Francis Derk, DPM discusses the theory and application of topical wound oxygen. Dr Derk examines the literature relating to the studies of topical wound oxygen and hyperbaric oxygen treatment in wound therapies. He delves deeply into the chemical processes involved in the healing process including Redox signaling and angiogenesis. He also demonstrates applications of topical wound oxygen.
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Release Date: 03/16/2018 Expiration Date: 12/31/2018
Francis Derk, DPM
South Texas Veterans Health Care System: Chief of Podiatry Services
University Texas Health Science Center: Adjunct Assistant Professor
San Antonio, TX
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TAPE STARTS – [00:00]
Male Speaker 1: Our next speaker -- I would like to hear what he has to say because he comes back and speaks to us every year on topical oxygen and I really like to turn the screw on people who do hyperbaric therapy because they vehemently oppose the use of topical oxygen. The topical oxygen is still relatively unstudied modality for applying oxygen to wounds. It's very poorly studied in the past and we're currently doing a multicenter multinational study on topical oxygen for healing diabetic foot ulcers to answer many unresolved questions. But someone with a great deal of experience for a number of years who frequently talks to us is Francis Derk, podiatrist at the VA in San Antonio, who has a great deal of experience and has presented a number of posters and presentations. So I'm always interested to hearing his new perspective 2016. Let's welcome Dr. Francis Derk.
Francis Derk: Good morning, Dr. Friedberg [phonetics], staff, colleagues. Again thank you so much for having me this year. Today this morning, I would like to discuss topical wound oxygen from theory to application.
Okay, learning objectives. These are actually learning objectives here. So what I would like to do is take a look at the literature and compare it with oxygen species and the study of use of oxygen in wound healing, launch into phases of wound healing, discuss briefly cell physiology and how the pathways are influenced by oxygen. I would like to then go into redox signaling, talk about ROS and then head right into redox biology, the science and the oxidative stress and the applications in wound healing. Let me put it this way, when one looks at oxygen in the use for wound healing, one has to look intrinsically and extrinsically. Extrinsically, if one looks in the literature, there are pros and cons to the use of oxygen, but intrinsically there are even pros and cons to use of HBO2 versus topical wound oxygen. So you take your pick, but what I would like to do is discuss some of the literature and leave it up to you. So I would like to begin with hyperbaric oxygen and in 2002 Kalani [phonetic] did a study. He took 38 patients, ulcers, full thickness that were gangrenous and you can see the results there. An HBO2 was utilized versus standard of care which is dressing changes, but however randomization was not sustained in the study. In 2003, Abidail [phonetic] compared oxygen or HBO2 to double blinded controlled study and he compared it to what is called hyperbaric air. Now, unfortunately there was no delineation of what this hyperbaric air is. And again the one problem with the study is utility and treatment of diabetic foot ulcers was not established. Wagner ulcers were identified, however, diabetic ulcers weren't. And then we launched into 2004, the Cochrane collaboration and basically bottom line upfront stating that more randomization placebo controlled studies were needed which leads us to the Landau study of 2010. I'll talk more in that detail. Let's look at the opposite spectrum with topical wound oxygen. We can go all the way back to 1969, the Fisher and he underwent a study with 52 patients, various types of ulcerations and basically all that were exposed to topical wound oxygen healed within about seven weeks. There were failures attributed to osteomyelitis and also failed wound conventional means; conclusion basically bottom line upfront on his study was that chronic wounds did very well with topical oxygen. However, no randomization and no blinding in the study.
