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Speaker: Cyaandi Dove did her DPM training in California then went to San Antonio, did her residency. Has been very active in academic pursuits and is going to talk to us about something we've heard a little bit about the past few days and that's oxygen therapy something that was pooh-poohed in the past and now there is no more and more science to support that. So we look forward to your presentation.

Dr. Cyaandi Dove: Good morning. I am coming here from Las Vegas and I want to thank the organizers for inviting me and I know that some people, some of the speakers have already talked about it, but I will talk about this in a slightly different way. So my talk is really to focus on the adjunctive management of VLUs and other chronic wounds using cyclical high pressure oxygen wound therapy. This is my disclosure and so in today's talk we are going to be focusing on VLUs and other chronic wounds, really diabetic foot ulcers and talking more about the pivotal clinical trial that was recently completed as well as impact of CHP topical wound therapy. When you look at it along the spectrum of wound healing, how it's very necessary and lastly we are going to look at the findings again of that pivotal trial. So I won't belabor this point because I think we all know an acute versus a chronic wound. Really an acute wound is a wound that heals in a timely fashion whereas chronic wounds, I would say, is anything over four or five weeks. A wound that's just persisting and really stuck in the inflammatory phase of healing and there are many papers that support that. So when we look VLU or venous leg ulcers, we know as clinicians that we are battling something very tough.

[02:05]

These wounds have a lot of comorbidities. They can have diabetes, well-controlled or poorly controlled. They can have concomitant PAD or coronary artery disease and a lot of lifestyle and behavioral factors that can play into why these wounds are not healing. We know that these are very predominant. About 1% of the world's population has a VLU at some time in their life and they are also very expensive. From a clinical standpoint, my main concern is really quality of life. These are patients who are coming in every year, every six months with recurrences and I would say the biggest complaint is chronic pain, a lot of depression, a lot of embarrassment over the odor. So the wound has a lot of other secondary issues that make it very problematic. A lot of my patients say that they would be fine with the wound if they didn't have to deal with the odor from heavily exudating wounds and the pain. We will get to the next one eventually. So when we look at diabetic foot ulcers, we know that as a whole 20% of our diabetic patients are going to have some form of a diabetic foot ulcer in their lifetime. They are incredibly expensive, not just the treatment but also the cost associated if they end up having to have an amputation and like Dr. Rogers eluded in his lecture or stated directly these are very sick patients. The five-year mortality rate is around 50%. So quite significant and quite sick patients that we are dealing with. So this is a slide of my favorite character from Greek mythology, Sisyphus, who had to roll a large boulder uphill and every time he get to the top it would roll back down.

[04:00]

And that's how I feel we are dealing with these chronic wounds with the patients coming back over and over and over. We all have the patients that we see on a regular basis for years and years with diabetic foot ulcers and venous leg ulcers. So now we will segue into talking about oxygen and its essential role. So I know when I was asked to do this talking when I also participated in the trial for topical wound oxygen therapy, I was thinking back to my days as a resident and there really wasn't a lot of data to support it. And I thought, okay, I was a little bit skeptical but actually times have changed, that was over 20 years ago, and we know that oxygen has a very, very important role in wound healing and it's a role across the spectrum of wounds healing. So no matter what we always need to maintain our standard of care, which includes obviously regular serial debridement, looking at making sure the wound is not infected and inflammation kept to minimum, wound care, wound dressings and as well as aggressive offloading. So we know that wounds they go through stages in terms of healing and what we were seeing with hypoxic wounds is that they are stuck in the inflammatory phase. In acute wounds, those wounds go from the inflammatory phase in a timely fashion to the proliferative phase and eventually these wounds end up healing, they mature and I think that's something that we are all familiar with. But one thing that's pivotal is that you need oxygen in each and every stage to get a completely healed wound. So when we look at different types of wound therapy or oxygen therapy that's available, this slide is what most of us who are in private practice are familiar with, which is systemic hyperbaric oxygen and this is a modality that I still use in my private practice because unfortunately I don't necessarily have access as a private practice doctor to topical oxygen.

