	Hematuria
R41.4	Neurologic neglect syndrome [cognitive impairment]
R41.81	Age-related cognitive decline
R41.82	Altered mental status [cognitive impairment]
R56.00 - R56.9	Convulsions, not elsewhere classified
R57.0	Cardiogenic shock
R65.10 - R65.11	Systemic inflammatory response syndrome (SIRS) of non-infectious origin
S04.011+ - S04.049+	Injury of optic nerve and pathways [ophthalmologic diseases (including diabetic retinopathy, retinal detachment, central retinal artery occlusion, radiation injury to the optic nerve, glaucoma, keratoendotheliosis)]
S06.0x0+ - S06.9x9+	Intracranial injury [cognitive impairment] [not covered for traumatic brain injury]
S09.8xx+ - S09.90x+	Specified and unspecified head injury [cognitive impairment] [closed head injury]
S14.101+ - S14.139+ S14.151+ - S14.159+ S24.101+ - S24.139+ S24.151+ - S24.159+ S34.101+ - S34.139+	Other and unspecified injury of cervical, thoracic, lumbar and sacral spinal cord
T20.00x+ - T25.799+ T30.0 - T30.4	Burns and corrosions of head, face, neck, trunk, upper limb, wrist and hand, lower limb, and multiple and unspecified body regions [skin, thermal]
T33.011+ - T34.99x+	Frostbite [face, hand, foot, and other and unspecified sites]
T53.0x1+ - T53.0x4+ T53.5x1+ - T53.5x4+ T59.0x1+ - T59.1x4+ T59.3x1+ - T59.6x4	Toxic effects of other gases, fumes, or vapors [other than carbon monoxide] [Acute thermal and chemical pulmonary damage, i.e., smoke inhalation (e.g., carbon tetrachloride, hydrogen sulfide) with pulmonary insufficiency]
T63.001+ - T63.94x+	Toxic effect of contact with venomous animals and plants [necrotizing arachnidism]
T81.30x+ - T81.33x+	Disruption of wound [dehiscence of operation wound]
T84.010+ - T84.498+	Mechanical complication of internal orthopedic devices, implants and grafts [bone grafts]
T84.60x+ - T84.7xx+	Infection and inflammatory reaction due to internal fixation devices and other internal orthopedic prosthetic devices, implants and grafts [bone grafts]
U07.1	COVID-19
Z40.01	Encounter for prophylactic removal 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 Z95.2 - Z95.4 Z95.811 - Z95.812 Z95.820 - Z95.828 Z96.0 - Z96.1 Z96.3, Z96.5 - Z97.16	Transplanted organ and tissue status, and presence of cardiac and vascular implants and grafts and other functional implants and other devices [organ transplant or storage]
Numerous options	Aftercare for healing fracture [Codes not listed due to expanded specificity]
Numerous options	Fractures, including malunion and nonunion [Codes not listed due to expanded specificity]
Numerous options	Intracranial injury, sequela [Codes not listed due to expanded specificity]
ICD-10 codes contraindicated for this CPB:
A28.1, A60.00 - A99 B00.0 - B19.9 B25.0 - B34.9 B97.0 - B97.89 L44.4	Viral infections and diseases
A48.1, B44.9 J00 - J99 M34.81, R09.1	Diseases of the respiratory system [lung disease including J93.0 - J93.9 untreated pneumothorax]
D58.0	Hereditary spherocytosis [congenital]
P07.00 - P07.32	Disorders of newborn related to short gestation and low birth weight, not elsewhere classified [premature infants (birth prior to 37 weeks)]
R50.9	Fever [high]

Background

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". 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”.

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".

An UpToDate review of chemotherapy-induced and radiation-induced hemorrhagic cystitis in cancer patients (Linder, et al., 2022) stated that "HBO appears to be effective for both RT-induced and chemotherapy-induced HC, although the bulk of the efficacy data are in patients with radiation-induced HC."

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.

You et al (2022) noted that IBD is a chronic idiopathic inflammatory disease that includes UC and CD. Available evidence suggested that HBOT might be an effective therapy for IBD; however, a quantitative analysis is lacking. In a systematic review and meta-analysis, these investigators estimated the adjunctive role of HBOT in the treatment of IBD and reduction of recurrence rate. The Cochrane Library, Embase, PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), and Wanfang databases were systematically searched by 2 independent reviewers. Meta-analyses were carried out using Review Manager (RevMan, version 5.3). A random-effects model was applied due to the heterogeneity between studies. A total of 29 out of the initially identified 606 articles were covered in this review, with a total of 2,151 patients (2,071 for UC and 80 for CD). No randomized data of HBOT for CD were included. Among UC patients, usual care plus HBOT were more likely to achieve a clinical response than usual care alone (RR, 1.24; 95 % CI: 1.17 to 1.31; p < 0.001). Subgroup analysis showed that the number of HBOT sessions had no statistically significant effect on overall efficacy (p > 0.05). The pooled data showed a lower recurrence rate in the usual care plus HBOT group (RR, 0.35; 95 % CI: 0.24 to 0.53; p < 0.001). The standardized mean difference (SMD) in the serum tumor necrosis factor (TNF) level between HBOT and non-HBOT groups was -2.13 (95 % CI: -3.09 to -1.18; Pp < 0.001). No severe AEs of HBOT were observed. The authors concluded that HBOT might be a safe and effective adjunctive treatment for IBD. Moreover, these researchers stated that further studies are needed to examine the optimal protocol of HBOT in the treatment of patients with IBD.