Gordillo [phonetic] in 2002 analyzed data from two simultaneous nonrandomized studies of 1800 patients and what he found was topical wound oxygen significantly reduced the size of the wounds in his study, but also the expression of VEG-F, vasoendothelial growth factor was expressed. Again, no randomization or blinding. Taufic [phonetic] in 2009 took 83 patients and did a topical wound oxygen study versus conventional compression dressings mainly silverlon dressings and he found after 12 weeks 80% of the topical wound oxygen patients did heal. 35% of the controlled group, they found significant reduction in pain and MRSA patients that were 19, 9 out 19 were found to be negative after five weeks in this study. Again, no randomization, no blinding which leads us to the Blackman study of 2010. I'm going to launch into these two studies at the top here, but before I do, I just want to mention overall in the literature, there is good though. In HBO2, it's found that it can significantly reduce the risk of major amputations and show healing in diabetic foot ulcers in about a year. Conversely, topical wound oxygen significantly reduces the size of the ulcers and expression of VEG-F. So let's look at the Landau study and basically the Landau study comes down to the treatment of diabetic foot ulcers chronic in nature with the use of hyperbaric oxygen versus hyperbaric air. This is a randomized single center, double blinded, placebo controlled clinical trial. His results, basically HBO2 versus hyperbaric air and I would like to delineate hyperbaric air again. In this study, there is no explanation of what hyperbaric air stands for. Does hyperbaric air indeed stand for 5 millibars of ambient pressure, I'm not sure. But anyways, he studied 94 patients Wagner grade 2-4 ulcers, greater than three months old, classified as chronic wounds. 95-minute sessions that included five minutes compression and five minutes decompression before and after. And all wounds were looked at by vascular surgeon and deemed adequate. Contraindications, you can see pulmonary disease, malignancy and untreated thyrotoxicosis, which is normal contraindications for HBO2. Complete healing one year follow-up 52%, however, with the placebo group of hyperbaric air was 27%. Again, I cannot stress enough what is hyperbaric air because if you look at hyperbaric air and topical wound oxygen today, they are two different animals; it's apples and oranges. For instance topical wound oxygen, I show you here the chamber and the boot which is utilized today in clinics. The chambers inflated to 50 millibars of pressure and once that’s attained, the pressure then is released down to 5 millibars and that’s ambient pressure, it decompresses. But that repetitive cycle repeats itself every 20 seconds, so you do get the surge, this oxygen burst three times a minute. This is important because it goes from distal to proximal. It helps with the edema in the limb. So when you talk about parameters between hyperbaric air and topical wound oxygen, they're totally, totally different. And I just wanted to bring this to light. Now, you may ask what's the benefit of topical wound oxygen. Does it really, really penetrate and the answer is yes. And it was a study done by Salinger [phonetics] with the probe placed sub-epithelial and it was found that the oxygen does permeate up to 2 mm and after several minutes of use, it's been shown that there is an attainment of greater than 40 mm of pressure. If you look at transcutaneous oxygen measurement in the literature with TCO2 levels, it shows that a wound will heal anywhere between 30 and 40 mmHG and that’s the gold standard and the study delineates that very, very well. Let's look at the Blackman study just briefly. This is a prospective controlled study and basically it's a comparison of healing rates in chronic diabetic foot ulcers with conventional means in a more stressing therapy. And they did look at the wounds 24 months afterwards, two years for reoccurrence. Again, it's a prospective controlled study. So here is the inclusion-exclusion criteria.
As you can see ABIs were at least 0.5. Wagner grade ulcers, DFU 2A utilizing University of Texas grading system. And the exclusion criteria are consistent with contraindications of the use of topical wound oxygen today.
Results; interestingly, Blackman, they did random samples from the wounds collected and submitted and showed an increase in VEG-F as well. Out of 28 patients, you can see the results; 14 out 17 ulcers did heal 82.4%, 56 days. Controlled group 5 out of 11 ulcers 45.5%, 93 days. There were no adverse events and no recurrence greater than 24 months. Again, however, absence of randomization and blinding. As Dr. Friedberg mentioned there is an ongoing study of an RCT which will answer these questions. But that’s what I wanted to show you. This is one of the pathways I'm going to delineate very shortly, the VEG-F pathway, but I would like to also introduce wound healing cascade. We have all seen this before. Now, we have all traditionally used the inflammatory, proliferative and remodeling phases. We have seen those before and there is another category added, hemostasis and coagulation. This is very important, why? Because during the coagulation period when a scab is formed, there is hypoxia. That hypoxia is very, very important for signaling to pathways. There is a release of factor VII which is called proconvertin. This is known as Aryoseven or Novoseven used in hemophilia. Lattice of aggregation of platelets are attained and you get angiogenic echinocytes which are released. These are the signaling factors which we're going to look at in redox biology. Leukocytes [Indecipherable] [0:11:56] the platelets, polymorphonucleocytes come in, mainly your neutrophils first. And of course, we all know the fibroblast takeover, but you see the echinocytes are still maintained. Platelets derived growth factors, transforming growth factor, fibrinogen growth factor and keratinogen growth factor. And of course remodeling phase where the collagen production dominates in this lay down. So when we talk about the pathways, this is another model I want to introduce. You see at the very, very top, we got injury. On the right hand column, if I may direct your attention, you see the overlapping phases of wound healing. On the left hand side, you'll see the pH imbalance of the wound and also vasoconstriction leading up to vasodilation. So number one, platelet aggregation cytokines are released, echinocytes are signaled. You do get VEG-F expression one pathway. Neutrophils play a very, very important role here as well as the macrophages. The fibroblasts come in. These three cells we're going to look at in detail.
