Robert Frykberg, DPM, MPH reviews advanced wound care modalities and examines the timeliness of utilizing them. Dr Frykberg discusses the importance of obtaining quick wound closure in the management of open wounds.
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Robert Frykberg, DPM, MPH,
PRESENT Editor - Diabetic Limb Salvage
Carl T Hayden VA Medical Center
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So advanced modalities are important, but as Steve very nicely said, it’s the basics that are absolutely the most important. So, that’s a nice segue into when do we use advanced modality? What advanced modalities are there? When do we consider these? Because it can get very confusing, I get confused everyday and each year I get more confused. So, let’s see, I guess I haven’t mastered this one yet. Here we go. My disclosures, I’m a consultant. I’m on the Speakers Bureau and have research support from a number of these companies. Let’s see. Okay. As it has been very nicely explained earlier, we need to define what distinguishes a chronic wound from an acute wound. Now, this comes from Lazarus’ 1994 paper. I think it was “Archives of Dermatology” where he was publishing on behalf of the wound healing society. And very nicely defined, a chronic wound has a failure to proceed through an orderly and timely series of events to produce a durable, functional, and cosmetic closure. So wound healing, as was mentioned earlier, needs to follow a normal temporal sequence of events to affect the final closure. Chronic wounds are stalled and they do not follow that course. And of course, diabetic foot ulcers, venous leg ulcers, other types of ulcers are the classic examples of chronic wounds for our purposes. Acute wounds, on the other hand, are those wounds that follow the normal temporal sequence of events which results in a healed wound in two to three weeks. So this is the simple lacerations, incisions, punctures, abrasions, et cetera or even a pitchfork wound as you could see here, very acute. But in the healthy individual, you’re going to have a normal sequence of events leading to healing at a timely fashion. Now, I often go back to Ralf Lobmann’s paper Diabetes Care 2005 because it really nicely summarizes the components of healing and the metabolic perturbations in the diabetic foot wound and it nicely describes a normal versus abnormal. But this one graph which I did borrow from Ralf describes the difference between a healing or an acute wound and a chronic ulcer as we can see on the top here. Now, this is obviously your chronic, nasty, old wound. But healing wounds are typified by those cells with high mitogenic activity. There are low levels of inflammatory cytokines, low levels of proteases, your MMPs 1, 2, 3, 9, et cetera, and mitotically-competent cells. Also we have high levels of your tissue inhibitors of matrix metalloproteinases here. So this is the normal [Indecipherable] [03:15] if you will for an acute wound that will lead to healing in a normal fashion. On the other hand chronicles, such as you see here, are those wounds where the cells are typified by low mitogenic activity. The wound environment has high levels of a proinflammatory cytokines, high levels of proteases, elastases and typified by senescent cells. So it impedes the ability of these wounds to heal. So our goal, in this regard, that is to convert the chronic ulcer, tip the scale, in this regard, it’s down, tip it so that we progress to a normal healing wound. And as Steve said, the way we do that is proper offloading and proper debridement. So we convert from the chronic unhealthy environment to an acute environment that is typified by cells which want to heal which are mitotically active, lower the levels of inflammatory cytokines. So, we don’t need to talk about this much. Diabetic foot ulcers, we all know and it has been mentioned earlier, their lifetime risk, 15% multifactorial ideology, many underlying metabolic perturbations. But I think the most important in here is to recognize the several classic studies have shown that nonhealing foot ulcers are the precursor to amputation in diabetes in 80% to 85% of diabetic foot or diabetic lower limb amputation. So it’s nonhealing chronic wounds that lead to the tragic outcomes that we try to avoid. I’ve used this graphic for many years because it really highlights all the underlying metabolic problems in the diabetic patients.