McCurdy et al (2022) stated that accumulating evidence suggested that HBOT may be effective for the treatment of IBD. In a systematic review, these investigators examined the safety and effectiveness of HBOT in various IBD phenotypes. They carried out a proportional meta-analysis. Multiple databases were searched from inception through November 2020 without language restriction. These researchers included studies that reported safety and/or effectiveness of HBOT in IBD. Weighted summary estimates with 95 % Cis were calculated for clinical outcomes for each IBD phenotype using random-effects models. Study quality was assessed using the Cochrane evaluation handbook and National Institute of Health (NIH) criteria. A total of 19 studies with 809 patients total were eligible: 3 RCTs and 16 case series. Rates of clinical remission included 87 % (95 % CI: 10 to 100) for UC (n = 42), 88 % (95 % CI: 46 to 98) for luminal CD (n = 8), 60 % (95 % CI: 40 to 76) for perianal CD (n = 102), 31 % (95 % CI: 16 to 50) for pouch disorders (n = 60), 92 % (95 % CI: 38 to 100) for pyoderma gangrenosum (n = 5), and 65 % (95 % CI: 10 to 97) for perianal sinus/metastatic CD (n = 7). Of the 12 studies that reported on safety, 15 % of patients (n = 30) had minor AEs. Study quality was low in the majority of studies due to an absence of comparator arms, inadequate description of concomitant interventions, and/or lack of objective outcomes. The authors concluded that limited high-quality evidence suggested that HBOT was safe and associated with substantial rates of clinical remission for multiple IBD phenotypes. Moreover, these researchers stated that well-designed RCTs are needed to confirm the benefit of HBOT in the treatment of IBD.

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 (2020) 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.

In a systematic review and meta-analysis, Chua et al (2022) examined the safety and effectiveness of HBOT in hypospadias repair. These investigators carried out a literature search in May 2021. Comparative studies examining the surgical outcome of hypospadias repair between control versus HBOT were identified and evaluated according to Cochrane collaboration recommendations. The evaluated outcome included hypospadias repair failures and graft failure for staged repair using a buccal graft; RR with corresponding 95 % CIs were extrapolated. A random-effect model was used to generate pooled effect estimates. Heterogeneity and inter-study variability were assessed using Chi-square and I-square. Subgroup analysis was carried out according to primary repair versus redo-hypospadias with buccal graft. A total of 5 comparative studies with 576 cases (301 HBOT versus 275 controls) were included. Overall pooled effect estimates showed that the HBOT group has significantly lesser hypospadias repair failure (RR 0.52, 95 % CI: 0.37 to 0.72). Subgroup analysis on the use of HBOT for graft take showed lesser graft failure compared to the control group (RR 0.20, 95 % CI: 0.05 to 0.75), while the use of HBOT for primary and redo single staged hypospadias repair showed lesser complication rate (RR 0.56, 95 % CI: 0.40 to 0.78). Based on ROBINS-I assessment, all included comparative studies were determined to be of serious risk of bias mainly due to presence of confounding. The authors concluded that the currently available low-quality of evidence suggested that compared to control groups, HBOT as an adjunctive intervention to complicated hypospadias repair was able to reduce surgical outcome failure and graft failure rates.

In a systematic review and meta-analysis, Anand et al (2022) examined the available evidence on the the use and safety of HBOT as an adjunctive treatment in complicated re-operative cases of hypospadias. These investigators searched the PubMed, Embase, Web of Science, and Scopus databases on August 5, 2021. Patients were divided into 2 groups: HBOT and non-HBOT. The main outcomes were graft failure rate and the incidence of complications following urethroplasty. The proportion of patients developing AEs due to HBOT was the secondary outcome. The pooled risk ratio and heterogeneity were calculated using the Mantel-Haenszel method and the I2 statistics, respectively. The quality assessment of the included studies was carried out using the Downs and Black scale. A total of 4 studies constituting 176 patients (101 in the HBOT group) were included. Variations were observed among these studies in terms of the age of subjects, the number and types of previous operations performed, and the protocol of administration of HBOT. The graft failure rate (RR 0.19; 95 % CI: 0.05 to 0.73, p = 0.02) and the incidence of complications (RR 0.40, 95 % CI: 0.20 to 0.77, p = 0.007) were significantly lower in the HBOT versus the non-HBOT group. Apart from myringotomy insertion (n = 10; 9.9 %) and claustrophobia (n = 1), no other AEs were associated with HBOT. All studies had a moderate risk of bias. An almost perfect agreement (kappa = 0.956, p < 0.0001) was observed between the 2 investigators assessing the risk of bias. The authors concluded that this systematic review and meta-analysis significantly favored the administration of HBOT versus no HBOT in terms of graft failure rate and incidence of complications following urethroplasty. Furthermore, the available data highlighted the safety of HBOT in complicated cases of hypospadias. Moreover, these researchers stated that well-designed RCTs are needed for an optimal comparison between the 2 treatment groups.

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.

Avascular Necrosis / Prevention of Avascular Necrosis

Mei-Dan and colleagues (2008) stated that talar neck fractures are a rare injury that account for less than 2% of all foot fractures. Displaced fractures are associated with an exceedingly high rate of avascular necrosis (AVN). The incidence of AVN following Hawkins Type 3 fractures of the talar neck may approach 100%, especially if diagnosis and reduction are delayed. Severe cases may present as pain and disability of the ankle and the subtalar joints due to a talar dome collapse, resulting in degenerative changes that usually require hind-foot arthrodesis. These researchers presented 2 cases of traumatic displaced talar neck fractures that were treated surgically more than 2 weeks following injury due to a delay in diagnosis. Both patients underwent HBOT following the operation and neither resulted in AVN of the talus in a 3-year follow-up. The authors suggested that this favorable result may be due to the beneficial effects of HBOT. Moreover, these researchers stated that further research is needed to confirm these findings and verify the mechanisms involved in HBOT and the optimal protocols and timing for initiating such treatment.

