Evan R. Ransom, MD
University of Pennsylvania
Otorhinolaryngology, Head & Neck Surgery
Faculty Discussant:
Kevin Hardy, MD
Emergency Medicine, Hyperbaric Medicine

Overview

History
– 1662  Henshaw built first hyperbaric chamber
• English physician and clergyman
• Called the chamber the “Domicilum”
•
• Hermetically sealed box with organ bellows & valves
"In times of good health this domicilium is proposed … to promote insensible respiration, to facilitate breathing and expectoration … of excellent use for prevention of most affections of the lungs."

Background
• Elemental Oxygen
– 1775  Discovered by Priestly (English)
• Surgical use
– 1870’s  Fontaine & Bert (France)
• Prolong anesthesia
• Improved surgical outcomes
– Wound healing
– Infection rates
• Decompression sickness
– 1910-30’s  Drager, then Behnke & Shaw
• Reduced morbidity of decompression
• Studies of cardiopulmonary effects initiated

Background
• Cardiothoracic Surgery
– 1950’s  Boerema (Dutch)
• Increase tissue oxygen stores prior to cross-clamping
• Repair of congenital heart defects
– With Brummelkamp, discovered effects on anaerobes
• Bacteriostatic
• Treat gas gangrene (Clostridium perfringens)
• Carbon monoxide poisoning
– 1962  Smith & Sharp (English) treated coal minors exposed to carbon monoxide
• US Military Research
– 1930’s  determine maximal pressure tolerated
– 1960’s  potentiation of radiation doses

Common Current Uses

Theory
– Respiration is good… so why not more of it?
– What if we increase tissue oxygen delivery to supraphysiologic levels?
– How about generating more reactive oxygen to kill pathogens and tumors!?

Theory

Physics

• Compression of a given volume of gas therefore elevates its pressure
• One-way valve to add gas volume to chamber

Physics

– Increasing the proportion of oxygen in the inhaled gas mixture increases its partial pressure
• Air at sea level is 21% O2
• HBO2 treatments use FiO2 100%

Physics
• Henry’s Law  the amount of gas dissolved in a liquid is directly proportional to its partial pressure at the liquid/gas interface.
– Increasing the partial pressure of oxygen results in more oxygen dissolved in the blood
– Blood oxygen carriage therefore increases
• In addition to saturation of available hemoglobin

Physiology
– Increase in PaO2
• Saturation of available hemoglobin molecules
– Hgb 97% saturated at atmospheric pressure
– Maximization does NOT significantly increase O2 delivery
• Increase in dissolved O2
– PAO2 is 100mm Hg at atmospheric pressure
– Using 100% FiO2 at 3 atm  up to 2000mm Hg
» Increase O2 from 3ml/L blood to to 60ml/L
» 20 times more O2 circulating in plasma

Physiology
– Dissolved O2 diffuses into RBC-impassible areas
– May also deliver O2 in absence of functional Hgb
– 100% O2 at 3.0atm  effects at capillary beds
• Doubles distance of venous diffusion
• Quadruples distance of arteriolar diffusion

Physiology
• Tissue & Cellular level
– Tissue PO2 is 55mm Hg at atmospheric pressure
– Using FiO2 100% at 3atm, increase to 500mm Hg
• Almost 10 fold increase in tissue oxygen tension
• Tissue PO2 > 40mm Hg needed to initiate any healing
– Tissue response proportional to O2 delivery
• O2 diffuses down the partial pressure gradient
• Gradient from arterioles  capillary bed  venous return is increased 37 fold
– Increase activation of fibroblasts & osteoblasts
– Promotes angiogenesis & neovascularization

Mechanism
• Limit ischemic damage, cell death, and inflammation
• Promotes collagen synthesis and angiogenesis
• Decreases lactate production and tissue acidosis
• Aids in oxygen-dependent killing of bacteria
• Facilitates oxygen dependent transport of antibiotics
• Limits leukocyte adhesion and degrannulation
• Decreases tissue edema

Dosing and Delivery
– All regimens use
100% O2
– Pressure more variable
• Most use 2.4 atm
• Maximum tolerated is 3 atm
• 4 atm induces seizures
Monoplace Hyperbaric Chamber.

Dosing and Delivery
– Dives between 30 and
120 minutes
• May be daily or BID
• Total number varies by indication
– Most treatments around 30 dives
– Optional addition of 10 or more dives
– Monoplace vs. multiplace chambers
Multiplace Hyperbaric Chamber.

