Jonathan Brantley, DPM discusses the significant advantages of treating wounds with oxygen and supports his statements with specific examples. Dr Brantley further describes the three main systems for delivering topical oxygen therapy.
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Release Date: 03/16/2018 Expiration Date: 12/31/2020
Jonathan Brantley, DPM
Chief, Podiatric Medicine and Surgery
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TAPE STARTS – [00:00]
Male Speaker: Our next speaker is Dr. Jonathan Brantley. Jonathan is the Chief of Podiatric Medicine and Surgery at Mcguire Veterans Administration Medical Center in Richmond, Virginia. Specializes in wound care and diabetic foot care. And we’ve asked Dr. Brantley to speak about the advantages of topical oxygen for wound therapy. Please welcome Dr. Jonathan Brantley.
Jonathan Brantley: So advantages of topical oxygen therapy. This is my disclosure statement. So let’s go over some of the learning objectives that you probably already have. Obviously, we want to describe the efficacy of oxygen supplementation in the process of augmenting chronic wound healing followed by the evaluation of candidates who are actually appropriate for and the ones that are inappropriate for hyperbaric oxygen therapy as long as we also understand the Michaelis Menten curve. So I'm going to get into that in a little bit later into the presentation.
And then finally explain the relationship between tissue viability, oxygen concentration and the functional capacity of the wound in order to allow enzymatic reactions to occur.
So take time in – let’s understand just the general benefits of oxygen utilization in wound healing.
Number 1, you’ve got immune system function. Of course, oxygen provides the ability for your neutrophils to actually synthesize bacterial [indiscernible] [0:02:11] to make them much, much more efficient and effective at oxidatively destroying these bacterial entities.
Number 2, you look at collagen deposition oxygen, not only improves the quality but it also improves the quantity of collagen that is deposed into that extracellular matrix. Angiogenesis cannot occur without the supplementation of oxygen into that particular tissue.
And then finally you have epithelialization. As you may know in regards to epithelialization migration of the epithelial cell is specifically affected by the degree of oxygen that is supplied to those particular cells. So there are really two types of oxygen delivery systems.
Number 1, you have the systemic oxygen delivery system which is otherwise known as hyperbaric oxygen therapy. And number 2, you have the topical oxygen delivery system otherwise known as a continuous diffusion of oxygen, a constant low pressure oxygen delivery device and a cyclic high pressure oxygen delivery device and they’re all illustrated here on the slide.
So let’s take a quick moment and just look at the difference between all three of the actual topical oxygen delivery devices. First of all, you have the continuous diffusion devices which actually provide no compression in these particular wounds. The delivery in and of itself of oxygen is about 1/200,000 of the flow of oxygen in that particular tissue and it creates a very, very low oxygen partial pressure across that particular wound so the gradient is truly affected if the actual component meaning the lacking dressing where the cannula is placed into begins to leak.
So therefore, the gradient is going to decrease as a result of that. Now, one of the biggest problems is now you need to have a wound that remains moist. You have to have a moist wound environment in order for yourselves to continue to thrive and function correctly.
Well, there is no possibility of providing humidification in this continuous delivery oxygen system.
The second type of topical oxygen delivery system is called the constant pressure or constant low pressure oxygen delivery system. Now, this particular system only delivers about 22 millimeters of mercury which is really not a lot of compression or at least oxygen diffusion into the superficial wound tissue. Now, the issue with that is with this low oxygen diffusion gradient.
The tissue really is not absorbing as much oxygen as you would typically desire. And with this small or minimal amount of oxygen diffusion and pressure, you don’t have the advantage of edema being truly resolved or at least pushing some of that edema out of the actual limit. So – and there is no capacity again to provide humidification.
The third type of oxygen delivery device is called the cyclical high pressure oxygen delivery device. Now, the difference between this particular device and the previous two topical oxygen delivery devices is this one here begins to vacillate between 3.7 millimeters of mercury all the way up to 37.5 millimeters of mercury before the cycle resets and starts back over again. So if you keep this in mind, what this is doing is it’s providing non-contact pressure into the actual limit itself, so now you’re not only reducing the edema but you’re also degrading or at least preventing some of the proteolytic enzymes from remaining in that particular wound, and you’re increasing perfusion in these particular wounds when you’re using cyclic high pressured oxygen devices. And last but not least, in this particular device, you are able to add humidification so that you’re able to maintain a moist wound environment.
There are some counter indications obviously to these two systems. First of all, if you look at the systemic delivery of hyperbaric oxygen, if you have individuals that have an untreated pneumothorax, an untreated chronic sinusitis, untreated seizure disorders, individuals with severe pulmonary disorders or even individuals with extremely high fevers over 102.5. Now a lot of your individuals, at least in our facility, have had multiple different types of a reconstructive surgeries. These patients are also contraindicated to utilizing hyperbaric oxygen. And if you have any type of individuals that have an altered mental status, if you do not plan on intubating those patients. And of course drugs, there are certain drugs that are contraindicated for hyperbaric oxygen therapy. And finally, if your patient is claustrophobic, that is the last thing that is going to be beneficial to that particular patient.
