CME Wound Care

Current State of Advanced Wound Care Therapies

Robert Frykberg, , DPM, MPH,

Robert Frykberg, DPM, MPH gives a brief summary on the most current principles of diabetic foot ulcer management. Dr Frykberg focuses on an earlier, multimodal treatment course with frequent re-assessment and willingness to change therapies as the wound changes.

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Goals and Objectives
  1. Understand diabetic foot pathophysiology
  2. Understand impediments to wound healing
  3. Understand basic management of diabetic foot ulcers
  4. Understand rationale for use of advanced therapies
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    Release Date: 03/16/2018 Expiration Date: 12/31/2018

  • Author
  • Robert Frykberg, , DPM, MPH,

    PRESENT Editor - Diabetic Limb Salvage
    Residency Director
    Carl T Hayden VA Medical Center
    Phoenix, AZ

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  • Lecture Transcript
  • Male Speaker: To give a general overview on the current state or status of Advanced Wound Care Therapies, this is going to be fairly generic from my own perspective based on my understanding of the literature and certainly my experience from a very busy wound care center in Phoenix. These are my disclosures. I’ve spoken for a number of companies. We do a lot of that, the research from a number of companies as well. These are the learning objectives that you have received. But let’s just go over nonhealing wounds. We know from the Lazarus definition in 1994 that a chronic wound is one characterized as having a failure to proceed to an orderly and timely series of events to achieve final closure. That’s fairly good because these wounds are just not following a normal sequence of events to heal within a several weeks’ time, let’s say. And this includes any type of chronic wound that we treat, most commonly diabetic foot ulcers, venous leg ulcers, atypical ulcers, depends really on your specialty. I tend to take care of more diabetic foot ulcers and venous leg ulcers than other types of pressure lesions or atypical ulcers. But acute wounds follow that normal temporal sequence of events leading to final epithelialization within two to three weeks such as lacerations, incisions, puncture, abrasions, et cetera. At least we hope that our incisions achieve normal healing in two weeks. I like to use this graphic that I borrowed from Ralf Lobmann and published in Diabetes Care in 2005. And I think even Ralf Lobmann borrowed it from Greg Schultz who published something like this in 2003 earlier. It just shows the balance of what’s going on between acute wounds and chronic wounds. On the left we see that the healing wounds, let’s say, and normal acute wound would be characterized by cells with high mitogenic activity, there’s low inflammatory level of cytokines, there’s low levels of proteases in the wound, and mitotically competent cells. As opposed to a chronic ulcer which is characterized by cells with low mitogenic activity, high inflammatory cytokine levels, high proteases, and senescent cells. So this is really the balance. What we do as wound care professionals is try to tip this balance from the chronic ulcers which are weighing this down against healing through the healing trajectory. This is, in effect, what we are doing with out debridement, our wound bed preparation. This is just a nice simplified approach in a simple graphic that really tells a story. This was just published in Advances in Wound Care Liebert last month showing the molecular and cellular deficiencies in chronic wounds. I’m sorry this is difficult to see, but it really illustrates what we had just talked about. Deficiency of cells, deficiency of stem cells, high levels of proteases, high bacterial loads, high inflammatory content, cells that can be characterized as being senescent, there’s very poor levels of angiogenesis, a lot of drainage, lot of noxious wound. Our job, again, is to change that spectrum into one that addresses each one of these components so that we can restore the normal balance to get these wounds to heal. I’m sorry this doesn’t project as well as I would have liked to. So really, it’s just taking that chronic wound, which I always view as a very noxious environment. Wound fluid is very noxious fluid and we need to remove that because that’s the antithesis of healing. By removing that with debridement, aggressive debridement, wound bed management we can change that into the acute wounds, in most cases. And many times, these people, as we just heard from Dr. Shoffer [Phonetic] have underlying serious deep infection. They have a serious peripheral arterial disease. I don’t like to use that word, small vessel disease, because it’s really a misnomer. But we need to correct every deficiency that we find within that wound bed. So let’s focus a little bit more on diabetic foot ulcer which really might mean a task. And I think it’s the main conundrum for many of us in this room. I like to approach it systematically because I don’t find that these are terribly difficult to manage once you understand the underlying pathophysiology here.


