Juan O Bravo MD CWS UHM Center for Wound Care and Hyperbaric medicine at Coral Springs Medical Center Medical Director

2. Objectives: Describe the mechanisms of action of hyperbaric medicine as it relates to the management of chronic wounds. Explain how management of the wound micro-environment is supported by hyperbaric oxygen therapy. Evaluate ways in which you could integrate knowledge from this activity into your practice.

3. Background on Hyperbaric Medicine: “The use of atmospheric air under different degrees of atmospheric pressure, in the treatment of disease is one of the most important advances in modern medicine, and when we consider the simplicity of the agent, the exact methods by which it may be applied, and the precision with which it can be regulated to the requirements of each individual, we are astonished that this method of treatment has been so little used” - C. E. Williams, Physician 1885

4. Mechanism of action The mechanism of action of Hyperbarics can be divided in primary and secondary mechanism. Primary mechanism- effects of hyper-oxygenation and pressure (oxygen is dissolved into plasma and tissue fluids by the pressure) (Transient) Secondary - results due to the hyper-oxygenation Will cause changes at cellular level to improve healing and fight infection causing (Permanent changes and wound healing).

5. Primary Mechanism The increase in partial pressure of Oxygen will drive the O2 into hard to reach areas like fibrotic tissue, cicatrix or edema. The distance at which the Oxygen will travel in the tissue will be directly proportional to Oxygen partial pressure. Angiogenesis, Fibroblasts function, White blood cells and peroxidase killing will not occur if there is lack of Oxygen.

6. Primary Mechanism Hyperoxygenation- It occurs quickly but effects are transient. 10 min plasma, 1-2 hrs for muscle, 6 hrs for subcutaneous tissue. If the blood flow is inadequate the tissue fluid will saturate more slowly.

7. PRIMARY MECHANISM Oxygen in high concentrations is able to “wash out” other gases and poisons like CO and He Decompression illness. Also Oxygen under pressure will be dissolved in plasma and will help keep tissues alive in the case that blood is needed and not available.

8. This secondary mechanisms results in more permanent changes. Vasoconstriction resulting in edema reduction, Gas wash out/decrease in bubble size, re-perfusion injury mitigation, antimicrobial killing and inhibition are some of the secondary effects of HBO.

9. SECONDARY MECHANISM related to Wound Healing The effects on microbial killing are one of the most important secondary mechanisms of action in wound healing. Adequate levels of Oxygen are needed for the Leucocytes to engulf and kill bacteria. Oxydative killing will not occur in the absence of Oxygen. This mechanism increases O2 consumption 100 folds. Fibroblast proliferation and function (collagen production, migration and proliferation) are O2 dependent as well as wound matrix production.

10. SECONDARY MECHANISM related to Wound Healing Another secondary mechanism that helps with wound healing is the enhancement of fibroclastic function to digest dead and infected bone. This increases O2 consumption 100 folds and in many patients is only noted when HBO is started. Angiogenesis, improve antimicrobial activity and reabsorption of dead bone are all integral part of wound healing and all of these procedures are O2 dependent.

11. What is Hyperbaric Oxygen Therapy ? Hyperbaric oxygen (HBO2) is a treatment, in which the patient breathes 100% oxygen intermittently while inside a treatment chamber at a pressure higher than sea level pressure (i.e., > 1 atmosphere absolute; atm abs).

13. Oxygen Therapy in Current Wound Management: Oxygen and Wound Healing: Oxygen clearly plays a large role in wound healing. It is one of the most versatile and powerful agents available in the management of chronic wounds. All of the major components of wound healing, collagen formation, angiogenesis, epithelization, and bacterial killing proceed in proportion to the amount of oxygen available.

14. Neovascularization and Angiogenesis: New tissue striving to fill dead space needs to be supplied by blood vessels, which follows the formation of collagen. Collagen forms a basement membrane that provides structure support for these budding vessels. Capillaries then grow into hypoxic areas and collagen synthesis is carried further into the wound forming new granulation tissue and further decreasing dead space. Increasing capillary pO2 tension with HBO increases the amount of oxygen reaching these advancing cells. Thereby allowing granulation tissue to migrate further from functioning capillaries. Hyperbaric oxygen enables this new vascular supply to advance quickly, thereby ensuring faster wound closure.