[05:04] I don’t believe every diabetic patient has every one of these problems but some of our patients really do. More complicated patients have all of these problems but as, also, has been mentioned in diabetes, neuropathy is our major problem whether it be diabetic foot ulcers, infections, amputations, of course, Charcot, it is neuropathy. Postoperative infections, it is neuropathy that drives everything. This is the key but neuropathy has a many splintered thing, as I believe, it’s also been mentioned earlier. It’s not just the sensory glove and stocking neuropathy that we all grew up with in school but also modern neuropathy and the various components of that. And of course, the autonomic neuropathy, which we often don’t think about but which plays a very important role, especially when we start talking about microvascular dysfunction, an abnormal response to injury where there’s actually an increase blood flow but an impaired ability for hyperemic response, that typical Lewis Flare Response is blunted in the diabetic patient. And also under vascular disease, as also have been mentioned, macrovascular disease, which we’re seeing in increasing number of people with peripheral arterial occlusive disease at a much younger age in diabetes. Especially in the veterans population that many of us work at, it’s astounding how many people in their 50’s have critical limb ischemia which is relatively silent until they have a major limb threatening infection, gangrene or ulceration. So it’s a very complicated system to which you apply trauma, and with an impaired response to infection which also has been mentioned, you could see how we can develop these very complex wounds that we’re trying to treat, to avoid amputation. So it’s very important that we understand all these metabolic perturbations. And briefly, I think a very important paper at 1999, Gayle Reiber from the Seattle VA, this is a multiple site investigation, show that the three most common component causes in those pathways leading to foot ulcers based on the Rothman model were of course neuropathy. You should always guess neuropathy is the leading factor. But not just neuropathy, but also deformity, whether it be Charcot, hammer toes, as was already mentioned, or even bunion, and of course trauma. What’s the primary trauma? Shoes, or where I live, in Arizona, walking barefoot. We saw several people show examples of burns on the bottom of the foot, which I see every summer, just walking out to the pool, walking out barefoot to pick up the mail, and these burns lead to major problems. So we can see there’s many different putative causes, but again, these were the most common underlying sequence of events in that pathway leading to diabetic foot ulcerations on this series. So again, we mentioned that nonhealing ulcers are major risk factor for subsequent amputations regardless of which study you read for the last 30 years, always is the case. So, as Steve had mentioned, this is not rocket science. You must pay attention to the basics of wound care always, always, always. That includes medical management, assessment for vascular disease, and when you detect underlying vascular disease, you seek consultation. Looking for revascularization whether it’d be endovascular or open-bypass graft, our goal is to restore a pulse. As someone has already mentioned, the putative role of hyperbaric oxygen, I am not convinced yet. I don’t think the data is really there, but in some case, it’s very helpful. Also we’ll be hearing more about the role of topical oxygen, which has been revived over the last 20 years or so when it was put to bed by the Leslie paper in 1988 wrongfully. We look for infection and we drain abscesses and deal with infection when it’s present. If there’s no infection, you don’t treat with antibiotics as have been very nicely said already. And then after our full evaluation, we provide for wound care including the debridement, bed preparation, offloading or compression if it’s VLUs, therapeutic agents and surgery, very nicely demonstrated in the previous lectures this morning. This is not rocket science but you need to pay attention to all the basics. One paper that I think was helpful, it was supplemental to a paper we’ll be talking about in a few minutes by Bob Warner who unfortunately died this year on Hodgkin’s lymphoma. Bob was a very, very brilliant guy and a very good speaker and friend. But they looked at several wound care randomized control trials and took 120 controlled patients from the intent to treat population.
[10:06] And they looked at those patients who had achieved a greater than a 50% reduction in four weeks which is our new mantra, if you will. And they found out there were certain percentages would fail to heal by 12 weeks even though they achieved 50% at four weeks. And what they found was that those who achieved greater than 90% at eight weeks had almost a threefold higher healing rate at 12 weeks. So not just looking at the four-week 50% marker, you also look at the eight-week marker. And the people who are going to heal will have about 90% healing at eight weeks, which means you just continue on with your care. If they have not achieved 90% healing by eight weeks, then there’s another prompt to consider some type of an advanced therapy. Again, we don’t use advanced therapy on every single patient, but we do recognize that we need to consider the possible utility of advanced therapy. So we try to rationally use advanced therapeutic products, but we rely primarily on good standard wound care to initially manage our wounds. But still the question remains, when do we need to consider advanced therapeutic agents in our wound care protocols? Further, we need to closely monitor subsequent progress. We don’t just keep applying expensive advanced wound care therapies for the next 12 months. We have to always step back and reassess. And that’s why we also need to ask our question, when do we stop using advanced agents? Sure we’ve all seen this now. This was brought forward by Peter Sheehan working with Aris Veves looking at the failed promogran trial. This is probably the best thing that came out of the promogran trial that failed. Why? Because of inadequate offloading. Getting back to what’s the Steve Covinsky had said. This is where we recognize that we look at the patients at four weeks after receiving good standard wound care. If they have achieved a 50% reduction in size of the ulcer at four weeks with good set of wound care, we continue following that course. However, if they have not achieved about 50% healing at four weeks with good standard wound care, then we consider adjuvant care, adjunctive care, advanced therapeutics agents, or we need to also step back and reassess for infection that we might have missed. We step and look back for circulatory impairment, PAD. Remember, many times PAD is silent in these patients because of the neuropathy. We have to look for it. If you look for it, you’re going to find it. Many of these patients do have underlying