Research Week 2 Part 4.docx

So after obtaining all of the IRB approvals and, of course, getting consent from the patient, let's begin our story. Our story begins in Iraq in a war zone. And it's important, first of all, to understand that service members who are injured in a combat zone, shown here in mini-slide one, are genera...

So after obtaining all of the IRB approvals and, of course, getting consent from the patient, let's begin our story. Our story begins in Iraq in a war zone. And it's important, first of all, to understand that service members who are injured in a combat zone, shown here in mini-slide one, are generally taken to a battalion aid station. From there, they go to a MASH unit. If they cannot be stabilized in theater, what they will do is they will be sent to Landstuhl Medical Center in Germany. It's a major medical center there. And from there, generally, they are transported across the Atlantic to Walter Reed Medical Center in the United States. And for those individuals who need neuro-respiratory rehabilitation, they will go to the Tampa VA Hospital. Several months later, he arrived in Tampa in the spinal cord injury neuro-rehabilitation unit to begin Phase I neuro-rehabilitation rehab. And Phase I is where the patient is placed on a mechanical ventilator like this one. They are monitored with volumetric capnography, as shown here, and they are stabilized to make sure that they can proceed forward. Eventually, the patient received chest optimization in Trindenberg, as you know it, and also went on to receive other therapeutics from physical therapy, nursing, and other members of the health care team. Just to review, you remember the clinical protocol and the clinical pyramid, and we know that he received daily chest optimization. He also received strength and endurance training and daily ventilator free breathing trials, most of which he was able to do for just a very few minutes and never got close to the two-hour mark that we were hoping he could get close to. The nurses placed an abdominal binder on this individual prior to his undergoing the spontaneous breathing trials, and here what I'm showing you is his midsection and superimposed upon that. You can see the abdominal binder underneath. Superimposed on the abdominal binder is this diagram. It's a cartoon of the underside of the diaphragm, just to show you how the diaphragm normally domes inside of the abdominal cavity. And so what that binder does is it makes sure that the diaphragm continues to be domed in this fashion. The other thing that this binder does is it helps to increase blood pressure. And as you know from your previous study of people with spinal cord injury, maintaining normal blood pressure is often a problem unless, of course, they have some sort of autonomic dysreflexic episode. Now, before we discuss diaphragmatic implantation, let's get a little background that we need in order to really understand why this is important. First of all, you probably remember the children's fable of the tortoise and the hare, and you know that the tortoise was very slow but also very methodical and ended up winning the race. Well, when it comes to breathing, it's better to be slow and steady like the tortoise, not like the hare. There are two types of muscles in the diaphragm. There are slow twitch and there are fast twitch muscles. Normally, slow twitch muscles make up the majority of the muscle fibers found in the diaphragm. And the reason that's important is because slow twitch fibers have a very high capillary density. Lots and lots of oxygenated blood is available to a slow twitch fiber. The other thing is slow twitch fibers are slow, but they have a very high resistance to fatigue. They can go on forever, sort of like the Energizer bunny. On the other hand, we have fast twitch fibers. There are fast twitch fibers normally in the diaphragm. Their capillary supply is not as robust as what we find in the slow twitch fibers, and their resistance to fatigue is also very low. They're really good at being fast twitchers, but boy, they poop out really, really rapidly. So, in mechanically ventilated patients, slow is what we want. Slow is good. We want a predominance or a preponderance of slow twitch fibers so that this patient can breathe any time that he needs to breathe. And that is the normal course of the vast. Slow is the way to go. Well, when you don't have the capacity to work your diaphragm because you have a C3 injury, and you'll recall that with a C3 complete injury, it means that only about 25% of your diaphragm is functional. Looking at it another way, 75% of your diaphragm is not functional. And so it's really difficult to ventilate if you have very, very few fibers that are able to help you to take a nice, big, deep breath. So it turned out that at this time, we were aware of what we call 21st century diaphragmatic pacing, which is a little different from 20th century diaphragmatic pacing. In those days, you had to basically open up a patient's chest and put little alligator clips on the phrenic nerves. But in the 21st century, fortunately, because of scientific advances, we were able to do something a little different. And we were able to use laparoscopic surgery that was developed by a physician that I'll introduce you to in just a moment. But with this laparoscopic surgery, it's possible to go in into the abdomen with a camera, with a scope that actually sees the underside of the diaphragm showing your regret. It's also possible to use a stimulator probe that looks just like a needle. As a matter of fact, it is a needle. And it's a needle that allows the site to be stimulated and also allows the physician to pass a very small, very, very small wire that actually implants into the