Robert Frykberg, DPM, MPH discusses the basics for diabetic foot syndrome, its importance in the population, as well as the epidemiology. Dr Frykberg also describes the pathophysiology of diabetic foot complications and ways to treat it.
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MALE SPEAKER: I usually like to start off by sessions, usually, the second day is primarily focused on wound care and diabetes problems that we are all dealing with. And I like to focus with topics that a lot of you might not like because it’s a lot of statistics, it’s a lot of data, but it’s important things for you to really understand because we’re all seeing so many more high-risk diabetic patients in our practices now and we need to understand the implications for our practice and certainly for our patients.
My disclosures, learning objectives have been published. So, we recognize that about… there are 29 million diabetics in the United States both diagnosed as well as undiagnosed and that number is increasing every year because of our problems with obesity, and influx of Hispanic patients, and others from all over the world. Total costs of diabetes… this is an old cost, but it is nearly $250 billion in both direct and indirect costs and growing every couple of years. New data comes out that just shows the number progressively increasing.
But what hasn’t really changed over the years is that diabetes is the seventh-leading cause of death in the United States. People don’t die just from diabetes as the primary cause, but it’s listed as a secondary or associated cause of death in a great number of people in America. This hasn’t changed in about two decades. So, obviously, patients are dying from renal diseases associated with diabetes, cardiovascular disease, and cerebrovascular disease, as well as amputations and infections. A big problem for us.
The good news is that in the last several decades, there have been significant decreases through education, through research in a number of complications. [00:02:02:05] Heart attacks, stroke, and certainly for our perspective almost. Almost a 52% decrease in the number of amputations in the United States and certainly kidney failure. So, again, we’ve seen some great progress in the last two decades. If you went back to data from, let’s say, 1989 and 1990, it was pretty bleak, even peaking in 1996 with a number of amputations in the United States. So, we made great strides over the last several decades.
So, what are the significant lower extremity problems for us to pay attention to resulting from diabetes? Obviously, I always talk about peripheral neuropathy as first because peripheral neuropathy underlies most of the following complications that you see. Can we have the lights up just a little bit, Steve, so we don’t have… it’s so dark in it? Yeah, that’s good. Even that’s good. So, peripheral neuropathy is the one thing that’s the most common. We all see peripheral neuropathy, but it underlies certainly diabetic foot ulceration or underlies infections, it underlies PAD, lower extremity amputation, as well as Charcot foot. So, we always have to pay attention to that.
But obviously, the most pathognomonic lesion of diabetes for centuries has been ulcerations. And even if you go back to King Asa and the Bible, so I think that’s the first chronicle sort of started talking about in the 29th year of his reign, he died of a foot affliction probably due to gangrene or some kind of an infection that he had diabetes, too. So, these are real problems and we’ll try to touch on a number of these if not all of them very, very briefly just to give you a good overview of what’s going on.
And, Steve, you want to start the timer too so we all stay on time, okay?
I have used this a long time. Those of you who have heard me speak, I feel sorry for you, over the years, but I like to refer to this because… this slide, because it reminds of me of all the inter-related, underlying, pathophysiologic problems in the complicated diabetic patient. [00:04:16:01]
Not all patients will have everyone these parameters altered, but many of your patients do, and obviously neuropathy is key but not just sensory neuropathy, we also have to pay attention to motor neuropathy as well as autonomic neuropathy, and the consequences of each of those.
We’re well aware of loss of protective sensation, but look at motor neuropathy leading to high plantar pressures, and we know high plantar pressures in the presence of loss of protective sensation leads to ulcerations, but it also can lead to osteoarthropathy of cervical foot.
Then we often do not pay attention to autonomic neuropathy which we should. Autonomic neuropathy leads to micro neurovascular disturbances, that loss of the Triple Lewis Flare response that we learned in school with the altered regulation of our neurovascular structures, the micro neurovascular structures leading to altered blood flow regulation. Sympathetic failure, for instance.
And then, of course, we have both microvascular disease and macrovascular disease. I don’t need to discuss much time talking about the complications associated with PAD in this perspective, but we have this high risk foot. We apply trauma to that high risk foot, then with the concurrent impaired responses to infection that are well-known in a diabetic host, it leads to diabetic foot ulceration. Often, that leads to infection, that leads to gangrene, and subsequently off to amputation. So we need to be aware of all these interrelated, underlying pathophysiologic problems in a diabetic patient, if we’re going to really, truly understand how to manage these patients appropriately.