Contraindications
• One absolute contraindication
– Pneumothorax
• Pressure converts to tension pneumothorax
• Circulatory disruption and collapse
– All patients get screening CXR
• Relative contraindications
– History of spontaneous pneumothorax
– History of throacic surgery
– Concurrent URI
– Emphysema and COPD
– Seizure disorders

Complications
– Middle ear
• Eustachian tube dysfunction or obstruction
• Poor pressure equalization
– May cause
• Significant pain
• Hemotympanum
• TM rupture

Complications
– Lung parenchyma
• Elevated pressures may damage alveoli
– Alveolar hemorrhage
– Hemoptysis
– Pneumonitis
– Alveolar rupture
• Pneumothorax
• Pulmonary interstitial emphysema
Tension Pneumothorax

Complications
– Dental abscess, sinusitis, laryngocele, etc.
– Very rare, but may cause seizures
– Controversial – more on this later…

Fire Risk
• Perfect set up for fire (especially monoplace)
– 100% oxygen
– Highly pressurized
– Enclosed space
• Rare… but not rare enough
– 50 deaths due to HBO2-related fires since 1980
– Must remove all flammable materials
– Fire safety protocol is essential
• Risk reduced in multiplace chambers
– Chamber pressurized
– O2 delivered individually via tight-fitting masks
– Attendants may enter in an emergency

Costs
– Monoplace chamber > $150,000
– Most facilities have multiplace chambers, which can cost millions
– Each 30 min costs ~ $170
• Average full course is 30 dives of 90 min
• Billed for ~$15,300
• Plus physician fees, hospital stay, meds, etc.
– But…
• Medicare reimburses for most accepted indications

Costs
– Studies from Europe, Canada, & Japan
• Significant cost savings for multiple indications
• E.g., osteoradionecrosis of the mandible
– Reduced surgical costs in ORN patients
– Reduced length of stay
– Overall 17% cost reduction in Europe
– U.S. studies focus on diabetic foot ulcers
• HBO2 cost effective for this indication
• Very limited U.S. data for ORL-HNS indications

Applications
• Proposed or Studied for ORL-HNS
– Osteoradionecrosis
– Chondroradionecrosis
– Enhancement of graft & flap viability
– Necrotizing infections
– Chronic wounds
– Fistulas
– Malignant otitis externa
– Skull base osteomyelitis
– Sudden SNHL
– Tinnitus
– Idiopathic facial paralysis (Bell’s palsy)
– Radiation sensitization

Applications
1. Osteoradionecrosis
2. Pharyngocutaneous fistulas
3. Enhancement of graft & flap viability
4. Malignant otitis externa
5. Sudden SNHL
6. Radiation sensitization

Osteoradionecrosis
– Weakens bone, predisposing to fracture
– Often painful, broken down mucosal coverage
– Decreases blood flow, difficult to fight infection
– Least redundant blood supply & muscle coverage
– Incidence decreased significantly in last 30 years
• Lower radiation doses, more targeted fields
• Currently less than 5% of patients receiving H&N XRT

Osteoradionecrosis
– Significant fibrotic changes in bone and marrow
– Reduction in caliber & number of feeding vessels
– Periosteal & mucosal damage  bone necrosis
ORN X-ray – Mandible ORN Histology – Mandible

Osteoradionecrosis
– Multiple staging systems & treatment regimens
– Marx, et al. 1982, 1983, 1990 (retrospective)
• Sequential treatment combining HBO2, debridement, surgical resection & reconstruction
• Over 90% success rate
– Neovius, et al. 1997
• Cured 12/15 patients with ORN, CRN, or tissue necrosis
– Combination HBO2, wound care, debridement, antibiotics
• Significant improvement over historical controls (7/15)
– Conservative measures alone

Osteoradionecrosis
– Prospective, randomized, controlled trial
• enrollment after 2 months conservative Tx
• 30 dives for 90 min at 2.4 atm vs. placebo
– Placebo = Pressurized 90% Nitrogen
– No significant difference between groups!?
• Was there a biologic effect of the placebo?
• Not enough dives?

