Section: CME Category: Wound Care

Evidence that Demands a Verdict - Hyperbaric Oxygen in Wound Healing

Tomas Serena, MD, FACS

Thomas Serena, MD discusses the mechanism for hyperbaric oxygen in healing, methods of application and studies that document its effectiveness.

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Goals and Objectives
  1. Describe the evidence for hyperbaric oxygen in diabetic foot ulcers
  2. Explain the mechanism of action for hyperbaric oxygen in wound healing
  3. Review the application of hyperbaric oxygen for appropriate patients
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  • CPME (Credits: 0.5)

    PRESENT e-Learning Systems is approved by the Council on Podiatric Medical Education as a provider of continuing education in podiatric medicine. PRESENT e-Learning Systems has approved this activity for a maximum of 0.5 continuing education contact hours

    Release Date: 03/16/2018 Expiration Date: 12/31/2020

  • Author
  • Tomas Serena, MD, FACS

    Vice President - American College of Hyperbaric Medicine
    Founder & Medical Director, Penn North Centers For Advanced Wound Care, Erie, PA

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    Tomas Serena has disclosed to be a consultant/advisor for Smith and Nephew, MolecuLight, Organogenesis, Mego Aflec/lympha Press USA, Molnlycke Health Care, Rogers Sciences, Integra, RedDress, Cardiovascular Biotherapeutics and Tissue Therapeutics.

  • Lecture Transcript
  • Moderator: What would a meeting be without a discussion of oxygen, the most important drug for arteriogenesis, angiogenesis, and wound repair? We’ve asked our perennial favorite Dr. Tom Serena to talk to us on the evidence for hyperbaric oxygen. We always want to have these conversations because the data is good in some respects and also good in other respects.

    Dr. Tom has been with us for several years for return engagements. He is President of the Serena Group now. Tom is a trained vascular surgeon who is exclusively practicing wound care and wound care research, moved his organization from Pennsylvania to Cambridge Massachusetts. So let's welcome Dr. Tom Serena to the podium.

    Dr. Tom: All right. Well, thank you very much. I always enjoy being here. I will tell you that I started off as a vascular surgeon, in actuality I started off as junior faculty, there was no one in the surgical oncology department. So I actually started in surgical oncology. You know, they say you remember your first and your latest. This is Ruby and she was my first patient as a surgeon, as an attending nonresident surgeon; you remember these cases well. 72-year-old woman, she has a T2, N1, M0, that's the grading system that was back in the drastic period of surgical practice when I started; the exact staging system for breast carcinoma.

    We took her to the operating room. After staging our cancer we did – I offered her a lumpectomy because I was young slick surgeon back then and I could do this new lumpectomy procedure, but she wanted a mastectomy. Postoperatively she came to the hospital every day and had radiation therapy. And I remember running into her daughter in the coffee shop and saying, boy, I'm sorry to make mom come here to the cancer center every day to have this radiation therapy. And her daughter says, well, you know, that’s really not a problem, we’re saving mom’s life, this is really – this is important.

    Ruby had chemotherapy as well lost her hair and I used to see her in church and she had the wigs on. But eventually I ran into Ruby 10 years after this surgical procedure at a church picnic. She had great grandchildren on her lap and she came back and she gave me a kiss, that’s why we do this. We’re not doing this work because we want to be a part of, that's for sure. So that was my first patient, and it was memorable. And you know, I wish that I could treat every patient like I treated Ruby.

    This is my latest picture – actually a little younger, diabetic woman. She has been on I don’t know how many different antibiotics. By the time she got to the wound clinic she had seen at least three or four practitioners, some would try debride some who hadn't.

    She had about five different types of [Indiscernible] [0:03:21] including Neosporin, Bacitracin and over-the-counter medications that have never been approved for diabetic foot ulcerations. So six months into her course or so, she eventually makes it to the wound clinic. You know, it's interesting; already her story doesn’t look anything like Ruby’s. The time between Ruby’s mammogram and the time that she saw me in the office was about 12 hours, not six months.

    But when you look at how we treat these diabetic patients, and not just diabetic patients, God forbid you have a pressure ulcer, that’s even more of an orphaned ulcer. We don't have a TNM classification for diabetic foot ulcers or at least one that we can use. We have some fairly decent classifications, but we can’t use them because we won’t get reimbursed. So the only reimbursable classification system is Wagner and just like the TNM classification it's been updated? No.

    It was published by Dr. Wagner who was an orthopedic surgeon in the mid-80s. It's never been updated in the last 30 years. It’s going to be 30 years since it has been published, and was a marginal classification then and it’s even worse now because we know that there are different types of diabetic foot ulcers. There are some ulcers that come in the clinic and I know if I debride the patient, put on something that makes a moist new healing environment, maybe a topical antimicrobial and a total contact cast, in eight weeks that ulcer is healed.

