Robert Kirsner, MD, PhD reviews the "document" consensus recommendations on advancing the standard of care for treating neuropathic ulcers in patients with diabetes. Dr Kirsner also gives us the benefit of his expertise and experience with diabetic wounds.
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Robert Kirsner, MD, PhD
Chairman (Interim) and Harvey Blank Professor, Department of Dermatology and Cutaneous Surgery; Professor of Epidemiology and Public Health Director, University of Miami Hospital Wound Center
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Robert Kirsner has disclosed that he receives Honorarium/Expenses from Healthpoint, serves as an Advisor to National Healing, Dermasciences and Molynecke and is a member of the Organogenesis Speaker's Bureau.
Male Speaker: Thank you, Ryan. Nice talk. Our next speaker is Robert Kirsner. He’s vice chairman and professor in the endowed Stiefel Laboratories Chair in the Department of Dermatology and Cutaneous Surgery at the University of Miami -- Miller School of Medicine. He’s a past president of Florida Society for Dermatology and Dermatologic Surgery. He sits on the board of the Wound Healing Society and is founding member and past president of the Association for the Advancement of Wound Care. He co-directs the largest multidisciplinary would care meeting in the United States, the Symposium for Advanced Wound Care. We’re going to compete with you I think for this in the future because I think you can never have too many outstanding programs like this. He’s received numerous awards for his research, teaching and clinical activities. Authored more than 300 peer-review papers and as a co-editor of the Compendium Comprehensive Local Wound Healing. Dr. Fitzgerald mentioned in his talk that what we need is a standard therapy. In the next 20 minutes, Dr. Kirsner is going to give us the evidence-based treatment guidelines for diabetic foot ulcers and solve all our problems. Dr. Kirsner?
Robert Kirsner: Well thank you very much and it’s a pleasure to be back on the podium. In 20 minutes, I may not solve all the problems but I hope to review at least in part and highlight some information related to the care of diabetic foot ulcers. As was pointed out in the last lecture, a group of us got together and developed this consensus recommendation that’s been published and I just want to touch on some major points that was found in that and some new things in the literature. The reason there’s a need for this is because unfortunately 30% to 40% of patients are not treated according to evidence and even worst up to 25% of patients, the care that’s given to them may even be dangerous. I think really looking at the evidence and looking at the level of evidence is quite critical as you decide what you’re going to do for your patients. This consensus document really took the evidence and tried to translate it to everyday practice, to make common sense recommendations for care of patients with the diabetic foot ulcers. Certainly, there’s a good reason for that. Diabetes is an epidemic. You're going to hear a lot about this over the next two days. It’s an epidemic worldwide that it's estimated but they’ll be well over 400 million diabetics by the year 2025. Whatever number I throw up there, it’s invariably going to be low because it continues to increase. The same thing is true for the United States, 26, 30 million. We’ll hear numbers thrown out over 8% of the population. One-third of those patients present with complications of diabetes. They’ll present to you not even knowing they have diabetes but having diabetic foot ulcers. At least in the United States, it’s largely driven by the epidemic of obesity or diabesity as it’s called. There’s a 2% annual risk of developing foot ulcer, 25% lifetime risk. The other thing I think that’s important to take home from this conference is that diabetic foot ulcers are a mortal disease. We saw the work by David Armstrong presented in the last presentation. But large data sets from Scandinavia, 65,000 patients population based data found that over a 10-year period of time, 10% mortality among nondiabetics, 35% among diabetics but if you had a foot ulcer, nearly half of those patients were dead within 10 years. Significant relative risk, 230% increase in death over 10 years in patients with diabetic foot ulcers compared to patients without diabetes and 50% risk increase in patients with diabetic foot ulcers compared to match patients with diabetes but without foot ulcers. It turns out there’s other supporting data. This is some nice work by Larry Lavery, looking at who dies. It turns out as we’d expect if you’d have a foot ulcer and have worsening chronic renal disease and if you look at the timeframe about 10 years moving forward that if you go from having no chronic kidney disease to having chronic kidney disease to being on dialysis, your risk of death goes from 60% to 80% to 90%. The same thing interestingly is the level of amputation. If you have a foot amputation compared to below the knee, compared to above the knee amputation, this increases your risk of death.