So now you look at the flip side, which would be the topical oxygen units or the topical oxygen contraindications. Currently, there really are none other than the one if you have a patient that has a undiagnosed or untreated DVT, or even if you are aware that that patient has a DVT, they definitely should not be using the cyclic high pressured oxygen delivery devices for fear of causing that thrombus to turn into an embolism. Now that’s not attributed to the constant pressure or the constant low pressure devices, that is really only for the cyclic high pressured oxygen delivery devices.
So there are advantages and disadvantages to both of these systems. Now the advantage or disadvantage is truly related to the patient. It’s not so much the system itself. Some patients simply cannot employ some of these particular devices. So like for instance with systemic hyperbaric oxygen, number one, it does deliver systemic oxygenation at 2 to 3 atmospheres, which is actually very, very beneficial.
It requires specialized facilities as well as personnel. It is relatively an expensive procedure and it relies on a vascular system that is truly intact in order to deliver some of the oxygen that would be beneficial to that particular wound. And if you have an individual with very poor vascularity, meaning the exchange between the plasma into the extracellular matrix where the cells are required and they reside in that ECM and they’re required to receive that oxygen so they can function, if there is any inhibition in that particular transfer then hyperbaric oxygen tends not to be quite as effective.
There is a risk of multi-system organ failure because of oxygen toxicity. And the relative evidence that is associated with hyperbaric oxygen, the outcomes are very, very good. However, the mechanism of action of hyperbaric oxygen, sometimes there is some variability in what the true MOA is for that.
So in contrast, you look at the topical oxygen delivery system where this oxygenates the actual wounded tissue and not through the vessels itself. It oxygenates the actual tissue at one atmosphere. It is usually done with portable devices. It’s relatively inexpensive. It can deliver oxygen directly to the superficial wounded tissue from a somewhat severed circulatory system of that specific tissue. And the oxygen is not dependent upon a vascular bed to provide the benefit of that delivery of the oxygen. There is absolutely no risk of multiple oxygen toxicity in the different systems.
Now the only drawback here is that there is still limited research data that is associated with topical oxygen. However, there are multiple randomized control trials that are in place, that are beginning to substantiate the validity of that particular delivery system.
So what I really wanted to do now is try to lay some concrete realities because I want to explain the relationship between tissue death, hypoxia and wound healing. But first and foremost, we really need to establish some concrete realities. Number one, the very ability of the oxygen concentration in skin, in subcutaneous tissue, is significantly governed by the rate of local skin perfusion. Chronic wound oxygen tissue actually happens to be lower than what you would find in an acute wounded tissue. So it stands to reason that, under the right circumstances, if you provide some type of oxygen supplementation to that particular wounded tissue, theoretically, you should have an increase in the oxygen concentration in both wound tissue as well as normal tissue. And it’s fairly well documented that if you have healing improving, a lot of times, this is going to occur as result of that additional oxygen supplementation to these wounds.
So when we look at this diagram here, basically all it shows you is where you would find the largest oxygen concentration levels within your wound. First of all, in the arterial system, this is where you going to find the largest oxygen concentration followed by a decrease once you get around to the periphery of that particular wound. And then in the center of that particular wound, this is where you will find the lowest concentration of oxygen.
So this kind of sets up some other issues that I really wanted get into. So if we know that the perfusion is inherently important to the concentration of oxygen so that you can have a reasonable conversation with your patient in regards to the ability for this wound to heal and so that you can make the proper referrals, you need to understand what systems actually diminish the amount of perfusion.
Well, first and foremost, if you have heart failure, that’s obviously going to diminish the amount of perfusion into your tissue if you have vessel constriction.
And vessel constriction can come in many different forms. Number one, you can have low blood volume. So if you have low blood volume, obviously, that’s going to diminish the amount of perfusion, that’s going to occur because of that vessel constriction. Cold will also cause basal constriction. Pain causes vessel constriction. And obviously, there are vessel constrictive drugs that will also impact the amount of diffusion. Arterial Hypoxemia will cause this loss or this decreasing perfusion, hypertension, if there is scaring in the lumen of the vessel, that will also cause the decreasing perfusion, and then finally your mouth or arterial diseases.
So this is really what I wanted to lead into because I need you to have a conceptual understanding of the relationship between tissue death hypoxia in wound healing, so follow me if you will.
The pO basically represents the oxygen concentration in a tissue. Now, I’m not going to continue to say sub straight but the oxygen technically is considered the sub straight. So oxygen concentration controls the rate of your enzymatic reactions. So if the amount of oxygen that a given enzyme can use over a specific time depends on the actual strength that enzyme actually binds with that sub straight, i.e. oxygen. So the concentration of oxygen, or that sub straight, that allows that an enzyme to actually produce its end product is considered to be the KM.
