• LecturehallAdjunctive Management of Venous Leg Ulcers and Other Chronic Wounds Utilizing Cyclical High Pressure (CHP) Topical Wound Oxygen Therapy
  • Lecture Transcript
  • TAPE STARTS – [00:00]


    Male Speaker: Cyaandi Dove is going to talk to us. She graduated from the University of Florida in Gainesville, then went to the California College of Podiatric Medicine. She did her postgrad training or residency at University of Texas, Health Science Center in San Antonio. She opened her practice as the director of podiatry at the Diabetic Foot and Ankle Center, Hospital for Joint Disease, NYU. She's been involved in research, has multiple publications and peer reviewed journals. She participates in numerous industry-sponsored clinical trials and looks at the latest technology available. So, please welcome her. She's going to be our speaker before the break. This is a technology that you're going to be amazed about, I promise you.

    Dr. Cyaandi Dove: Good morning. Thank you, guys, for having me here. So, we're going to switch gears a little bit and talk about a new modality that I think may be unfamiliar to quite a few of you. Can I see a show of hands in the audience? Anybody who's familiar with topical oxygen therapy? Okay, so a few. So today, we're going to be talking about the adjunctive management of venous leg ulcers and other wounds using cyclical high pressure topical wound oxygen therapy, and I will stress the adjunctive use because anything we use for treating chronic wounds has – this is an adjunctive management. We always have to maintain good standard of care, venous leg ulcers and diabetic foot ulcers. Uh, oh, what did I do? How do I go forward? This one? Okay. It's stuck. Thank you.

    [00:02:00]

    The previous slide was my disclosure. It's supported – some of the research is supported by advanced oxygen therapy. So, the learning objectives for today's talk are we want to talk about some of the challenges that we as practitioners face in treating chronic wounds such as venous leg ulcers and diabetic foot ulcers. Also, we want to talk specifically about the mechanisms. How does the – what's the impact of multimodality cyclical high pressure topical wound oxygen therapy along the continuum of wound healing?

    And lastly, we're going to look at two important studies using cyclical high pressure topical wound oxygen therapy. And I want to spend some time with that because this is a very new topic to a lot of you guys out there. So, I don't want to beat this to death but when we look at wounds, on the left, you have an acute wound. On the right, you have a chronic wound. And really, the distinction between the two is chronological. An acute wound is a wound that passes through all the phases of healing in a normal fashion timewise. So, if you look, that's not something that we have walking into our clinic. That's a simple laceration that will heal without a lot of work, a few sutures or good wound care.

    A chronic wound is a wound that's stuck in the inflammatory phase of healing. It's stalled, and these are the patients that we see coming into our office in a daily basis. So, we have challenges and we have these patients coming into our office. In particular, you have to look at the comorbidities. If we look at diabetic patients, we know those are usually accompanied with peripheral arterial disease, renal disease. You can have compromised nutritional status. We look at our patients with venous leg ulcers, they have a failure of the calf muscle pump. Autoimmune patients who come in with chronic wounds, how active is this patient?

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    Is this a patient who's bedridden or in a wheelchair? And also, if you look at psychiatric illnesses, is this going to be a compliant patient? And that tends to be a big issue in particular with our diabetic patients. Lifestyle and behaviors play a role. Some of these things, we can control and others, we can't. In particular, smoking. I always put that out there. I never ever in 20 years, been able to change that behavior in a patient. And compliance is a big issue with these patients. So, when we look at venous leg ulcers, this is the most common wound that you're going to have in the lower extremity.

    At some point in time, 1% of the world's population has a venous leg ulcer very, very, very common. We know that these patients are repeat offenders. After you heal them, and they will be back eventually because the disease is very tough to treat. And most of my patients in the private world, the wound is the main problem but secondarily, these patients suffer tremendously with chronic pain. A lot of these patients are depressed. And also, it's a big burden in terms of psychological well-being. A lot of these patients are embarrassed of the wound.

    It's very large. It's draining. There's an odor. So, the wound creates an entire cascade of other problems that the patient has to deal with. So, this is something that I see in my wound care center quite frequently, and they're tough wounds to heal. So, on the bottom, we have some illustrations talking about how the pathogenesis of these ulcerations and I think we're all familiar with this, and that you have a failure in the valvular system of the veins which leads in turn to a failure of the calf muscle pump.

    [00:05:56]

    Diabetic foot ulcers, I'm sure you guys are all familiar with those. Not as common but very, very difficult to heal, and just like venous leg ulcer patients, these are also repeat offenders unfortunately. About 20% of the patients with diabetes will get a foot ulcer. These tend to be, with a few exceptions, pretty non-compliant patients. And the cost in taking care of each episode of a diabetic foot ulcer is tremendous with or without hospitalizations. And these are very – typically, these are very sick patients. If you look at studies, multiple studies, you'll see that the five-year mortality rate on these patients is over 50%. So, very sick patients.