Nitric oxide, if you look in the endothelial cells right there, they do release nitric oxide between the fibroproliferative phase and remodeling phase, very important for vasodilatation. At then at the very bottom, once you get in to the granular stage, you have an off balance here of tissue inhibition of metalloproteinases vice matrix metalloproteinases. This is very, very important. The body is in a delicate balance. Hypoxia is good initially, but sustained long-term is bad. So little goes a long way, but too much goes the wrong way. So the question is why is oxygen so important? Okay, up to this point, we looked at some pathways. We did a review of the literature, but let's dig down deeper. In the collagen synthesis of oxygen, utilizing oxygen, we looked at the fibroblast, this is the main stable slide of mine because it does delineate and demonstrate that oxygen is very vital and crucial in the production internally times two pathways of hydroxylysine and proline. Externally, it's involved with collagen cross-linking which gives you helix formation, which creates collagen fibers, which leads in turn to extracellular matrix. You want that to become very stable. Let's look at the neutrophil. Oxygen-dependent healing mechanism. Now, this is very, very interesting. At the very top, oxygen is needed when those neutrophils come in. As the oxygen is absorbed within the lysosomes, very very important.
It's converted to superoxide anion there. Via superoxide, this mutates which is known as SOD. It's converted to H2O2 which we know as hydrogen peroxide. Intrinsically, there is an enzyme called myeloperoxidase which can take this H2O2 and converts it in to what is called hypochlorite anion. This is hypochlorous acid and guess what folks, this is what kills your bacteria. This is how the neutrophil absorbs and eats and destroys the bacteria. It's all because of these pathways, but all is because of oxygen. This is how the neutrophil kills bacteria. Let's look at the mitochondria. Again, you have production of H2O2 and we all thought H2O2 was bad, right? But again, there is a source needed. At the very top at 12 o'clock in the slide, you'll see the source up here, oxygen is needed. So this leads to what we call redox signaling. Believe it or not H2O2 is what we called redox biology. This is becoming a very, very important science of study today. It's intellectually challenging, but I'll tell you it's highly intellectually appealing. So I'll take this model here. Wound; production of H2O2 as demonstrated prior. That H2O2 is very, very important, why? Because number one, hemostasis is attained. Hypoxia, so the release of echinocytes, your cytokines, VEG-F mainly, but also it's drawing in what? It's drawing in number two, your neutrophils are attracted to that H2O2 as by demonstration of the pathway. Number three; now that the neutrophils are within the vicinity, they start destroying the bacteria via myeloperoxidase enzymes, but they're still releasing H2O2. That’s going to signal later on your lymphocytes, mainly your monocytes that all end up into tissue repair. So I'm showing you redox biology here and the use of H2O as an echinocytes signaling factor. So in essence what are the ROS or reactive oxygen species? I have it listed here and we talked about H2O2 as being one of the main signalers. We got the superoxide anion here, negatively charged. We got the hydroxic molecule and so forth. These are all signaling factors. Yes, they can become very detrimental to the wounds if left unchecked and unbalanced. And again, there is a very, very delicate balance. So in the acute phase, you look at the mitochondria. I discussed mitochondria. It needs a large amount of oxygen to get jump started, why? Production of ATP. We all know ATP is adenosine triphosphate, that’s the energy utilized in the cell to maintain wound healing, but ATP is formed by electron transport chain and you get, guess what, intentional leaking of electrons. Those electrons tag themselves to the oxygen molecules, thus the superoxide anion. And as you recall, the superoxide anion is very important within the neutrophil, why? Because it converts in the H2O2 and then hypochlorous acid which kills the bacteria. Neutrophils, macrophages in acute phase. Again increased oxygen consumption up to 98%, dedicated enzymes and phagocytic cells and production of H2O signaling redox biology. So reactive oxygen species are nothing more than byproducts. Initially you get the redox signaling, the mitochondrium platelets are very important why? Because you are releasing H2O2 which is utilized from the present oxygen available that includes the neutrophils as well as the macrophages. And basically this leads directly to what we call an antioxidant reaction. This is called redox biology and this is basically a review here. 50 fold O2 consumption involving all elements within the cycle, 50 fold increase in what? oxygen. So what happens if we lack oxygen? If oxygen is not maintained during wound healing what happens then we go into a chronicity state of acute inflammation. And if left unchecked and unbalanced, you get what is called oxidative stress. This results in a chronic wound that will not heal.