So, now let’s move this down to the cellular level so that you have a much better understanding of what’s going on in the next slide. So mitochondrial cytochrome oxidase, which is a very, very important enzyme that is necessary for wound healing, can actually produce water which is its end product at the maximal rate when the pO, or the oxygen concentration, is less than one millimeter of mercury. So think about what that’s saying. What that’s actually telling you is that if you really don’t have a high oxygen concentration, then the affinity of the enzymes that are in that particular mitochondria are still able to utilize oxygen to its maximum ability. So tissue oxygen therefore must literally fall to a lethal level before that cytochrome oxidase is even affected. So cytohcrom oxidase is working, is working, is working in respective of how low that oxygen concentration is.
Now, the reparative cells such as your fibroblast, your epithelial cells, your inflammatory cells, they have very few mitochondria. Now, those particular cells, the enzymes that are required for wound healing, well, those enzymes need a relatively high concentration of oxygen, so therefore, they function very very poorly if you have a low concentration of oxygen. As a matter of fact, they function so poorly that they are really capable or incapable of functioning even at a low concentration of oxygen that’s necessary to… that can sustain life of the tissue. So what does that actually tell you? That basically tells you that you can have tissue that is under the influence of very, very low oxygen. However, if you injure that tissue, the reparative process is completely inhibited.
So that’s a huge statement, because that really lets you know that there has to be some type of introduction of oxygen to maintain the capacity for repair, because your skin, or that tissue, can basically survive under such a low concentration of oxygen, but don’t let anything happen, because you’ll never recover from it.
So one of the biggest problems is that, if you have bacteria, that come down to that particular area where the tissue is either damaged, or there is a low oxygen concentration, what’s the first thing that your neutrophils require? It’s an oxidative burst, so that oxidative burst further pulls down the oxygen concentration which now drops it even below the survival level of the tissue, so not only can you not repair the tissue, but the tissue fails to survive.
So all of that really is something that you learn in basic chemistry, in the Michaelis Menten curve. So if you think about it, the substrate concentration is no more than oxygen, so that’s on your X-axis, the Y-axis, represents the rate of the enzyme reaction. So it’s pretty easy to see if you have more oxygen, well guess what, the rate of your enzymatic reactions can occur that much more readily, until you get to the point of saturation.
And the converse is true. If you have very little substrate, then the rate of your enzymatic production is also going to be low.
So what does that mean? All you need to do is superimpose the enzymes that are critically important for wound healing, and that diagram basically tells you exactly what happens. So in the green, you can see that is the normal oxygen concentration.
So all of those particular enzymes, cytochrome oxidase works well, prolyl-hydroxylase and NADPH works very, very well.
But now, you take a patient who has a wounded tissue, and if you can look at that little yellow line there, there is very little substrate. And what does that to those particular enzymes, it prevents from producing those products that are required to synthesize the necessary materials to heal that wound.
So this basically demonstrates how topical oxygen can actually diffuse into human tissue. If you look at the source here, this was out of Wounds International, where they took wounds that basically were considered ischemic, gave them topical wound oxygen. And after one day, you can see that the TcP02 was elevated so that those wounds were no longer considered ischemic. And the bottom diagram there basically shows you once topical wound oxygen was introduced over a four-week period into a failed second and third resection, there’s a nice beef, you have granulation tissues available.
It’s also very, very beneficial for neovascularization, so the image on my left basically shows where there is a biopsy. And after approximately seven days, the little green rings would demonstrate the amount of angiogenesis that occurs without using topical oxygen. The image on the right basically shows what happens when you are employing topical oxygen therapy with multiple other green rings in there which represents the actual angiogenesis occurring.
And here is a very, very interesting study done by Dr. Dirk where there was a comparison between hyperbaric oxygen and topical wound oxygen therapy to see what would truly be the benefit. One patient basically lives so far away that they were not able to use hyperbaric oxygen, and the other patient basically used hyperbaric oxygen. These are two cases that the first ray was excised secondary to osteomyelitis. And the result was after, I believe it’s 100 somewhat days, that there was a 17-day difference. That’s it. Just less than three weeks.
And the results were actually the exact same. So both wounds healed, as you can see here on the bottom. And there was only a 17-day difference in the individuals that received topical wound oxygen, but the cost difference was over $11,000. So now you can see that there’s a relative similarity in the actual outcome in using the two devices, and the cost difference is substantial.
And for instance, if you have a patient that simply cannot get to a hyperbaric oxygen therapy unit, there is definitely an alternative for them to utilize.
So in conclusion, we see that on our topical oxygen therapies, there are three. You have continuous diffusion, you have constant low pressure, and cyclical high pressure. There is strong evidence as far as the mechanism of action. Right now, there is inconclusive data as far as randomized control trials for CDO and CLP, but the strongest evidence to date really lies with the cyclic high pressure oxygen delivery systems. And currently, there is an extremely large randomized control trial that is going on to provide further validity to the effectiveness of the CHP.
With that being said, I’d like to thank you for your attention and your consideration. If there’s any questions, I’d be more than happy to answer.
TAPE ENDS - [26:14]