Furthermore, an UpToDate review on “Treatment of nontraumatic hip osteonecrosis (avascular necrosis of the femoral head) in adults” (Jones and Mont, 2020) considers hyperbaric oxygen as one of the unproven therapies. It states that “Hyperbaric oxygen may improve osteonecrosis by increasing oxygen early in the ischemic case, but the evidence is mixed. One study evaluated hyperbaric oxygen use compared with compressed air on pain and radiographic outcomes in early osteonecrotic lesions of the hip (Ficat stage II). Patients who received hyperbaric oxygen had a significantly lower pain score compared with controls. After 7 years, all patients demonstrated lesion improvement on MRI and none required total hip arthroplasty. In a study, treatment with hyperbaric oxygen in osteonecrosis patients resulted in a decreased amount of the circulating proinflammatory cytokines tumor necrosis factor (TNF) alpha and interleukin (IL) 6. This may ultimately result in improved healing of the osteonecrotic lesion. These results give reason to believe that further investigation of hyperbaric oxygen as a treatment for osteonecrosis of the femoral head is warranted”.

Bone Healing / Bone Reconstruction

In a systematic review, Ferreira Junior and colleagues (2020) examined the benefits of HBOT after bone reconstruction procedures in humans and identified information that may be useful for the development of optimal protocols for HBOT to stimulate bone healing. These investigators searched the electronic data-base PubMed/Medline for studies published between January 1999 and December 2018, using the key words: "bone" or "bone graft" and "mandible reconstruction" or "jaw reconstruction" and "hyperbaric oxygen" or "HBO". First, the titles and abstracts of the studies found were evaluated and those that corresponded to the objectives of this review were pre-selected for analysis of the full text. Subsequently, the full texts were analyzed, and those that met the eligibility criteria were pre-selected for the review. The full texts of studies whose abstracts did not provide enough data for decision were also evaluated; 2 examiners independently evaluated eligibility, risk of bias and extracted data. A total of 2,237 studies were found according to pre-established criteria for data collection, of which only 5 studies were included in this review. Although these researchers observed positive findings in the included studies, there were still few standardized clinical studies in the literature, assessing HBOT after extensive bone reconstructive procedures. The authors concluded that it was difficult to compare results found in different studies due to the variety of methodological and clinical conditions assessed.

Livedo Reticularis

Dean and Werman (1998) reported the case of a 66-year old woman with diabetes mellitus (DM) and end-stage renal disease (ESRD) who presented with painful bilateral lower extremity livedo reticularis and necrotic ulcerations. Her distal lower extremity pulses were intact and plethysmographic studies confirmed relatively normal large vessel arterial perfusion. Extensive laboratory analysis was remarkable for an elevated calcium x phosphorous product and parathyroid hormone (PTH) level. An ulcer biopsy revealed small vessel medial calcinosis, and calciphylaxis was subsequently diagnosed. Despite aggressive wound debridement, antibiotics, and subtotal parathyroidectomy, her ulcers failed to improve significantly prompting a trial of HBOT. After 7 weeks of HBOT, her ulcers had essentially healed. The authors concluded that considering the often dismal outcome of conventionally treated calciphylaxis, novel therapies are needed. These preliminary results with HBOT were encouraging; larger trials addressing new therapeutic approaches such as HBOT are needed.

Banham (2013) stated that livedoid vasculopathy (LV) is a painful, ulcerating condition of the lower legs, ankles, and feet with the typical histological feature of hyalinizing vascular change of dermal blood vessels with minimal inflammation. Therapeutic interventions have been diverse and varyingly successful. These investigators reported a biopsy-proven case in a 27-year old man who responded rapidly and completely to HBOT. A few such cases had been reported previously, but only in dermatological journals, not in the hyperbaric medicine literature.

Micieli and Alavi (2018) noted that LV is a painful, ulcerative condition of the lower extremities for which no established treatment exists. Current treatment paradigms rely on low levels of evidence, primarily case reports and case series. These researchers systematically reviewed the treatment for LV and synthesized the available clinical data. They carried out a systematic review of the literature using Ovid Medline (covering the period January 1, 1946, through June 9, 2017) and Ovid Embase (covering January 1, 1947, through June 9, 2017) data-bases with a broad and inclusive search strategy along with a subsequent search of the references of retrieved articles. All case series reports published in the English language and in a peer-reviewed journal discussing the treatment for LV diagnosis were included. A total of 29 case series reports published in the English language and in a peer-reviewed journal discussed the treatment for LV. These reports represented a total of 339 patients, of whom 230 (68%) were female and 69 (20%) were male; sex was not stated for 40 patients. Treatment with anti-coagulants, anti-platelets, anabolic steroids, thrombolytics, HBOT, intravenous immunoglobulins (IVIGs), vitamin supplementation, ultra-violet (UV) light, and a combination of 1 or more of these among other therapies had a favorable outcome. Anti-coagulants were the most commonly used monotherapy, achieving a favorable response in 62 of 63 patients (98%). Anabolic steroids, IVIGs, and anti-platelets were the 2nd, 3rd, and 4th most commonly used treatments, respectively. All of these therapies were associated with good clinical outcomes; AEs were observed in 44 patients (13%). The authors concluded that a variety of treatments with varying degrees of success had been used to treat LV; however, randomized clinical trials should be performed in the future to better establish these treatments in clinical practice. HBOT was described as the sole treatment for LV in 1 case series; HBOT was not used as a 1st-line therapy in any patient, but was used in combination with danazol in 1 patient who was able to achieve remission. Minor AEs were reported in 5 of 8 patients (63%).

