Post-ROSC Care with Dr. Mike Burla

Jason Hine: Hello everybody and welcome back to the SimKit podcast. We are going to be talking about post ROSC care: caring for the patient who has suffered a cardiac arrest and is now back to life. I have a special guest with me here today, Doctor Mike Burla. Mike, say hello to the audience, tell them a little bit about yourself. 

Mike Burla: Hello everyone! As Jason mentioned, my name is Mike Burla,  and I am helping with a project through Maine Health. That is led by Doctor Theresa May, one of the critical care physicians at Maine Med, something called P-CALC, which is a post cardiac arrest learning community. And with that, we’ve been trying to improve the quality of care that we deliver to these patients who have unfortunately suffered a cardiac arrest and, and we’re doing that through, you know, education, protocolization and things of that nature. 

Jason Hine: Perfect. Perfect. So trying to kind of, you know, bring evidence-based medicine and standardization may be to a point, you know certainly standardization sometimes has a negative connotation to it. But getting us all sort of up to date in terms of current literature and guidelines about how to best care for these people that are now back from the dead. And we’re really going to cover two areas of conversation today: temperature and hemodynamics. So Mike, if it’s alright with you, I’d like to dive into temperature first. How’s that sound? 

Mike Burla: Sounds great to me. 

Jason Hine: Perfect. So, we in emergency medicine, we know that there’s something protective in the body’s physiology after being cold, you know, lower metabolic rate, fewer oxidative stresses, I don’t really know. I’m not sure if anyone knows exactly the elements of that, but Anna Bågenholm, who survived a core temperature of 13 degrees Celsius and lived to go on to be a radiologist, certainly knows that being cold is protective, neuroprotective, collectively protective. Who knows? But being cold and then dying is rather different than dying, being revived and then being cooled. So you definitely need to extrapolate at your own risk on that a little bit. We’ve had some data over the evolution of our training and into our practice now, the HACA trial, 2002, told us that you know, mildly cooling was ideal. Right? The targeted temperature management, TTM, of 2013 said you know, this is superficial interpretation, but 33 was not necessarily better than 36 degrees Celsius. So basically, don’t let them get a fever or hyperthermia is probably okay. And now we’re kind of into TTM2, published in 2021, New England Journal. This study was for a large part negative for a survival benefit or improved neurologic survival, for those that did go on to survive. Mike, with all of this sort of back and forth and changing and high-quality data that is somewhat variable. Where do we currently lie in the realm of temperature post-cardiac arrest? 

Mike Burla: Well, you know, there’s a lot to unpack. And, as with most studies, we got to kind of get a little granular and take things with a grain of salt, so to speak. You know, to look back to 2002 with these landmark starters, both HACA and Bernard et al., looked at hypothermia and treating these post ROSC Patients. With Bernard’s patient population of 77 patients and the HACA trial of 275 patients. So not huge patient populations, but because of the profound findings it really made its way into standard of care through the AHA guidelines, which is what one of the things that Nielsen and all who conducted TTM1 and TTM2, really wanted to examine because you know two relatively small trials, kind of changing the way we practice is a little bit against the grain. So. So, you know TTM1 as you mentioned came out and and looked at 33 degrees Celsius versus 36 and didn’t find any changes and really led to the idea of TTM2. Well, if there’s no difference in outcomes between 33 degrees Celsius and and 36 degrees Celsius, is there really a difference between cooling the patient and just not, you know, just preventing fever, preventing hyperthermia? And so, you know, they defined normothermia as anything over anything as 37.8 degrees Celsius with a target of 37.5 degrees Celsius, so anything over 37.8 degrees Celsius was considered hypothermia and… 

Jason Hine: Okay, 37.5 

Mike Burla: 37.5 and this is for the TTM2 trial.  

Jason Hine: Okay. 