It also results in pathways affected nitric oxide and DNA synthesis decreases. ECM becomes unstable if that’s your extracellular matrix. MMP expression, mainly MMP 1 and 9 are exposed and you get decreased in VEG-F. So this is why oxygen is very, very important. This is called redox signaling, redox biology. And when we look at VEG-F, we talk about angiogenesis now. This is the second pathway and real briefly we have to look at the terms vascular genesis, angiogenesis and arteriogenesis. Vascular genesis is nothing more than the embryonic formation of the circulatory system. Angiogenesis is the actual budding of local circulation which results in arteriogenesis or increase in size of those vessels. This is because of one cell called the endothelial cells. It's actually dormant, doesn't activate more than 100 to 300 days out, very dormant but it is activated by VEG-F. This is the building block for ACM and fibrin. But you need recruitment of oxygen species to maintain this process of angiogenesis. So using this model, initially there is a hypoxic reaction again. The echinocytes are released, VEG-F mainly, results in budding of the nearby circulatory system, migration and tube formation within the wound. Now, as these two migrations mature, what you end up with is arteriogenesis or maturation or increase in size of the actual tube formation. This is very important, why bottom line upfront; endothelial cells produce nitric oxide. Guess what, nitric oxide detoxifies the reactive oxygen species. So this in turns your checks and balance systems because why? That goes right back and decreases the instability of hypoxia, thus altering the ROS keeping things in balance. This is a delicate cycle, but it's maintained by oxygen substrates. And if one wants to look in the literature also about VEG-F expression, there is a study done showing that after several days of use of topical wound oxygen, the increase in vascular foramen here and VEG-F expression. So there you have it. So briefly, let's look at a few applications here and I apologize for the slides here. I'm not sure why they colored out as much as they did, but this is a transmetatarsal amputation after two weeks of dehisced. Two weeks afterwards using oxygen, we slowly debride it back. The wound was slowly debrided. And after six weeks here is the actual TMA leading to nine weeks. Again, the wound was not debrided totally as the scar was falling off as it was debrided and after 13 weeks, healing was attained. Another TMA here post I&D. After three weeks of oxygen use, five weeks and then onto healing. Plantar incision here and one thing I would like to mention about the use of oxygen. Here you see the microdeformation of tissue. It's very large, it's cauliflower like unlike negative pressure which shows an even microdeformation pattern. This is what we see with the use of oxygen. Again at nine weeks, we got healing. Wound, third-degree burn debrided in OR. Markers were studied including CRPHs, white blood cell counts, sed rates and radiological studies to make sure there is no osteomyelitis. Oxygen was then used after two weeks and then four weeks respectively leading to healing in nine weeks.
So in conclusion, again I apologize for the slide. I hope everyone can see that. We conducted a literature review and basically bottom line upfront what is needed, the bluff is quantification, randomization and blinding. We looked at cell physiology, why is oxygen so important and I hope I showed that today with certain cells and substrates in the phases of wound healing and why it's important for the pathways or redox signaling and angiogenesis. We talked about ROS, redox biology and oxidative stress in chronic wounds and of course the application. Thank you very much.
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