David Campbell, MA discusses changing trends in the treatment of small vessel disease and impacts of neuropathy in the diabetic patient. Dr Campbell examines current perspectives in prevention and treatment, and includes an overview of non-invasive studies available for diagnosis.
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David Campbell, MA
Associate Clinical Professor of Surgery
Harvard Medical School
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Host: Okay. Jack touched on an area that I think is important. And that is of the misconception of small vessel disease which still is alive and, well today even amongst you, vascular surgeons. And so I wanted to give somebody who is ingrained in the misconception years ago, a talk on microvascular dysfunction in the diabetic foot which really is a real entity. And so I've asked an old friend and colleague of mine, David Campbell to come and speak to us. David is a well-regarded vascular surgeon trained at the Deaconess Hospital in Boston where I trained also and practiced for many years. I believe even Jakamo referred to one of the papers that he was coauthor on most�most of you who are at least familiar with the vascular surgery literature know the name of Frank LoGerfo, Frank Pomposelli, Gary Gibbons, etc. Well on all of those papers, almost all those papers, David Campbell is also a coauthor. As I said Dave is an excellent vascular surgeon, a great wealth of experience, and probably comes from one of the premiere vascular surgery groups recognized around the world. So I want to introduce Dr. David Campbell.
Dr. David Campbell: Thanks Bob. It's a great pleasure to be here. And, you know, both Dr. Anderson and Bob have referred to the fact the myth of small vessels is use and asked me to talk about Microvascular Dysfunction. That seems to be lacking from some old vessel disease, microvascular dysfunction, and I will give you some Greek origins as we go through, and I'll try and sort it out. But what I thought I do is I'll give you a little history of our institution as an insight as to what was going on.
I do the vascular surgery for the Joslin Diabetes Center, and Elliot Joslin here is a friend of Banting and Best. And so we got insulin in 1924 before anybody else did. And in fact I've actually operated on patients who are in a starvation diet waiting for insulin and have survived until their 80s and need vascular surgery later on down the line. And he recognized as early as the 1930s the menace of diabetic gangrene. Now, we in today we think of gangrene only in terms of arterial insufficiency, but these were young Type 1 diabetics, and it wasn't arterial insufficiency. You've just got to remember that gangrene is the final common pathway of a lot of processes, suppression necrosis, infection, as well as arterial insufficiency.
This was the old Joslin Clinic. This was taken in late '60s and Elliot Joslin�I knew a lot of these people and I actually operated on a few of them when they developed ischemic legs as they got older. So at our hospital, Dr. Baker donated this, the money for the Baker Building which you can see here and this hospital in the 1930s was already taking care of diabetic foot problem so it's a very old disease. And this is how it roots. Dr. Joslin realized that he couldn't handle the surgical complications. Patient weren't dying of coma, they were getting foot complications, and he asked Leila Makitrick, one of the local surgeons to help him. And it's been a whole succession of surgeons since then. They're employed by the Joslin Clinic have done the work for the Joslin Diabetologist. And they quickly realized that the diabetic foot infection was a balance between peripheral arteriopathy, immunodeficiency, and peripheral neuropathy.
And, for example, you can have all�just one, all of them, or little bits of one the other. I saw a patient in the office a couple of years ago with gangrene of the tips of all five of his toes, and he had no infection and he had good pulses. And I said to him, you know, the last time I saw this somebody left a sock in his shoe, he picked up his shoe and pulled out a sock which he had been missing for a week and being crammed in the end of the toe. Neuropathy pressure necrosis equals gangrene. The bit that we never really have understood very well was the thing we labeled as immunodeficiency. We didn't understand it but the diabetics acted as if they were immunocompromised, and we talked about an impaired immune response, a defect in leukocyte function and effects of hypoglycemia. It was clear that based on membrane thickening predominated and it related to how good the diabetes was under control. And these surgeons found that with all the neuropathic changes on the foot, you could solve a lot of them with a transmetatarsal amputation, and that for many years was known as the diabetic operation. It was an effective operation that gave a patient a functional foot.
Even in 1975 which were the patient presented like with today would say this is clearly an ischemic lesion and they do a TMA. And then when it failed they go back into fem-pop bypass graft. Why was that? That was because diabetics had atherosclerosis of their tibial vessels. And that to the doctors in the day was a small vessel, and so they said diabetics have small vessel disease and that is why you can't bypass them. The next step was, this just shows the results of the TMAs which are remarkably good when you think about it 97�neuropathic patients you would expect to do well, but even patients they felt were ischemic did pretty well without revascularization but in the 1980s led by Leather and Karmody at Albany. We started learning how to bypass to the distal tibial vessels to go past those blockages and this is an in situ bypass taking place. And this made a huge difference and a large number of these bypasses were done.
