FEMALE SPEAKER: Welcome to Mayo Clinic COVID-19 expert insights and strategies. The following activity is supported in part by an independent medical education grant from Pfizer Inc and is in accordance with ACCME guidelines.

ALEX NEVIN: Welcome to the Mayo Clinic Critical Care Insights-- COVID Edition. My name is Alex Nevin. I'm a consultant in the division of pulmonary critical care and sleep medicine here at Mayo Clinic in Rochester, Minnesota. And also the education chair for both our division and for the independent multi-specialty critical care practice.

The COVID pandemic has changed the way that we practice, likely forever. And the critical care community has been particularly impacted by the current pandemic. Critical Care Insights-- COVID-19 Edition is intended for health care providers who are caring for patients with COVID-19 across the world in the ICU. Best practices to care for these patients have been rapidly evolving, and busy bedside providers-- I know I have-- struggled to keep up with the volume of information, especially given that the information sources that are providing it are frequently less than rigorously peer reviewed.

In response, Mayo Clinic has developed and asked Mayo experts COVID-19 task force that have collected and curated the available contents into a free public websites under the Mayo Clinic-- Ask Mayo Experts-- COVID-19 Navigator. This source provides, basically, a curated site for best practice recommendations in the care of COVID-19 patients developed collaboratively by an interprofessional stakeholder group of Mayo Clinic subspecialists.

And these information is continuously informed by rapid literature scoping reviews performed by the current Center for the Science of Health Care Delivery. This online CME course is designed to speed dissemination and implementation of these best evidence-based guidelines, best practice innovation, and provide discussion of ongoing clinical controversies that we face in critical care as we take care of these patients.

These discussions will feature the original authors of the contents that is available on Ask Mayo Expert, and allow them to discuss the evidence and best practices that they have used to provide these recommendations. And the why behind the information that they've shared.

We will be continuously updating this content as time goes on based on the available high-quality evidence that comes through our rapid scoping reviews and our evolving innovations and evolution of clinical practices within our own health care delivery platform here at Mayo Clinic. This initial CME offering consists of seven lectures, including topics from intubation safety, infection control, workflow considerations, navigating drug shortages, maximizing team performance, mindset training for the individual, humanizing critical care, respiratory therapy innovations, among others.

We will continue to evolve this content as time goes on with new information on the epidemiology, virology, clinical features of COVID-19 patients, and also evolving recommendations with regards to testing and the care in addition infection control considerations in this challenging population. We hope that you enjoy this work. This information has been has been provided as a series of Grand Rounds presentations to our critical care community over the course of the last five weeks, and will continue to evolve over time Welcome to Critical Care Insights. I hope you enjoy our work.

MODERATOR: Well, welcome to the Critical Care Grand Rounds. My name is Dr. [INAUDIBLE] and I serve as the vice chair for the subcommittee of the education of the [INAUDIBLE]. I will be moderating today-- the session for today. And we have a fantastic panel with our pharmacists and one of our NICU consultants. Welcome.

We're going to talk about pharmacologic agents in COVID patients. For that we have our pharmacists and NICU consultant. I'll let you guys please introduce yourself.

FEMALE SPEAKER: I'm [INAUDIBLE]. I'm one of the NICU and trauma ICU pharmacist. I did residency here and I've been on staff since 2014.

FEMALE SPEAKER: I'm Victoria [INAUDIBLE]-- critical care pharmacy resident.

MALE SPEAKER: And I'm [INAUDIBLE]. I work in no medical ICU as a consultant and did my fellowship here, as well.

MODERATOR: Perfect. Thank you for being here. So--

MALE SPEAKER: Can I just add a little bit? You know it's interesting you mentioned phenobarbital, because on one of the patients we actually ended up using that.

FEMALE SPEAKER: Mm-hmm.

MALE SPEAKER: In this patient, it wasn't so much a drug shortage issue, but it was a lot of adverse effects. His triglycerides went to 1,000 with the use propofol. So we couldn't use propofol. He was status post cardiac surgery. So he was just on 0.3 of ketamine and he developed a lot of arrhythmias so we couldn't use that. He was developing renal failure, so we had him on Dilaudid. So that continued. He was on-- he was receiving benzodiazepines. So he wasn't lorazepam. It ended up being escalated to the point where he started developing propolineglycol toxicities. So we couldn't use that anymore. So we got to a point where-- we literally, we were running out of options. And we actually give 5 milligrams [INAUDIBLE] of phenobarbital. And that really helped reduce our sedation dosages quite a bit.

And you know, since these people, we expect that they might remain-- they're not going to be a quick 48-hour intubation. This is something that can be really considered if you're running into issues where you're seeing a lot of side effects. Because, you know, if you have someone on a lot of propofol for many days, many people might develop hypertriglyceridemia and so on. So this is a really good option to consider, which we don't generally consider for a lot of other ICU patients. That's because we know that these people will need ventilation for quite a few days.