    So, I like this slide because this is a Greek mythological character, Sisyphus. He was punished by the gods for some minor infraction, so he had to push this boulder up a hill, and as soon as he got to the top, it would roll back down. And that's how you feel when you're treating these patients with a diabetic foot ulcer. Mr. Jones [phonetic], you get him healed and he's back in a few months with the same problem. So, when we look across the spectrum of wound healing, we know that you have to treat these patients with standard of care.

    Every patient who comes in with a diabetic foot ulcer or with a venous leg ulcer, debridement, you have to do them no matter what else you add adjunctively. If you don't debride, it's not going to heal. If you don't control underlying inflammation edema, it's not going to heal. You have to make sure that this wound is clean if it's infected or it's very contaminated or very colonized. You're going to have difficulty healing. And in particular with diabetic foot ulcers, you have to make sure that you have appropriate offloading.

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    So, when we look at cross spectrum, we'll see the three phases of wound healing, the inflammatory phase, the proliferative phase and the maturation phase. So, when we're looking at chronic wounds, chronic wounds, they are stuck in the inflammatory phase. Normally, the inflammatory phase should only last for a few days and you should progress on to proliferative phase. So, what happens in the inflammatory phase, a lot of key things. Your metabolism within the cell is very much increased. You're creating reactive oxygen species which serve as an antibacterial mechanism within the wound.

    And also, you have growth factors. You have angiogenesis. Chronic wounds cannot get out of that phase. And if you look at all the three phases, the thing that they all have in common is that oxygen is what drives all of these phases. Oxygen is what pushes the wound out of the inflammatory phase into the proliferative phase and into the maturation phase. So, we have a catch-22 because in chronic ulcers, we are typically in a hypoxic environment.

    So again, just to repeat, in the inflammatory phase of wound healing, you have a higher oxygen demand, again, for the increase of metabolism. The wound needs a tremendous burst of energy that you get by increased metabolism that you don't have in a hypoxic wound environment. You need that production of reactive oxygen species to act as an antibacterial effect. And also, you need to produce extracellular matrix and regulation tissue. Again, the catch-22 situation.

    So, I think that this slide is really great in showing, demonstrating what a typical wound looks like in terms of partial pressure of oxygen within the wound. So, if you look at the bottom left of the slide, the arterial partial oxygen pressure in the arterial aspect of the wound is 100 millimeters of mercury.

    [00:10:02]

    Now, if you look at the wound margins, it's 60 millimeters of mercury. But what's pivotal is when you look at the center, typically, the deepest part of the wound, the partial pressure is only 10 millimeters of mercury. So, we know that in order to heal, all of these different processes to heal in terms of angiogenesis increasing the metabolism, forming reactive oxygen species, you need at least minimal, a partial pressure of 40 to 60 millimeters of mercury. To make sure that you have adequate metabolism, you actually need 100 millimeters of mercury.

    So, we look at a chronic wound, then we're scratching our heads and wondering, why is this wound stagnating? Why is it not healing? Because if you look at this partial pressure, less than 10 millimeters of mercury, the wound is stalled. It doesn't have the fuel. It doesn't have the oxygen that it needs to progress to healing. So, why is the partial pressure so low in chronic wounds that are stalled? So, we know there – it's multifactorial. You do have damage, trauma in the adjacent capillaries. Also, in particular in venous leg ulcers, you have quite a bit of edema which is secondary to trauma or infection.

    And secondarily or thirdly, you may have comorbidities. A lot of these patients, they have compromised arterial systems. They smoke. They may have autoimmune diseases, so there are many reasons for low oxygen partial pressures. But the question is, how do we address that? So, we get into the next phase of the talk, I'm going to talk a little bit about the different therapies. We'll talk about hyperbaric oxygen therapy with the multiplace and the single, mono chambers. First is topical oxygen therapy.

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    And I will say that when I was a resident, I think we – I was maybe introduced to the idea of topical oxygen therapy once. I wasn't familiar with it, then I really had a bias against it because I hadn't seen it practiced in our – during my residency. So, if you look in this slide, we have some photos of hyperbaric oxygen chambers. We have the multiperson unit and we have the single. In the US, it's typically a single unit. I think in European counties, they – especially in Italy, they'll have the bigger chambers. So, what is hyperbaric oxygen?