Furthermore, an UpToDate review on “Approach to the patient with retiform (angulated) purpura” (Kelly, 2020) does not mention HBOT as a management / therapeutic option.

Noise-Induced Sensorineural Hearing Loss

Heyn and Van Opstal (1976) compared 2 series of patients with noise-induced hearing loss treated by vasodilators or vasodilators and HBOT. This (combined) therapy appeared to give better results than the vasodilators only; however, the patients had to be treated before 10 days after the noise exposition. In the 2 series of acoustic trauma the authors rarely observed a complete recovery from the hearing loss.

Salihoglu et al (2015) stated that most commonly used treatment modalities for acute acoustic trauma (AAT) include steroid and HBOT. These investigators examined the effectiveness of combined steroid and HBOT in patients who develop AAT during firearms training and the effect of delay to treatment on treatment success. Patients admitted with the complaint of hearing loss after firearms training between January 2011 and April 2013 were evaluated retrospectively. Patients were grouped according to date of admission; patients admitted within the first 10 days were included in Group A and those admitted between Days 11 and 30 in Group B. A total of 48 patients (73 ears) with AAT were included. There were 37 ears in Group A and 36 ears in Group B. The number of ears with complete treatment response, partial treatment response and treatment failure (unchanged) were 1 (2.7%), 7 (18.9%) and 29 (78.4%) in Group A; and 0 (0%), 3 (8.3%) and 33 (91.7%) in Group B, respectively. There was no statistically significant difference between the groups (p = 0.095). Late-term results (at Week 6) demonstrated Group A showed higher hearing gain on high frequencies than Group B (p < 0.05); however, this result was not consistent with clinical outcome results. The authors concluded that the success rate of combined HBOT and steroid therapy was very low (2.7% and 18.9% for complete treatment response, and partial treatment response, respectively) in this study; however, early initiation of treatment resulted in better outcomes. These researchers stated that protective measures had great importance in preventing AAT.

Lamm et al (2016) noted that concurrent HBOT and intra-tympanic steroid application (ITS) are beneficial as salvage therapy for therapy-refractory sudden sensorineural hearing loss (SSNHL). The findings encourage further research on the treatment of noise-induced and idiopathic SSNHL with concurrent use of HBOT and ITS respecting also patients with long-term or therapy-refractory SSNHL.

Sun et al (2018) compared the efficacy of intra-tympanic dexamethasone (ITD) therapy and HBOT for the salvage treatment of patients with high-frequency SSNHL after the failure of conventional therapy. A total of 104 refractory high-frequency SSNHL patients were enrolled in this trial. Among them, 31 received ITD alone (ITD group), 32 received HBOT alone (HBOT group) and 41 received no salvage therapies (control group). Hearing outcomes were determined by pure-tone average measured by audiometry. The total effective rates in the hearing recovery and improvement of tinnitus were calculated before and after salvage treatment. There was no significant difference of the total effective rates in the hearing recovery between ITD and HBOT group (p = 0.368). However, ITD therapy showed much better improvements of tinnitus than HBOT (p = 0.039). After ITD and HBOT, there were no significant differences in hearing gains at 2- and 4-KHz between ITD and HBOT group (p = 0.468 and 0.934, respectively). Nevertheless, ITD therapy showed significant improvements of hearing gains at 8-KHz (p = 0.049) compared to that of HBOT. The authors concluded that ITD therapy may have better improvements of tinnitus and hearing gains at 8-KHz than HBOT in patients with refractory high-frequency SSNHL.

Bayoumy et al (2020) stated that AAT is a SSNHL due to exposure to an intense impulse noise that resulted in cochlear hypoxia; HBOT could provide an adequate oxygen supply. In a retrospective study, these investigators examined the effectiveness of early treatment with combined HBOT and corticosteroid in patients with AAT compared with corticosteroid monotherapy. This trial was carried out on military personnel diagnosed with AAT between November 2012 and December 2017. Inclusion criteria for HBOT were hearing loss of 30 dB or greater on at least one, 25 dB or more on at least 2, or 20 dB or more on 3 or more frequencies as compared with the contralateral ear. Absolute hearing improvements showed significant differences (independent t-test) between patients receiving HBOT and the control group at 500-Hz (p = 0.014), 3,000-Hz (p = 0.023), 4,000-Hz (p = 0.001) and 6,000-Hz (p = 0.01) and at the mean of all frequencies (p = 0.002). Relative hearing improvements were significantly different (independent t-test) at 4,000-Hz (p = 0.046) and 6,000-Hz (p = 0.013) and at all frequencies combined (p = 0.005). Furthermore, the percentage of patients with recovery to the functional level required by the Dutch Armed Forces (clinical outcome score) was higher in the HBOT group. The authors concluded that early-stage combination therapy for patients with AAT was associated with better audiometric results at higher frequencies and better clinical outcome score.