musculature. And it's a wire through which later on will shoot electrical impulses to get the diaphragm to actually contract. What I'm going to show you next is the work of Dr. Raymond Anders from Cleveland Clinic. Dr. Anders is a physician, a rehabilitation specialist who specializes in implanting diaphragmatic tasers in those individuals who lost their ability to ventilate. And what we see happening here is, first of all, this is a laparoscopic image of the surgery that our patient underwent. And what they're doing is they're using this little electrode with what appears to be a hemostat-like device. And what you do with this device is you basically use this sensor to go up to the underside of the diaphragm, which is what this is. And you test. You actually shoot an electrical impulse, and you test to see where the motor points are. And you can see that they've mapped a few of the motor points already. Here's one. Here's another one over here. They can actually put these little dots on the underside of the diaphragm. What you see down here is a greater momentum, which is that large mass of adipose tissue that overlies the small intestines and the large intestines. And the reason why you have this huge space in the abdomen, of course, is because you have carbon dioxide gas being pumped into the abdomen to separate the diaphragm from the rest of the organs that are inside of the abdominal cavity. All right, and here is the patient after surgery. And so just to set things up for you, toward your left side is the patient's head. You can see the abdominal binder in the background. You can see the patient's pajamas below that, and that's his waist. And then you can also see where there is a dressing applied to the chest. And this is where all of the small wires that have been implanted into the diaphragm have been connected to. They've been connected to a plug that then plugs into the pacer, the diaphragmatic pacer that you can see at the bottom right of the screen. So the question that I would have for you is, is this a ventilator? It's shooting electrical discharges into the diaphragm, causing the diaphragm to contract. And when the diaphragm contracts, then, of course, the lungs elongate. So the other question that I would have for you is, if it sounds like this might be a ventilator, is this something that a registered respiratory therapist should be concerned with? And the answer to that is absolutely. The registered respiratory therapist is going to connect this pacer. He's going to or she's going to set the rate, the tidal volume, and other settings as well, and will help to manage the patient while he is on the pacer. So after much preparation, the patient is transported via AC-130 aircraft to Portugal for this experimental procedure. At this point, you might be asking, well, why not undertake this in the United States? And the answer to that is because there were no teams in the United States that had the authority to be able to proceed forward with this type of experimental procedure. Well, let's look at this procedure as developed by Dr. Carlos Lima, a neurosurgeon in Portugal. This procedure involves taking the mucosa from the cribriform plate that's found here and removing that mucosa. And as is shown here, the mucosa has several different kinds of nerve cells in it. One of these is the olfactory sheathing cell, which is really, really good at being able to place a myelin-like sheath around the nerves that have been damaged. So it's crucial to be able to do that and to place these cells from the cribriform plate directly into the area of spinal cord damage. Now, these olfactory sheathing cells are glial stem cells. If that sounds familiar, it's because these cells are very similar to astrocytes, the same astrocytes that provide not only a physical supportive function, but also a physiological supportive function for neurons. So after resection of the spinal cord scar tissue, removal of the scar tissue, and we'll see that in just a moment, they actually mince up or cut up the olfactory mucosa and the associated glial stem cells. And this gets transplanted into the spinal cord in hopes that they will grow and in hopes that they will also wrap myelin sheaths around the neurons and help other neurons to grow as well. And here's what it looks like when they actually have the tissue. This is from the actual surgical procedure, and you can see at the upper left the area from which they take the cells, and then right across from that in the spinal cord area where C3 is located, they're going to remove the scar tissue and place these olfactory sheathing cells inside of the scar. And if you look down at the bottom left, you can see where they're already mincing components of the patient's cribriform plate mucosa. The cribriform plate mucosa, again, is replete with these special cells, and so these cells are going to then be taken and placed into the scar tissue that you can see in the lower right. That scar tissue that you see has to be removed. The membrane that you see separated there is actually the dura mater that has been separated to have access to the spinal cord tissue itself. So when the patient comes back for phase two, he comes to a gymnasium that looks like this. He gets placed on the machine that you see here where it says Erigo. That's toward the top of the body, down at the bottom of the machine. You can see a couple of foot pads where his feet go. And then this patient is basically strapped into what is really a dynamic tilt table, or sometimes known as a robotic walking machine, to try to improve his not only motor function but also his sensory function after stem cell implantation. The objective here is to exercise this individual intensively so that those