    Hyperbaric oxygen is when a patient is having their blood oxygenated at two to three millimeter – or I'm sorry, two to three atmospheres. You need very specialized equipment. It's quite expensive. And you really need to have an intact vascular system to make sure that that oxygen is going to be delivered to the wound. That's the main component because you're delivering this oxygen systematically, so you need to have that intact vascular system. Hyperbaric oxygen is not risk-free. There are many, many dangers with it. And one of the biggest issues is the potential for multi or oxygen toxicity.

    Now, I have to say, I've never – I've worked in hyperbaric oxygen centers. I haven't had many problems other than a few problems with the ears. But it's not a benign treatment, and personally, a lot of my patients are somewhat leery when I suggested to them because if you look at the bottom right, it's a big deal to go there. It's very time consuming to get the patient at the correct pressure, to bring them out of their pressure. And typically, these patients are going five days a week for up to 40 dives, 60 dives, 100 dives. So, it requires a lot of work on the patient's part. And if you have a patient who's claustrophobic, they're not going to sign up for this even with medication.

    [00:14:03]

    So now, we look at topical oxygen therapy. And there are many different systems on the market. And so, in terms of topical oxygen therapy, this is somewhat controversial, and I think a lot of the controversy comes from the fact that it's a newer concept but relatively speaking, but it's actually been around for about 50 years. It's just now emerging as a newer adjunctive therapy on the market, but we really need to push for more publications and better literature so that we can fairly evaluate it. So, the different systems in terms of delivering the oxygen, a lot of the systems in the bottom right are a continuous oxygen flow.

    The system on the left is a – it's an oxygen flow, but it has some different components to specialize it from the others, and we'll go into that in more depth on the future slides. But some of the benefits of topical oxygen are that you do not have to have an intact vascular system because the wound is going to be penetrated directly by oxygen. This is something that is relatively inexpensive. It can be done in the home or in the clinic. The patients tolerate it quite well, and there is no risk of any organ toxicity from the oxygen.

    However, the big flaw in it or I shouldn't say flaw, but a drawback is for new providers is that there isn't a lot of literature that is coming from a well-designed, randomized, controlled, placebo-controlled clinical trial. So just in terms of the origins of topical oxygen therapy, when I was preparing for this talk, I was going through some of the literature and oxygen, it was discovered around 1790 and since then, practitioners have anecdotally known that there's some value to this new thing called oxygen.

    [00:16:07]

    And one of the things I've found previously was that even Jacques Cousteau, the famous oceanographer, he actually built an underwater city that was 10 meters under the sea level at the Mediterranean Sea. And just anecdotally, he and his staff noticed that they had cuts or bruises in that very humid and pressurized, highly oxygenated environment, things healed up quickly. That's not a study, it's anecdotal, but I thought that was interesting. One of the earliest doctors to publish a paper on topical oxygen therapy was actually a neurosurgeon, Dr. Boguslav Fischer.

    He was a neurosurgeon in New York and he actually built his own unit for topical oxygen, and the results were reported in the Lancet in 1966. One of the things that he found was that if the oxygen pressure was under 10 millimeters of mercury, it wasn't quite effective, but he also found that when you apply a relatively low amount of oxygen at a pressure of 22 millimeters of mercury, that after one hour, the partial pressures of oxygen increased to 115 millimeters of mercury.

    Now, if we think back to that previous slide, looking at the partial pressures of oxygen in the arteries, in the wound margins and centrally, we saw that it was under 10 millimeters of mercury. So, in his study, when he applied it topically with a very low pressure, he got the pressures actually to increase to 115 millimeters of mercury. And we know that to drive these processes to drive cellular metabolism, formation of anti – or reactive oxygen species and angiogenesis, you need that pressure of 100 millimeters of mercury optimally.

    [00:17:59]

    So, we'll dive a little bit deeper into how does cyclical high pressure topical wound oxygen therapy work. So, this system is going to attack the problem of healing a chronic wound that's hypoxic from three different levels. So, oxygen is cycled. It's between two different pressures. It cycles from five millibars to 50 millibars. So, we know that when you have this gradient where it's not a constant flow at 10 or 20 or 50, when you're cycling, it actually helps the oxygen to penetrate into the tissues quite a bit better.

    So, you'll actually see a five times increase in the oxygen in the wound tissue. However, you're not reducing distal perfusion. Also, this is the lowest pressure but the most effective pressure that they found to be effective in creating – taking the wound from a hypoxic environment to oxygenating that wound. Something very important in particular for venous leg ulcers is that with the cyclical component of the topical oxygen therapy, you're actually reducing edema quite a bit. And lastly, we all know and there are many, many papers to support this, that a dry wound is difficult to heal.