Furthermore, an UpToDate review on “Sudden sensorineural hearing loss in adults: Evaluation and management” (Weber, 2020) states that “Hyperbaric oxygen therapy (HBOT) may be used an adjuvant to initial glucocorticoid treatment, although there is a lack of high-quality data supporting this approach. In a retrospective study of almost 300 patients with SSNHL comparing the addition of intratympanic glucocorticoids or HBOT to systemic glucocorticoids, adjuvant intratympanic glucocorticoid therapy was associated with a higher rate of hearing recovery than HBOT … Adjuvant HBOT may be of benefit when used with glucocorticoid salvage therapy for those with an inadequate response to initial treatment, particularly for those patients with a more profound (> 70 dB) hearing loss”.

Radiation-Induced Gastro-Intestinal Complications (e.g., Diarrhea, Pain and Rectal Bleeding)

Yuan and colleagues (2020) noted that radiotherapy is a routine treatment for pelvic cancer patients. While it had been proven effective, gastro-intestinal (GI) side effects remain a concern, impairing the QOL. A few studies focused on the effects of HBOT to alleviate radiation-induced GIcomplications. In a meta-analysis, these investigators examined the effectiveness of HBOT for the treatment of radiation-induced GI side effects. They carried out a literature search with PubMed, Embase, and Cochrane Library up to March 14, 2019. Literatures regarding HBOT on patients undergoing pelvic cancer (endometrial, cervix, rectum, or prostate cancers) radiotherapy were collected, and the effects of HBOT on radiotherapy-induced GI complications were evaluated. A random-effects model was used to calculate the pooled effect size; subgroup analyses were performed to search for sources of heterogeneity. Publication bias was detected with Funnel plots and Egger's test. A total of 3 different radiotherapy-related GI complications, including diarrhea, pain, and rectal bleeding were analyzed after screening. It was revealed that the improvement rates were considerable in rectal bleeding (0.81, 95% CI: 0.74 to 0.89) and diarrhea (0.75, 95% CI: 0.61 to 0.90) and slightly in pain (0.58, 95% CI: 0.38 to 0.79). Subgroup analysis revealed factors that significantly influenced the heterogeneity of diarrhea, pain, and rectal bleeding (evaluation criteria, follow-up time, and scoring system, respectively). No significant publication bias was detected. The authors concluded that HBOT might have the potential to alleviate radiotherapy-related GI complications, including diarrhea, pain and rectal bleeding; however, more data are needed for further conclusions. Other symptoms were not further analyzed, as the number of studies was insufficient. These researchers stated that more large-scale and prospective studies are needed to better examine the therapeutic values of HBOT.

The authors stated that this meta-analysis had several drawbacks. Among all the articles included in the 3 symptoms analyzed, there was only 1 prospective study and 2 RCTs, making it difficult to determine how much of reported improvement was attributable to HBOT rather than the placebo effect. Although these investigators presented the improvement rates in control group as a baseline data in supplementary materials, there could be some bias as only 2 RCTs were included in this work. And since the population of included studies was small, additional large-scale studies are needed to increase the quality of data. Furthermore, there were several methods of evaluating the degree of symptoms, adding complexity in cross-study comparisons.

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.

COVID-19

Thibodeaux, et al. (2020) reported on outcomes of a series of COVID-19 positive patients (n=5) at a single institution who received hyperbaric oxygen therapy (HBOT) between April 13 and 20, 2020. All the patients had tachypnoea and low oxygen saturation despite receiving high FiO2. HBOT was added to prevent the need for mechanical ventilation. A standard dive profile of 2.0ATA for 90 minutes was employed. Patients received between one and six treatments in one of two dedicated monoplace hyperbaric chambers. All the patients recovered without the need for mechanical ventilation. Following HBOT, oxygen saturation increased, tachypnoea resolved and inflammatory markers fell. At the time of writing, three of the five patients had been discharged from the hospital and two remain in stable condition. The authors stated that this small sample of patients exhibited dramatic improvement with HBOT. Most importantly, HBOT potentially prevented the need for mechanical ventilation. The authors concluded that larger studies are likely to define the role of HBOT in the treatment of this novel disease.

Gorenstein, et al. (2020) evaluated the safety and efficacy of hyperbaric oxygen for COVID-19 patients with respiratory distress in a single-center clinical trial of COVID-19 patients at NYU Winthrop Hospital from March 31 to April 28, 2020. Patients in this trial received hyperbaric oxygen therapy at 2.0 atmospheres of pressure in monoplace hyperbaric chambers for 90 minutes daily for a maximum of five total treatments. Controls were identified using propensity score matching among COVID-19 patients admitted during the same time period. Using competing-risks survival regression, we analyzed our primary outcome of inpatient mortality and secondary outcome of mechanical ventilation. The investigators treated 20 COVID-19 patients with hyperbaric oxygen. Ages ranged from 30 to 79 years with an oxygen requirement ranging from 2 to 15 liters on hospital days 0 to 14. Of these 20 patients, two (10%) were intubated and died, and none remain hospitalized. Among 60 propensity-matched controls based on age, sex, body mass index, coronary artery disease, troponin, D-dimer, hospital day, and oxygen requirement, 18 (30%) were intubated, 13 (22%) have died, and three (5%) remain hospitalized (with one still requiring mechanical ventilation). Assuming no further deaths among controls, the investigators estimated that the adjusted subdistribution hazard ratios were 0.37 for inpatient mortality (p=0.14) and 0.26 for mechanical ventilation (p=0.046). The investigators concluded that, though limited by its study design, their results demonstrate the safety of hyperbaric oxygen among COVID-19 patients and strongly suggests the need for a well-designed, multicenter randomized control trial.

