Jonathan Brantley, DPM discusses cyclical high pressure topical wound oxygen therapy as an augmentation to regular therapy. Dr Brantley outlines the advantages of cyclical high pressure over other oxygen delivery systems, discusses appropriate and inappropriate patients, and delves deeply into the biochemical processes behind adding oxygen to the wound. He supports his lecture with evidence from various trials and studies.
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TAPE STARTS – [00:00]
Male Speaker 1: Wrap it up there and move on to the next presentation. We're going to welcome back to the stage Dr. Bromley [phonetics] who is going to enhance our knowledge about oxygen therapy.
Male Speaker 2: First of all good morning and I would like to thank the entire present staff for inviting me to speak to you this afternoon or actually this morning about cyclical high pressure topical oxygen wound therapy as an augmentation to your wound therapy. So there are specific general benefits obviously to implementing additional or supplementing oxygen to wound healing such as improved immune system function, collagen deposition as well as angiogenesis as well as epithelization. So, currently there are two main mechanisms for delivering oxygen to injured tissue, first being the systemic mechanism, which we all are very familiar with, which is referred to as hyperbaric oxygen and the second one is topical delivery of oxygen to these particular wounds. Now, this is basically divided into three different types. You have continuous diffusion oxygen, you have continuous low pressure oxygen delivery and you have cyclical or cyclical high pressure delivery of oxygen. And there are several differences between these topical types. For the sake of time, I'm really going to refer more to the cyclical high pressure ones. So first of all, cyclical high pressure oxygen delivery systems. Right now, there is an incredibly strong and robust randomized control ongoing multi-centered and multinational randomized control double-blinded study that’s going on to really provide much more efficacy to both of mechanism of action as well as the end result of using this particular type of modality. The oxygen diffusion is actually deeper into the wounded tissue when you try to compare it to the other forms of topical oxygen delivery systems. And the cyclical nature is essentially it drops down to 3.7 mmHg and then it increase as high as 37.5 mmHg. So this is a very fluctuant type of system, so there are multiple benefits when you're increasing and decreasing the pressure on this type of procedure. So the cyclical pressure actually reduces edema. And in addition to reducing edema, now you're able to increase the expression of any exudate that might be in that particular wound as well as human assisting things such as lymphatic systems. So allowing additional movement of the lymphatic tissue and lymphatic flow through those systems. So the sequential pressure that increases and decreases also is non-contact. So it's not as if the boot is actually the touching the skin, it's actually the air pressure itself or the oxygen is pushing in and releasing, pushing in and releasing on that lower extremity to provide that cyclical high pressure on the extremity. So when we kind of take a look at the actual contraindications to these two delivery systems, as you can see here from the slide, there are several that are attributed to the systemically delivered hyperbaric oxygen compared to the topical. So with systemic modalities, you have things such as if you have patients with untreated pneumothorax, untreated chronic sinusitis conditions, uncontrolled seizure disorders, patients with elevated temperatures or they are febrile, individuals that have recently had reconstructive ear surgery. When you have patients with various degree of pulmonary disorders and altered mental status. And of course if you have patients that are either claustrophobic and believe it or not there are certain drugs that are contraindicated when you're using systemic or hyperbaric oxygen therapy.
Now, in regards to topical cyclical high pressure oxygen, the only contraindication is if that patient has either an untreated or undiagnosed deep venous thrombosis. So let’s just kind of take a look at some of the advantages to both of these. Now, both modalities are actually extremely good in terms of wound healing, but there are things that you need to consider as far as can the patient actually receive this, is that the patient really somebody who is suitable to receive specific types of delivery modalities. So first of all, if you're looking at systemic hyperbaric oxygen, yes it does deliver two to three atmospheres of oxygen, which is very good. The topical delivery of oxygen, specifically high pressured cyclical delivery of oxygen can delivery approximately one atmosphere. So you're getting an increased degree as opposed to some of the lesser forms of topical oxygen delivery systems. If you're looking along the lines of your systemic, they do require specialized services, specialized facilities as well as personnel to assist you in delivering this particular hyperbaric oxygen. Where topical delivery is a very portable unit, it can be used at home, it can be used bedside, it can be used in the field. So it has a certain advantage to it. The relative expense, HBO is as you know is extremely expensive whereas topical oxygen therapy is relatively inexpensive. It relies and this is hyperbaric oxygen actually relies on a vascular system that is relatively intact because what you're doing is you're actually saturating the plasma and the plasma that lies within that vessel has to be extruded into the extracellular matrix whereas topical oxygen therapy is being delivered directly to that affected extracellular matrix. So therefore poor vascularity in an individual that’s receiving HBO and that’s extremely poor vascularity. That might be a deterrent to using that as opposed to using topical oxygen therapy. And you do have a risk of multi-organ oxygen toxicity if you're using hyperbaric oxygen compared to using topical oxygen where that problem does not even exist. So now as far as the clinical data, there is a significant amount of clinical data that does demonstrate that HBO, the end point or the end resolve of using it has been found to be very effective, but the mechanism of action is still not quite elucidated as opposed to looking at topical oxygen where the data is still somewhat limited, but there is a significant amount of data that’s out here illustrating both of those points. Now, this is what I really want to get into. Number one, the first thing that you really need to understand is if you're looking at the concentration of oxygen and tissue and I'm so glad that Dr. Anderson actually kind of led me into this because this makes us very easy to explain. So the variability of the concentration of skin and oxygen by the concentration of oxygen into that particular tissue is specifically governed by the perfusion as Dr. Anderson alluded to. So chronic wound tissue generally has a much lower pO2 compared to acute wound tissue. Now, under suitable conditions if you're going to supplement these particular wounds with oxygen, then obviously that’s going to increase the concentration of both chronic wounds as well as acute wounds. So the theory is if you're going to increase that concentration, then wound healing should theoretically improve as well.