15. Oxygen Consumption and Infected Wounds: As oxygen tension falls, infection begins to dominate. Leukocyte bacterial killing is further impaired. This downward spiral can be interrupted in several ways. Warmth (enhance perfusion) Debridement (remove infected tissue) Drainage of abscesses (remove infection) Antibiotics (reduce infection) Reduction in sympathetic stimuli (reduce vasoconstriction) Edema control (enhance perfusion) Each of these interventions either increases supply of or decreases demand for oxygen thereby enhancing oxidative killing and tissue perfusions.

16. Vasoconstrictive Effects of Oxygen: Vasoconstriction occurs during hyperbaric oxygen therapy without component hypoxia. This is helpful in managing intermediate compartment syndrome and other acute ischemia in injured extremities, and reducing interstitial edema in grafted tissue. Hyperbaric oxygen reduces edema by increasing diffusion of oxygen. The resulting vasoconstriction reduces inflow by approximately 20% while maintaining outflow, thereby, reducing edema by the reabsorption of tissue fluids.

17. Re-perfusion Injury: Most of the damage associated with re-perfusion is brought about by the inappropriate activation of leukocytes. Following an ischemic interval, the total injury pattern is a result of two components: Direct irreversible injury component from hypoxia. Indirect injury which is largely mediated by the inappropriate activation of leukocytes. HBOT reduces the indirect component of the injury by preventing activation through the down regulation of leukocyte receptor sites. Basically HBO inhibits leukocyte endothelial intravascular adhesions. This effect has been reported to last up to 8 hours post-HBO.2 The net effect is the preservation of marginal tissues that may otherwise have been lost to a ischemia-re-perfusion injury.

18. Hypoxic Tissue Benefits Restoration of microcirculation. Decreased local edema. Improved cellular metabolism. Improved local tissue oxygenation. Improved leukocyte-killing ability. Improved effectiveness of antibiotics.

19. Sheikh AY, et al. Effect of hyperoxia on vascular endothelial growth factor levels in a wound model. Arch Surg 2000; 135:1293-1297.

21. Stem Cell Mobilization by HBO HBO mobilizes stem/progenitor cell release from bone marrow through a nitric oxide dependent mechanism Population of CD34 cells in peripheral circulation doubled in response to single HBO treatment (2 ATA, 120 min) Over course of 20 treatments circulating CD34 cells increased 8 fold, total WBC count unchanged Number of colony-forming cells increased from 16±2 to 20±3 CFCs/100,000 monocytes plated Increased cell growth occurred only in samples obtained immediately post treatment

22. Hypoxia and the Oxygen Gradient

23. Wound Healing Impairment with Decreasing PtcO2

24. Periwound Normoxia

30. The PO2 Wave:

31. Clostridial Myonecrosis and Gas Gangrene

32. HBO indications as it relates to Wound Care

33. Clostridial Myonecrosis and Gas Gangrene Could be caused by Clostridium or other bacteria like: Facultative Staph and Strep; E. coli, Enterobacter cloacae among others. Clostridium perfringens grows is restricted by Oxygen tensions above 70 mm/hg. Many exotoxins are produced by the organisms causing Gas Gangrene and some including the “alpha toxin”; the most destructive, can be inactivated by high O2 concentrations (>300mm/hg) HBO forms O2 free radicals in the absence of free radicals degrading enzymes like superoxyde dismutase, catalase and peroxidases that are absent in anaerobe organisms.

34. Clostridial Myonecrosis and Gas Gangrene Cont… Increase pressure also reduces the size of the bubbles improving perfusion and reducing pain. HBO clarifies the demarcation of dead tissue reducing the extent of debridments. HBO is an adjunctive to therapy to SURGERY and antibiotics 3 HBO treatments at 3.0 ATA for first 24 hrs, then BID until infection controlled. Typical length 7 treatment.

36. Fournier’s Gangrene: 96 hours post surgical debridement and 2nd VAC dressing change.

37. 12 Weeks later, no secondary surgery 30 HBO Txs at 2.0 ATA for 120 minutes.

39. Refractory Osteomyelitis

40. Refractory Osteomyelitis Defined as recurring bone infection despite appropriate antibiotics and surgical intervention. HBO increases the O2 levels in hypoxic infected bone… Promotes collagen production by fibroblasts and capillary angiogenesis, promoting healing of hypoxic tissue. Affects directly and indirectly helping in anaerobic bacterial killing. Works in synergy with some antibiotics like; aminoglycosides, vancomycin, quinolones, and some sulfonamides helping with the transport of these molecules through the cell wall. Promotes Osteoclastic activity that is O2 dependent. 30-40 treatments at 2.0-2.4 ATA for 90 min.