    Sometimes they are difficult to manage when you cannot correct the underlying metabolic perturbations of course. But we know that the diabetes as a whole, there’s a 15% lifetime risk for ulcerations which are a multifactorial etiology. The simplest classification scheme that you can use or to look at these globally would be neuropathic ulcers, ischemic ulcers, or more commonly, certainly in my setting in the realm of law, we’re seeing an increased incidence of neural ischemic ulcers. I think the days 30, 35 years ago when we saw a preponderance of nice, healthy, neuropathic ulcers come into our clinic has changed. It’s rare that I see a nice, beautiful, healthy neuropathic ulcer that’ll heal basically with a total contact cast. We know that foot ulcers are a precursor to amputation in about 85% of cases. Now, we recognize in the most recent data from the CDC that there are about 73,000 nontraumatic diabetes related to lower limb amputations in the most recent year that they have a data for, and that’s 2010. So this is a very big problem. We’re not going to go on to the pathophysiology around amputation but we know that the life expectancy hasn’t really changed much in the last 50 years. A general 50% five-year survival rate on major diabetes-related amputation still holds through today. This is a graphic slide I’ve used quite a lot over the years. It really gives you an insight into the only underlying metabolic perturbations that are present in many of our diabetic patients. Always neuropathy is job one for us to recognize, manage if we can. But neuropathy is the main risk factor for most of the lower extremity complications. It’s not just sensory motor, it’s also autonomic neuropathy and we can see the various complications that occur. As we’ve heard from the last speaker, vascular disease becomes a big problem, not just macrovascular disease, although that’s the major component, we have a lot of microvascular disease as well but not microvascular occlusive disease. And then we have microneurovascular disturbances related to autonomic neuropathy. All of these lead to our uncared response to wound healing as well as infection and then this leads to diabetic foot ulceration in some cases, infected diabetic foot ulcerations, gangrene, and then lead to amputation. So we need to understand the physiology here. This comes from Gayle Reiber’s paper 1999 looking at causable pathways to foot ulcers. This came from Roger Pecoraro’s 1990 paper looking at causal pathways to amputation. And looking at the seven various risk factors and then identifying a critical triad that was present in the majority of causal pathways leading to foot ulcer, neuropathy, deformity, and trauma. These are key components that need to be addressed in not just managing our existing ulcers but also in our prevention pathways. And then again, we recognize that foot ulcers are major risk factors for subsequent amputation. Any risk factor for amputation is a risk factor for ulcer. Any risk factor for ulcer is usually a risk factor for amputation as well. So the principles of wound care as we well know, good medical management, usually with a multidisciplinary team, vascular assessments, diagnosis and management with revascularization. We’ll be hearing about hyperbaric therapy in the next speaker. My job is to try to get my vascular colleagues to restore a pulse. Once I have a pulse in the foot, I can do almost anything I need to do. It’s getting that pulse, that’s the difficult part. Infection, that’s one major reason why people lose their limbs from infected ulcers or from ulcers. And many times these infections, because of neuropathy, are not recognized as being deep or serious infection especially since diabetic patients don’t have the usual clinical signs and symptoms of infection because it’s masked by the neuropathy. So we need to assess for underlying deep infection through proper probing and inspection of the wounds, looking for osteomyelitis and managing it. And then of course, wound care, basic tenets of wound care, debridement, wound bed preparation. Absolutely important is offloading or compression if it’s a venous ulcer. And that’s usually what’s not paid aggressive enough attention to. Simple offloading can usually make a profound difference in the management of most of these wounds but we need to pay better attention. There’s a recent consensus paper on this showing that only about 2 to 4% of people with plantar diabetic foot ulcers are adequately offloaded when this is a very basic tenet.


    We then recognize the role for various therapeutic agents when simple basic care does not work, and then surgery. Surgery is indeed an important component of care. Surgery to some extent, whether it’s vascular surgery, resection of infected bone, bone deformity, correction or even surgical incision and drainage for infected wounds. Again, I don’t think this is going to come out as well as I like it to. I’m sorry about that. This is going to be published in the Journal of Vascular Surgery where we just completed a consensus paper on management of diabetic foot ulcers. And it really says what we’ve been saying all along, diabetic foot ulcer assessment and therapy relies on our vascular assessment. It relies on our assessment from infection. It relies on imaging because we never know whether there’s gas present under wound, whether there’s bone changes, bone deformity, foreign bodies and what have you. Once you do your thorough assessment of your wound and classify it according to either the PEDIS scale or University of Texas, or even Wagner, as long as you recognize the role for underlying ischemia there, you have a guideline that can help facilitate treatment. I think that’s the important purpose of a classification scheme to help manage your further treatment because you’ve gone to the trouble of properly assessing that wound in a systematic fashion. Then down the next line we see the role of the debridement, offloading, TCC, an EZ TCC or a CAM boot or what have you. The days of putting people back into a shoe are gone. You cannot put people with a plantar ulcer into a shoe and expect them to heal. We need more aggressive offloading. Then we talk about wound bed preparation with our dressings, other agents to help address that noxious environment on the wound, surgery, vascular surgery, surgical debridement, I&D, correcting deformity, critical component here, and of course concurrent medical management. All these things are done at the same time or concurrently with your team approach which is really critical. We all know we reassess those wounds after four weeks looking for a 50% reduction that was based on Peter Sheehan’s paper published in 2003 from the failed Promogran trial. If we see that the wound has healed with that magical 50% mark then we just proceed with our good standard offloading and a good center care. Once healed, we follow with our good surveillance. If they are not healing then we need to reassess. What are we missing? Are we missing underlying infection? Are we missing underlying occult ischemia? Are we not offloading? Are we missing nutritional problem? After we reassess we address each one of those components and then we need to consider advanced therapy and then we continue on so we can achieve final healing. So the rational use of advance products are such that we rely primarily on good standard wound care to initially manage the wounds. But when do we need to consider advanced agents in our wound care protocols? We all have to ask ourselves this. And then we need to closely monitor for subsequent progress. And then I ask myself when do we stop advanced agents. The panel in 2010 led by Bob Snyder recognize the important role of 50% reduction in wound at four weeks to make that determination. And we tend to want to employ advanced therapies sooner rather than later to many of our cases now. There are many wound care technologies. I’m certainly not going to talk about everyone but we have isolated growth factors, acellular, extracellular matrices, including amniotic membrane products, acellular products of all types, cell-based tissue technologies, bilayered, monolayered keratinocytes, fibroblast. And coming on the market recently, of course were mesenchymal stem cells with amniotic tissue, living amniotic tissue. And of course, where would be without negative pressure therapies. We tend to use this in a multimodal fashion. I don’t use one or another. Many times I’ll combine or sequentially treat patients with these. Many have evidence, many have no evidence but they have good experience. So this is the conundrum that we all face. It’s nice to always use evidence but very few of these products, at least in the past had had any good level on evidence to support their use, just some anecdotal evidence so we try to look for that. Then other advanced or adjunctive therapies, obviously hyperbaric oxygen therapy or topical oxygen therapy. There’s a trial going on now for even topical oxygen therapy. Platelet-rich plasma, many of you might like to use that modality as well. There had been some studies on that. Ultrasonic glycol spray or MIST had a poorly designed and poorly executed study but we tend to use MIST for wound bed preparation.