[06:07]

But there are some limitations with systemic hyperbaric oxygen. So if you look below, you will see the multi-person chamber whereas in my community and most in the US you have the mono-person therapy. Hyperbaric oxygen is delivered at pressures of two to three atmospheres. You are relying on an intact vascular system. You need that system make blood flow to get oxygen to the area. This is not a benign therapy. There are risks associated with it, and also from the patient's perspective, it's a big issue in terms of their quality of life. It's very burdensome in terms of time and in terms of cost. These patients typically when I send them to my local hyperbaric oxygen facility, they are going five times a week and anywhere from five to eight weeks or as needed for treatment of their wound. There is always a risk of multi-organ oxygen toxicity, but there are a lot of research papers that show that this is an established treatment and we know that there is definitely a benefit to it. However, we do now have the availability of topical oxygen therapy. So if you look at the pictures below, this is one that -- I am not sure if this is still available, but this is continuous delivery of oxygen with no pressure. These devices are continuous delivery of oxygen with some pressure and here you have a system that delivers cyclical high pressure oxygen. So my biggest caveat from this is when they have a patient who has a hypoxic chronic wound, I would love to have this available to me. This is delivered at room temperature. It's a portable device, so they have this therapy when they are at home or they can have it bedside.

[08:01]

So their time isn't as affected as when they are going to systemic oxygen therapy and for this type of therapy, we are not relying on intact vascular system because the oxygen is driven directly into the tissues via the pressure and also it's very safe. There is no risk of systemic organ oxygen toxicity. The only true contraindication or things that you have to look out for when you are looking at the cyclical high pressure is the presence of an underlying DVT and that the patient has [indecipherable] [08:35] you can resume therapy with it. So in terms of how this works exactly, cyclical high pressure topical wound oxygen therapy, it addresses the wound from different standpoints. So the oxygen is cycled at 10 to 50 milibars of pressure inside the chamber and what this creates is a non-contact compression. So in particular for venous leg ulcers that's very important because I know in my office for compression, I do either Profore or unna boot, but this is something very novel with this type of therapy. And even with DFU, diabetic foot ulcers, edema is also a concern. So if you have a device that reduce the localized edema, you are going to facilitate healing of that wounds. The humidification that's offered and with this particular device if the wound is heavily exudative, you don't necessarily need to add that and that's something that you can modify, but because the oxygen is cycled between 10 and 50 milibars, you get higher diffusion gradient of oxygen and if you look at the local oxygen pressures in the tissue, they actually increase five folds and this has been demonstrated as well in research papers.

[10:00]

And the benefit of this is that when they pump in this oxygen, it's the lowest pressure but it's the most effective pressure. So there is not really a worry about damaging ischemic tissues as well if the pressure is potentially too high. So this slide, we are looking at a cross section of a chronic wound. We know that the partial pressure in arteries is around 100 mmHg. But when you look at a wound, a chronic wound, we know that also these wounds starve for oxygen but the levels of oxygen they change as you go from the wound margins to the center of the wound. So in the chronic wound ideally you are going to have around 60 mmHg at the wound edge whereas in the center of the wound, the deepest part, you may be around 10 mmHg or even less and that's something that we are aware of even if we are not measuring these levels in the practical sense when we are seeing these patients. So this slide, there is a lot of information on it. But what we are looking at are three pivotal processes that we need in a wound to go from an inflammatory stage to healing. So if you look at the green line right here, that's at 100 mmHg that we would see in an arterial bed. So if you look at that line, we will see that the metabolism is fairly normal 100%. Collagen production is around 80 and then looking at in terms of fighting infection, that is around 60% and that's normal. The problem is when you have a chronic wound, all of those functions are very minimal at best. So this yellow line right here if you look at the graph at the pressure we are here say around 10 and these three activities are significantly reduced.

[12:06]

When you add an adjunctive therapy, topical wound oxygen, you will see that these functions if we look at the graph as we go out to 800 mmHg. All of these functions are significantly increased at normal and that's what is going to help to drive wound healing when you are adding topical wound oxygen. So this is a great study by Frieze [phonetic] and it just sort of exemplifies, explains in a little bit more depth what goes on when you add topical oxygen to a wound that's not healing. So they took a pic and they created a wound and they placed the probes about 2 mm underneath the depth of the surface of the wound and they measured the oxygen levels. So if you look here, you will see when the wound starts, the oxygen level which we know in a hypoxic wound is very, very low, 5 to 10 mmHg of partial pressure. However, after only two minutes, you will see that those numbers increase significantly and after four minutes, you will see that the levels are quite high. So I thought because I truly was skeptic, this was a really pivotal study in showing that even after a short time oxygen therapy does have an effect and longer you use it, the more of an effect it has. So if you look here at topical oxygen in terms of promoting the growth of new blood vessels, they took punch biopsies. This is the same paper and you will see if you look at the vascularization, this is after one week, it's very fragmented and very little, very minimal, but if you look at the animal that was treated with topical oxygen, quite significant growth of new blood vessels.