    I'm not even worried about that patient, and yet there is the other patients. They have a different biology; they clearly are different. I don't think the Wagner classification in any way shape or form it allows us to classify the ulcers, to pick which patients are going to be good patients for hyperbaric. That may be why although I'm going to show you some really super great efficacy studies, it may be why we don't see some of the effectiveness data that Bob was just mentioning in the beginning in this introduction, that we should be seeing with hyperbaric oxygen therapy.

    So we know that in actuality Ruby had a much better prognosis and my most latest patient really probably should have picked breast cancer rather than a diabetic foot ulceration particularly if she had ischemia associated with it, because her mortality would have been much better. And we certainly don't have football players around in pink tights celebrating our diabetic patients.

    As a good segue from the last talk and that was a super description of angiogenesis and arteriogenesis, and it's a perfect segue into discussion of hyperbaric oxygen, the one modality that we know for sure induces new blood vessel growth. The work was initially done on angiogenesis as we know from the growth of small vessels was done largely by TK Hunt in the late 60s and early 70s, and which he showed that angiogenesis is dependent on oxygen gradient.

    So if we take a patient and we make the tissues around the hypoxic wound, really hyperoxygenated, we’re going to dry blood vessel growth into that wound, and that's exactly how one of the main mechanism by which hyperbaric oxygen functions. Again, we've known that for quite for quite some time.

    We already heard about nitric oxide molecules, in the year 1998 three pharmacists from the United States won the Nobel Prize for discovering this gas. At that time they realized it was produced by endothelial cells in a very important communicating molecule. And from the last lecture we saw that our diabetic patients or patients with arterial disease and other chronic diseases do not have enough of this nitric oxide.

    So let’s take a look in a paper by Steve [Indiscernible] [0:07:10] at the bone marrow of a diabetic. So on the left side of this slide is a normal patient, and we just heard about endothelial progenitor cells, those really super important cells that will go to the wound and create vasculogenesis or arteriogenesis as we just heard about. You got to have those if you’re going to heal wounds, but the problem is diabetics don't produce enough EPCs, and more importantly they can't release EPCs from the bone marrow because they don't have enough nitric oxide in the bone marrow.

    You got to have nitric oxide in your bone marrow if you’re going to release endothelial progenitor cells. And then they get to the wound site by a homing molecule, and we heard about this one earlier too, SDF-1α. SDF-1α says to the stem cells, I'm here, this is a wound, and come stick to me. And one of the interesting things about the molecules we saw in the last lecture, and we didn’t plan this either is that hyperbaric oxygen stabilizes SDF-1α and actually it increases the expression of wound as well as the expression of growth factors such as vascular endothelial growth factor which also is increased at the time of our hyperbaric oxygen treatment.

    So in that fashion hyperbaric oxygen will cause the release of human stem cells, and this is done in rats and in humans, and if you see, after about 20 treatments if you look at circulating endothelial progenitor cells you have an eight-fold increase in EPCs after the patients received 20 treatments. And that's why a lot of our regimens will call for 20 hyperbaric treatments maximize angiogenesis.

    So if you look at it diagrammatically, you have angiogenesis which is caused by oxygen gradient and vasculogenesis which is caused by a nitric oxide mechanism increasing endothelial progenitor cells in circulation.

    So we have a diabetic foot ulceration; this would be considered a Wagner 3 again, lousy classification. And we treat the patient with hyperbaric and good wound care, and we’re going to talk about that in a minute. And at this point I'm not going to talk quite about multimodality therapy yet, but what we do this point? Do we just continue hyperbaric?

    I think the problem in the way we practice and I'm guilty, is that yet we do that, they’re doing great, but I’m going to show you some things that we’re looking at now and suggest to you that what we really should be doing is to take an approach that was more like Ruby’s. And in this case this is from one of our case studies in which we used a bioengineered or CTP is now called, and the patient was healed by the time they left hyperbaric oxygen therapy. And I think that really should be our goal.

    Quickly I’m going to go over the evidence for hyperbaric oxygen therapy. There are 13 peer-reviewed published studies, 7 trials; there are a total of 600 patients have been treated in HBO groups. The technology assessment done by the government has suggested hyperbaric oxygen therapy be included as a regimen.

    American Diabetes Association agrees there are three RCTs which allowed us to get approval through Medicare. Most of these are done by our [Indiscernible] [0:10:28] in Italy including a terrific study done by [Indiscernible] [0:10:33]. More recently Magnus Londahl has published a 94-patient study where we had HBO group – I shouldn’t say [Indiscernible] [0:10:41] because the patient did get oxygen in the form of air. And in those patients at one year, they had much better closure rates.

    And you put all those studies together they published, you see that major amputation rates are lower in hyperbaric group and healing is more effective, and I would ascribe this to angiogenesis and vasculogenesis. When my students asked me when do I choose hyperbaric oxygen therapy, I choose it when I need angiogenesis and hyperbaric.

    So how should we be doing it? Well, I would love to go back and treat my latest patient like I treated my first patient in really a multimodality way of doing it. You know, everyone gets together and the radiation oncologist talk to the surgical oncologist, and we have this coordinated approach. We have a cooperative group which participates in literally dozens and dozens of trials that are ongoing to find the best regimen of evidence-based materials and treatments that will take us to closure.