Again, sometimes the old data is still the best data. And this is a simplified approach but I like to keep things simple because it can take a complex disease state and make it more simple for us to understand. [00:06:13]
This goes to the Ken Rothman model of disease causation, but this paper was published by Gayle Reiber and colleagues in 1999 from about 150 or so patients for several centers throughout the US and even the UK. And they looked at these seven underlying, potential, punitive component causes that might lead to ulceration, and they found, as you can see, neuropathy, deformity, and trauma, was that critical triad present in 63% of the causal pathways that led to the foot ulcer.
So we recognize the underlying importance of neuropathy, but what about deformity? Well, deformity can be a high plantar pressure. It can be a bunion, a hammer toe, permanent metatarsal, certainly a Charcot foot.
What is the trauma? Trauma is walking barefoot, repetitive stress inside of his shoe, blunt injury, what have you. So we recognize that all of these component causes do play a role, but these are the most frequently combined causes called a sufficient cause that will invariably lead to that outcome. So we need to be aware of all the underlying punitive risk factors.
Now, look at infection. Only 1% of the people had infection prior to ulceration. That was insightful to me because it recognizes the fact that a very few people will developed an ulcer from an infection. But many, many people will develop infection, of course, from a long-standing ulcer, so nice to keep that in mind.
But are you aware that diabetic foot ulcer itself is a predictor for early mortality? And this is independent of vascular disease and amputation as has been shown. [0:08:04] Usually, we think, while it’s primarily related to amputation and PAD, but several studies over the last decade or so have shown that patients who have diabetic foot ulcer with diabetes, compared to diabetic patients without diabetic foot ulcers, have a earlier mortality. So this is an important marker for us to pay to attention to. These patients are sick with all the annoying problems that we saw.
Now, many of you have seen a slide like this before. That actually comes from Delcha’s paper in Archives of Internal Medicine in 2003, where he compared peripheral arterial disease five-year mortality with those of common cancers. It’s been extended into a lot of the diabetic foot complications over the years as well, but it originally comes from Delcha’s paper in 2003. And what we can see here – this is from his original paper – 32%, five-year mortality in patients with peripheral arterial disease. But then, from more recent studies, look at foot ulcer, where we see 44%. Look at Charcot foot, 41%, five-year mortality. Look at amputation from a very good study out of Sweden years ago, 68%.
So this really goes to show you that diabetic foot complications really do have an adverse effect on survival of these patients. Oftentimes, worse than other types of cancers you can see, like prostate, Hodgkin’s and breast cancer here, colorectal cancer is right in the middle. So important – sobering to realize these important statistics, but important for you to recognize why it’s so imperative that we make these diagnoses early and provide for proper treatment, because these people are really at risk of premature mortality. [0:10:00]
To the same point, this paper where I always like to quote is from William Jeff Coates group and Von Ball out of Nottingham in the UK, and they compared their mortality rates. You can see one, three and five-year mortality rates of their Charcot foot patients with their diabetic foot ulcer patients. So this is a very good group. They are very good researchers. They really follow the patients closely.
And here we can see that the five-year mortality rate of Charcot patients, 41%, five-year mortality and 40% five-year mortality in their diabetic foot ulcer patients and these are separate patients. So we see again these patients are at risk of earlier mortality, you know, they didn’t compare them with their non-diabetic cohorts in this slide, but still, here’s good data for you to suggest that these people are at risk for early mortality.
Here’s another paper also from a large number… over 414,000 people with diabetes enrolled in a group or in general practices, the GPs in the United Kingdom to isolate the relationship between diabetic foot ulcers and death. So again we’re looking at the association between diabetic foot ulcer and death in diabetic patients.
And this…out of this 414,000, over 20,000 developed foot ulcers and importantly, 8% of people with new ulcers died within 12 months of the first diabetic foot ulcer visit. And 42% of the people died within five years. Look how similar that is to Nottingham data that was put published by van Baal. So we’re seeing some consistency in data points here, that makes us say, “Well, you know what, maybe it’s about a 40%, five-year mortality rate on patients with a diabetic foot ulcers. [00:12:02]
Then if we look at a full-year adjusted hazard ratio of almost a two and a half fold risk for mortality compared to those patients who do not have ulcers. So when the diabetic patients has an ulcer, they’re two and a half times more likely to die within five years compared to your diabetic patients who do not have an ulcer, very, very, sobering statistics. So they recommend that diabetic for the ulcer should be seen as a major warning sign for mortality. Necessitating closer medical follow-up and that’s the whole message here of our talk.
Here’s another one from the VA, a large cohort, retrospective cohort 66,000 of veterans with type 2 diabetes who developed foot ulcer between 2006 and 2010. So the one good thing about the VA database is it’s very, very large, and controls a lot of people, and a lot of good data.
So these people were followed until 2012 at the end of the study period. And they characterized the ulcers as early stage osteomyelitis or gangrene, really looking at severity and seeing what severity of all throughout the onset really would predict for these patients mortality.
