Lawrence Lavery, DPM, MPH discusses the preparation of a wound bed via various methods of debridement and cites studies to support the discussion. Dr Lavery emphasizes the goals of wound bed preparation and how to achieve them.
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Lawrence Lavery, , DPM, MPH,
Professor and Director of Clinical Research
Department of Plastic Surgery
University of Texas
Southwestern Medical Center - Dallas, TX
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Bob [Phonetic]: Our next speaker, we’ve asked to speak on something that’s less high tech for certain, not considered advanced but I think is still critically important as basic wound care that helps one debride a wound and are very important for wound bed preparation. That is the role of collagenase in wound healing, which probably use all the time and sometimes I think it’s just the basic that can prepare you for moving on to other more advanced therapies as necessary. We’ve asked Dr. Lavery to return once again to speak on collagenase. Thank you.
Dr. Lavery: Thanks, Bob. Again, these are my conflicts. Really, I want to talk about the importance of debridement. I’m going to talk a little bit about sharp debridement and then discuss a collagenase in biosurgical debridement and enzymatic debridement to prepare the wound bed. This is a slide that I don’t know if I stole or aggressively borrowed from the Rogers, Dave Armstrong. But this talks about the spectrum of things that we do to take care of wounds. I think there are things that we do from the beginning to the end of treating wounds, such as debridement and other things that we do periodically in the wound treatment process. There are number of things that we can use to debride wounds. There are fancy ultrasound devices and other kinds of high-tech scalpels, if you will. We can use larva. We can use enzymatic debriding agents. There’s not a lot of perspective information on any of these to help direct us. Certainly, we offload throughout the course of the wound healing process, meaning we used to talk about using negative-pressure wound therapy for a lot longer period. I think we’ve really focused that so it’s really to treat an interim stage while we continue to debride the wound. We’ve talked and we will talk probably more about using advanced wound healing products during the treatment process, acellular products, cell-based products, stem cell products. Then perhaps surgery to close wounds, rotational grafts, split-thickness skin grafts, et cetera. But I think in this process, debridement is important throughout the process. There’s a lot of discussion in the medical literature about the factors that contribute to chronic wounds or nonhealing wounds, high inflammatory cytokine burden, high bacterial content in the wounds, senescent wound cells, high MMPs. I think part of the rationale for debridement is, if you have a wound that’s full of slough and dead tissue, it just contributes to this chronic inflammatory low activity wound. If you simply debride these wounds, make sure they’re all perfused and debride them, you shift from a chronic nonhealing inflamed wound to an acute wound that doesn’t have those characteristics. There’s a number of ways to attempt debridement and when I was a resident, Larry Harkless was an advocate of a dent gauze dressing you put on the wound and then when he drive, it torn off and you mechanically debride everything that’s in your piece of gauze. I mean, I think there’s still value in that. I think the typical tenant for wound care that we’re familiar with and I think it’s true, this surgical debridement is surgically excising devitalized tissue and remove it from the wound bed. It’s fast, it’s effective. When you know the anatomy and you understand the depth of a wound, it’s very practical and the fastest way to get rid of dead tissue and create an acute wound. Especially in Europe, they really like using biosurgical approaches. There’s a more maggot use in the Europe than there is in the United States. But if you look at who’s taking care of wounds in Europe, it’s not podiatrist or surgical training, it’s internist that don’t do any surgery. The colon, their little buddy used to do debridement naturally because they’re not comfortable doing it surgically. Finally, there’s enzymatic debridement and I’ll finish talking about that today.