    We have an ongoing – and I apologize I didn’t get a chance to block the trade name there. We have an ongoing trial looking at the use of growth factors, PDGF in conjunction with hyperbaric. We have good evidence for both HBO and we have good evidence for topical growth factors, why don’t we use them together. In actuality Bill Zamboni published a paper about a decade ago showing that the patients in h hyperbaric oxygen therapy have an up regulation of their PDGF receptors.

    So in actuality PDGF should work better if the patient is receiving hyperbaric. This crowd should hopefully start in like 2014. Diagnostics are actively under development and on Friday we’ll talk a little bit about bacterial protease activity and elevated protease activity that’s host related. But I think this will also help us to guide.

    I think there are some excellent other diagnostics out there in the exhibit hall that may also help us to make a better choice, to have a better way to choose which diabetic patients should receive this therapy, and when they do, what other therapies should we combine with hyperbaric. Because I think the idea of treating a patient with just hyperbaric and not combining with multimodality therapy will be like treating the breast cancer patient with only surgery and not doing the radiation and doing the chemotherapy. I think we need to think more. We need to put our oncology hats on.

    Another combination therapy that we’ve done some case studies on. This is a patient who has been in the wound clinic where I first started a wound clinic in 1997, and I think he was one of my patients back in 1997. He has had 15 diabetic foot ulcers over the years. You can see he has lost all his toes on both feet. This is the 2013 version of his diabetic foot ulceration. We treated with a topical antiseptic, and it was a Wagner 3 ulcer, and we were just going to put him in hyperbaric, and we had a brand-new machine that we’re playing around with. And we thought, wouldn’t it be great if we put some epidermis on this patient's foot.

    And [Indiscernible] [0:13:49] had also done some work on oxygen and their epidermal response or the keratinocyte response in patients on high dose oxygen, and he found the epidermis really loves oxygen. So we thought this makes great sense. We got the wound nice and clean, the patient has had basic wound care, now he is going to get hyperbaric, and at the same time we’re going to use the CelluTome device to take epidermal grafting from his inner thigh and place the epidermis on his foot. We did in the hyperbaric unit, it doesn't require any anesthesia. It took us about 25 minutes. This is one week.

    So this every day, this is daily hyperbaric therapy and epidermal grafting. Two weeks, three weeks, healed, four weeks. Now I can tell you that that's about five times faster than this gentleman has ever healed any of the other ulcers, and we haven’t experienced about a dozen other diabetic foot ulcerations.

    Do I have a good randomized clinical trial to show you on the epidermal grafting in combination with hyperbaric? I don't, although it’s something we’re looking at and we’ll probably study in the future, but maybe we should be doing epidermal grafting, topical growth factors, debride him on, good wound healing, antibiotics, hyperbaric. Maybe the regimen ought to look like that, and maybe it shouldn’t. But I think with all of us working together and enrolling these patients in clinical trials I think would be very helpful because I really think that if you want to see effectiveness with hyperbaric, I think we really need to think about using all of our modalities in a combination fashion.

    And I think in the end of the day if you can get these patients healed sooner, you’re going to have a lot less complications, and you certainly have a lot less problems with osteomyelitis and other difficulties.

    We have some talks coming up and I know Bob is always interested in my thoughts on other types of oxygen therapy, so I'm going to be my two cents at the end here. If you can’t get in a chamber it’s not hyperbaric. If you put your leg in a bag, you might blow air on it, and topical oxygen doesn't work, because if it really worked I would take the dressings off in hyperbaric chamber. But I don't, I leave them on, I don’t care about endoscopically.

    Now I tell you that I said that on purpose just to be cantankerous, and Bob knows that. So I'm hoping the next speaker will prove me wrong. You can go to Vegas and you can get oxygen in colored nasal prongs, and it's really a lot of fun but it’s not hyperbaric.

    If you ever go to the Mumbai airport, you can go in the oxygen spa and actually it’s very nice, it’s very cool, and they blow oxygen all over you, and it’s very nice to be outside of the crowd in Mumbai airport, but it’s not hyperbaric.

    You can put oxygen in your facial creams and increase the ratings of your skin by over 300%. I couldn't find the reference I’m sorry, but it’s not hyperbaric. If you’re interested in increasing your vitality, you may want to try to oxydam [Phonetic] [0:17:05] and see if that doesn't work, but it’s not going to be hyperbaric. I really was disappointed by this one – Oxy-Moxy, it is supposed to help jetlag. It’s sort of a solution with dissolved oxygen, it doesn't work for jetlag and it’s not hyperbaric.

    One slide missing is that you can also put your child in a zip-up hyperbaric chamber and if you’re on the Housewives of New Jersey and treat them for autism which the FDA has now said is really hocus-pocus; whether it's hocus-pocus or not I don't know, but it's definitely not hyperbaric. All right. Well, thank you very much.