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Board Review Diabetic Foot

DFU - Amputations: Pathophysiology and Risk Factors

Robert Frykberg, DPM, MPH

Robert Frykberg, DPM, MPH discusses diabetic foot ulcers, their causes, risk factors and complications. Dr Frykberg further explains the close association with DFU and amputation. Case studies are cited to support the statistics and data.

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Goals and Objectives
  1. Describe the major risk factors for diabetic foot ulcers
  2. Review the interrelationships in diabetic foot pathophysiology
  3. Explain the implications for neuropathy as a component in the pathway to ulceration
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  • CPME (Credits: 0.5)

    PRESENT eLearning Systems, LLC is approved by the Council on Podiatric Medical Education as a provider of continuing education in podiatric medicine.

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

  • Author
  • Robert Frykberg, DPM, MPH

    PRESENT Editor - Diabetic Limb Salvage
    Phoenix, AZ

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  • Lecture Transcript
  • Male Speaker: Okay, good morning, everyone. Welcome, it’s the Superbones again. Traditionally, we start with a day of wound care and high risk foot inflammation since that consumes such a great part of our practices nowadays. And I’m happy that we’re able to get together a fine group of lecturers and topics for you to round up this full day. We have a nice audience here this morning. I usually put myself on first because I don’t get offended if nobody’s in the room. And I like to give an overview of the topic. I think it’s critically important that we fully understand what we’re dealing with so that the rest of the day will make sense to you. These are my disclosures. You’ll be seeing disclosures from everybody according to CME guidelines. And this is just to make things relevant to you all so that people will identify who they’re speaking for or what the research interest and support might be. You’ve had one of the objectives published. You’ll see this on everybody’s lecture as well due to a very rigorous CME guidelines. With that said, I just wanted to talk about diabetes itself since I said that it consumes such a great part of our practice. The latest data from several years ago in the case of about 26 million persons in the United States have diabetes, both diagnosed and undiagnosed. And this is probably an underestimate because of the immigration into our country, because of the prevalence of obesity and that we just don’t have a good handle. It seems like a lot of people, 8.3% of our population but other parts of the world are higher. China, about 10%, that’s 130 million people. In the Middle East, about 20, 25%. Malaysia, where I just was last week, 20%. This is a huge growing epidemic in the world. In the United States, it’s the seventh leading cause of death. So a major problem affecting just 8.38% of our population. And it’s growing, so very important that we have a good handle on the underlying pathophysiology of this set of disorder. We know that numerous complications occur in the diabetic lower extremity. First of which is always peripheral neuropathy. You’ll be hearing our next speaker speak more about this. But ulceration is the classic pathognomonic foot lesion of diabetes. If you read classic literature, you can go back 200 years and find our classic description, I think I have one in New York Medical Sentinel from Matt [Phonetic] in 1805, 1820, something like that, classically describing a neuropathic ulcer as you would see it today. So, a classic problem. But most of these complications are subsequent to or closely related to peripheral neuropathy. That is the key component, peripheral neuropathy in most cases. But of course, infection causes a great deal of consternation for us all as peripheral arterial diseases and of course these have a final pathway of lower extremity amputation that we’ll be talking about. And of course, Charcot foot which we’ll talk more about later on this afternoon. All of these are highly relevant to us all, big problems for patients as well as for ourselves trying to manage these more complicated patients. You might have seen this diagram. It actually came from a 2003 paper by Belch. Some people in our profession have taken credit for this but it’s absolutely not. They never referred to the original source which is Belch. A lot of you may have noticed that, I would presume. Belch was talking about how peripheral arterial disease has a five-year mortality that’s pretty much the same as many types of common cancers and even less so than others. In this slide, what I have done is just put in other common complications of diabetes besides peripheral arterial disease. So what we can see here is of course pancreatic cancer, five-year mortality of 95%, lung cancer, also similarly high. But look here, 68% five-year mortality for amputation and this comes from a very center in Sweden.