Guo, et al., (2020) reported on the outcomes of hyperbaric oxygen therapy in two male patients ages 57 and 64 years with pneumonia and hypoxemia. Each met at least one of the following criteria: shortness of breath; respiratory rate (RR) ≥30 breaths/minute; finger pulse oxygen saturation (SpO2) ≤93% at rest; and oxygen index (P/F ratio: PaO2/FiO2 ≤300 mmHg). Each case excluded any combination with pneumothorax, pulmonary bullae or other absolute contraindications to HBO2. Patients were treated with 1.5 atmospheres absolute HBO2 with an oxygen concentration of more than 95% for 60 minutes per treatment, once a day for one week. Patients' self-reported symptoms, daily mean SpO2 (SO2), arterial blood gas analysis, D-dimer, lymphocyte, cholinesterase (che) and chest CT were conducted and measured. The authors reported that, for both patients, dyspnea and shortness of breath were immediately alleviated after the first HBO2 treatment and remarkably relieved after seven days of HBO2 therapy. The RR also decreased daily. Neither patient became critically ill. The decreasing trend of SO2 and P/F ratio was immediately reversed and increased day by day. The lymphocyte count and ratio corresponding to immune function gradually recovered. D-dimer corresponding to peripheral circulation disorders and serum cholinesterase, reflecting liver function had improved. Follow-up chest CT showed that the pulmonary inflammation had clearly subsided. The authors concluded that their preliminary uncontrolled case reports suggest that HBO2 therapy may promptly improve the progressive hypoxemia of patients with COVID-19 pneumonia. However, the limited sample size and study design preclude a definitive statement about the potential effectiveness of HBO2 therapy to COVID-19 pneumonia. It requires evaluation in randomized clinical trials in future.

Clincal trials of hyperbaric oxygen therapy for COVID-19 are currently ongoing (UHMS, 2020).

Preventive HBOT for Improvement of Surgical Outcome

Boet and colleagues (2020) noted that a primary underlying cause of post-operative complications is related to the surgical stress response, which may be mitigated by HBOT. Promising clinical studies have emerged suggesting HBOT's efficacy for reducing some post-operative complications. Notwithstanding, the effectiveness (if any) of HBOT across a range of procedures and post-operative outcomes has yet to be clearly quantified. In a systematic review, these investigators evaluated the available literature on peri-operative HBOT to examine its potential to optimize surgical patient outcome. They carried out a systematic review of RCTs with narrative summary of results; Medline, Embase, CINAHL and the Cochrane Central Register of Controlled Trials were searched without language restrictions through to June 19, 2018. Studies were included if they involved patients of any age undergoing any surgical procedure and provided with at least 1 HBOT session in the peri-operative period. Two independent reviewers screened the initial identified trials and determined those to be included. Risk of bias was examined using the Cochrane Risk of Bias tool for RCTs. The search retrieved 775 references, of which 13 RCTs were included (627 patients); 10 RCTs (546 patients) reported treatment was effective for improving at least one of the patient outcomes assessed, while 2 studies (55 patients) did not find any benefit and 1 study (26 patients) found a negative effect. A wide range of patient outcomes were reported, and several other methodological limitations were observed among the included studies, such as limited use of sham comparator and lack of blinding. The authors concluded that although limited in terms of both quantity and quality, there is some evidence to suggest that peri-operative preventive HBOT may be a promising intervention to improve surgical patient outcome. However, the HBOT literature relevant to this research question is heterogenous and limited by methodological issues that need to be addressed in the future. In particular, a sham group and blinded assessment of outcome should be considered for future studies along with a standardized core outcome set for hyperbaric medicine.

Diabetic Foot Ulcers

In a systematic review and meta-analysis, Zhang et al (2022) examined the effectiveness of HBOT in the treatment of diabetic foot ulcers (DFUs). Relevant articles were retrieved from PubMed, the Cochrane Library, Embase and other databases through November 2020. A total of 20 randomized clinical trials and 1,263 trials were included in the meta-analysis. For each trial, the average difference, OR and 95 % CI were calculated to evaluate the effectiveness. Hyperbaric oxygen therapy increased the healing rate of DFUs (RR, 1.901; 95 % CI: 1.484 to 2.435, p < 0.0001), shortened the healing time (MD = -19.360; 95 % CI: -28.753~ to 9.966, p < 0.001), and reduced the incidence of major amputation (RR, 0.518, 95 % CI: 0.323 to 0.830, p < 0.01). The authors concluded that the findings of this meta-analysis confirmed that HBOT offered great benefits in the treatment of DFU and the reduction of amputation. Moreover, these researchers stated that larger and well-designed RCTs are needed to verify this conclusion.

Cruz et al (2022) stated that HBOT is increasingly being used in the treatment of DFUs; however, definitive evidence regarding its beneficial effects is still scarce. In a systematic review, these researchers examined the role of HBOT in the prevention of limb amputation along with improvement of ulcer healing in patients with lower limb DFUs. A total of 3 databases were searched: PubMed, Scopus, and ISI Web of Knowledge. The search was conducted in October 2020. Both titles and abstracts were examined by 2 independent reviewers. Only RCTs reporting a comparison between standard DFU treatment and standard treatment associated with HBOT were included. In all studies eligibility was assessed and data regarding studies characteristics, methods and considered outcomes was obtained; OR was used to evaluate amputation and complete ulcer healing rates. Percentage of ulcer reduction at 2 weeks was evaluated using the inverse variance method, and the values were compared using mean difference values. Meta-analysis was performed using a fixed-effect model if I2 values were under 50 %, and a random-effects model if not. A total of 11 RCTs were included, with a total of 668 patients studied. Patients undergoing HBOT had lower risk of amputation (OR 0.53; 95 % CI: 0.32 to 0.90, I2 = 31 %). No difference was found in minor amputations (OR 0.89; 95 % CI: 0.35 to 2.24, I2 = 69%). Regarding, healing rates, HBOT patients had greater chances of ulcer healing (OR 4,00; 95 % CI: 1.54 to 10.44, I2 = 70 %). It has also shown higher percentage of ulcer area reduction after 2 weeks of treatment in the HBOT group (MD 23.19 %; 95 % CI: 14.86 to 31.52; I2 = 0 %). The authors concluded that the present review offered evidence that adjuvant HBOT lowered risk of major amputation while promoting wound healing when combined with standard treatment in the management of DFUs. These researchers stated that these findings may have clinical relevance in a selected group of patients; however, further larger studies are still needed.