Mike Burla: And when you look into this trial, they’re very… Like as you mentioned, it’s very well done study very robust patient population with the two arms being balanced, both the hypothermia arm and the normothermia arm and the hypothermia arm had 930 patients with the normothermia having 931. But when you really dissect the inclusion exclusion criteria, I think this is where you know, we get to talking about how applicable this study really is to our patient populations. I mean, they included adult patients, nontraumatic, which makes sense, presumed cardiac causes of cardiac arrest and a stable ROSC, which they defined as stability of 20 minutes post ROSC, and they excluded unwitnessed asystole limitations to care, any intracranial bleeding, which again makes sense, but then also patients with COPD on long term oxygen. And when you start to look at the exclusion criteria, you start to think about well, you’re kind of excluding a lot of you know patients at higher risk. So the COPD patients who had limitations to care. So what that means essentially, is limitations to, you know what had been done for them in the initial cardiac arrest setting. And so when you look at the breakdown, the patient population they examined was relatively healthy. I mean, 82% of the hypothermic group had bystander CPR and the normothermia group had 78%. 19% and 18% for diabetes, 37% / 32% for hypertension, a history of MI was 15 and 17% and again, that’s both the hypothermia and normothermia groups. And the majority of the patients were male. It was 80% male. So you know, you know that at least from my perspective. You know, I practiced both in Michigan and and now in Maine, the majority of the cardiac arrest patients I see, you know most of them have hypertension. They are not that. Most of them have hypertension. 

Jason Hine: Yeah, 16% diabetes rate. II yeah, that’s that’s curious. Where was the study performed? 

Mike Burla: Uh, Scandinavia. 

Jason Hine: Okay. Interesting that makes sense. 

Mike Burla: So it’s not a yeah, it’s not a uh, American population and and when we look at a lot of the literature for post cardiac arrests, there’s there’s plenty of European studies that that have great data just from an actual applicability standpoint for our post cardiac arrest population, it’s just tough to extrapolate their findings. And so, I do think there should be some hesitancy when taking that at face value. I mean it’s a great study, but I don’t think you know, we should all of a sudden be, you know, we should stop cooling these patients and just say, well, that should be okay, if they’re normothermia. I think there is more research that needs to be done. And you know the current AHA guidelines reflect that it still recommends hypothermia prognostication at 72 hours. All these all these good things that we’ve known to do for you know as standard of care for the last 20 years. And so that would be my first point with TTM2. You know, the second point is, you know we’ve gotten to, as I mentioned, like a 20 year mark now essentially when both the HACA trial and Bernard et al. came out and in those twenty years you know a lot has been done to improve the care of post cardiac arrest patients. And so I think our standard of care has changed drastically as well. And I kind of compared to when E Rivers came up with Early Goal-Directed Therapy (EGDT) and sepsis patients, you know and it was very groundbreaking, he was able to demonstrate up to 30% mortality benefits with Early Goal-Directed Therapy and then all the subsequent external validation trials of ARISE and Process really didn’t show a difference in standard of care versus Early Goal-Directed Therapy. Well, those happened years after the fact and during that time standard of care change, people were focused more on acutely treating sepsis patients and you know maybe they didn’t need a central venous pressure or an intensivist at bedside to improve outcomes. But they certainly were focused on the patient much more than pre–Early Goal-Directed Therapy and I think something similar could be said for post cardiac arrest patients now in the last 20 years, how much has been done from focusing on the patient, not just from a temperature standpoint but their overall acute care standpoint?

Jason Hine: I like that analogy in comparison because to your point, yeah, we got better at preventing death and sepsis and it, it seems initially like oh, it’s this bundle package that Rivers created that is of value. And as you peel away the layers of the onion, it’s actually that we are paying attention, that we’re caring, that we’re at bedside, we’re reevaluating. You know, like you said, CVP, okay, it’s probably not what’s leading to survivability or survival in these patients. But our increased attention to it and now all of this extrapolation is done with caution, right, because, is hypothermia or prevention of hyperthermia a surrogate? Is it showing this person’s post ROSC? We are paying attention to them at their bedside watching their hemodynamics and their all of their vital signs more closely. But we come in because we’re interested in where they’re at from a temperature standpoint. And that’s changing the you know value or quality, it’s hard to say. It’s hard to, It’s definitely hard to say and it sounds like the ideal would be a an American based study on you know, a TTM3 in the United States. 

Mike Burla: Yeah, I agree with you. And I mean there are studies being done now to, to look at American populations. But you know at the at the end of the day, I think that’s what it will take to maybe have a more robust base of literature to suggest. You know, we don’t necessarily need to cool these patients. But as it stands now, I mean that’s still an AHA guideline and I think the patient population that would benefit most are sicker patients who have cardiac arrest. 

Jason Hine: Yep, and and I was actually going to bring that up as a sort of a a devil’s advocate point of, what about the, the prior MI diabetic hypertensive patient is, you know different than these sort of healthy Scandinavians in that hypothermia or, you know, temperature management is going to act differently in those cases? 