I think our perception of when and how long that should be used may change or maybe some new thoughts. I think the first question is, the importance of debridement and healing the wounds. I know CMS has been all over this and you shouldn’t debride wounds frequently. But most of the literature flies in the face of that and supports that wounds that are healed or wounds that are debride more frequently heal faster and a higher proportion of wounds are healed. I think there’s growing evidence, almost all it is post hoc analysis from phase three clinical studies, because there are large number of patients. Often they take digital photographs of the wounds of someone later, it can look at, at that and judge the adequacy of debridement. Most of us just don’t have resources to look at large cohorts of these wounds. It’s easier to use existing data. A lot of these were fell off at the back early of post hoc analysis of the Regranex gel that was the first author was David Steed. If we look at the study, the Regranex study included people that were all perfused. It’s not that veteran that you just looked at, it’s not probably a growing proportion of our patients that having an ischemic component. But this was, this was evaluation of 118 patients. It was a 20-week trial, most phase three studies are 12 weeks, 48% of the Regranex people healed compared to 25% of the controls. There was essentially identical debridement frequency in those two groups. The mean proportion of visits in Regranex group where the physician reported that it was débrided was about 47% compared to 48% of the control group. In Regranex group, the site of the highest debridement, the centers not the anatomic site had the highest healing rate. The clinical sites, the investigation sites that had the lowest debridement have the lowest healing sites. This was kind of popery of medicine, there were dermatologists, there were vascular surgeons, there were podiatrists in the study and some internists. In a placebo group, the sites that had the highest debridement, there was no obvious relationship but the sites with the lowest debridement had the lowest healing rates. This is some value that shows a few sites and their healing percentages. You can see that the sites have had the highest percentage also had very high healing rates in active and a little bit different in the sham treatment group. This next study is a post hoc analysis of the Apligraf data. What they did was they developed a debridement performance index that not only looked to see if you self-report, yes, I debride the wound. But if the wound needed to be debrided and actually was debrided and the adequacy of the debridement. They looked at talus undermining and the chronic tissue in the wound bed and then they gave a debridement score that was zero, one or two. Zero if it needed to be debrided and it wasn’t done. One if it needed to be debrided and it was. And two if it did not need debrided and it wasn’t done. An interesting approach is fast rate. if you tried to look at wounds that either measure them or evaluate them from digital photographs even when they’re sitting right next to you. We’re doing this now with a number of studies because we take digital photographs and we try to match the wound. It’s really difficult to look at a two-dimensional photo even in the patient that you had just laid your eyes on and come up with very meaningful data often. The score people could get was zero to six, the higher the score, the better. As I’ve said, this was a post hoc analysis, again, of the Apligraf database. It was 144 people, 73 got Apligraf, 65 had standard of care. It was a 12-week study, 60% percent of Apligraf and 40% standard of care field. Okay, so the debridement performance index scores, if the score was three to six, so optimal or lower than optimal. Patients with higher scores were 2.4 times more likely to heal compared to subjects with lower scores. Really kind of the first study trying to put some numbers around debridement. There wasn’t a significant difference when Apligraf and standard therapy were evaluated separately. Probably because they just run out of numbers, you know, you need a lot of numbers when you’re looking at this kind of databases. And this is relatively newest, it’s 2012, I guess it says impress year.
But this looked at 310 DFU patients and 366 VIU patients and debridement from clinical studies. And, these were based on wound area reduction which all these are superficial wounds. It’s not really volume, probably isn’t as important of a variable. Both venous ulcers and diabetic foot ulcers had the higher median wound area reduction following weeks with debridement. This DFU database, there were about 3,000 wounds, 2,975 study visits with 310 study ulcers, 96% of the study visits for patients in the treatment arm contained wound debridement. We’ve kind of moved away from 50-50. And I bet if you look at who’s treating these wounds, frequency of debridement is probably directly related to training. There were 95% from the control arm. So, hard to just see that there’s really a difference because everyone is getting their wound debridement. In the VIU database, there were 3,200 study cases with 366 wounds. Twenty one percent of the study visits had wound debridement, and 20 and 19.5% of the control arm. Everyone gets debrided in the DFU study, very, very low percentage in the VIU study. As we just said, low debridement in a group. Of the study visits that had debridement, there’s a higher likelihood that they’re going to heal. In the DFU study, patients that we see debridement at every study visit, well, you don’t have a lot of room because they’re 95% of people. But people who’ve had debridement at 12 weeks had a better chance of reaching complete wound healing during the study. Okay. Now, not significant. Difficult in those two databases because they were extreme, I think. Let’s switch and talk a little bit about using maggots for wound debridement. This has been around for a long, long time. I worked when I was a teenager at some Vietnam medics and they talked about using maggots in the field when they