    [05:00]

    If we go down here, we see foot ulcer from the Mullet [Phonetic] paper, 44% five-year mortality. Charcot foot even 41% five-year mortality based on the Landau paper in 2010. So we’re seeing that these complications of diabetes have even a higher five-year mortality than colorectal cancer, higher five-year mortality than breast, Hodgkin’s or prostate cancer. I’ve often said some people have malignant diabetes. It was a flippant comment but then this brings it home. These are serious life-threatening problems that we’re taking care of. People don’t die from their ulcer, they die from the underlying disease most often, sometimes from the sepsis related to these things. We need to pay attention to this because these are very serious complications that we’re dealing with in very sick people. Our patients aren’t getting healthier with their diabetes, they’re getting sicker. And I think most of us realize that. To that point, we’re going to the Vanball [Phonetic] study here which is published in 2010, and this is from Nottingham, a very good researcher William Jeffcoat will be at Desert Foot meeting next month in Phoenix. And he was comparing the mortality associated with both Charcot foot compared to diabetic foot ulcers. Previously, it was thought that Charcot foot had less mortality than diabetic foot ulcers and less than amputations. But here, you can see in green, five-year mortality for Charcot foot, 41% at a large population of their patients versus 40% for diabetic foot ulcers, no significant difference. So the first time we’re saying that that Charcot foot patient is marked for an earlier mortality. Very, very important day. It’s a worsening in these big robust patients with these deformed feet. We have to treat them with a great deal of respect and caution because they are sick people and we need to appreciate the underlying pathophysiology as they often say. So let’s focus on foot ulcers here. We know from old data, there’s about 15% lifetime risk of ulceration in the larger diabetes population and ulcers are due to multifactorial etiologies. The easiest way to classify ulcers as a neuropathic origin, ischemic or very commonly known neuroischemic. And a lot of times, this is the classification scheme that I won’t use because it really sets a safe for what I need to do and how vigilant do I need to do. But neuropathy, ischemia, and a combination of the two really play large roles in our patient population. And most importantly, several studies have shown that the diabetic foot ulcer is the precursor of amputation in about 85% of diabetes-related lower limb amputations, nonhealing foot ulcer leads to 85% of those diabetic-related lower limb amputations. Not that 85% go on to ulceration, go on to amputation but you look at anybody amputated with diabetes, 85% or so will have a nonhealing ulcer, and that pathway leading to the amputation, and that’s very important. As we can see here, diabetic foot ulcer incidence varies based on year, based on society, of course. But if you look at the numbers here, it’s about 2% incidence in any given population per year. That’s incidence, that’s new cases. Obviously, prevalence is going to be much higher. So, this is a growing problem as our patient population grows as well. Many possible risk factors, both intrinsic and extrinsic neuropathy, not just sensory neuropathy but also autonomic and motor neuropathy red flag, vascular disease, not just macrovascular but microvascular, immunopathy, susceptibility to infection. All of these intrinsic complications of diabetes, all through the metabolic perturbations associated with the disease. Plus, extrinsic factors. Most notably some type of mechanical trauma, five kinds of pressures, shoot pressures, high impact, walking barefoot. Even a callus has been shown as we’ll see to be potential predisposing factor in the neuropathic patient to lead to ulcers. That’s why we practice preventive care to prevent ulcers before they start. So you need to be familiar with the various curative risk factors. This paper from Gayle Reiber. I believe, Larry Lavery was on this paper as well, I think they took the Pecoraro paper that we’ll talk about later on this afternoon referring to the Rothman model of disease causation and look at the causal pathways to foot ulcers. And they look at these seven punitive risk factors, obviously neuropathy, minor trauma, deformity, edema, ischemia, callus, and infection.

    [10:00]