[14:07]

And they also measured the partial pressure and oxygen. This is at 22 days and you will see the control when they looked at the partial pressure was very low whereas in the ones that we treated after about three weeks were quite high over 40, which is significant. Another thing that was found in this trial with Frieze where they actually took biopsies and they looked at the epidermis. So you will see in the controlled patients. Yes, the tissue did heal, however, the epidermis was not as organized, but if you look to treat it, the patient that was treated with topical oxygen, it was much more robust. And I think we extrapolate that we may have lower recurrence rate when you have this healthier more vibrant tissue. So this slide is referring to the reverse gradient phenomena. When you are treating patients with topical wound oxygen, an observation that some of the clinicians have noted is that you will see healing from the center, from the deepest part of the wound. So typically you will see little islets of epithelial tissue that will begin and it will spread out to touch the margins, which is typically not what we usually see. We usually see healing from wound edges and ingressing then towards the center of the wound. So to summarize when you are looking at topical wound oxygen, what we were doing with this therapy again is three-fold. We are supplementing it with oxygen. So we can jumpstart those inflammatory processes. We can start to lie down collagen. We can impair angiogenesis and we can get a better immune response. Especially with these patients who have wounds from months and months, we know there is a heavy bio-burden there and we need something else in our armamentarium to get that going.

[16:04]

Also with cyclical compression, you are getting a significant reduction in edema. Again that non-contact sort of milking effect to reduce edema that's invaluable for venous leg ulcers, you must have that in hopes of healing a venous leg ulcer, but also quite important with diabetic foot ulcers as well. And we are looking to stimulate the damage in arteries and lastly humidification. You need to have a moist wound environment and this also helps to drive the oxygen into the tissues better. This is a list of lot of different studies and we will talk about the top two in more depth, but a lot of the earlier studies, they were not randomized, they were not blinded, they were not controlled, but they still provided some value and some insight that we can look at today. So this study it's from a university setting in Ireland by Dr. Taufik [phonetic]. This study is looking at topical wound oxygen and what they did was they divided patients into two treatments, conventional compression dressings versus topical wound oxygen. They had 132 patients and they were roughly split. Now, the study was not rigorous. The patients weren't blinded. The patient actually presented with the option. They talked to the patient, to the patient's families and said what would you like. We have this conventional compression dressing or would you like to try the topical wound oxygen and the patient could decide for themselves. But what was significant is that they looked at these patients for a total of three years and also what I thought was really fascinating was these patients had wound for a minimum of two years. Having done a lot of clinical trials with big pharmaceutical companies, it's very, very atypical.

[18:02]

I don't think I have ever in the past 20 years participated in the trial where the wound could be over 18 months. So this is a special subset of patients. These are truly refractory wounds that we were looking at and the endpoint was what was the proportion of ulcers that were healed at 12 weeks, reduction in the ulcer size, time to healing and recurrence rate at 36 months and again 36 months very, very unusual. So if we look here at the slide, we are looking at the demographics. Again, the number of ulcers even though they self-selected, it still came out roughly equal topical wound oxygen 67 patients, conventional compression 65. Something that I thought was interesting because I also haven't seen this a lot. They looked at MRSA. They looked to see if it was eradicated at the end of the study using topical wound oxygen versus conventional compression. Also if we look here at the location, mostly ulcers were in the medial malleolus and the rest lateral malleolus and then a smaller number in the calf and the shin. Some of these ulcers were quite large. So if we look here at 21 x 40 cm square, there is a significant number of patients who were in that group alone and these are very old ulcers. Again, minimum age two years. So if you look here we have ulcers that were four to five years and even 6 to 10 years. So very sick patients and these are ulcers that when I see them in my office, I think there isn't much I can do. It's very, very difficult to heal an ulcer when the patient comes in and says I have had this for 5 or 10 years. So if we look at the results of this trial and again it wasn't blinded obviously, we see that 86% of the ulcers show signs of healing within three weeks, but 76% had healed by three months.