So looking at this quick diagram, this basically demonstrates where you see the lowest and the highest degrees of the concentration of the oxygen. Obviously in the vessel itself, you're going to see the highest concentration of oxygen, but as you move closer to the periphery of that particular wound, yes the concentration does drop, but it may be as high as 60 mmHg. But the closer you move towards the center of that particular wound, this is where you're going to find the lowest concentration of oxygen, which can be as low as 10 mmHg or even less. So what actually causes or what are some of the chief etiologies of a decrease in the perfusion of oxygen. First of all, you have individuals with heart failure. So obviously if the pump is not functioning properly, you're going to have a decrease in oxygen perfusion. Vasoconstriction, Dr. Anderson actually alluded to autonomic dysfunction, yes that is definitely one of the causes that can decrease oxygen diffusion to a particular area. Blood volume, if you have low blood volume, that can cause it. Cold, so temperature can also reduce it. Pain, because obviously with pain you're going to have a certain degree of vasoconstriction and obviously vasoconstrictive drugs. Arterial hypoxemia will cause it. Hypertension, repetitive scarring of the vessel itself. So now there is a true impediment of flow to that particular area and then obviously arterial disease. So now that we've kind of understand what decreases the perfusion, it's pretty a logical point at this stage to really make the contact between tissue death, hypoxia, and the concrete reality of how these particular cells that are designed to repair the injured tissue can or cannot function. So pO2 basically represents oxygen or substrate and that concentration of that particular substrate in tissue. So the oxygen or that substrate the concentration actually controls the enzymatic reaction. So each one of your reparative cells produces some type of an enzyme that actually is necessary to repair this injured tissue. So if the concentration of oxygen is lower, then obviously the enzymatic reaction that’s going to occur or be produced by that specific cell is going to be lower. So the amount of oxygen a given enzyme can use over a specific time really determines the strength at which that enzyme and the oxygen or the substrate can actually combine. So the shorter time that they can combine, the less effective the enzyme is going to be. The less of the substrate or oxygen that’s available, the less effective the enzyme is going to be. So the concentration of the oxygen that actually allows the enzyme to produce its end product at half the maximal strength and the reason I put this term in there it's referred to as KM because you're not dealing with someone who has the maximal amount of that particular substrate, i.e., oxygen. You're dealing with somebody who is compromised. So we really need to look at what's going to happen with that enzyme at half that maximal rate. So taking you right back to bio-chem and cell bio, every cell has a mitochondria in them and inside that mitochondria if you remember oxidative phosphorylation, there are certain compliments and the fourth compliment is called cytochrome oxidase and what is the end result of that particular compliment is the production of water. Now, it has the ability and this is in tissue, it has the ability to continue to produce this water even at less than 1 mmHg. So you can actually have a very, very low concentration of oxygen and the tissue still survives, but that’s not the problem.