didn’t think they were going to be able to get someone out of a combat zone in a relatively short period of time. But now, they said they were used by aboriginal people in Australia, in the United States for hundreds and thousands of years. We’ve been using this for probably 10 years. Usually, these are patients that are not surgical candidates or they’ve been seen by vascular surgeon and they’ve had stent or their perfusion has been optimized, usually they have open amputation wounds. They respond when you debride them and then their wound dies. Those are the people that we use among mostly in our, in our practice. We don’t use them on ulcers very frequently. As I said, these have been used by Mayan Indians, they’ve been used in the Civil War, in the Crimean War. There’s a very interesting paper in JAMA in the 1920s, where William Baer described using maggots to treat children with osteomyelitis. And at that time, there’s supposed to be a thousand hospitals in the United States who've had facilities in their lab to kind of breed insects, like maggots for therapy. Certainly in the 1940s when penicillin became available for treatment, a lot of those kind of higher risks in more unpleasant therapies went by the wayside. In the United States, we mostly use the green blow fly because it eats dead tissue. There’s some species of flies that will eat good and bad tissue. It’s one of the reasons why when someone comes in the ED and the nurse screens and calls you in because there’s maggots that we get rid of the maggots because we don’t know where they’re coming from. We get these maggots FedEx overnight, we usually got a bottle of about 200 larva. They eat for three to five days and then they need to go to dirt to pupate. The mythology that you open someone’s dressing and a bunch of flies leave the wound is not true unless the wound is really, really dirty. You have about a three to five-day window for these guys to heal. There’s a couple theories of why maggots might work. The first was that they secrete some kind of proteolytic enzyme that’s probably similar to collagenase. There’s been a couple of groups in the UK and Nijmegen in the Netherlands that’s trying to isolate exactly what they secrete so they can make it, so they can reproduce it.
So far, I don’t think they’ve been successful. The second through is that they simply just eat and ingest devitalized tissue. There’s also some evidence that they change the pH in the wound bed so they make it less desirable for bacteria to live in the wound. There’s also some evidence that they consume bacteria like MRSA and excrete it from the alimentary tract so it’s inert. People have done some work looking at using larva therapy for patients that were MRSA positive and resistant to most of the antibiotics available. This is an example of a patient that was pretty much what I described earlier. This one has a transmetacarpal amputation. He had a stent of tibialis anterior that when you’re debriding this wound, it bled, but it wasn’t really impressive to anyone how well it was perfused. This gentleman had transmetacarpal amputation that was closed, it dehisced, and he has this wound that is predominantly fibrotic. When we get these little rascals, they’re very, very small, literally it look like a period in a paper that you would write in 12-point type. This is the larva after about four days of feeding. They go from very small through centimeter or centimeter and a half after gorging themselves on this person’s foot. You can see this gentleman, three days after therapy and five days after therapy, really the amount of granulation tissue and the decreasing terpenes tissue in the wound bed. Dave Armstrong had done some work looking at larval therapy with decreased antibiotic utilization and looking at antibiotic-free days when patients are treated with maggot therapy. If you look at antibiotic-free days in six months following application of maggots and found that there was a significantly greater or less treatment with antibiotics after larval treatment. Especially if you’re in an environment where there’s a high concentration of bacteria resistance, this might be something that you can try. My slide, they’re a little bit misplaced. This is my gentleman again and you can see that his wound gets these terpenes tissue, it’s progressing, it’s now predominantly granular at the top and still a lot of devitalized tissue at the bottom. These were about weekly intervals of photographs for this gentleman. One of the nice things about maggots is if you have exposed bone, the maggots will literally crawl in and out and around the bone and remove all the devitalized tissue. Finally, we ended up treating this gentleman for about three months because every time we stop therapy, his wound would get worse and open up again. Finally, you can see our little friend is up here. Finally, the wound started to contract, we were putting five, six, 10 maggots in the wound bed. But as soon as we stop therapy, his wound would open up again. We ended up using maggots until it completely epithelialize. Then about six months later, he went on a trip with his wife, stabbed his foot, open up his wound, his wife brought him in a few days later and we started maggot therapy again. It was probably the only option that really kept him healed. There are a number of papers in the literature that talked about larva therapy and their effectiveness. This is a study with 273 wounds and 435 patients, 261 patients were in the hospital, 174 were ambulatory patients. Most of them were leg wounds, and with a smattering of diabetic foot wounds. The wound duration was 240 months. It’s a long wounds. There’s a couple papers from this group in Israel. Remember if treatments range from one to 48, which is similar to our guy in Central Texas, the duration of treatment was one to 81 days. This is less expensive than someone going to hyperbaric, but it’s pretty expensive therapy. Eighty two percent have complete debridement of the wound with larva therapy, while 73 patients or about 70% of the patient debridement was partial and then five patients that was ineffective.