    Wounds need to be in a humid environment, so this air is humidified at about 60% to 80% to create an optimal wound healing environment. And this is just a reiteration. Again, it's multimodality. We are – by just driving that oxygen into the tissue along the gradient of between five millibars and 50, you are penetrating those tissues very effectively. We're getting edema reduction with the cyclical compression. And last but not the least, work a new modification, creating the optimal wound healing environment.

    [00:20:02]

    So, there are several papers out there talking about topical oxygen therapy. A lot of these are not very well-designed. They're not perfect, but I think that even if it's a case study, there's still some values to some of those research. But I would like to talk about two papers in a little bit more depth. So, this is a study that was done in Ireland in a wound – outpatient wound care center for treatment of chronic venous leg ulcers. And they were looking at conventional compression dressing versus topical wound oxygen therapy.

    They had a fairly large patient population, 132 patients. And 67 were randomized into topical wound oxygen and 65 had conventional compression dressings. I will say that that was unusual. One of the things that was unusual in the study is that the patients actually could select which treatment group. They were presented with the options. They were educated on the options and they got to choose which is very unusual. And then, the endpoint was looking at how many of these ulcers were healed at 12 weeks, overall reduction time to healing.

    And another really good component is they actually followed these patients out at 36 months. I've done a lot of industry-sponsored clinical trials, and typically, it's one year. To have the value of looking at these patients in three years is pretty rare and pretty valuable, I think. So, the inclusion and the exclusion criteria in the study, they were allowing patients with ulcers over two years with no improvement. And again, I've done many, many, many clinical trials through the industry and typically, the wounds have to be six weeks to a year.

    [00:22:01]

    So, on this study, I would say, they were not stacking out in their favor. They were looking for difficult wounds over two years old. These typically are the patients in my office when I see them. If I have a wound that comes in that's five years, six years, I tell them realistically, "we can try but I really don't know what your chances are because there's a lot of literature to show that wounds that old, you really can't heal them especially a chronic venous leg ulcer."

    The patients could not – they could have – they need to have a normal ABI. You could have some very mild peripheral vascular disease but nothing where the wound was truly ischemic, or you've thought the wound would become gangrenous. If the patient was bedridden or they had bone infection, they were not allowed in the study. And obviously, no malignant ulcers were allowed within the trial. So, the enrollment was over five years. The patients were managed with the intent to treat population. So, all patients whether they finished or not, all of that data was included in a statistical analysis. And that patients again were given the option of conventional compression dressing versus topical wound oxygen. And the patient, one of the facets that the patients and the investigators were not blinded, it would be impossible in this situation to blind them when the patients who had conventional compression dressings, it's very clear versus the wound, topical wound oxygen patients, they had no dressing. Their legs were actually left open to the air.

    So, in this study, the patients' ulcers were swabbed. Pictures were taken and it was measured with the Visitrak system. And if you chose to go on to the treatment group with conventional compression dressings, you came in one to three times a week. The patients who got the Hyper-Box therapy, they had that for 180 minutes twice daily.

    [00:23:59]

    And they could come into the clinic or they could come into their home. And I thought it was really interesting because I treat a lot of venous leg ulcers, and I don't know how they convinced these patients, but they had no dressings. The wounds were cleaned. And they were open in between, and they had no compression dressings. So, when I read this paper, I thought, how – I was very intrigued because I – my first line of defense for venous leg ulcer is obviously, a compression dressing, a PROFORE or Unna boots.

    And also, the patients were compliant with this. So, if we look at the results, let's see. What I want to focus on, if you look at topical wound oxygen therapy versus conventional compression, if you look at the three-month benchmark, at three months, 76% of the patients who received topical wound oxygen therapy were healed versus 46%. I was pretty amazed by this considering I've always believed – been a big proponent of compression dressing.

    But with this particular treatment that the patients received, the device actually offers compression. They didn't have to have a PROFORE, Unna boot on. If we look at the recurrence at 36 months, only 6% of those patients who got topical wound oxygen therapy were reopened versus almost half of the conventional compression dressing. And another issue is they swabbed these wounds throughout the study, and they saw that almost half the patients who had topical wound oxygen, they had MRSA elimination whereas none of the patients in conventional compression dressings had any resolution of the MRSA.

    [00:25:54]

    So, although this study wasn't perfect, I think it was a beacon showing that we do need further data, and I thought it was very valuable in terms of the fact that we see that there are different modalities. We don't always have to rely on compression dressings when we have this new modality out on the market. So, this is a patient who comes in with a wound that is nine years old. This is a patient in my private practice where I'd say, "We're going to do palliative care. We're going to manage your exudate, manage infections and your pain. This is a wound that I would think, even with biologic, different biological therapies, I really couldn't heal."