cells that have been placed in the spinal cord can receive a stimulus that hopefully prompts them to grow and do what they need to do so as to improve the patient's neurologic function. You can see from this picture that very prominently displays the mechanical anexa layer. There's a blood pressure monitor next to it, and in the distance a little bit is the NM3 monitor with which we monitored physiologic variables. So this is very much a team undertaking with several team members helping this patient through each and every one of his rehabilitative sessions. Here is a picture of the actual patient, and he is in the Erigo. You can see him in this mirror, and he's looking at his body. That's what this mirror is for, so that when he sees his right leg moving forward, he has to consciously push as much as he possibly can along with the robotic walker. When he sees his left leg do the same, he needs to do the same. The NM3 monitor is at the bedside because we are monitoring different types of variables, as we've already said. After he finishes on the robotic walker, he begins doing inspiratory-expiratory resistance strength training with spring-loaded valves as shown here. These are the spring-loaded valves. There's one for inspiration, there's one for expiration. You can set these spring-loaded tensions depending upon what the patient's needs are. You can think of these spring-loaded valves as being equivalent to what you do when you go to the gymnasium and you're trying to exercise your biceps. Here's a young lady actually using a spring-loaded valve, and you can see that she has a nose clip on as well. Here's our patient. He happens to have a baseball cap on, and he is in a sling that transports him from his wheelchair onto a mat where he can do this exercise. He just finished doing his aerobic training on the robotic exerciser as if he had finished jogging. Now he's going to do his anaerobic component, in other words, his strength training using these specific spring-loaded valves. If you're thinking that we're doing this because we're trying to strengthen his diaphragm and strengthen any residual function that he may have in his intercostal muscles, you would be correct. That's exactly why we're doing this. And here's where we end our case study. This is the patient and his wife today. They have developed a rehabilitation institute where they welcome not only veteran patients but also non-veteran patients. It is a spinal cord injury recovery center. It is supported by Toyota. The patient continues to be a C3 Asia A patient. He does use his diaphragmatic pacer. He uses a crate cap with the cuff deflated, of course. He still has those olfactory sheathing cells in his spinal cord. And as a result of all of that, he's able to spend his time off the mechanical ventilator most of the day. He does go on the mechanical ventilator at night in order to be able to sleep. And the reason for that is because sometimes when a patient, any patient, or any individual goes to sleep, their diaphragmatic function declines a little bit. And so above and beyond that, if you have a patient who is receiving diaphragmatic pacing, that pacing really wears out the diaphragm during the course of the day, which means that at the end of the day, that diaphragm has to be recuperated, and it has to be restored, and it has to rest. And the best way to do that is to stop the diaphragmatic pacer from firing and simply placing the individual on a mechanical ventilator so that they can sleep overnight on the ventilator, and they can return to diaphragmatic pacing in the morning. So again, my question to you is, with all of this information that we have presented during this case study, if you were a registered respiratory therapist and you were working with this patient, what types of information would you want to include? You certainly wouldn't be able to include every single thing that I have shared with you. And actually, there's much, much more than I have shared with you. But what kinds of things might you include in your case study of your journal article prior to submitting it to a journal for publication? After reading Article 2.2, this is Unit 2.3, a randomized control trial. The article that you read was an article of a randomized control trial. And you'll notice that in that article, there was an experimental group and a control group. This is the distinctive feature of a randomized control trial, and it is why we refer to randomized control trials as the gold standard. Ideally, we would like to be able to have nothing but randomized control trials when we examine the scientific literature, trying to design and then later implement a protocol for our patients. This is a very, very strong experimental design. In this unit, we'll define what a randomized control trial is. We'll explain why it's so important to have a control group and an experimental group. We will explain the role that the NN3 monitor played in constructing and modifying the clinical protocol that you read about in that article. I will explain why we study samples of patients instead of all possible patients. In order to do the study about which you read, approval had to be obtained from not one, but two institutional review boards, as well as the research and development committee at the James A. Haley Veterans Hospital. Institutional review boards at the University of South Florida and also at Toro University International in California gave the consent for us to be able to proceed based upon the data that we provided to them. So what is a randomized control trial? Well, a randomized control trial is many things, but the best way to think of a randomized control trial is a trial in which there is an experimental group and also a control