Gender Reassignment Surgery

Stizzo et al (2022) noted that several urological conditions that share an impairment of tissue oxygenation could benefit from HBOT; limited evidence is available of its impact on patients undergoing male-to-female gender affirmation surgery. In a retrospective, observational study, these researchers examined safety and effectiveness of HBOT as adjuvant treatment for surgical site infections in patients undergoing male-to-female gender affirmation surgery. Subjects undergoing male-to-female gender affirmation surgery at the principal investigators' institution from January 2009 to September 2019, with a discharge diagnosis of complicated superficial or deep wound infections, were included. All patients underwent standard management of wound infection. Subjects received/not-received HBOT at the surgeon's discretion and were assigned to the HBOT versus non-HBOT group accordingly. Complete wound healing rate (primary outcome), duration of antibiotic therapy, perineal drain time, bladder catheter time, and hospital length of stay (LOS) were recorded. All AEs that occurred during the study period were described. A total of 156 patients underwent male-to-female gender affirmation surgery in the study period; 33 patients were enrolled – 15 subjects belonged to the HBOT group, the other 18 to the non-HBOT group. No statistically significant differences were found between the 2 groups at baseline. Penile inversion vaginoplasty and intestinal vaginoplasty were performed in 9 (60 %) and 6 (40 %) patients of the HBOT group. Only penile inversion vaginoplasty was carried out in subjects of the non-HBOT group. Complete wound healing was obtained in 15 patients (100 %) of the HBOT group and 17 patients (94.4 %) of the non-HBOT group (p = 0.35). Duration of antibiotic therapy, perineal drain time, bladder catheter time, and hospital LOS were significantly lower in the HBOT group (p < 0.05). The authors concluded that these preliminary findings suggested a role of HBOT as adjuvant treatment for surgical site infection in patients undergoing male-to-female gender affirmation surgery. Moreover, these researchers stated that properly powered RCTs are needed to confirm these findings.

The authors stated that the main drawbacks of this study included its retrospective design and the small sample size (n = 33). Other limitations were the absence of randomization, which may have resulted in a selection bias because of the assignment of patients with the most severe infections to the HBOT group, and the lack of follow‐up data, which did not allow evaluation of any long‐term differences between the 2 treatment arms. The lack of a standardized HBOT protocol and antibiotic therapy not based on the antibiograms were additional issues to be considered. Finally, although not included among the study objectives, functional outcomes and patient satisfaction were not examined.

Optic Neuritis

Apinyawasisuk et al (2016) reported on the case of a 19-year-old man who developed visual loss in the left eye 1 day following a martial arts kick to the head. Vision worsened over a week, when visual loss was noted in the right eye without further trauma. The fundus was initially normal, but visual field testing showed temporal depression right eye with diffuse depression left eye, and traumatic chiasmopathy was suspected; MRI of the brain demonstrated an enlarged chiasm with intrinsic signal abnormality, but no enhancement. Treatment with IV corticosteroids and HBOT did not result in visual improvement. Ancillary testing for atypical optic neuritis was negative; however, testing for Leber hereditary optic neuropathy (LHON) was positive for the 11778 mutation. The authors concluded that this case raised the question of trauma as a precipitating factor for LHON and showed the rare occurrence of intrinsic signal abnormalities of the chiasm in this disorder.

Furthermore, an UpToDate review on “Optic neuritis: Prognosis and treatment” (Osborne and Balcer, 2022) does not mention HBOT as a management / therapeutic option.

Cerebral Palsy

In a systematic review, Laureau et al (2022) reported current evidence regarding the safety and effectiveness of HBOT on the impairments presented by children with CP. PubMed, the Cochrane Library, Google Scholar, and the Undersea and Hyperbaric Medical Society database were searched by 2 reviewers. Methodological quality was graded independently by 2 reviewers using the Physiotherapy Evidence Database assessment scale for RCTs and the modified Downs and Black (m-DB) evaluation tool for non-RCTs. A meta-analysis was carried out where applicable for RCTs. A total of 5 RCTs were identified; 4 had a high level of evidence and 7 other studies were observational studies of low quality. All RCTs used 100 % O2, 1.5 to 1.75 ATA, as the therapeutic intervention. Pressurized air was the control intervention in 3 RCTs, and physical therapy (PT) in 2. In all but 1 RCTs, similar improvements were observed regarding motor and/or cognitive functions, in the HBOT and control groups. AEs were mostly of mild severity, the most common being middle ear barotrauma (up to 50 % of children). The authors concluded that there is high-level evidence that HBOT is ineffective in improving motor and cognitive functions, in children with CP. In addition, there is moderate-level evidence that HBOT is associated with a higher rate of AEs than pressurized air in children.