Chronic wounds, people who have failed other therapies, it’s an interesting option. Pain or discomfort during therapy was reported in 38% of patients. I have patients that have profound neuropathy and report significant pain when they’re being debrided with maggots, you have to kind of prepare the patient and the family for this. This is data from an open label perspective study with 25 patients, 43 wounds, 35 wounds on foot or calf, one thumb, six pressure ulcers. Complete debridement was achieved in 38 wounds or 88% of the patients. Notice, most of these don’t talk about complete wound healing. If you look at these studies, they talk about adequacy of debridement but not at the wound heal. I wasn’t able to find one study that showed there’s a significant improvement in wound debridement, or wound healing, I should say. I want to switch by talking about using collagenase ointment. There used to be several products on the market. Currently, there’s only one that is available and has been around, I think, since the ‘60s. It’s the only FDA-approved product, it’s indicated for debriding chronic ulcers of any location and in burns. It’s a biologic process that requires sterile manufacturing process. I think the thought behind this and what the marking message has been for a long time with these products was that you debride the wound until you have 100% granulation tissue on the wound bed and then you can stop. I think part of the argument is that we may use this longer is that our ability to say, well, the bioburden of this wound or the MMPs in this wound are too high and perhaps this is a mechanism to look at that, or to use this in an ongoing way. There’s a couple clinical trials in this area. There’s only one in the diabetic foot. This is a study with looking at treatment with decubitus ulcers. It’s a double-blind randomized clinical trial. This is the highest level of data with this, it’s not on the diabetic foot. It’s a small study, there are 28 pressure ulcers. They were treated once a day with collagenase ointment or placebo. You can see it was a 30-day study period and 17 of the pressure ulcers were treated with collagenase and 11 were in the placebo group. Whoever was handling the randomization, I think, did a lot of complement maybe on the [indecipherable] [22:54]. Again, the study is looking at debridement. A good result is achieved in 82% of the ulcers treated with collagenase. The placebo group really didn’t respond as you might expect. Does this accelerate wound healing, it debrides the wound and these people did, they just get a fibrotus wound that doesn’t function again if you stop or not. I mean, this 30-day study is the pinnacle of RCTs in this area. This is a diabetic foot study, the first author was Moore Altman [phonetic], I think when you set the VA in Albuquerque, it’s an open label prospective study, again, it’s a small study. These are 30 ambulatory patients with neuropathic foot ulcers treated once a day with collagenase. In the study, 66 of the patients had complete debridement in less than two weeks. Eighty-six of patients had complete debridement in four weeks. This effective in debriding of wounds? Okay, it looks like it is. Is it better compared to other modalities? We’re still not sure. We’re still not sure when to start or when to stop with this therapy. Response was based on digital assessment by the reviewer, your wound looks like it’s good enough, which I think is what happens in clinical practice. I think if you look at the database of the study, this was published in 1978. I mean, I think now we rely more on digital photographs which didn’t exist in 1978 and third-party reviewers of this data. This is another collagenase study that compares collagenase to hydrogel and wound debridement. A debriding agent, an agent that’s designed to keep your wound moist, this is a single-blinded randomized clinical study, 27 institutionalized patients with pressure ulcers.
Again, pressure ulcer study, not diabetic foot study, the ulcers were treated daily, which is kind of what happens with all these studies with either collagenase or hydrogel. The investigator was blinded to the randomization and evaluated weekly with wound photographs for necrotic tissue in the wound bed. Again, this is 13 patients with collagenase, 14 with hydrogel, very small study. And if you look at the study results, the average wound sizes are relatively large. They’re old patients exactly what you would expect. Eighty five percent of wounds adequately debriding with the hydrogel, I’m sorry, with collagenase, only 29% hydrogel. They had comparison debriding agent, moisturizing agent. I mean, I don’t think a big surprise that there’s going to be a significant difference in that treatment arm. I think debridement is a pivotal part of removing devitalized tissue, reducing bioburden, and changing the exudate of characteristics of the wounds. I think there are bunch of ways to approach that. In our practice, I think more and more were sharply debriding wounds, and we’re using collagenase as a daily application for patients to maintain their wounds, not to completely debride their wounds but to stay on top of the bioburden and other aspects of the wound healing. Keep this scale tilted in the healing wound or complete wound category. I think obviously this is scenario that needs more evidence for all of the modalities that people offer us. Right now, there’s no evidence that says one approach is better than the other. Thank you.