group. And you're going to compare the experimental group against the control group. Often, the control group receives no treatment whatsoever, in which case we refer to that as a placebo. But often, a control group can receive a non-experimental treatment. This might be a situation where there's already a medication that's being used, and all of a sudden a brand new experimental medication comes on the scene, and we want to compare those two. We can give the experimental version to the experimental group, and we can give the usual, customary drug to the control group. So it is not true that the control group receives no treatment. It can receive a treatment. It simply receives a treatment different than the one provided to the experimental group. Now let's turn our attention to a little bit of philosophy when it comes to research. Yes, we do use philosophy when it comes to research. All experiments begin with what we call the null hypothesis. And in the null hypothesis, we assume that there's no difference at all between group means. That's the basic assumption. And what we're saying is we're going to assume that there's no statistically significant difference between these two groups until we perform statistical analyses that prove us wrong, prove otherwise. If there is a statistically significant difference between those means, then what we do is we reject the null hypothesis, and we accept the significant difference between groups. And you'll get much more of that philosophy when you enter your statistics class. The experimental group mean is compared against the control group mean using a t-test. So a t-test is usually used as the first test when you have a couple of groups, and you're trying to find out what the difference is between these two groups. It's a mathematical way of improving your confidence that there really is a difference between these two groups, when in fact there is. Now, if in fact you have not two groups, but you have three or more groups, well then you're going to need to use a different test called an analysis of variance, or an ANOVA, not a t-test. And at this point, I'm not trying to give you all of the different tests that you could conceivably use. That would be appropriate for a statistics course. But I am wanting to provide you with at least some knowledge of what's ahead, and to also remind you that if you do decide to go into research as a principal investigator, someone who leads research, you should be prepared to study a considerable amount of statistics and statistical analyses and experimental design, because it will fall to you to make decisions about how to structure the research, and you will need at least a modicum of statistical expertise. Statistics that are used to make inferences about group means are referred to as inferential statistics, and when you use statistics just to describe the population, we refer to that as descriptive statistics. Now, what I've given you is kind of a very, very shallow overview, but that's what we need here at the beginning. When the control group and the experimental group in a randomized control trial are developed, they should be very similar in terms of age, in terms of gender, chief complaint, and every other variable. So, when we compare an experimental group to a control group, they should be very, very similar to each other, so that the only real difference between those two groups is what we are seeking to evaluate. That should be the only difference. Why take all of these precautions? Well, because we fallible human beings are really good at confusing ourselves, and we're really good at duping ourselves into thinking something is happening when in fact it's not. And more on that when you take your statistics coursework. The only difference in the experiment should be the treatment that each group receives. That's why we want to make sure that both groups, the experimental group and the control group, are very similar in terms of age, gender, chief complaint, and any other variable that you wish to use. We want to reduce the bias that can affect the outcome of this experiment. An experimental design can be single blind or it can be double blind. In a single blind study, usually either the patients or the researchers do not know what type of intervention the patients are receiving. In a double blind study, both the researchers and the patients are unaware of the intervention that the patients are receiving. Finally, what's the usual number of subjects per group? Well, as a general rule, and this is a very general rule, each group should have about 30 subjects or 30 participants. Now, there are some pilot studies that may use a lot less than that, maybe five subjects. But again, as a general rule, about 30 subjects per group is the norm. All right, just a few definitions and statistics. First of all, the term statistics really refers to a mathematical analysis of randomly generated samples. It enables us to generalize from a small sample to a large sample. As an example, if we are dealing with the COVID-19 problem and we have a vaccine on hand that we think might be effective for all of the patients that might conceivably need the vaccine, it would be impossible for us to go out and try it on every single patient right off the bat. What we would need is a representative sample of a larger group, and we would then give the vaccine to that small representative sample drawn from the larger group. And then after we get the results, we would perform a statistical analysis to see if there is a statistically significant difference between the groups that received the vaccine and the groups that did not receive the vaccine in terms of things like the infection rate and other factors, other