41. Ionizing Radiation Injury

42. Ionizing Radiation Injury Tissue breakdown following radiation injury. Basic pathology of irradiated tissue is normal tissue with cellular kill and sublethal cellular damage leading to progressive endarteritis obliterans that causes tissue ischemia and fibrosis. HBO should be paired with debridement, antibiotics and surgery as needed. HBO Creates a steep artificial O2 gradient inducing neo-vascularization and collagen production. 2.4 ATA for 90 min for 40 treatments. Marx Protocol

44. Compromised skin grafts and flaps

45. Compromise Skin Grafts or Flaps Oxygen availability is critical to skin graft or flap success. HBO increases O2 in hypoxic and ischemic wounds. HBO stimulates angiogenesis and formation of granulation tissue very important for people with previous compromise wounds (XRT, Diabetes, etc) HBO is NOT effective if large vessel blood supply is insufficient. Treatments should start at first sign of tissue death. 2.4 ATA for 90 Min BID until flap Stabilizes then once. For split thickness grafts 2.4 ATA for 90 Min, BID for 3 days. Full thickness Graft might require a week of BID therapy.

46. Allegedly HBO helped at some point…

47. …but HBO does not do miracles.

49. How viable is this flap?

50. Compromised Flap: post trauma 81 year old male

51. Compromised Flap: post 25 HBO txs at 2.0 ata x 90 minutes 74 days post surgery.

53. Is HBO alone sufficient?

55. Crush Injury, Compartment Syndrome & Traumatic Ischemias

56. Crush Injury, Compartment Syndrome & Traumatic Ischemias cont… Acute traumatic ischemia occurs when an injury interrupts blood flow to an extremity. Increased O2 reduces edema by causing vasoconstriction that further promotes oxygenation. HBO Speeds demarcation of non-viable tissue. HBO reduced re-perfusion injury by preventing lipid peroxidation, neutrophil adherence and free radical buildup.

57. Crush Injury, Compartment Syndrome & Traumatic Ischemias cont… Treat at 2.4 ATA for 90 Min TID for first 48 hrs, BID for 48 hrs, then daily for 48 hrs. If there has been a replanted finger use 2.0 ATA since its been shown that it gives better results. Therapy usually lasts less than a week.

60. Diabetic Wounds of the Lower Extremity Diabetes is a major risk factor of impaired wound healing, making diabetic foot ulcers one of the major problems in DM. Most of the amputations in the US are due to DM. Diabetics have Growth factor and cytokines deficiencies as well as endothelial dysfunction resulting in decrease angiogenesis and abnormal fibroblast function. Diabetics have extensive micro- and macro- circulatory dysfunction resulting in hypoxia and delay wound healing. HBO helps in improving tissue oxygenation improving angiogenesis, collagen production and bacterial killing by enhancing neutrophils function. HBO is indicated for non healing neuropathic foot ulcers that are not healing despite adequate therapy for at least 30 days. Ulcers need to be Wagner grade III or higher.

62. What Is the Likelihood of Benefit From HBO in Diabetic Wounds?  Baseline sea-level air PtcO2 identified the degree of tissue hypoxia but had little statistical relationship with outcome prediction because some patients healed after hyperbaric oxygen therapy despite very low pre hyperbaric PtcO2 values. Despite an air PtcO2 of <20 mmHg, 64% (164/256) of patients were helped (this may demonstrate the efficacy of HBO)

63. What Is the Likelihood of Benefit From HBO in Diabetic Wounds?  PtcO2 measured in chamber provides the best single discriminator between success and failure of hyperbaric oxygen therapy using a cutoff score of 200 mmHg.

66. HBO group (mean session = 38 +/- 8), 3 (8.6%) underwent major amputation, 2 BKA, 1 AKA Conventional group, 11 (33%) underwent major amputation, 7 BKA, 4 AKA Difference statistically significant (P=0.016) TcPO2 on dorsum of the foot significantly increased in HBO treated subjects…14.0 +/- 11.8 mmHG in HBO group, 5.0 +/- 5.4 mmHg in the nontreated group (P=0.0002) Multivariate analysis of major amputation on all the considered variables confirmed the protective role of HBO Negative prognostic determinants were low ABI values and high Wagner gradeHBO group (mean session = 38 +/- 8), 3 (8.6%) underwent major amputation, 2 BKA, 1 AKA Conventional group, 11 (33%) underwent major amputation, 7 BKA, 4 AKA Difference statistically significant (P=0.016) TcPO2 on dorsum of the foot significantly increased in HBO treated subjects…14.0 +/- 11.8 mmHG in HBO group, 5.0 +/- 5.4 mmHg in the nontreated group (P=0.0002) Multivariate analysis of major amputation on all the considered variables confirmed the protective role of HBO Negative prognostic determinants were low ABI values and high Wagner grade

67. Cianci C, Hunt TK. Long-term results of aggressive management of diabetic foot ulcers suggest significant cost effectiveness. Wound Rep Reg 1997; 5:141-146. 94% of patients maintained an intact limb (healed wound) at 55 months post closure.