Osteoradionecrosis
• Cochrane review 2005
– Outcome measures
Primary: Survival, resolution of disease
Secondary: Mucosal coverage, bony continuity, pain (poor data)
– Identified 6 trials that met evidence standards
• Treatment algorithms differed slightly
• Pooled data for mandible
– 92% resolution with HBO2, 65% in control group
– Improved mucosal coverage (93% v. 67%)
» RR 1.4 (95%CI 1.2-1.6, p< 0.001); NNT = 4
– Improved bony continuity (92% v. 65%)
» RR 1.4 (95%CI 1.1-1.7; p=0.009); NNT = 4
– Conclusion: HBO2 is safe and likely effective for ORN

Chronic Wound Data
– Cochrane review 2005
• Lower incidence of wound dehiscence with HBO2
– 6% v. 37% post-XRT for H&N SCCA
– Significant result only in subset with flaps or grafts
• Limited data on speed of healing, major vessel bleeding, decannulation, or need for laryngectomy
– Implies that HBO2 would be useful in H&N reconstruction specifically

Chronic Wound Data
• Generalizing from other fields
– Diabetic foot ulcers
• Significant reduction in morbidity
• Significant improvement in functional outcomes
• Significant cost savings
– Mechanism shown in laboratory analyses
• Enhances fibroblast activity
– Collagen synthesis
– Neovascularization
• Improves infection control (especially anaerobes]
– Treatment response can be predicted
• Based on measurement of tissue PO2 (TcPO2)
• >40mm Hg predicts at least some response

Pharyngocutaneous Fistula
• Post-laryngectomy
• Significant increases
– Morbidity
– Cost
• Incidence
– Varies widely (3% to >50%)
– Consensus 10-15%
• Pathophysiology
– Incomplete healing or breakdown of pharyngeal suture line
– Connection develops between mucosa and skin
– First sign is generally post-op fever
Post-laryngectomy Fistula

Pharyngocutaneous Fistula
• Complications
– Major vessel bleed
– Aspiration pneumonia, infection, sepsis
– NPO status associated with poor patient QOL
• Treatment
– Most fistulas respond to conservative measures
• NPO & enteral nutrition
• Local wound care & antibiotics
– Delayed surgical closure
• Non-healing fistulas
• Large fistulas
– Local rotational flaps
– Pectoralis major flap
– Hyperbaric oxygen?
• Prophylactic? Adjuvant?

Pharyngocutaneous Fistula
• Davis, et al. 1979
– 15/16 patients with soft tissue necrosis neck post-XRT
– Poor patient descriptions, scant wound documentation
• Marx, et al. 1993
– Tested prophylactic HBO2 in post-XRT resections
• Prospective with80 patients, 80 controls
– Decreased rate and severity of wound complications
• 11% dehiscence in HBO2 vs. 48% without
• 6% infections in HBO2 vs. 24% without
• 11% prolonged hospital stay in HBO2 vs. 55% without
• Neovius, et al. 1997
– 15 patients with post-XRT wounds
– 4/5 patients with fistulas healed (3/4 with pharyngocutaneous)
• Narzony, et al. 2005
– 8 post-XRT patients successfully treated with HBO2
– 1 pt had a post-laryngectomy fistula & polymicrobial infection
• Partially closed with HBO2, infection fully treated
• Definitive closure with local muscle flap post-HBO2

Pharyngocutaneous Fistula
– Small {N}, patients grouped (i.e., not all fistulas)
– Timing and dosing of therapies differ
– Mostly retrospective data
– Post-radiation laryngectomy
– Effects of HBO2 on wound status & outcome
• Prospective data
– Predictive model for wound healing
• Tissue hypoxia
• Angiogenesis

Skin Grafts & Free Flaps
– Grafted or transplanted tissue may be healthy
– But… implantation site may be hypoxic
• Due to tissue bed disease, vasospasm, edema, infection
• Oxygen & nutrient supply compromised
• Must establish vascular connection for survival
– Improves tissue PO2
– Promotes angiogenesis
– Augments immune response & limits inflammation

Skin Grafts & Free Flaps
• Compromised skin grafts & flaps
– Ueda, et al. 1987
• Retrospective: HBO2 post-OC composite resection
• 95-100% recovery of compromised flaps & grafts
– Waterhouse, et al. 1993
• Retrospective: HBO2 for salvage of ischemic free flaps
• HBO2: 75% salvage vs. 46% without
– Tx within 24hrs  100% survival rate
– Tx > 72hrs  0% survival
– Marx, et al. 2002
• Prospective, randomized post-XRT resection
• 11% wound healing delay HBO2 vs. 55% without
• 3.5% major wound dehiscence HBO2 vs. 33% without
• 2.5% major wound infection HBO2 vs. 16% without