Mike Burla: And you know, I guess it’s tough to answer that question. I mean, certainly baseline comorbidities may to may lead to, you know, chronic poor perfusion of organs in general, especially the brain, which would make it more susceptible to injury. I mean maybe that’s one of the reasons that you know these chronic COPDers, who were excluded, who are on … too. I mean, maybe that’s one of the reasons it’s tough to say. But at the end of day, there’s still patients we see and and we treat in the emergency department and so, you know, we should be doing as much as we can for them. 

Jason Hine: Right. We need to have definitive studies of the people that we’re seeing and there are healthy arrest patients.  

My realtor was one actually had a, you know, generally healthy person I think had a vfib arrest by standard CPR got shocked by EMS and you know, did our mortgage or was actually, you know, functioning relatively well, I think maybe we should review the contract, but yeah… 

Mike Burla: Do the mortgage… 

Jason Hine: Those, those cases happen. But to the point in the beginning, you know, if you look at the demographic of patients that are experiencing out of hospital cardiac arrest. They are not the majority, certainly in our country. 

Mike Burla: Yeah, I think that’s a fair statement, so. 

Jason Hine: OK, OK, so now let’s talk a little bit about hemodynamics. This I have to say is an area where I’m a little less well versed. What are the current recommendations regarding heart rate, blood pressure or even MAP, in the post ROSC patient? 

Mike Burla: So I I think this is an area where, again, probably more work needs to be done but there there’s a significant amount of literature out there that already suggests blood pressure is super important to manage in these post ROSC patients maybe more aggressively than we think about and it’s just not something that you or I, I think are exposed to as emergency medicine physicians and our training, at least I don’t remember learning too much about these things when I was in residency. So just to start, you know the current AHA guidelines do put an emphasis on, you know, avoiding hypertension. As well as preventing Hypo and Hyperoxia, you know which is something we can certainly get into at some other point, because I don’t, I don’t think we have enough time during this current podcast. Now they give they give pretty manageable and what I would say conservative targets, so maintaining a systolic above 90 millimeters of mercury and mean arterial pressure above 65, which is that typical number we think about with, you know, sepsis or shock in general, you know mean or till pressure above 65, but there’s there’s literature out there to suggest that we really should be more aggressive. And some of this even dates back into the 90s where there were studies done that, on on dogs, where they actually induced the vfib and vtac arrest, unfortunately, and then resuscitated them. Gave medication to elevate their blood pressure. Noticed that the higher blood pressures were associated with better mortality outcomes. Now that was extrapolated into the human studies, mostly retrospectively, that I looked at blood pressure associations with post ROSC Care. Now, most of them looked at the evidence of avoiding hypotension, which is what the AHA guidelines recommends. Specifically, in the 1^st 24, 24 hours and even more specifically, in the first six hours. Now, what was found was, there’s a few studies out there, so there was one study done by Stroke et al. that did look at MAP 2 hours post cardiac arrest that demonstrated amine arterial pressure above 75, was associated with better neurologic outcomes. You know which is higher than the typical 65, we think of now. That specific study, they did have at the hospital protocolization where if a MAP dropped below 70, they would give epi, you know, which isn’t again isn’t typical standard of practice in the United States and so, but it still it still was an important finding, you know, fast forward to the 2000s, 2010s and and even now there’s been multiple retrospective studies that have kind of reflected you know these type of findings. So, you know, some of the more recent studies have demonstrated kind of this six hour mark of preventing hypotension. There was a study done at a single center institution between 2009-2012 at at Cooper University in New Jersey, where they were able to assess neurologic outcomes with the mean arterial pressure, and they found that mean arterial pressure of 70 and up, was more associated with better neurologic outcomes than below. That,  

Jason Hine: Retrospectively? 

Mike Burla: Retrospectively,the all these, all these other ones are are are retrospective and the next one kind of in that same timeline the, Fin resuscitation group, so a Finish group looked at a cohort of 412 patients from 2010 to 2011 and again have found good neurologic outcomes or better neurologic outcomes associated with a higher average MAP within the first six hours. At a lower, lower MAP in that first six hours was associated with worse outcomes. And so you know there’s several studies that you know, I could provide the links to kind of going over the benefit of aggressive blood pressure management, specifically in the acute setting of post ROSC care that have been associated with better neurologic outcomes. There’s currently a prospective study going on as well in the United States and we’ll see what that shows. But because of this literature, which again is not something when I was training, really was emphasized on and I mean I I graduated residency in 2017, so it’s not that long ago. 