68. DIABETIC FOOT WOUND TREATED WITHOUT HBO

70. Duration 6mo. MRI shows fistula tract extending from the plantar aspect of the foot up to the area btw the 2nd and 3rd toes with a 1cm abscess btw the 2nd and 3rd toes. Osteomyelitis. Surgical debridement, IV ATB, Wound Vac and HBOT started.

71. HBO can’t fix everything!!

72. Because Dead Tissue is Dead Tissue

73. Conclusion: An in-depth understanding of wound healing and hyperbaric medicine, combined with an advanced knowledge of current wound management allows for increased control over and manipulation of the micro-wound environment throughout all stages of wound healing.

74. The primary goal with a diabetic foot wound is to preserve all of the patients little piggies.

75. References: Gesell, L.B. Chairman and Editor. Hyperbaric Oxygen Therapy Indications, 12th Edition. The Hyperbaric Oxygen Therapy Committee Report. Durham, N.C: Undersea and Hyperbaric Medical Society. Williams CT. Lectures on the compressed air bath and its uses in the treatment of disease. Br Med J. 1885;1:824 936 Gottrup F: Oxygen in wound healing and infection. World Journal of Surgery 2004; 28: 312-315. Hunt TK & Aslam RS: Oxygen 2002: wounds. Undersea & Hyperbaric medicine 2004, 31 (1): 147-153. Niinikoski JH: Current concepts of the role of oxygen in wound healing. Annales Chirurgiae et Gynaecologiae 2001; 90 suppl. 215) 9-11. Roeckl-Wiedmann I, Bennett M, Kranke P: Systematic review of hyperbaric oxygen in the management of chronic wounds. British Journal of Surgery 2005; 92 (1): 24-32. Tandara AA, & Mustoe TA: Oxygen in wound healing-more than a nutrient. World Journal of Surgery 2004; 28: 294-300 Zamboni WA, Browder LK, Martinez J: Hyperbaric oxygen and wound healing. Clinics Plastic Surgery2003; 30: 67-75. Trabold O, Wagner S, Wicke C, et al: Lactate and oxygen constitute a fundamental regulatory mechanism in wound healing. Wound Repair and Regeneration 2003; 11: 504-509.

76. References: Hammarlund C: The physiologic effects of hyperbaric oxygenations in Kindwall E. Whelan H. Hyperbaric Medicine practice. Best 3rv 2008; 39-70. Gimbel M. & Hunt T.K.: Wound Healing and Hyperbaric oxygenation in Kindwall E. Whelan H. Hyperbaric Medicine practice. Best 3rv 2008; 317-354. Clark J., Bonne V, Falzon C & Whelan H.: Oxygen toxicity in Kindwall E. Whelan H. Hyperbaric Medicine practice. Best 3rv 2008; 71-88. Critz D: Indications for hyperbaric oxygen therapy. In Larson-Lohr, V. & Norvell HC. (Eds.) Hyperbaric Nursing. Fagstaff, AZ: Best Publishing Co. 2002, p191. Fife CE, Smart DR., Sheffielf, PJ, Hopf HW, Hawkins G, Clarke D. Transcutaneous Oximetry in Clinical Practice: Consensus statements from expert panel based on evidence. UHM 2009; 36 (1): 43-53.

77. References: Orsted, HL and Inlow,S. The Team Approach to Treating Ulcers in People with Diabetes, in Krasner, DL, Rodeheaver, GT, & Sibbald, RG. Chronic Wound Care: A Clinical Source Book for Healthcare Professionals: 3rd Ed., 2001. Wayne, PA: HMP Communications; 2001. Steed, DL. Diabetic Wounds: Assessment, Classification, and Management, in Krasner, DL, Rodeheaver, GT, & Sibbald, RG. Chronic Wound Care: A Clinical Source Book for Healthcare Professionals: 3rd Ed., 2001. Wayne, PA: HMP Communications; 2001.