So, a very nice paper confirming diabetic foot ulcers are a mortal disease and the risks associated with that mortality. This consensus document went through several things. I’m going to highlight some of them. The first importantly is to determine the duration of diabetes and quality of glucose control. We’ve heard about both macrovascular and microvascular complications of diabetes. Glucose control may be different for each of these complications. For example, numbers of studies have recently come out where randomized trials of patients with tight glucose control versus those with less tight glucose control. Looking cardiovascular outcomes, this is one in veterans that maybe many of you are familiar with. Essentially, when there was tight glucose control compared to not tight glucose control successfully achieved, it had no difference in death either from cardiovascular disease or from mortality at least over the course of the study which was about eight years. For large vessel vascular disease maybe tight glucose control at least in this time period may not be critical. However, some new information just published this year suggest that a hemoglobin A1C level at least over a four-week timeframe, which we’ll talk about later, may help predict healing rate in diabetic wounds. As you’re actively treating someone with a diabetic wound, there may be some benefit to having better glucose control in those patients. I will say that this is new data and it’s not always consistent to the role of hemoglobin A1C in predicting diabetic foot ulcer healing. One thing that is interesting is the advanced tissue products. For example, Dermagraf seem to behave better when given in a better glucose state. This is a data from the randomized controlled trial where they looked at hemoglobin A1C over a 12-week period. When the hemoglobin A1C and the patients got worst, Dermagraf didn’t behave better than standard of care. But when the hemoglobin A1C improved during those 12 weeks, there’s dramatic benefit of the Dermagraf product. Monitoring and educating patients about glucose control may benefit some of the wound therapies we currently use. Certainly, we want to assess for neuropathy, that doesn’t mean we have to be a neurologist but we have to have a tuning fork and a monofilament. We also want to classify the wounds. Our group felt that the University of Texas System was the best system because it combined both the depth of the wound and the combination of either infection, vascular disease or both. So that the worst scenario is if you went from the top left to the bottom right and as you move from the top left to the bottom right, this also predicts prognosis in these patients. Now certainly, other wound classification systems may be also used, for example the Wagner System is related to reimbursement. At least outside the VA system, it may be important to classify patients for the Wagner System as well where you go from normal skin to relatively superficial wound to a deeper wound from grade 0 to grade 2. As you go from grade 3, grade 4 and grade 5, you add on infection, either localized infection, gangrene distally or gangrene of the whole foot. Not only might this predict reimbursement, it helps compare apples to apples when you look at your healing rates compared to others and it may also suggest certain therapies that may be indicator in certain classification types, for example, hyperbaric oxygen. In addition to classifying the wounds, we mentioned infection is quite important. The cardinal signs of infection are hip pain, redness and swelling. But because they do not always manifest in patients with diabetes, secondary signs should also be looked for like friable granulation tissue, kind of a pale gray granulation tissue fallowed or pocketing delayed healing and wound breakdown may be a clinical sign of infection in your patients. But importantly, and I want to stress this, is that infection is a clinical diagnosis. It’s not a microbial diagnosis. Routine swabbing of wounds with diabetic foot ulcers is not recommended. We don’t treat the swab results. We treat the patient. If they do have an infection, we heard about the IDSA classification system where you go from someone who has two or more manifestations of inflammation but the redness is localized to the ulcer and that’s a mild infection.
But when that redness spreads beyond 2 centimeters in people who are least systematically well and metabolically stable, that’s considered a moderate infection. Of course when they become systemically toxic and metabolically unstable in that same scenario, becomes a severe infection suggesting that hospitalization and IV antibiotics are critical. But remember, patients with diabetes often have impaired response to infection. A high index of suspicion is required and delay of diagnosis is often seen in patients with diabetes and diabetes wound infection. Part of the evaluation of a patient with a diabetic foot ulcer is taking a probe. There’s evaluation. If you do probe-to-bone that’s suspicious for osteomyelitis, certainly, certain lab markers such as ESR and C-reactive protein may help you. But really radiography and advanced, these are critical, especially the role of MRI which seems to be our best noninvasive test to diagnose osteomyelitis. In some patients, other tests may be used such as triple phase bone scans and it can be used in combination with other tests. But just to give you an example of the sensitivity and specificity, here’s some data from the Archives of Internal Medicine, 98% sensitivity and 82% specificity for an MRI and maybe even better as our MRI techniques improve over time. This is compared to the probe-to-bone, radiography, bone scan and leukocyte scan that have slightly less sensitivities and specificities described here. MRI is your gold standard noninvasive test. With regard to therapy, the most important thing you can do, the highest level of evidence, the most critical thing is offloading. When we talk about offloading, we’re talking about adherence to offloading. Because when you give somebody even a high level offloading device such as a removable walker, they only wear it one out of every four steps. It’s critical that patients adhere. One way for them to adhere is to use total contact casting because it forces compliance. It does other things such as shorten stride length, decrease the pace, reduces activity, reduces peak pressures. But most importantly, is it forces compliance for these patients. Now some people have suggested that you don’t have to be a skilled cast placer to take advantage of force compliance. You can do something called the instant total contact cast where you take a removable walker, put a $1,000 worth of Coban around it or a plaster and lock the patient in to force compliance. But certainly education and explaining to the patients how critical this is, is the most important step of care. You can see here there’s good data that if you put somebody in an instant contact cast, meaning you lock them in a removable cast walker compared to a cast walk themselves, you get improved healing. The second line of therapy is surgical debridement, which means not only removing eschar or slough from the wound bed but also getting around the wound, getting beyond the callous and to normal tissue. You do this initially with an excisional debridement and then as needed with maintenance debridement. The concept here is you look at this and you say, “Well, that wound looks pretty good.” But no. What you want to do is you want to get around that area because we know through a variety of studies that the tissue right next to the wound is abnormal. It has an abnormal genetic profile. It has abnormal histology both in terms of epidermal proliferation, inflammation, collagen formation. But as you move away from that wound, it becomes more normal with regard to genetic profile with microarray analysis, histology and so forth. Getting beyond the edge of the wound is critical and I mentioned the presence of stem cells in more normal tissue in my last lecture. You want to go from this hypoproliferative nonmigratory edge epithelium to more basket-weave edge epithelium seen here. Now, there’s never been a randomized controlled trial for debridement so the level of evidence does not match that of offloading. But there’s secondary analysis of trials that suggest that the more you debride, the better the healing rate you get.