Prior to this point, podiatrists would refuse to see diabetic patients. And the reason they refused to see them was because a patient would come in with what looked like a worn foot and an ingrown toe nail, it get a little bit of a procedure done for the toenail and the toe would be black the next day and they would get sued, but as we started to understand more about that relationship between neuropathy and arterial insufficiency and infection, it became clear that the podiatrists increasingly took on that role and now they took over from us. I used to provide basic foot care when I first started trimming calluses and ensure proper shoeing, and the most important thing, instead of doing a TMA, they've change the shape of the foot. Anatomies, osteotomies and so forth to give the patient the foot that they can�they could walk on.
And what happened in the '80s? The number of bypasses dramatically increased, this is from our institution. And the number of amputations decreased. And Dr. LoGerfo who became chief of our department, when he was still at BU, wrote a journal about no such thing as small vessel disease. But we now know that the difference between a diabetic and a non-diabetic, we call it microvascular dysfunction, which is just Latin for small vessel disease. But we're talking about the small vessel disease at a different level. We're talking about the capillary level with involvement of the basement membrane thickening. There's a huge amount of research going in to try to elucidate this to fit that immunocompromise, I don�t know if that triangle that I showed you. And Dr. Feldman in 2005 did this review article and summed up all the puzzle that the various mechanisms of this microvascular dysfunction. Oxidative stress, a unifying mechanism, high glucose [indiscernible] [0:07:55] respiration to the glycolytic pathway, vascular occlusion, that's capillary and very small vessels, ischemia by the hexamine pathway inhibits the ability of glutathione to function as an antioxidant by the polyol pathway, increased formation of advanced glycation end-products, AGEs. And that is why the callus, the rigid callus in a diabetic is an offensive weapon. It's like having a stone take the under surface of your�because it's not the soft callus of the non-diabetic. And that's why you have to aggressively d�bride it because it caused damage to the underlying tissue. Also alters the gene expression of key proteins, decreasing blood flow and promoting angiogenesis, capillary occlusion, inflammation, damaging lipids and proteins for the protein kinase C pathway.
It kind of reminds me of all the science of wound healing that is very interesting but doesn't make much difference in terms of how it works except to know that it is there. So this is the way I like to think of diabetic vascular disease. You have a microangiopathy, but the linguist among you would know that angiopath is simply a Greek for small vessel disease and macroangiopathy. And the microangiopathy consists of that whole range of phenomena, the retinopathy, nephropathy, neuropathy, all the basement membrane thickening and calcification of the media is prominent. The macroangiopathy is just like a non-diabetic and macroangiopathy is a disease of the intima, thickening of the intima. And though smaller the tibial vessels are more frequently involved, it's exactly the same process.
Neuropathy is part of the microangiopathy, diffuse distal neuropathy, you all know it's related to duration of diabetes and degree of control, but the interesting thing is 30% also have an autonomic neuropathy. None of you are probably old enough to remember what happened when we did lumbar sympathectomy for peripheral vascular disease. We didn't improve the circulation or cause ulcers to heal, but the foot went warm because blood that was previously concentrated in vessels was now going to the skin. And instead of associated autonomic neuropathy which has given the diabetes�the doctors of the day such a hard time in terms of making the diagnosis of peripheral vascular disease.
This is a study from Europe which took about 1100 patients without�with Type 1 Diabetes but no neuropathy and followed them for eight years. And what they found was at follow up a quarter of them had developed neuropathy. And they looked at glycosylated hemoglobin and duration of diabetes as we all know were important factors, but after adjustment for other independent risk factors, total cholesterol, LDL, TGs, high body mass index, hypertension and smoking were all independent risk factors. So it's almost as if you have a disease which on the one hand causes diabetes and on the other hand causes the macrovascular complications. So�and if you have cardiovascular disease at baseline the likelihood of getting neuropathy it doubles. So they're not two separate processes but working along different pathways. You all understand the effects of neuropathy and sensate feet easily traumatized, the intrinsic muscle paralysis causing a clawing of the foot and major trauma leading to Charcot disease. And these are typical neuropathic lesions, rocker bottom foot and clawed foot.