variables. Mean is simply the average of a group of scores, and that's something that you need to know in order to be able to compute a t-test. Standard deviation is something else that you need to compare t-tests, and this is a measure of how tightly scores are clustered around the mean. The p-value is a probability value. It's a statistical probability that an experimental outcome could have happened purely by chance. For example, if we have a p-value of less than or equal to 0.05, what that means is that if we had reproduced, if we had done that experiment 100 times, 5 of those times we would have gotten the experimental outcome merely due to chance. The other 95 times we would have gotten the experimental outcome as a result of whatever intervention we happen to have applied at the time. This probability value is a way of helping us fallible human beings to be a little less fallible, given the fact that, again, we're so good at fooling ourselves into thinking that something is there when it's not, or thinking something isn't there when it really is. All right, this is a basic experimental design. An experimental design is basically a plan that scientists have, that scientists devise in order to determine how they're going to extract the information that they're looking for. You read about this experimental design in that article that you read before beginning this slide overview. As a matter of fact, what we have here are two groups. We have an experimental group at the top. We have a control group at the bottom. The experimental group at the top is a group that's placed in Trendelenburg and receives chest optimization in that position. The group at the bottom, on the other hand, because it is a control group, is going to be placed simply supine, and they will receive chest optimization in the supine position. In both cases, you can see an NM3 monitor that's associated with little diagrams. This denotes that, of course, we're measuring different physiologic variables in both of these groups. In the experimental group, there are six individuals, and in the control group, there are six individuals. Each individual has a 50/50 chance of being either in the experimental group or in the control group. The reason for this is that we randomized the assignment to these groups, which means they each had an equal chance of ending up either as an experimental subject or a control subject. You'll also notice that after a member of the experimental group completes the chest optimization protocol, they begin a period of spontaneous breathing training, as evidenced by the SBT box, and they do the spontaneous breathing training in an upright position in both cases. So really, the only thing that is different between these two groups is the position in which they receive the chest optimization protocol. This means that whatever happens during the spontaneous breathing training should be due to the fact that the differences were strictly positional. And that's an important way to think about this, because that's why the experimental design has been designed this way. It's to be able to make sure that there are no other variables that might account for the kinds of changes that are occurring in the physiologic variables of these individuals that are undergoing a spontaneous breathing trial. Now, in the introduction to the scientific article that you read just prior to this presentation, all of the information that you see on this slide is discussed. And you know from your previous exposure to chest optimization that that consists of body positionings, immobilization, airway bronchodilation, and mechanical hyperinflation. The reason this study was undertaken also has to be clearly explained in the introduction. And the reason why this particular study was done was because we simply did not know whether body positioning really had an impact on the patient's ability to do a spontaneous breathing trial. So the study was undertaken with some patients in Kronenberg, as I've shown you, and some patients in Supine, in an effort to try to determine if there were any differences. So now knowing what we know, we can say that the independent variables for this study consisted of positioning. And this is a dichotomous variable, meaning it can go one of two ways. We can either place the person in Kronenberg, or we can place the person in Supine. In any case, the reason why we refer to these variables as independent variables, and this is very important, is because we, the experimenters or the researchers, are in a position to control what this individual or what these individuals receive. They can either receive Trindelenburg, or they can receive Supine. Because we have randomly assigned them to both of these groups, they have a 50/50 chance of either getting Trindelenburg or getting Supine. The independent variable is what the researcher controls. If a researcher controls a variable, it is an independent variable, because it is independent of everything, except, of course, the researcher who is making the determination as to when to select the variable, when to institute the variable, and what types of variables to institute. The dependent variable is referred to as a dependent variable, because it is dependent on the independent variables. The dependent variable in this case is the spontaneous breathing trial duration. How long did the spontaneous breathing trial last? So, the longer the duration, the better. The shorter the duration, the less impressed we are with the results. And our hypothesis for this study was that either Trindelenburg or Supine would be associated with a statistically significantly longer breathing trial. And from the study that you read, you should know already what the outcome was.