Jason Hine: Right. 

Mike Burla: You know, we’re currently, at least with the P CALC group that we have through Maine Health, advocating to trying to achieve a MAP of 80 with our post cardiac arrest patients. I mean and that’s a theory I think makes sense. You’re trying to adequately perfuse the brain as much as possible. And any dips, I mean it’s well documented. Any dips in pressure in that first hyperacute setting it just leads to poor neurologic outcomes. It could be devastating. 

Jason Hine: Sure, interesting. And so, yeah, so let’s please, we’re going to get those references into the show notes for you all. But to summarize, what you were just going over, Mike, they we have some animal model data that suggests that higher MAPs or higher pressures are, you know, beneficial from a neurologic standpoint or neuroprotective, you know animal model based. We have some retrospective data correlating higher, probably cerebral perfusion pressures, but we’re looking at MAPs realistically, 

Mike Burla: Yes 

Jason Hine:  with improved neurologic outcomes. And we have the AHA recommendations of a MAP greater than 65 and a systolic blood pressure (SBP) over 90. Targeting, you know that sort of magic time of six hours post ROSC, but ideally for the first 24 hours post ROSC. 

Mike Burla: That is correct and you know, like most guidelines, they typically lag behind the most current literature and I don’t know if the updated AHA guidelines are going to suggest anything more aggressive, but currently yes. MAP of 65 or greater is what’s recommended. 

Jason Hine: At 65. But certainly some researchers out there and some institutions recommending higher MAPs, as you mentioned in 80 for this particular cohort that we’re doing. 

Mike Burla: Yes 

Jason Hine: Okay. And now the the obvious area of question is going to be and unfortunately, I think the end answer is going to be we’re going to need prospective data is, you know, if you think people that have lower blood pressures do worse, well, is it because they’re doing worse that they have low blood pressures and that it is the egg and not the chicken or that it is the sequelae of the problem rather than the culprit to the problem? If someone has, you know, poor hemodynamics because their heart has sustained a or brain, has sustained a significant hypoxic event during their arrest, they’re going to be more difficult to maintain a a high MAP and they’re going to trend toward worse outcomes, of course. 

Mike Burla: Yeah, I think. You hit the nail right on the head with that. I mean that’s that’s that is something that’s going to be hard to to determine in the in the future, and like you said, I mean more more studies are going to need to be done, but it’s it’s just it’s a hard population to study and and even what you had mentioned that that’s a hard thing to determine too, whether or not they had already had some horrible anoxic injury that is leading to these little MAPs, and you know and vice versa. 

Jason Hine: Mm-hmm. And I mean, that is very. I think that’s very possible in retrospective data, right? Those are hard to parse out, but when you’re randomizing people to a MAP of 60/65 versus a MAP of 75/80, then you might be able to remove or at least equilibrate the worse spectrum of a ROSC patient versus the high end spectrum of a ROSC patient, and see which of the two does better prospectively. 

Mike Burla: Okay. Yeah, that’s a fair point. 

Jason Hine: And so, but that’s important for us to know because yeah, the AHA recommendations that’s as you mentioned, you know that seemed to be an area that was more nebulous for me in training and I did not have some of these specific targets in my mind. So we can at least state the AHA is recommending a MAP of 65 easy to remember, probably a little bit of a transfer over of information there, and a systolic blood pressure of 90 during our magic hours: six hours post ROSC MAP of 65 SBP of 90. 

Mike Burla: Exactly, and you know, and that, like you mentioned, those are hours, you know, this is literature that I think most intensivists of this would be familiar with. But the reality is it’s the emergency medicine physician that’s caring for these patients during this very critical time and the patients… 

Jason Hine: Trajectory here. Yeah, yeah. 

Mike Burla: For lack of better words, trajectory, prognostication and things of that nature. 

Jason Hine: And now tell me a little bit if you have, you know, a personal sense or data based driven opinion on agents. So what’s the best agent or combination of agents to achieve these targets for patients? I have to say that I’ve probably been a little rudimentary in my approach and kept it simple. Simple in that, you know, we use epinephrine in a CLS. We use epinephrine in the patient who’s experienced a cardiac arrest. Now, paramedic 2 trials going to certainly put a little bit of a wrinkle in the idea of the utility of epinephrine in managing an arrested patient. But I’ve sort of translated now if this person gains ROSC, we’ve been using epinephrine in the the creation of that ROSC for that patient and they transition often onto epinephrine for their hemodynamic care. Is that the right approach? Is norepinephrine better? Is there a better agent or combination together? So Mike, what agent or agent should we be using for the hemodynamic parameters we just reviewed? 