    So, as we progress, this is one week out with topical wound oxygen therapy. Two weeks, three weeks, and we'll progress to a completely healed leg. Very impressive nine years of patient suffering with this wound. And that was a study that was done in Ireland which I think is a springboard to talk about the next trial.

    But some of the highlights, again, MR – I'm sorry, recurrence at 36 months, 6% versus 47% or almost half, and those who only got conventional compression. The MRSA elimination, almost half the topical wound oxygen therapy versus none with dressing, conventional dressing alone. And the pain score which I didn't really talk about much before, the pain score decreased from eight to three in almost under two weeks. So, this study that I'd like to talk about now, this is a landmark pivotal trial.

    And I've been eluding or referring to the fact that we don't have a large body of research that is truly placebo-controlled, randomized, looking at the therapy for topical wound oxygen. But this study, this was a multinational, multicenter, prospective, randomized, double-blinded trial that was placebo-controlled.

    [00:28:03]

    This was really the first of its kind and looking at topical wound oxygen therapy. And I believe the FDA was quite happy with this trial. Let's see. So, I want to go back. One of the components of this trial that I want to stress is when the trial started, when they picked what statistical analysis model they would use, they chose something called group sequential design. So, when you choose this analysis to look at your data, you are mandated to stop the trial whenever you reach statistical significance.

    So, they had two interim analyses and they had a final analysis. So, if you reached that, the first, second or second or – you had to stop. If not, you could go on to the third. Let's see. So, in this trial, when they got to their very first A priority interim analysis, there's only 73 patients, they actually reached statistical significance. This is something that is mandated at the start of the trial. It's not something that comes up as the trial is going on. And they found that 41% of the ulcers healed, first is 13.5% at 12 weeks.

    So, the trial was stopped because they reached statistical significance very, very early. They saw that when they are looking at the topical wound oxygen therapy that those patients were four times as likely to heal compared to those who got sham treatment. So, talking a little bit more in detail about the study, the study was very rigidly made – very rigidly done. A few things as a principal investigator today were very significant is the blinding in the study. The patients receive their investigational treatment in their home.

    [00:30:04]

    As an investigator and my staff, we had absolutely no idea what the patient was getting because there is a home health care nurse who would go to the patient's residence, apply the treatment, and the patients would only come to me for photos, debridement and evaluation and to make sure there was no infection. After doing over 20, 30 trials, that is probably one of the best examples of blinding I've seen. Also, in terms of the offloading, the offloading was very rigid. They had very, very high patient compliance with their offloading.

    It was over 90% within the treatment arm and the sham arm. Patients were very, very compliant, and part of that is because they had a very specialized boots that actually, itself, underwent a lot of rigorous testing to make sure that this was going to be sufficient in terms of offloading. So, I think the study design was very strong from the standpoint of the group sequential design, very, very good compliance with the offloading. And also, a very rigidly maintained blind, the investigators, the patients that truly had no idea of what they were giving.

    So, if we look here, one of the other things that they want to make sure that when they were treating patients, they truly only had wounds that were recalcitrant. We didn't want the wounds that were going to heal as soon as you put them into an offloading device. So, on the first two weeks, it was a two-week running period meaning that you saw the patient. You consented them and then you saw them for two weeks. If that wound healed by over – by 30% or more, they were excluded from the trial, so really, truly only recalcitrant ulcers.

    So, when we look at the study, I think and – that this is one of the most rigorous, probably the best study we have out there. I'm looking at topical wound oxygen therapy in terms of making sure that there are no biases in terms of blinding.

    [00:32:08]

    And also, the standard of care was very, very rigid, and they also ensured the other study design that you really only had recalcitrant wounds that were included in the study. So, looking at this very rigorous, very robust, randomized clinical trial, I think that it shows that it's superior in healing diabetic foot ulcers at 12 weeks compared to excellent gold standard of care. Even the larger ulcers, they saw, were on a trajectory to heal. And actually, in the sham treatment, the larger ulcers actually increased a little bit.

    And if you look at the ease for the patients to use this modality, very easy, and patients were very compliant with it. So, in summary, really, when you're looking at a wound that is hypoxic, you know that this is a chronic wound and you're scratching your head, what should you do? Really, you should start considering in your practices, topical oxygen. This should be a frontline adjunctive therapy. Obviously, you still have to perform good offloading, debridement, wound care, good dressings, but as another tool in your armamentarium, really, topical oxygen therapy should be something that you consider. Thank you very much.


    TAPE ENDS [00:33:37]