PADs. So you need to look for it and check for it and treat it when it’s found. This was from a panel in 2010, Bob Snyder was the lead author and as was the panel looking at a consensus for standard wound care, this was in North America, in neuropathic foot ulcers. And they recognize that it’s important to look at the four-week point and they also recommend utilization of this parameter as a prompt, as I said for using advanced therapies, that four week 50% rule haven’t been achieved, and also recommended that advanced modalities should not be used as a last resort but used rationally on a rational basis earlier rather than later. And this is really the way that we practice now. And several others poster abstracts and initial papers have also supported the rule for early and aggressive treatment including the use of advanced wound therapies earlier rather than later because the longer these wounds remain open and wherein healing is stalled, the more likely they are to become infected, get deeper, develop osteomyelitis, gangrene, et cetera. So we tend to be very aggressive on our use of advanced agents when the wounds are not progressing the way we like them to. And I, also, am great proponent of total contact casting, nothing beats total contact cast but you need to know how to use that modality. So what are the advanced wound care technologies? We’re certainly not going to talk about all of this, but you might have heard some people speak about it. You’ll hear other speak especially about the Regranex, becaplermin. You’ll have a speaker on that later on. You’re going to hear about a number of these extracellular matrix products which I often use very aggressively. Cell-based therapy, especially cell-based therapies, we’ve been using very liberally for the last several of years with very good results, and we have our vendors outside to speak about that. Also, I think stem cell, new stem cell products, very intriguing for me as another type of living cellular construct that we can use for these wounds. And of course, negative pressure wound therapy, which we’ve already heard about and you’ll hear more about later on. We use all of these different types of agents plus other agents, depending on the problems that we see in our wounds.
[15:04] Other topical therapies, you can see platelet-rich plasma, HBO has already been mentioned, topical oxygen, you’ll be hearing more about these. Ultrasonic sprays, ultrasonic debriders, superoxidized water, Manuka honey even have some data to support its use, medical reliable therapy, you’ll be hearing about later, an ancient therapy but also something that we need to consider and use, and even pulse radio frequency energy, so many things. I developed this several years ago. We looked at RCTs on around margin of effect between various wound care agents that have been subjected to clinical trials, most have not. But we see the marginal of effect here from one to the other compared to a controlled group where the standard being a TCC. And as I said, the TCC really is our gold standard. Nothing beats the rate of healing that we could achieve with total contact casting. But all of these have efficacy proven by prospective randomized trials, and we need to consider the role of these. This gets a little bit difficult. This is from Howard Kimmel at the Cleveland VA. Also showing that in their experience that those people at higher risk, those with underlying PAD with very complicated past histories, so say prior amputations, renal insufficiency, marginal or neuroischemic ulcer, basically what this is saying is that go to advanced products earlier rather than later and that’s really our theme of we’re having problems reaching that 50% mark at four weeks. So aggressive early therapy is our new mantra here based on even the severity of the wound. It’s rare that I see, and those of you who work in the VA settings know, it’s rare to see a beautiful healthy neuropathic ulcer walk into your clinic with good palpable pulses. That is the rarity. Those are the ones that usually get into these trials. I usually get the ones neuroischemic, renal insufficiency, PAD, osteomyelitis, already infected, or very complicated patients. So I think the spectrum is changing. So again, if you see these more complicated patients, be aggressive earlier rather than later. These advanced products are not last resorts. So our Phoenix VA wound care protocol would include four weeks of good standard wound care, not always. If we have a patient with a chronic wound and we see it’s a problem that might have been referred to us, we might intervene earlier. But generally, these four weeks of good standard wound care with good offloading, good debridement, vascular assessment, everything that Dr. Covinsky was saying, we practice on a regular basis. Looking for ischemia because the ischemia is present, looking for underlying infection, if you’ll look for it, you’re going to find it. That might mean just probing that wound, probe to bone test is my favorite diagnostic maneuver. Okay. Look for it and you’re going to find it. And then we start advanced therapy earlier rather than later. And our favorite advanced therapy most frequently used, although not exclusively, it’s been with human fibroblast derived dermal substitute. But we often and most frequently use multimodal therapies, acellular matrices, combine these things with other growth factors, other products, and concurrent use of negative pressure therapies. So, multimodal therapies become the rule for us rather than the exception. And we try four weeks of advanced therapy and follow our patients closely. If not achieved, a good reduction in another four weeks, then we step back and we reassess once again because we’re looking for underlying problems. Nutrition, ischemia. Is the patient anemic? Is it renal failure? Et cetera, et cetera. Have we missed underlying ischemia? Have we missed underlying infection? So we need to constantly step back and reassess our patient. We don’t want to use these expensive advanced products indefinitely without getting some kind of good results. So, we use a number of these agents. I’m not going to go over them on. You can see what we have listed here. I use all of these products. We continue to use these products not on every patient of course but depending on the need for the patient. There are other products as well as we could see here. We’re starting to get our experience now in amniotic membranes. We’ve already done the PRP trial, becaplermin, collagenase, we use quite regularly. So we use of all of these products. We’re very fortunate that we have all these products available to us for the selected patients. Just for some case examples here and I’m not going to bore you with these and you might have done this before but this is how we approach a problem. These are patients with severe ischemia, they are very sick, they got cardiomyopathy, some type of renal efficiency, PAD usually, having already had bypass that might have gone down, required an amputation.