    Super-oxidized water has been looked at not just for any microbial activity but also for wound healing. This came from Alberto Piagessi in Italy. Manuka honey, medical larval therapy had been published in the literature, electrical stimulation, mainly used by physical therapist, not so much by podiatrist, maybe not by you but physical therapists like electrical stimulation therapy but I don’t think data is that good at it. And even pulse radio frequency, some limited data on that as an adjunctive therapy to help boost reparative processes. Now, if we look critically at published randomized controlled trials perspective data, I like to look at the percent improvements over control groups through each one for these product with TCC as we can see on the far right as our standard. And we can see that most fell into the 30, or the 40, or maybe 60% range. This is the marginal effect of the active agent therapeutic agent compared to the standardized control. Previously, the monolayered fibroblast-derived that dermal substitute showed the greatest difference, we just had our recent paper there and then the last year showing a 69% improvement of a small intestinal submucosa dressing over standard of care as a marginal effect. And then last year the greatest effect that we’ve seen was on the mesenchymal cell therapy with a viable wound matrix that was published Larry Lavery where they found 191% marginal effect over the standard care in a randomized control perspective trial. This is nonexhaustive, it’s not everything. There’s other trials that have not yet been published yet but this is the state of affairs right now. So I try to look for things with evidence. I have used just about every one of these products and I continue to use them depending on each patient’s circumstances. But it’s nice to look at that level one evidence to see what really works for us in getting these wounds heal. Here’s our Phoenix wound protocol. Four-week rule, we give the four weeks of good standard care in most cases assess for 50% healing. We will start advanced therapies earlier when we’ve have referrals and these wounds are just chronic and nasty. And we’ll use multimodal therapies, whatever I think is appropriate once that wound bed has been properly prepared. And I think that’s the key. You can’t just throw these advanced agents, of course, on a improperly prepared wound bed. So we’ll give four weeks of therapy assess for healing. If they’re not progressing with healing by a total of eight weeks then we step back and reassess once again. The big question is, do we need to operate on this patient, do we need to stop therapy, should we resume or continue on with the therapy because it’s working very well for our wound? And then more often than not I’m looking to the wounds at what point can I put a skin graph on because I’m tired of taking care of these wounds and I want to get them healed. The longer these wounds exists, open, the more likely they are to get infected. I’m leaning more towards doing a skin graft now that I had been in the past years but I think I want to use these advanced therapies to give me that nice, healthy granular wound bed with some wound contraction and then proceed with either an epidermal graph or traditional skin graft. This is just a simple case we all see. This is a well-perfused photo of nasty infection post amputation and drainage. We, like many of you, were instantly, right away put on a negative pressure device of some sort. Here we see marked improvement in that wound. All signs of infection have resolved. The wound is getting smaller but we’re getting impatient. So then we’ll start some type of a tissue substitute in combination with negative pressure therapy which is my preference. I like to do this. And then we stop the negative pressure when I really come up with a very nice healthy superficial smaller wound. And then here we can see that we have the patient completely healed. Many times this take a number of months, many patients don’t want to go back into the hospital for skin graft. So, in previous days I tend to get these things completely healed with just some regular therapy. Now, I tend to move faster towards a skin graph because I want to get them healed and on their way back to our prevention clinic. In summary, multimodal therapies, I think, are most consistent with current clinical practice. Earlier is always better. Evidence is better although certainly limited. Wounds change over the course treatment so be prepared to change with therapies. If something is not working, stop, reassess, and try something else. Always pay attention to the basic tenets and reassess as necessary.


    Nothing supplants good basic wound care principle, so offloading, debridement, and infection management, ischemia management, et cetera. And remember that four to eight-week rule. It’s not absolute all the time but it is something that’s going to be helpful to guide your therapist. Okay, thank you very much for your attention. Hopefully that wasn’t too confusing for you.