Here we can see even worst data, a 71.4% of five-year mortality. So this is much higher than the mortality that we saw in the UK. Those of you who worked in the VA know that our veterans are much sicker. When I get patients with a foot ulcer, they are usually quite sick or associate with gangrene or underlying osteomyelitis, PAD, real failure, et cetera.
So here we can see in this survival curve also, some really survival, but, I guess, in this case the mortality curve the patients with gangrene obviously fall off much quicker. [00:14:07] So they obviously they found that the patients with… who presented with gangrene were associate with their ulcer, obviously died at a much faster rate than those who came at an early stage, or even who had osteomyelitis, where you can see the two curves coinciding there.
So gangrene marker also for premature mortality because that means these people are sick, could be at very severe neuropathy, many of them have underlying undiagnosed PAD until the time of their diagnosis of gangrene, and many of them have concomitant renal failure as well.
This is a very important paper. It was published by David Armstrong and my friend, Andrew Boulton. This was last year going on a journal medicine, and truly looking specifically at recurrent ulcers. What are the risks for recurrent ulcers? And it’s data that’s collated from a number of other papers that were preexisting to this, looking at what are the risk factors for patients who have had one ulcer for developing another. So we can just see obviously increased vibration perception threshold with biothesiometer, the greatest risk factor, neuropathy, right? Neuropathy is always the greatest risk factor, presence of a pre-ulcerative lesion, a callous, a hemorrhagic callous, presence of peripheral arterial disease, pre-ulcerative lesion, presence of pre-ulcerative lesion once again, plantar ulcer, but remember, any risk factor for ulcer, ulcer includes, for recurring ulcer, also includes risk factors for that original ulcer, any risk factor for a foot ulcer in a diabetic is also a risk factor for amputation, and amputations are risk factor for ulcer, as is ulcer is a risk factor for subsequent ulcer. [00:16:00:00]
So it’s kind of circular thing, but they just put this data into proper perspective, and here, you can see general pathways that we’re all pretty much familiar with, on the propagation of an ulcer patient, who’s a high risk patient with neuropathy, developing a callous, the callous gets inflamed, and then the inflamed callous becomes an ulcer when the soft tissue on the lobe is broken. And then we know the... the course of events goes from that point on.
And this graph is very telling as well, when this paper is spoken about this graph, is usually the first thing that’s put forth. And what it shows you is a curve, based on a number of studies over the years just looking at recurrence rates of ulcers. Most people are talking about ulcer remission now, because we know that once a patient has a foot ulcer, they’re highly likely to have a recurrent ulcer. And in fact, if you look at five years, and the curve out here, 60% to 70% of people will likely develop a recurrent ulcer in five years, after they’ve had one ulcer. And that data goes far back.
And if you extend this line out, it almost gets to be 100% as you go 10 years, 15 years out. So that’s why these patients are... patients have for life, that’s why we have to practice such aggressive prevention efforts when we’re managing these patients, because we know once ulcerated, they’re going to likely ulcerate again.
So what about amputations and what about the risk of ulcers for amputations? This is an older paper from Germany, Stephan Morbach, a friend of mine, did a 10-year perspective follow up of almost 250 foot ulcer patients. And he was really looking at incidents of major amputation. And 15% of his cohort, developed major amputation in 10 years, and most... all of them had underlying peripheral arterial disease at entry and almost 52%, 51% had severe PAD at entry. [00:18:09:01]
So if we look at the multi variant analysis, the multi variant predictors of first major amputation, we see age per year, 5% increase in probability for ulcer, for every increased year, hemodialysis as you would expect, 3.5-fold risk for amputation, compared to those who were not on hemodialysis, and peripheral arterial disease, 35-fold increased risk for amputation. And these are multi-variant, these are controlled, these are adjusted, so they’re adjusting for each other here. So PAD, very, very significant risk factor for subsequent amputation in these patients.
This paper comes from University of Michigan, and from one of our podiatry colleagues, Jim Wrobel, and this data is taken from a prospective observational study from a health plan in Michigan, of almost 7,000 patient with 10 years of follow up. And what they were looking for was risk for mortality on these patients.
And so they looked at these unadjusted factors, those patients with Charcot or arthropathy, an 87% increased risk for mortality in this time period. Diabetic foot ulcer, 93% increased risk for mortality. And large extremity amputation, over a threefold risk for mortality in that time period.