    And they look to see how many of the patients who developed ulceration had these various risk factors as part of their pathway leading to ulceration. And they found that there was this critical triad, 63% of the pathways. And within those pathways, we would see that neuropathy, deformity, and trauma played very significant roles in most of those pathways, the constellation of these barriers, risk factors. These three were present in 63% of those causal pathways. It gives us evidence that we know that neuropathy is a major predisposing risk factor as I’ve said. Not just for ulceration but for amputation and for infection, Charcot foot obviously. But also deformity, a simple bunion deformity, a prominent metatarsal head, a hammertoe deformity, and trauma. What’s the trauma? Shoe wear, walking barefoot. In my part of the world, walking barefoot can lead to second and third degree burns in five minutes, so we need to pay attention to that. And here we can see the percentage of patients who have had these various risk factors. By looking at a number of different papers, we get an idea of what are the important risk factors that we need to address when we’re managing patients as well as when we’re practicing prevention as we should all be practicing. From this paper from Dave Margolis from Philadelphia, basically he was looking at the association of renal failure between foot ulcer or amputation. And I pulled this out not to just discuss renal failure which is a major risk factor as we all know but also looking at their adjusted hazard ratios for these very important other risk factors for both diabetic foot ulcer and lower extremity amputation in any level, prior diabetic foot ulcer, prior lower extremity amputation. Anybody who has had a prior ulcer or a partial foot amputation is at the highest risk for subsequent ulceration or amputation. We need to recognize that and they need to be carefully managed in practice. We also know that A1c is over 9, important risk factor, history of peripheral arterial disease, especially not just for diabetic foot ulcers but also look at lower extremity amputation, how important these risk factors are for leading to amputation. Also recognize if I haven’t said it already, any risk factor just about for diabetic foot ulcer is also a significant risk factor for amputation showing how closely these two complications are related. Here we are at lower loss of protective sensation, twofold risk for diabetic foot ulcer compared to those without loss of protective sensation and similar for lower extremity amputation, probably overshadowed by these other problems. But neuropathy is often the most important strongest risk factor and, of course, endstage renal disease. Sixfold risk for ulcer in patients with ESRD and almost a 16-fold risk for lower extremity amputation. Obviously, consistent with most other papers that we read in the literature. This is our insight into the importance of these various risk factors for these very important limb threatening complications. I’ve used this graphic for many years showing you the complexity of diabetic foot patient, a high risk patient. Whereas, we know patient with diabetes has neuropathy, especially the longer duration with diabetes and neuropathy is not just sensory neuropathy. It’s also motor neuropathy and autonomic neuropathy and we can’t forget about that because each one of these has very important components or results of these neurologic deficits as we can see here. Then we go to vascular disease, also closely associated with longstanding diabetes. And we don’t just have macrovascular or occlusive arterial disease but we also have very important microvascular changes including structural changes, as well as neurovascular changes associated with autonomic neuropathy. We see alterations in blood flow which can impair healing of existing ulcers. We put all these together into a high risk foot, apply trauma to that high risk foot, then with the impaired response to infection that we also know is a consequence of longstanding diabetes. We had this patient, this high risk patient who develops an ulceration, easily can get infected if it’s not managed properly and then go on to amputation. So this is a very complicated foot you’re dealing with which is why you need to be very respectful and cautious of it and not be cavalier in the management of these patients. You have to understand the underlying pathophysiology here. We know that there is increased mortality associated with ulcer. We already talked about the cotton ball paper from 2010. But papers before them have shown us from that boycott twofold increased risk of death in persons with ulceration.

    [15:06]