Even though that tissue concentration of oxygen falls down to a lethal level, this actually affects not just the rate of the tissue survival, but think about if that tissue becomes injured. Now, it also affects the reparative cells that are there to fix that injury or fix that ulcerated tissue. So the reparative cell such as fibroblast, endothelial cells and other inflammatory cells unfortunately have few mitochondria. So if you have fewer mitochondria, then the affinity or the attraction of oxygen is going to be a little bit less than what it is inside of tissue. So their enzymes actually have a much lower affinity for the oxygen and function very poorly at very low oxygen concentrations. So if you kind of understand the logic behind that, that basically is telling you right then and there that, yes you can have a low oxygen concentration and your tissue is surviving, but God forbid something happens or disrupts the tissue, the actual reparative cells that are designed to fix that problem, they're not working. So wound healing fails long before tissue viability is in danger from hypoxia. So obviously with tissue death, you know you're going to have this migration of neutrophils that are going to come to the area. When they come to the area, what is the first thing that they go through, it's called an oxidative burst. With that oxidative burst, they're taking that additional oxygen, putting it into its lysosomes so that it has the ability to oxidatively degrade some of that denatured collagen, but what's happening? You're lowering the concentrations of oxygen, which brings it to a lethal level, therefore you can't fight the infection and you cannot allow the tissue to survive any longer. So when we look at the Michaelis Menten curve, which is something that you all learned way, way back in biology class and chemistry class, this explains this perfectly. So all you're looking at is on the X-axis, the rate of the reaction and on the Y -- I'm sorry -- on the Y-axis, the rate of reaction and on the X-axis, you're basically just looking at the amount with the concentration of that substrate. So when you superimpose or you populate some of the most critical enzymes that are required for wound healing, now you can really see where the problem lies. So like for instance cytochrome oxidase, when you only have less than 10 mmHg in the center of that particular wound or ATP production is very, very stagnant. Then when you look at prolyl-hydroxylase, which is necessary for collagen production, that’s also lower and finally when it's time to fight an infection and you need neutrophils to perform their activity, well NADPH oxidase is also being affected by that. So you might ask the question, well if you're going to use topical oxygen, just how well does it penetrate into the tissue. So [Indecipherable] [0:18:40] what he did is he took a few patients just to see after 24 hours what would be the transcutaneous oxygen pressure after 24 hours of treatment using topical oxygen. And you can see that all five of these particular patients had a relatively high degree of transcutaneous oxygen pressure measurement even after 24-hour period of using this particular therapy. So looking at two models, here you have got the pig model as well as the human model. You can see that in both of these models using topical oxygen, there was an increase in VEGF. There was also an increase in fibroblastic growth factor in the human model, which allows for fibroblast activity and obviously VEGF allows for angiogenesis to occur. Now, this is a very interesting study and what I liked about this study is it's an ultimate comparison of two almost identical first ray resections done by Dr. Derk [phonetics] and what Dr. Derk looked at was if we take one of these patients and we use topical oxygen on and we take another patient and use hyperbaric oxygen on those particular patients, which one is going to; number one, heal faster; which one is going to cost less to actually get that patient to heal.
What the result was, was that the patient who received HBO therapy and mind you the patients basically had pretty much the same comorbidities, so there is really on difference on that front, but what the patient that used systemic delivery of oxygen, which is HBO therapy, they went through their 40 dives, which cost them X amount of money, but they still needed to go through the remainder of the normal care or the conservative care for the remainder of 56 days and that wound did heal up in 88 days, where the second patient who lived 65 miles away from any type of clinic that could have provided them with this particular care, they actually used a high pressured cyclical hyper delivery of oxygen therapy, which took them only 17 days longer to come to the exact same result. So when you look at the cost difference, there is almost a $12,000 cost difference over a 17-day period. So money is always going to be issue when wound care and the faster you get the wound closed, obviously the better it is for that particular patient because now you're decreasing the opportunity for osteomyelitis, for cellulitis and such. But when you're only talking about 17 days at a cost at around $12,000 more for hyperbaric oxygen therapy and the patient really wasn't even able to get to the hyperbaric oxygen chamber, that’s a significant savings that if you're faced with that challenge that you really should think about using high pressured cyclical oxygen therapy. So with that being said just to summarize, there are three distinct approaches for topical oxygen delivery. You have the continuous diffusion oxygen therapy. You have constant low pressure oxygen therapy and you also have cyclical high pressure delivery oxygen therapies. Now, the two previous ones that I had mentioned, which was the CDO and [Indecipherable] [0:22:55] have some evidence but not very high evidence of efficacy or mechanism of action, but there is a developing stronger mechanism of action with more research. So currently they have inconclusive studies with those particular type of procedures, but there is, as I had mentioned early, a very robust randomized controlled international study going on with the high pressured cyclical modalities. So with that being said, I would like to thank you for your attention and your consideration. If you have any questions, I will be more than happy to answer them at this time.
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