But these are just crude rates, they’re non-adjusted for the other complicating factors. So if we look at the fully-adjusted model here, we can see that large extremity amputation, when adjusted for all these other complications and more in diabetes, was an independent predictor for earlier mortality within 10 years, 84%, 1.84. [00:20:04]
So very important that we recognize. And I think we all did recognize that major large extremity amputation is indeed a risk factor for early mortality. But this is just large extremity amputation. This is any amputation. So any of your patients who have amputation are a higher risk. I’m sure if they just put in major amputation here alone, it would have been a much higher risk factor for it.
And here, we see our survival curve or mortality curve, so we can call them patients with no lower extremity amputation, survive longer than minor. And, of course, the major amputation patients drop off much earlier, much sooner than those patients who do not have any amputation. Again, very sobering data, but well-published and consistent with all other data that we’ve seen for the last 50 years.
So what are the risk factors for amputation? Pretty much the same as the risk factors that we normally expect for ulceration. Ulceration is probably one of the strongest risk factors for amputation.
This is from a large paper. This was just published this year from the VA Ed Blyco controls that you see out of diabetic foot study, and it’s now going on for 22 years, 1,461 male diabetic veterans. And this was not in a podiatry clinic, this was in a general internal medicine clinic. And they just look at the lower limb amputation level for all of these patients, as well as looking at their mortality.
So over this time period, 136 amputations had occurred. But if we look at the multivariate cox model, again, like we’ve seen before, what are the independent predictors when a fully-adjusted model? Sensory neuropathy – as you would expect, it always comes up first. Almost a fourfold risk for – excuse me, a threefold risk for amputation. [00:22:06]
If we look at lower ABIs, it’s almost a fourfold risk. Even an elevated ABI was over a twofold risk. But also, look at age. Age over 70 years versus under 57. It’s got a hazard ratio of 0.13. That means it’s protected. So when these patients get older, when they’re over 70 years old, they’re actually protected against having an amputation, because if they were likely to get an amputation, they would have had it earlier in the course of their lives, okay. And you see that consistently, too, from one study to another.
So one of our co-chairs published this. We did an issue in Journal of Vascular Surgery in 2010, and just like stairway to heaven is a stairway to amputation. We have that high risk for it at the bottom. If you sustain some kind of an injury, even a careless, or walking barefooted in Phoenix in the summer time, you develop a wound, it becomes chronic. The chronic wound is untreated, becomes infected, then gangrene ensues and, of course, once gangrene ensues, amputation at some level is always required. And this is very nice simplistic approach. And also points to several different areas along this stairway for opportunities for prevention and early interventions, prevent the constellation of events leading to that amputation.
So how can we prevent limb threatening, diabetic foot problems? And that goes Charcot, it goes infection, ulcer amputation, education of patients and providers, protect their footwear, regular preventive foot care, prophylactic foot surgery foot surgery and including deformity correction at the appropriate time when necessary, certainly multidisciplinary management, the diabetes control, vascular, orthopedic, the dietary collaboration. [00:24:01] And this data comes from international working group publications, as well as the ADA consensus panels and standards of care. This is not new. This is 20, 30 years old as well.
Just to show you how the instruments a multidisciplinary service can improve your amputation, right, this data comes from Scotland where they instituted around in 2004 a multidisciplinary diabetic foot team as this is very common now in the UK. These are totally amputation in green, but let’s just look from 2004 to the last day of 2008, there was a decrease in total amputation, right, of almost 30%. Major amputation rates went down almost 41%, just by instituting a coordinated and multidisciplinary foot team, which believe it or not, was not common 30 years ago, but now as very, very common in all your wound centers, and all your major universities are starting to develop diabetic foot teams. But this is data that has been repeated by many other groups over the years just to show the positive effects of multidisciplinary foot service.
So this is a model that I have used, gosh, for many, many years where in the old days when we talked about gatekeepers, we’re anxious was the gatekeepers, many of you are still hospital referrals, primary physician referrals, when you work with your vascular surgeon, diabetologist, interns, endocrinologist, and all your ancillary consultants and laboratory services.
The foot represents the patient in the middle because without the patient’s involvement, we’re not going to be successful. But this is just one model and that can be a lose model, it doesn’t’ have to be meeting the patients at the same time, but it has to be a close referral network for it to be effective. But this is just one scheme that’s been followed that’s been successful for years. [00:26:00]
So in summary, diabetic foot complications are leading causes for diabetes-related hospitalizations, neuropathy, PAD, ulceration and infection are major risk factors for amputation. Both ulcers and the amputation adversary effects are viable, I think, I’d beat that to death, but I think it’s important for you to realize that. And certainly, knowledge of risk factors for complications provides an opportunity for early intervention and prevention. So you have to be armed with this knowledge of what really underlies these very tragic complications and what can we do to ameliorate them or at least aggressively threat them once they make their appearance.
So with that, I want to say thank you for your attention. Hopefully that was… that was some news to you.
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