This is secondary analysis of the platelet-derived growth factor study. Other studies have supported this. Lilliana Saap and Vince Falanga used something called debridement performance index. They found when this was high, you over double the likelihood of healing. The debridement performance index is looking at callous, edges and undermining and the necrotic tissue. The callous and edges and undermining are critical. If you didn’t debride when you needed to, you got a very low score. If you debrided when it was needed you got a score of one. If debridement wasn’t needed that was the best scenario and you got a score of two. But the higher the score, the more likelihood you are going to heal. Now, as mentioned in our last lecture, we don’t want to let these patients go on forever. We chose and based on data that you give the standard of care for four weeks and then decide whether or not they’re healing and move on to advanced therapies. If it’s not progressing in four weeks, you want to move on and continue the standard of care, so adjunctive standard of care. We’ve already heard about Margolis’ data showing that there’s very poor healing rates and randomized controlled trial standard of care arms. Even in real life clinical scenario, less than 50% of patients heal in large data sets from United States at seven months. As I mentioned early in my last lecture, even in the most optimistic large data set, your dialed registry, less than 2/3 of patients heal without amputation. How do you predict healing? Well, I’ve already mentioned the idea of stage being a predictor and I also just touched on the idea of four-week healing rates. In the last lecture, we heard about Peter Sheehan’s data that suggested that 50% wound size reduction is a nice cutoff. If you do not have 50% wound size reduction at four weeks, the likelihood of you healing is tremendously low. Do something different. You’re wasting time, money and putting patients at risk for amputation and death if you wait beyond that. Here’s another study that confirms this. Time into healing year and then the percent would closure and you could see that by 28 days, there’s a dichotomy of those patients that get on to healing curve and go on to heal and those that don’t. For this population, you want to use advanced therapies. Is this true? Will it help? Well, Dave Margolis and others from University of Pennsylvania did a very nice study where they randomized 80 wound centers with nearly 2,000 patients. What they did was for some of them, they gave them no information, some of them they gave baseline prognostic information, some of them they gave four-week healing rates and some of them they gave both. The rule of data of these nearly 2,000 patients found that the best group was the group that had four-week healing rates. In fact, if you look at modeling data, you see that if you use this four-week change in wound size, you’ll get 50% improvement in healing just by that knowledge, knowledge is power. You’ll improve your healing rates by 50% if you use that four-week change in healing rate to help you guide your therapy. Now how will you guide your therapy? Well, there are three currently FDA-approved products for the care of diabetic foot ulcers. There’s the bi-layered engineered skin Apligraf, the dermal-engineered skin Dermagraf and the Recombinant Growth Factor, platelet-derived growth factor. In the remaining few moments of my talk, I do want to highlight this idea of dosing. Although these two products are engineered skin products, they’re not approved as drugs. I want you for at least the purposes of the next couple moments to think of them as drugs. Because they’re biologic agents and they work as pharmacologic agents to stimulate healing. And drugs, pharmacologic agents need dosing. We had this idea about traditional skin grafts back in 1993. When we published this paper, the biology of skin grafts, skin grafts as pharmacologic agents where we said, yes, your own skin, autologous skin graft works as skin replacement but it also works as a stimulus to healing. Here’s an example as it works as skin replacement. You put your own skin, skin from your thigh onto the patient’s leg, from their thigh onto their leg. It appears to be graft taken goes on to healing.
But in this example, in this chronic non-healing wound, we use the pinch graft. We placed little pinches of skin, of the patient’s own skin on their wound and we came back and the skin wasn’t there. But was this a failure? No, because something that that skin did imparted to that wound that let it to go on to heal, stimulated healing. Another example is this punch graft technique highlighting the granulation tissue which is yellow and maybe imperfect. If you come back about 10 days later, you see improved granulation tissue. What suggests here is that this graft that we placed on the wound delivered cytokines and growth factors that stimulated angiogenesis and eventual healing. Autologous skin is a drug. Certainly growth factors are a drug and you should view engineered skin as a drug and apply it in a dosing fashion. For Apligraf, the FDA studies were five applications over four weeks and for Dermagraf eight applications over eight weeks. The best data is back in 1996 where Dermagraf did a dose finding study looking at one piece of Dermagraf weekly, two pieces of Dermagraf every two weeks, one piece of Dermagraf every two weeks were a control. You can see in a very nice dose finding response that weekly application of Dermagraf, one piece every week was the optimal dose. I’m going to stop here and I very quickly wanted to go over some of the highlights of this document. Of course, I invite you to read it. It goes in detail in many aspects. But I think if we do file evidence-based care, both in evaluation and treatment, there are high hopes for patients with diabetic foot ulcers. Thank you very much for your attention.