    Mullet, 2003 paper that we mentioned, 44% five-year mortality rate, highest in ischemic ulcers. Iverson from Norway 10% mortality of 49%, okay. And 47% increased mortality in those patients with ulceration versus those without ulceration. So we’re seeing hard data from multiple sources that indicate those patients with a diabetic foot ulcer have an earlier mortality compared to those patients who do not have ulcers. They don’t die of the ulcer but they die of the underlying complications that leaves them to develop these ulcerations most often. And as we said, foot ulcers are major risk factors for subsequent amputation, very, very important. I know this movie is getting old and I believe some of you might not even have seen it. We’re going to focus a little bit on the cousins of the foot ulcer, closely related amputations. We need to recognize the close association between these two obviously. We know that more than 60% nontraumatic LEAs, lower extremity amputation in the US are performed in patients with diabetes, only 7%, 8% of our population. We know from numerous studies, rates are elevated in men. The elderly patient population, minorities and those with renal insufficiency, so renal insufficiency is a marker for that high risk patient. We know as we’ve said that amputation negatively impacts survival. Higher level of amputation, the higher the mortality. And of course, the average cost is hard to determine. It’s based upon the level, the complexity of the patient. So we need to be concerned with that. In the US, we had a rising rate of amputation up to about 1996 and then with our emphasis on prevention is kind of dropped a little bit. The last data we have was 2006, 2007 so it’s kind of leveled off but this is just from a public data. It’s not from private sources. It’s not from VA data. It’s not from Department of Defense data or any health service data, so it’s an underestimation. But the problem remains large, not just in United States but worldwide. And the world, it’s ravaging the healthcare systems around the world. What are the risk factors for amputation? It looks very similar to the risk factors for ulceration, doesn’t it? Neuropathy is always at the top of my list, ischemia, infection. Infection is not really a risk factor for ulceration. I used to think it was but the Reiber paper from 1999 showed that I think only 1, 2 or 3% of the patients with ulceration had a preceding infection. Infection, however, is a major risk factor for amputation as we all know. Ulceration, key, because that’s the break in the skin envelope that leads to the infection, it leads to the gangrene, it leads to the sepsis, it leads to the amputation. Prior amputation, also, very important risk factor as is trauma. So we’re going back to that causal pathways scheme. This, from a friend in Germany, Stephan Morbach published in 2012, long-term prognosis of patients with presenting to single German diabetic foot center with a diabetic foot ulcer, 247 patients. Mean age, about 69 years old, little older than most of our patients here with a long-term duration. And he looked at first major amputation which occurred in 38 patients, about 15% of his population. Fairly similar to a lot of our data, 15% of your foot ulcer patients belonged to amputation but they are focusing on major amputation here and they looked at levels of PAD. Those with severe PAD had a faster drop off into amputation than to those patients obviously without PAD. If we look down here at the adjusted risk factors or predicted factors leading to amputation, we know that age per year, significant, hemodialysis, as you would expect, 3.5 full risk and, of course, peripheral arterial disease, major risk for subsequent amputation, 35 full risk as we know. Again, very insightful, so it just to practice greater vigilance when we have our patients with peripheral arterial disease and renal failure. Also, he looked at mortality, 174 deaths in his patient population of 10 years, 70% of his patients had died out. What are the significant predictors? Of course, age, male sex, chronic kidney disease, hemodialysis and, of course, peripheral arterial disease, although much less of a risk factor than ones on hemodialysis.

    [20:02]

    Again, we’re seeing the same things come up over and over and over again and this leads us to believe, hey, these are very important risk factors that we need to pay attention to. I’ve often used this flowchart or diagram as what my idea of a multidisciplinary foot service would look like. This is nothing new going back to the ‘30s, people were talking about multidisciplinary management of a diabetic foot. But over the last 25, 30 years, it’s become clearly evident to us all that this is the way we need to practice. And the rest of the world recognizes this as well. Podiatrist is a gatekeeper up here since we tend to see our patients more frequently than most other physicians. And when there’s a wound threatening foot problem, we usually get the initial affirm. We must work with a vascular surgeon, with a diabetologist, our internist and our various consultants working as a team along with our ancillary services focusing on limb preservation. And this is the key and you’ll hear this throughout the day that multidisciplinary management is the key, whether or not it’s in one setting or combined group of people who you can refer to is critically important. And you have others who you can work with because we know this is the best way to save limbs and you save limbs, you’ll save lives. Here’s just one paper that’s often talked about. It’s from Christian and Gerry Rayman who's a group in the UK where they evaluated a series of patients before they started in a multidisciplinary foot service and then after they started in multidisciplinary foot team. They looked at amputation rates. If we look at the blue, we see the total rates of amputation here in 1995 and 1997. And this, the second panel is major amputations. The red portion is after they started the multidisciplinary diabetic foot center. A 70% drop in total number of amputations in the second period of time with the multidisciplinary service, and an 82% drop in instance of major amputation after the development of that service. So the data is clear, multidisciplinary management is absolutely that key to effectively manage these very, very complicated patients. In summary, we recognize diabetic foot ulcers from multifactorial etiology. Neuropathy, TID, trauma, and renal disease are major risk factors as we’ve said for diabetic foot ulcers. And any risk factor for diabetic foot ulcer is closely associated with those for amputation as well and we must recognize that fact, the two are very, very closely associated. Both ulceration and amputation as we’ve shown adversely affect survival of these patients. And I believe knowledge of risk factors for complications provides an opportunity for early intervention and prevention. You have to understand the underlying pathophysiology. It helps you to manage these patients better. And it’s very clear, multidisciplinary management is absolutely not only optimal but essential if we’re going to effectively manage these patients. Thank you very much. Hopefully that was a useful overview for you.