[20:05] Now, this patient had, I believe it was a Chopart amputation after having a bypass for gangrene. The bypass went down and we’re left with a nice large dehiscence, every surgeon’s regret here. We debrided this. It didn’t looked too bad though after debride. This is necrotic gangrenes, we debrided it, and it had a nice healthy base which gave us hope. Remember, this patient was an outpatient in an extended care facility. So we try to avoid readmission and rehospitalization as someone had said because the cost of advanced care in the long run are less than the standard care without them by avoiding hospitalization and for the surgery. So, in this regard, we debrided this in our office, in our clinic because the patient is neuropathic. We applied negative pressure addressing, very poor job here by the way. And we also use the human fibroblast dermal substitute very liberally underneath the negative pressure device. And we were able over the course of, let’s say, 10 weeks/12 weeks, with intermittent use of these products to secure complete closure of this very high risk problem without the need for further hospitalization. So this is the rationale. This is the way that we would approach these problems. Try to treat people who are very complicated even these complications postoperatelly that make you nauseous. We try to treat them aggressively when we can as an outpatient, recognizing that we’re actually saving cost by using these advanced therapies earlier by avoiding hospitalization further amputation surgery. And another one very similar post fifth degree amputation for an infected gangrene on his toe with plantar absences. You can see here, we did a full debridement. You could see we had a healthy wound bed. We applied negative pressure dressing to that in the hospital. Our patient went home with this. We were getting nice granular tissue developed here. We used liberally the human fibroblast derived dermal substitute. And once again, I believe we also used pulse radio frequency in concert with the tissue substitute and with the negative pressure dressing. And we noted progressive healing and he subsequently healed completely all as an outpatient. We try to get these people out when we can if they don’t have ischemia and treat them very aggressively as outpatients using these advanced therapies with some type of rational basis after we fully assess them for their needs and underlying comorbidities. So that’s our approach to this because as I say, I have advanced therapies coming out on my year sometimes with all these people trying to push new products on us and I’m always interested, but you always have to pay attention to the basics and have a rational approach to these problems. So, in our mindset, multimodal therapies are most consistent with current clinical practice. We rarely use just one modality from start to finish. We always use combinations of thing in concert with all-important good basic wound care as has already been mentioned. Nothing supplants the role for good basic wound care. Earlier is better when we consider the use of these advanced products. And I believe evidence is better. Evidence. Many and most products have no evidence to support their efficacy. They’re like, I’ve got a case study, I’ve got a case history. Well, that doesn’t mean much. That’s level five evidence or level four if you’re lucky. So I tend to gravitate towards those products that have some level of evidence. Some RCT or some type of respective study or comparative study showing me yeah, this is really worthwhile. Even if it’s not an RCT, if there’s some kind of perspective comparative evidence, I’m going to go to those products before I try something that has no evidence whatsoever except for a pretty salesperson or something like that. You know, they don’t give those pens out anymore. Anyway, so I only have pens anymore, they’re like gifts from these people. Remember that wounds change over the course of time, over the course of your treatment. Be prepared to change your therapy as the wound characters exchange. We’re constantly stopping and starting or changing things. This is very very important. We always pay attention to the basics and we always reassess as necessary. And remember that four-week, eight-week rule, look for it, look for consistent improvement and you’re going to find that your outcomes are going to be far better. I want to thank you. This is our typical patient. I’ve been trying for years to get a picture like this. One of our old patients already lost both of his legs sitting outside in the wheelchair smoking. That’s the typical DA patient, classic. Thank you very much for your attention.