[20:07]

And when we look at conventional compression dressings, 72 showed signs of healing but again 46% were healed at three months. So we know that overall they healed a lot faster when they had topical wound oxygen, 57 days as opposed to 107 days, but I think this is also of great value. If you look at the MRSA elimination, 11 versus 0 in conventional compression dressing. And again they looked at ulcer recurrence and we see 6% at 36 months and 47% at 36 months and I think we could possibly extrapolate that. From the previous slide with Frieze when you are using topical wound oxygen, you tend to see a more robust, more organized type of healing, stronger epidermis. And this Kaplan Meier slide is just to reiterate the fact that we see a much quicker separation on the graft with Kaplan Meier between the conventional compression dressing versus the topical wound oxygen. Again, we see 57 days as opposed to 107 days for healing. So this is a patient who was in the study. She had the wound for nine year and this is her pre-treatment. We see her at a week. She had topical wound oxygen. Here we are at two weeks, three weeks, four weeks, six weeks, seven, eight weeks and healed. And again this is not a perfect study. This was university based. There was no blinding.

[22:00]

It was not randomized but I still think that there is a lot of value to the study. Again, recurrence at 36 months, 6% versus 47%, which is incredibly significant. MRSA elimination 46% versus 0% and the pain score, which is a big factor. Clinically, for these patients, it went from 8 to 3 in 13 days when they had topical wound oxygen. So now we come to a very important study that Dr. Frykberg participated in and I was actually a principal investigator in this trial and this was a multinational, multicenter, prospective randomized double blind placebo controlled trial looking at the efficacy of cyclical topical wound oxygen in the treatment for chronic diabetic foot ulcers. So the goal was to have a patient population with intend to treat for 220 patients and it was established at the beginning that there will be two analysis, one at 73 patients and second set of analysis at 146 patients. This study allowed for a fairly high A1c 12, sometimes it can be 10 and a lot of clinical trials that the patient were a little bit sicker and also they were not excluded that they had some mild-to-moderate diabetic nephropathy. There was a very, very rigid standard of care. It was gold standard of care. In particular, the offloading I was quite impressed. They used an offloading boot that was validated through trials that was shown to be equivalent to total contact cast. The patients came in weekly and any patient within that two-week screening period who healed over 30%, they were eliminated.

[24:02]

Because we are looking really for only refractory ulcers. We don't want ulcers that are going to heal just because they haven't been offloaded properly. Anybody who healed under 30%, they were kept into the study. So what they found is that very first in-term analysis with 73 patients, they found that at 12 weeks, 41% almost 42% of patients treated with topical wound oxygen were healed as opposed to the sham treatment of 13.5%, which shows that when you are using topical wound oxygen, it's nearly four times as likely to completely heal in 12 weeks. Now in terms of the study, I had a slide earlier referring to that earlier trials that were very poorly designed. This study was first of its kind and that it was truly blinded. When the patients were randomized, there was a third party who applied the device, so I was totally blinded as well as the patient and also we had very, very good standard of care in this study. So if you look at Kaplan Meier curve, we know that no other covariates achieved any type of significance and also there was a fairly high screen failure rate, 23% fail to run in period because they were under trajectory to heal. So I would say in conclusion really when you are looking at these chronic wounds that you know are hypoxic, really adjunctively topical wound oxygen therapy should be considered. We know that from the study that I just mentioned, which was very, very well-designed that at 12 weeks, we are going to have superior results in healing that are significant.

[26:00]

So I think if you have a patient who is coming in with an ulcer that it's lingering for a long time and you suspect hypoxia and you are doing that offloading, you are doing that wound care, they are having serial debridement, we should consider using some of these modalities earlier and instead of letting the wounds linger on for a long time. And then just to refer back to the study, this really was one of the most regressed protocols that had ever been designed looking at topical wound oxygen in a blinded and truly randomized fashion. I would mention that Dr. Frykberg, he actually participated in the consensus paper that was really excellent looking at hyperbaric oxygen versus topical wound oxygen and in that review, he can correct me if am wrong, that really identifying anything that was similar compared to this trial that was recently undertaken. And that is my conclusion. Thank you.


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