This is a 29-year-old Type 1 Diabetic from Puerto Rico as I remember, and it looks like an arteriogram but it's exactly�it's actually an extensive medial calcification. And�and it's important because that medial calcification affects your ability to treat the atherosclerosis because one is not related to the other particularly but if they're both present, much harder to deal with the vessel surgically and endovascularly. So if you got this microvascular disease, how does it impact? When you have big vessel disease as well, and this was the study, looking at transcutaneous option on the chest and foot, and then looking at patients who have peripheral vascular in the major vessels as well. And what you find is�is that it magnifies the lesion. In other words a small arterial lesion is going to have much bigger effect when the severe microcirculatory disorder. So when you see a patient who has significant signs in terms�and neuropathy is the easiest way to be evaluate it, then a much smaller arterial lesion is likely to lead to tissue loss and loss of limb.
So how does microcirculatory disorder affect diagnosis and management of arterial insufficiency? As you know in the nature�in the macrovascular disease in flow that is disease of the iliac vessels is much less common. Outflow disease particularly the tibia is much more common. And neuropathy affects the symptoms at presentation and you're much more likely to present with gangrene.
I've had patients who say, do you have any pain in walking? No. Do you ever walk? No. Why don't you walk? I don't like to. And that's as close as you can get to the history of claudication. Obviously you may not have no rest pain but present with an ischemic lesion. On physical exam the location of the lesions can tell you whether they're primarily ischemic or primarily neuropathic. Pulses are hard except�first of all people are very poor at evaluating pulses by hand. If the vessel is calcified it may have no pulse but may have perfectly normal circulation. Dependent rubor as Dr. Anderson said, this is showing it here is a great way if you have nothing else to look for signs of ischemia when you see the patient in the office. And this is because of the autonomic neuropathy. And these are some ischemic lesions. Let's get back there. Showing as you can see it. At the end, not on weightbearing here, but the heel and the toes primarily. So non-invasive studies in peripheral vascular, there's many available. We don't like the ankle brachial indices because they are artifactually elevated.
Fine segmental post volume recording. Measuring the change in volume in the foot with a cuff on it. Very helpful later on when we are trying to determine whether a lesion will heal with conservative measures of whether we have to intervene. Transcutaneous oxidation and genome flow studies, you know we found that they were helpful where we could tell clinically what the answer was. And they weren't helpful when we weren't sure so they didn't add anything from our perspective but if you're used to use them and if it works through that great. And I totally anchored on Dr. Anderson as the most useful and cost effective as the hand held Doppler.
As you can see when you are listening to a pulse, it normally has a triphasic sound lub, dub and that's blood goes forward, stops and reverses when the aortic valve closes, and then goes forward again with elastic recoil. And if you have a total obstruction as you do here, it changes to become monophasic. So if a patient comes in to the office perhaps with some more congestive heart failure, I'm asked what's the circulation like, I can't feel any pulses, I stick the Doppler on, I have good triphasic pulses. I can reassure them that the circulation is fine and if it's monophasic then further evaluation will obviously be necessary.
So what we said about microvascular dysfunction of the diabetic foot. It's responsible for neuropathy. Its basement membrane thickening, medial calcification, impaired perfusion of the tissues. And I think�I think that's the key, you have to understand is that arterial insufficiency effects become magnified when they have significant microvascular dysfunction.
One phenomenon and I don't know�I didn't ask anybody actually that we've seen in the last 10 years is the aging of our population. And we are now seeing many, many patients in their 80s and 90s who are non-diabetic but look like diabetics. And what so I thought, is microvascular dysfunction was the phenomenon related to diabetes, it's also a phenomenon of the aged. And 80 and 90 year olds would look like non-diabetics. And if you think about it�did you ever think why? First of all think about yourself. When you were 20, you could run down the stairs quickly without thinking about it. As you get older you may still be fit but you can't run down the stairs like you did because you need a very intense proprioception to safely get down the stairs without breaking your ankle and you feel secure, you hang on and so forth. This elderly people lose their proprioception and obviously I'll have retinopathy or get cataracts. When do people�when the man fall is when they go to the bathroom in the middle of the night because they can't feel the ground. They don't bother to turn the light on because they know where the bathroom is crash and they break their hip and they break neck. So what we originally thought was a diabetic phenomenon is now become a phenomenon of the very elderly.
So we see quite frequently these very complicated cases of peripheral, you got to have a bypass, obviously neuropathic foot, lot of tissue loss, skin graft. And it requires a lot of effort to think about all the factors that are involved and take care of them as one can, but it's very gratifying when we do it. So I hope that has elucidated microvascular disease. It means small vessel disease, we don't mean the small vessels, there's nothing special about the tibias, but there really is a problem at the capillary level. So I'm going to end there, and I think I'm back again in a short while.