Topical Oxygen Therapy Gayle Gordillo, M.D. Assistant Professor Division of Plastic Surgery and The Comprehensive Wound Center Set B1 – Title Slide

Overview Review significance of wound tissue oxygenation Identify determinants of wound tissue oxygenation Demonstrate TO enhancement of wound tissue oxygenation Report TO clinical outcomes Set A1 – Content Slide

All wounds are hypoxic 45-60 mm Hg 0-10 mm Hg Set A1 – Content Slide

Oxygen Promotes healing Collagen synthesis Positive correlation between wound pO2 and collagen deposition demonstrated Wound strength determined by collagen cross-linking Angiogenesis Stimulates VEGF expression in wound macrophages upregulates PDGF-B receptor expression Set A1 – Content Slide

Oxygen promotes healing Resistance to infection Oxygen as a rate-limiting substrate for NADPH oxidase Km= 75 mmHg Loss of oxidative burst pO2 < 20mmHg ischemic wounds more susceptible Set A1 – Content Slide

Determinants of Oxygen Availability Wound pO2 determined by Arterial pO2 Diffusion distance Blood flow rate rate of O2 consumption Local perfusion a predominant factor Set A1 – Content Slide

Optimizing Oxygen Availability Avoid vasoconstriction body temperature intravascular volume pain anxiety Smoking Decrease diffusion distance Decrease peripheral edema Debride wound surface Avoid petrolatum based dressings Set A1 – Content Slide

Why Topical Oxygen? Large potential patient population Low risk Convenient patient use Good scientific evidence to support the concept Set A1 – Content Slide 8

Topical Oxygen Administered at 1.03 ATM Used at home 90 min treatment intervals that are cycled 4 days on and 3 days off Set A1 – Content Slide 9

Topical Oxygen Increases Wound Oxygenation Fries R, Wallace WA, Roy S, Kuppusamy P, Bergdall V, Gordillo G, Melvin WS, Sen CK, Mutation Research 2005; 579:172-81. Set B1 – Title Slide 10

Pre-clinical Wound Healing Model 2 sets 5 wounds – dermal excisional 1x1 inch 5 wounds -topical O2 3 hours x 7days 5 wounds – room air only Set A1 – Content Slide 11

Topical oxygen increases wound pO2 real-time pO2 measurement (mmHg) 20 40 60 80 100 120 O2 treatment begin 1 2 3 4 time (minutes) Set A1 – Content Slide 12

Topical oxygen promotes wound closure days after wounding 5 10 15 20 25 (% of original wound) wound closure 40 60 80 100 120 140 160 * ** Day 0 Day 4 Day 10 Day 23 A B Set A1 – Content Slide 13

Skin histology in response to TO treatment – day 22 Control G A B Set A1 – Content Slide control oxygen treated 14

Angiogenic responses A C * B A = VEGF day 7 B = SMA day 15 C = pO2 day 22 control oxygen treated A B 5 6 C pO2 (mmHg) * Set A1 – Content Slide 15

Conclusions – topical oxygen Increases wound tissue pO2 Promotes new blood vessel formation in wounded tissues favorable wound epithelialization structures Significantly improved wound closure rates Set A1 – Content Slide 16

Clinical & Experimental Pharmacology & Physiology Topical Oxygen Therapy Induces Vascular Endothelial Growth Factor Expression & Improves Closure of Chronic Wounds Gayle Gordillo, Sashwati Roy, Savita Khanna, Richard Schlanger, Sorabh Khandelwal, Gary Phillips and Chandan K Sen Clinical & Experimental Pharmacology & Physiology (2008; 35(8):957-964) Set B1 – Title Slide

Objective Identify mechanism mediating beneficial effects of TO in promoting wound healing Set A1 – Content Slide

Study Design Each patient serves as own control All wounds O2 naive Wound tissue biopsy taken immediately prior and immediately after completion of oxygen treatment at 3 different time points (6 biopsies) T0 day of 1st O2 tx = baseline T1 50% closure (TO) or 50% tx completed (HBO) T2 < 1 cm2 wound area (TO) or 14 weeks, last tx (HBO) Set A1 – Content Slide

Study Design Tissue samples analyzed using real-time PCR for change in expression of VEGF Difference between pre-treatment levels (baseline =1) and post-treatment levels of mRNA quantitated by real-time PCR – generates fold change per patient Wound measurements Demographic data Wound healing outcomes Set A1 – Content Slide 20

Results – TO VEGF Set A1 – Content Slide

Scatter plot analysis of VEGF expression in TO patients 54 63 52 46 58 50 47 68 64 55 53 40 48 67 numbers indicate patient age Topical Oxygen .05 .1 .2 .5 1 2 5 10 20 VEGF Ratio (T1:T0) a VEGF Ratio (T2:T1) .01 .025 .25 2.5 b 60 VEGF Ratio (T2:T0) Wound Volume Ratio (T2:T0) c Scatter plot analysis of VEGF expression in TO patients Set A1 – Content Slide 22

Topical oxygen as an adjunct to wound healing: a clinical case series Kalliainen LK, Gordillo GM, Schlanger R, Sen CK Pathophysiology 2003; 9: 81-87. Set B1 – Title Slide 23

Patient Outcomes A Total # patients = 32 Total # wounds = 58 E D C B healed top O2 only (n=38) did not heal (n=11) lost to follow up (n=2) died during tx (n=3) healed top O2 + surg (n=4) Set A1 – Content Slide 27

TO case series - conclusions No reported adverse effects to top O2 tx 75% overall healing rate achieved Average length of tx time = 10 weeks Upper ext & trunk wounds most responsive Decubiti & neuropathic ulcers least responsive Size matters Set A1 – Content Slide 28

Summary Oxygen is a critical requirement for wound healing Supplemental oxygen administration can improve wound outcomes TO can increase wound tissue oxygenation TO promotes angiogenesis through increased expression of VEGF in healing wounds Set A1 – Content Slide

Acknowledgements Chandan Sen, Ph.D Sashwati Roy, Ph.D Savita Khanna, Ph.D Gary Phillips, MS Lynn Lambert, RT Richard Schlanger, MD, PhD Samantha Bellamy, RN Set A1 – Content Slide 30