Glioblastoma

Costa et al (2022) noted that glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults. The mainstay of management for GBM is surgical resection, radiation (RT), and chemotherapy (CT). Even with optimized multi-modal treatment, GBM has a high recurrence and poor survival rates ranging from 12 to 24 months in most patients. Recently, relevant advances in understanding GBM pathophysiology have opened new avenues for therapies for recurrent and newly diagnosed diseases. GBM's hypoxic micro-environment has been shown to be highly associated with aggressive biology and resistance to RT and CT. Hyperbaric oxygen therapy may increase anti-cancer therapy sensitivity by increasing oxygen tension within the hypoxic regions of the neoplastic tissue. Previous studies have examined the use of HBOT in combination with cytostatic compounds, with an improvement of neoplastic tissue oxygenation, inhibition of hypoxia-inducible factor (HIF)-1α activity, and a significant reduction in the proliferation of GBM cells. The biological effect of ionizing radiation has been reported to be higher when it is delivered under well-oxygenated rather than anoxic conditions. Several hypoxia-targeting strategies reported that HBOT showed the most significant effect that could potentially improve RT outcomes, with higher response rates and survival and no serious AEs. Moreover, the authors concluded that further prospective and randomized studies are needed to validate HBOT's effectiveness in the “real world” GBM clinical practice.

Vaporous Hyperoxia Therapy (VHT) for Non-Healing Diabetic Foot Wounds

Kruse et al (2021) stated that vaporous hyperoxia therapy (VHT), a patented FDA-510 (k) cleared technology, is an adjunct therapy used in conjunction with standard wound care (SWC). VHT is said to improve the health of wounded tissue by administering a low-frequency, non-contact, non-thermal ionic anti-microbial hydrating mist alternating with concentrated topical oxygen therapy (TOT). VHT was used to treat 36 subjects with chronic diabetic foot ulcers (DFUs) that were previously treated unsuccessfully with SWC. The average age of DFU in the study was 11 months old and the average size was over 3 cm2. Wounds were either Wagner grade 2 or 3 and most commonly on the plantar surface around the mid-foot. Treatment consisted of twice-weekly applications of VHT and wound debridement. Subjects were followed to wound closure, 20 weeks, or 40 treatments, whichever came first. The combination of SWC and VHT in the group that met and maintained compliance throughout the study period achieved an 83 % DFU closure rate within a 20-week time-period. The average time for DFU closure in this study was 9.4 weeks. Historical analysis of SWC showed a 30.9 % healing rate of all wounds, not differentiating chronic wounds. Accordingly, SWC/VHT increases chronic diabetic foot ulcer healing rates by 2.85 times compared with SWC alone. The purpose of this study was 2-fold: First, to observe the effect of VHT on healing rates and time-to-healing in previously non-healing DFUs; and second, to compare VHT with SWC, TOT and HBOT and ultrasound (US) therapies.

The authors stated that this study had several drawbacks. First, this study had a small number of subjects (n = 36). These researchers stated that these findings showed that VHT is a promising treatment for DFUs. Second, these investigators only examined DFUs; many other studies have mixed wound populations; thus, could extrapolate healing rates with many wound etiologies. Third, this trial was not randomized; these researchers stated that larger studies using VHT need to be carried out to properly examine their product head-to-head with similar products on the market; therefore, conditions could have been different, and these findings are potentially subject to bias. However, these results have value in providing a benchmark for healing rates using VHT in future studies.

Furthermore, UpToDate reviews on “Overview of treatment of chronic wounds” (Evans and Kim, 2022), and “Management of diabetic foot ulcers” (Armstrong and de Asla, 2022) do not mention vaporous hyperoxia therapy (VHT) as a management / therapeutic option.

Glossary of Terms

Table: Glossary of Terms
Term	Definition
Deep ulcerations	Reaching tendons or bone

Appendix

Wagner Grading System

Table: Wagner Grading System
Grade	Grade Value
Grade 0:	Intact skin
Grade 1:	Superficial diabetic ulcer
Grade 2:	Ulcer extensionInvolves ligament, tendon, joint capsule or fascia; no abscess or osteomyelitis
Grade 3:	Deep ulcer with abscess, infectious tendonitis, or osteomyelitis
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.

Transcutaneous Oximetry (TCOM)

Transcutaneous oximetry (TCOM) is a noninvasive test that measures how much oxygen is reaching the skin via blood circulation. Normal TcPO values measured in the feet of healthy adults are as follows:

Between 50 mmHg to 90 mmHg at sea level, i.e., 1 atmosphere absolute (ATA), while breathing air
Between 250 mmHg to 450 mmHg at 1 ATA while breathing 100% oxygen
Between 700 mmHg to 900 mmHg at 2 ATA while breathing 100% oxygen
Between 900 mmHg to 1300 mmHg at 3 ATA while breathing 100% oxygen

Source: Ercengiz and Mutluoglu, 2021.

Normobaric Oxygen Challenge Test

The normobaric oxygen challenge test TcPO measurement at sea level while the patient inhales 100% oxygen may also provide some clues on the potential benefit of HBOT in wound healing.

If TcPO levels remain under 35 mmHg while the patients inhale 100% oxygen, or if the increase in TcPO levels remains under 10 mmHg, almost 89% of the patients will fail to heal with HBOT.

In-chamber TcPO measurement:

TcPO levels increase above 200 mmHg inside the chamber, there will be a 74 to 88% success rate with HBOT.
TcPO remains under 100 mmHg, the failure rate with HBOT might be as high as 90%.
In-chamber TcPO2 levels under 50 mmHg are almost always associated with HBOT failure.