Malignant Otitis Externa
N Results Conclusion • Data is of poor quality
– Mostly case reports
– No prospective data
• But…
– Supports use
– Need prospective data
– Need standardization
Bath, et al. 1998
Gilain, et al. 1993
Shupak, et al. 1989
Pilgramm, et al.
1986
Davis, et al. 1992
Martel, et al. 2000
Tisch, et al. 2003
Design
Case series
Case report
Case report
Case series
Case series
Case series
Case series
1
1
2
Patient cured,
CN2 function saved
Patient cured,
CN7 function returned
Patients cured
HBO2 + Abx is beneficial
HBO2 + Abx is beneficial
HBO2 + Abx is beneficial
4
16
22
(10)
22
Patients cured
Patients cured,
4 year followup
Patients cured; used HBO2 in
10 cases
Patients cured; relapse 27% at
5 year followup
HBO2 +/- Abx is beneficial (one cure with
HBO2 alone)
HBO2 + Abx is beneficial; used 30 dives
Surgical debridement +
HBO2 (15 dives) + Abx is beneficial; Abx alone cures most cases
Surgical debridement +
HBO2 (20 dives) + Abx + anti-pseudomonal IG can cure extreme cases, but with some recurrence

Malignant Otitis Externa
• Cochrane Review 2005
– Data poor quality
• No control groups
• No randomization
• All retrospective
– Suggestion of effect
– Well-characterized and plausible mechanism
• Improved efficacy of immune response
• Enhancement of bacteriacidal antibiotic effects
– Conclusion: Need RCTs to truly evaluate this indication

Sudden SNHL
• Cochrane review 2007
– Data is of poor quality
– Found 6 trials meeting minimum standards
– Conflicting data in hearing recovery
• No difference in improvement of 50% on PTA
• Significant difference of 25% on PTA
– 22% greater chance of this amount of hearing improvement
– Clinical significance? (NNT =5)
• Data do not support use in chronic idiopathic SNHL
– Summary
• Routine use not recommended due to effect size relative to costs
• Need larger trials with randomization to determine efficacy

Radiation Sensitization
• Among first studied uses of HBO2 (1960’s)
– Areas of hypoxia in tumors are resistant to therapy
– Increasing oxygen pressure in the tumor can aid tumoricidal therapies
• Increase FiO2, increase ambient pressure (i.e., HBO2)
• Administration of radiation sensitizing agents (oxygen donors)
– Radiation concurrently (i.e., in HBO2 chamber)
• Technical difficulties (equipment)
• Multiple XRT regimen & HBO2 parameters
• Overall suggestion of survival benefit in the literature

Radiation Sensitization
• Systematic review (Bennett, et al. 2008)
– Found 19 randomized trials of HBO2 with XRT
• H&N, cervix, bladder, rectum, esophagus, brain
– H&N
• Significant mortality reduction (1 & 5 yrs)
– Difference seen between fractionization protocols
» >12 : trend to significance
» <12 : RR 0.69 (95%CI 0.53-0.89, p=0.004), ARR 20.9%
• Significant decrease in recurrence (1 & 5 yrs)
– Side effects are amplified, too…
• Significant increase in radiation morbidity
• ORN, tissue necrosis, xerostomia, etc.

Radiation Sensitization
– Timing of XRT (Concurrent? Sequential?)
– Fractionization & dosing
– XRT side effects are already difficult…
– Saving more lives with lower QOL???
– More complications = higher treatment costs

Tumor Growth!?
• Theoretical & historical concern
– HBO2 in malignancy
• Microscopic disease, positive margins, metastasis
• Does HBO2 improve tumor survival? Enhance growth?
• Data are conflicting
– Handful of case reports suggest growth
• GYN malignancies mostly, a couple in H&N CA
– Other reports suggest tumor suppression
• Currently, experiments do not show tumor progression
– Animal models
– Human SCCA cell cultures
• Systematic reviews have failed to support this concern

Tumor Growth!?
• Schonmeyr, et al. 2008
– H&N SCCA cell culture & xenotransplantation
– Measured growth
• In culture & in mice (tumor implanted on flank)
• HBO2 90 min/day for 8 days at 2.1 atm, 100% FiO2
• No significant difference in culture or mouse
– No significant difference in
• DNA synthesis
• Angiogenesis
– Trend toward less tumor hypoxia in treatment group
• This did not translate to tumor growth
• May actually be helpful for XRT or certain chemotherapeutics

Summary
– Increase in the oxygen delivery to hypoxic tissue
– Promoting native mechanisms of healing
– Decreasing tissue edema & reperfusion injury
– Most commonly 30-40 dives of 90 min at 2.4atm
– Significant, yet analyses support cost savings in proven indications

Summary
– ORN & CRN, radiation soft tissue injury
– Flap & graft survival
– Sudden SNHL, tinnitus, Bell’s palsy
– Likely effect: MOE & skull base osteo, fistulas
– Poor side effect profile: radiation sensitization

Summary
– Molecular mechanism incompletely understood
• Animal studies
• Human tissue bank studies
– Need ethical randomized control trials
• Variety of indications
– More combination regimens for cancer treatment
& post-XRT reconstruction salvage
• What are the optimal dose & delivery shemes?
• Maximize oncologic control & quality of life