Mike Burla: Well, I think. I think you, know you’ll start to notice a theme. it’s a little up in the air. Exactly what we should or shouldn’t be using. Now, there is some literature out there to suggest norep (norepinephrine) might be a better choice, but before we get there just to touch on the Paramedic 2 trial. You know I do think there is some controversy with this topic. You know, it makes sense, right? Epinephrine is very similar to Norepi. But you know, theoretically you’re maybe getting a little bit more squeeze out of the heart, there’s a little bit more positive, inotropy in Epinephrine. And so it’s like the thought is maybe we we do that as a drip and like you said, we’re already using it resuscitation now the paramedic 2 trial, was able to take a pretty good look at resuscitating out of hospital cardiac arrest patients with epinephrine, which is is something we do on a daily basis. It’s something, you know, our EMS providers do. They had 8014 patients randomized across 5 ambulance services in the UK where they had a epinephrine versus placebo resuscitation and between the groups, you know what we would expect, epinephrine did have ROSC achieved more, it was 36% versus 11. However, they were associated with worse neurologic outcomes, which was 31% worse neurologic outcomes compared to 11% with the placebo group, which you know it kind of leads us in this kind of dilemma where you know, epi from the beginning and resuscitation really isn’t evidence based. Again, it’s, you know, we we continue to touch on this. It’s a hard, patient population to study, but it makes sense in the in the fact that it’s it’s catecholamine, it has positive inotropy. We’re trying to get the heart going to perfuse the organs to, get the person resuscitated. And, you know, doing as best we can to keep them alive or get them back to life. But you know one thing that this study didn’t really look at is, you know, these patients who ended up with, while the patient populations were randomized between placebo and epinephrine, we were able to kind of control the comorbidities. The reality is the patients who may have been sicker, both groups may have actually survived to get to the hospital, you know, as opposed to the patient who may have been sick and received the placebo didn’t. And those were associated with worse outcomes, but maybe they were just sick at baseline. You know, and so I think I think the study shed some great light on, you know, you know, is epi really helping us out in these instances, but the reality is we, I think there’s still a lot of unknowns out there. While our sickest patient populations, you know what they have survived to the hospital without epi and maybe in general they have more worse neurologic outcomes. But you know, maybe some of those patients don’t. So you know, from that perspective, I think that there’s still some questions. Now, from a ROSC standpoint, you know, as we had mentioned earlier, it’s really important to prevent hypotension. You know to continue drip because I’ve traditionally done that too. Let’s just keep them on the epi, let’s keep it going. There’s some recent literature to suggest that norepi might be better, published this year in intensive care medicine. I’m going to butcher the name, but Bougouin et al. was able to compare EPI and Norepi in a pretty robust patient population: 766 patients across 5 hospitals. And among these patients with post ROSC care epinephrine was associated with higher all causes of mortality and cardiovascular causes, specifically. There’s other studies that have been done too, specifically looking at cardiogenic shock, epinephrine versus norepinephrine. And epinephrine was associated with refractory hypotension, refractory shock. And just think again, things we don’t think about when we’re in the emergency department because we’re seeing the patient hopefully only for a couple of hours. I mean the way things have been we’ve been holding on patients longer. 

Jason Hine: Right. 

Mike Burla: But, but the reality is, I mean, you know, these agents are being looked at closely in the ICU. And I think at the end of the day, as long as you’re able to achieve aggressive blood pressure management, preventing hypotension with whether it’s norepi or epi, you’re you’re doing the patient right, but literature is suggesting norepinephrine’s probably a better agent of these post ROSC patients. And that’s something that our intensivists are currently recommending so… Is that? 

