Hyperbaric Oxygen in ORL-HNS: Facts, Fictions, and Evidence

1. Hyperbaric Oxygen in ORL-HNS:Facts, Fictions, and Evidence Evan R. Ransom, MD University of Pennsylvania Otorhinolaryngology, Head & Neck Surgery Faculty Discussant: Kevin Hardy, MD Emergency Medicine, Hyperbaric Medicine

2. Overview • Why HBO2? • History • Basics • Details • ORL-HNS Applications • Data • Discussion

3. History • Initial discovery • 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."

4. 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

5. 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

6. Common Current Uses • Decompression Sickness • Gas Embolism • Crush Injuries • Anaerobic Infections • Osteomyelitis • Chronic Wounds • Necrotizing Infections • Osteoradionecrosis

7. Theory • Why did we think HBO2 would work? • 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!?

8. Theory • Some physics we’ve all forgotten… • Boyle’s Law • Dalton’s Law • Henry’s Law

9. Physics • Boyle’s Law at a constant temperature, the pressure and volume of a gas are inversely proportional. • Hyperbaric chamber • Compression of a given volume of gas therefore elevates its pressure • One-way valve to add gas volume to chamber

10. Physics • Dalton’s Law in a gas admixture, each component gas exerts a pressure proportional to its fraction of the total volume (i.e., partial pressure). • 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%

11. 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

12. Physiology • Cardiopulmonary • 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

13. Physiology Cardiopulmonary 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

14. 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

15. Mechanism • Three main effects of HBO2: 1) Delivery of O2 to hypoperfused tissues • Limit ischemic damage, cell death, and inflammation • Promotes collagen synthesis and angiogenesis • Decreases lactate production and tissue acidosis 2) Generation of oxygen free radicals • Aids in oxygen-dependent killing of bacteria • Facilitates oxygen dependent transport of antibiotics 3) Vasoconstriction • Limits leukocyte adhesion and degrannulation • Decreases tissue edema

16. Dosing and Delivery • Parameters • 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.

17. Dosing and Delivery • Common regimens • 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.

18. 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

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

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

21. Complications • Lens deformation causes temporary myopia • Exacerbation of other processes • Dental abscess, sinusitis, laryngocele, etc. • Claustrophobia, anxiety, etc. • Oxygen toxicity • Very rare, but may cause seizures • Potential effects on tumor growth • Controversial – more on this later…

22. 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

23. Costs • HBO2 is relatively expensive… • 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

24. Costs • Cost efficacy analyses • 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

25. 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

26. Applications Today’s review • Osteoradionecrosis • Pharyngocutaneous fistulas • Enhancement of graft & flap viability • Malignant otitis externa • Sudden SNHL • Radiation sensitization

27. Osteoradionecrosis • Damage to osteocytes from XRT • Weakens bone, predisposing to fracture • Often painful, broken down mucosal coverage • Decreases blood flow, difficult to fight infection • Body of the mandible most affected • 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

28. Osteoradionecrosis • Pathophysiology • 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

29. Osteoradionecrosis • HBO2 used for ORN since 1960’s • 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

30. Osteoradionecrosis Not all data agree (Annane, et al. 2004) 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?

31. 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

32. Chronic Wound Data • Relatively little data from H&N • 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

33. 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

34. 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

35. 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?

36. 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

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

38. Skin Grafts & Free Flaps • Pathophysiology • 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 • HBO2 Mechanism • Improves tissue PO2 • Promotes angiogenesis • Augments immune response & limits inflammation

39. 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

40. Malignant Otitis Externa • Data is of poor quality • Mostly case reports • No prospective data • But… • Supports use • Need prospective data • Need standardization

41. 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

42. 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

43. 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

44. 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.

45. Radiation Sensitization • Data support survival effect • Need more RCTs to determine • Timing of XRT (Concurrent? Sequential?) • Fractionization & dosing • Is it worth the costs? • XRT side effects are already difficult… • Saving more lives with lower QOL??? • More complications = higher treatment costs

46. 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

47. 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

48. Summary • HBO2 derives its clinical benefit via • Increase in the oxygen delivery to hypoxic tissue • Promoting native mechanisms of healing • Decreasing tissue edema & reperfusion injury • Dosing • Most commonly 30-40 dives of 90 min at 2.4atm • Costs • Significant, yet analyses support cost savings in proven indications

49. Summary • Supported ORL-HNS indications • ORN & CRN, radiation soft tissue injury • Flap & graft survival • Unsupported ORL-HNS indications • Sudden SNHL, tinnitus, Bell’s palsy • Areas of uncertainty • Likely effect: MOE & skull base osteo, fistulas • Poor side effect profile: radiation sensitization

50. Summary • Further research • 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