References
• Books
– Handbook on Hyperbaric Medicine. D. Mathieu (ed.); Springer (Netherlands),
2006.
– Hyperbaric Medicine Practice. Kindwall P, Whelan H (eds); Best Publ. Co.
(Arizona), 2002.
• Marx RE. Radiation injury to tissue. Pp. 665-723.
• Cochrane Reviews
– Bennett MH, Feldmeier J, Hampson N, Smee R, Milross C. Hyperbaric oxygen for late radiation tissue injury. Cochrane Database of Systematic Reviews 2005, issue 3.
– Bennett M, Feldmeier J, Smee R, Milross C. Hyperbaric oxygen for tumour sensitization to radiotherapy. Cochrane Database of Systematic Reviews 2005, issue 4.
– Bennett MH, Kertesz T, Yeung P. Hyperbaric oxygen for idiopathic sudden sensorineural hearing loss and tinnitus. Cochrane Database of Systematic Reviews 2007, issue 1.
– Kranke P, Bennett M, Roeckl-Wiedmann I, Debus S. Hyperbaric oxygen for chronic wounds.
Cochrane Database of Systematic Reviews 2004, issue 1.
– Phillips JS, Jones SEM. Hyperbaric Oxygen as an adjuvant treatment for malignant otitis externa. Cochrane Database of Systematic Reviews 2005, issue 2.

References
• Articles
– Annane D, Depondt J, Aubert P, Villart M, et al. Hyperbaric Oxygen Therapy for Radionecrosis of the Jaw: A
Randomized, Placebo-Controlled, Double-Blind Trial from the ORN96 Study Group. J Clin Onool 2004; 22:
4893-4900.
– Bennett M, Feldmeier J, Smee R, Milross C. Hyperbaric oxygenation for tumour sensitisation to radiotherapy: A systematic review of randomised controlled trials. Cancer Trtmt Rev 2008; 34: 577-591.
– D’Souza J, Goru J, Goru S, et al. The influence of hyperbaric oxygen on the outcomes of patients treated for osteoradionecrosis: 8 year study. Int’l J OMFS 2007; 36(9): 783-787.
– Daruwalla J, Christophi C. Hyperbaric Oxygen Therapy for Malignancy: A Review. World J Surg 2006; 30:
2112-2131.
– Gal TJ, Yueh B, Futran ND. Influence of prior hyperbaric oxygen therapy in complications following microvascular reconstruction for advanced osteoradionecrosis. Arch ORL HNS 2003; 129(1): 72-76.
– Gill, AL & Bell, CAN. Hyperbaric Oxygen: its uses, mechanisms of action and outcomes. Q J Med 2004; 97:
385-395.
–
Hirsch DL, Bell RB, Dierks EJ, Potter JK, Potter BE. Analysis of microvascular free flaps for reconstruction of advanced mandibular osteoradionecrosis: a retrospective cohort study. J OMFS 2008; 66(12): 2545-2556.
–
London SD, Park SS, Gampper TJ, Hoard MA. Hyperbaric oxygen for the management of radionecrosis of bone and cartilage. Laryngoscope 1998; 108(9): 1291-1296.
–
Marx RE, Ames JR. The use of hyperbaric oxygen in bony reconstruction of the irradiated and tissuedeficient patient. J OMFS 1982; 40: 412-420.
– Marx RE. A new concept in the treatment of osteoradionecrosis. JOMFS 1983; 41: 351-357.
– Myers R, Marx RE. Use of hyperbaric oxygen in postradiation head and neck surgery. NCI Monogr.
1990; 9:
151-157.
– Neovius EB, Lind MG, Lind FG. Hyperbaric oxygen therapy for wound complications after surgery in the irradiated head and neck: a review of the literature and a report of 15 consecutive patients. H&N 1997; 19:
315-322.
– Shi Y, Lee CS, Wu J, Koch CJ, et al. Effects of hyperbaric oxygen exposure on experiemtnal head and neck tumor growth, oxygenation, and vasculature. Head & Neck 2005; 27(5): 362-369.
– Schonmeyr BH, Wong AK, Reid VJ, et al. The Effect of Hyperbaric Oxygen Treatment on Squamous Cell
Cancer Growth and Tumor Hypoxia. Ann Plast Surg 2008; 60(1): 81-88.
– Wreford-Brown CE, Hampson NB. Hyperbaric oxygen protocols for mandibular osteoradionecrosis.
Undersea Hyperb Med 2003; 30(3): 175-179.