Jason Hine: Yeah, I think I’m a lot to unpack there. I, back on the paramedic too, I think my take away on that was we don’t want a weekend at Bernie’s people. We don’t want, you know, bodies that are alive with dead brains. And so if it’s going to be effective, it seems like we want it, you know the early dosing makes sense to me. Give it, give it and you know the college effort would not be particularly academic in the descriptor of that. But at, you know, 25 minutes, hour or 25 minutes into the resuscitation, do we really need to be giving boluses of 1 milligrams of epinephrine? Probably not. 40 minutes? Probably not. We’re bringing back dead bodies, but to the post ROSC patient, yeah, I think that makes sense. I mean, you know, we are probably more facile with norepinephrine drips because of their utility and sepsis in the ER and certainly it, so if you’re saying that the data has a signal toward it being more beneficial, that makes sense to me as a start point. For those of us that are, you know, consider themselves resuscitationists, or at least if they are pocus friendly or capable, we can look at the heart and see, right? I’d imagine you can look and see our our squeeze is very hyperdynamic, heart that’s beating away, probably not one I’m going to want to put a lot of epinephrine to or if it’s just kind of barely getting by with a pretty significantly decreased EF and you’re having a hard time getting the MAP that you’re desiring, then maybe a little more inotropy is going to be valuable, but leaning toward norepinephrine it sounds like, unless you can get additional data through POCUS or other means to see which agent is preferred. 

Mike Burla: And I think that makes complete sense. You know, especially as board-certified emergency physicians, most of us are trained and that said ultrasound as you’d mentioned and you know if, if you’re seeing a hyperdynamic heart, I mean, and the pressure is still low, you probably should be looking elsewhere as to why the pressure is low or what’s going on. Because at the end of the day, you know, it really is about maintaining these aggressive hemodynamics to do what you can to serve the patient best. So they have the greatest chance at a a good neurologic outcome and being discharged from the hospital at some point with some quality of life. 

Jason Hine: Fantastic, I like that actually as a wrap up point. I’ll do a quick summary and then we’ll close out. So we started kind of talking about temperature a little bit. We had the HACA trial, TTM1,TTM2. We’ve seen through the data over that time frame saying okay, maybe really cold is good. Maybe just not having a fever is good, and then TTM2 has kind of been more of the maybe we just don’t, you know, we we don’t need to be doing true hypothermia as TTM 2 showed, but Mike pointed out that there is a little bit of an apples and oranges comparing that patient population to the average American who experiences cardiac arrest. Probably not enough definitive data right now, from Doctor Burla’s perspective, in our our groups analysis of that data, to fully abandon the idea of temperature control in these patients and something that you should be looking at with your ED group, as well as your intensive care physicians, to decide where you guys land on that final, decision point. We then went on and talked a little bit about hemodynamics and the management of blood pressure after cardiac arrest. We dove a little bit into the paramedic 2 trial and the idea of epinephrine to bring people back. But mostly we were focusing on what should be our MAPs and our goals, when we bring someone back, truly back. And you mentioned that the American Heart Association recommendations right now are for 65, a MAP of 65 or higher, and an SBP target of greater than 90. But there is some data supporting higher targeting MAPs and again, if you and your intensive care group are pursuing those, there’s data to support your decision. As you mentioned, our group is targeting a MAP of 80. And we went over how to achieve this and norepinephrine probably could be a lean in these patients. One, there’s a signal in the data to support it. Two, our nurses and ourselves are pretty comfortable with dosing it. All in all, we need to think about what’s best for that patient in front of us, right, knowing their comorbidities, knowing their down time, knowing what we’re seeing in their recovery. These are difficult patients to care for, we do not want to bring them back to later be pronounced in the ICU, but we also want to give them the best chance at a proper neurologic survival, as we can. And there’s certainly more prospective data that’s needed. But this is helpful to guide the care that we provide in the ER. How’d I do Mike? 

Mike Burla: I thought that was brilliant, thought it was a really good summary. Obviously there’s so much more we could talk about. 

Jason Hine: Yep, there’s plenty to talk about in these patients, they are fascinating. They’re fascinating because they’re cognitively challenging, they’re procedurally heavy, we have the potential to really influence the course of someone’s life, a family’s trajectory, both for the positive but also, as we mentioned briefly in the negative direction as well. So we want to be up to date on the stuff, we want to do the best that we can for the patient in front of us, with the current data we have. Well, Mike, thank you so much for chatting with us on this. Again, folks, we’re going to put all of the references that we put together in the show notes for you to review. If you do have questions on the topic matter, we’ll have points of contact for ourselves so that we can talk through things further. If you have contrary points, we would love to hear your perspective, your opinion, because this is an area that’s growing, evolving quickly and it’s going to continue to do so. So hopefully this has informed your care some. So Mike, thank you so much for joining us today. 

Mike Burla: Thank you so much for having me, it’s been a pleasure.