MODERATOR: But as of now, we should consider our normal routine--

MALE SPEAKER: Right.

MODERATOR: --for paralyzing and sedating this patient that's necessary. But the phenobarbytol could be an excellent resource if we go through the other trauma medications considering charges. [INAUDIBLE]. So from the NICU's standpoint, any challenges regarding sedation-- other than this excellent example-- that anything different that we've learned already with the care of the COVID patients?

FEMALE SPEAKER: I think one thing they are noticing is elevated triglycerides, like has been mentioned previously with many of these patients they're having elevated triglycerides. So I think that's something that we're monitoring daily. In addition, and looking after creatinine kinase and then also lactase and amylase if we have additional concerns that their triglycerides are above 500 specifically. But we're starting to think of other options, as well. That's usually something that if patients have elevated triglycerides, we try to avoid propofol. But in this situation, it's tricky.

MODERATOR: And you start checking those triglycerdies right away as soon as we start them on propofol? Or is there a different system now with the COVID patients?

FEMALE SPEAKER: So we've been surprised to see that even at normal, low doses of 30 to 40 mgs per kilo per minute of propofol, people are getting about 500 within 24 to 40 hours. We came together as an ICU pharmacy group we talked about how we wanted to handle this and, sort of, what we would do consistently moving forward. And there is some data on the fact that triglycerides aren't really associated with [INAUDIBLE] PRIS. And so we are comfortable pushing triglycerides to 800 to 1,000 with checking that daily CK like Victoria mentioned.

There is some data in a trauma population looking at pushing propofol doses and checking CKs. And in patients that have CKs less than 5,000, none of them developed CRISP. So that's our current approach. And as she's also said, also checking lactase as you get in that 500 to 1000 range to be sure that you're going to catch pancreatitis before it becomes an issue.

MODERATOR: Excellent.

MALE SPEAKER: So in the data that you found-- because typically when you think of PRIS, it's like, when it develops, you know, that is a very high mortality rate. So if the CBK is going up like you said, is there enough time to rescue at that point? Like, if someone develops a CPK of whatever number, if you stop it at that point, do they progress or do they not?

FEMALE SPEAKER: That's a great question. So this study, it was a-- designed to be kind of a monitoring process for their patients going forward. And when they set that CK level of 5,000 and they discontinued propofol in patients who were getting close to that, they didn't have any incidents of PRIS in their period moving forward of using that protocol. So we felt like we were monitoring it, we started seeing an increasing trend, and then we would recommend switching off the propofol.

MALE SPEAKER: OK. At least in this example that I mentioned earlier, what we ended up doing was we gave the phenobar, we continued the opioid. And then we added propofol at a cap rate of 20.

FEMALE SPEAKER: OK.

MALE SPEAKER: And then there was no further increase in triglycerides. The triglycerides came down [INAUDIBLE].

MODERATOR: What about paralyzing agents with all this heavy-- also be using paralyzing agents or just very strong sedatives? What has been the experience as of now?

MALE SPEAKER: So, you know, at least my real practicing, which I think reflects most people, has been too paralyze if there is a significant ventilator asynchrony. So not everybody might need paralysis. Or if sedate to a rascal of, say, minus four to minus five. I think most people, you are able to blunt that asynchrony with that. But if it still persists beyond that, then I think using paralytics, you know, either as an intermittent dose, long-acting paralytic like [INAUDIBLE] or using a drip for, say, 24 hours or so. But if that is the most significant ventilator asychrony, I don't think they need paralysis.

MODERATOR: Perfect. So let's set it, use sedation first.

MALE SPEAKER: Yeah.

MODERATOR: Use it well with all the things that we've been discussing, and if necessary, then that will be the next step.

FEMALE SPEAKER: Yeah. And I think one of the key things that we, as a practice group, are trying to really push is that not to forget our good, baseline management of ARDS. There's a lot about COVID that we don't understand, but we do understand the physiology of ARDS and we know how to handle it. And so we're really trying to consistently follow what we know is good practice and good support care for these patients until something comes out that suggests that we can actually treat the virus itself.

To continue on the sedation note, just other options that we've done. We're seeing a lot more midazolam usage in these patients because of the lack of effective propofol or the toxicity with propofol. We're also using a lot more ketamine. And the data behind ketamine sedation is mixed and varied. Our most common usage the we're used to seeing in the NICU is a pain-related dosing, which typically goes from 0.1 to about 0.3, or even 0.5. To really be sedated, you need to push dosage more like 1 mg per kg per hour. I'll go as high as 5 personally, there's some evidence for that. But we typically will start a patient around 1.5 to 2, see where that gets the rascal. Then before that, starting paralysis.

The [INAUDIBLE] did also discuss that, in light of the risk of propofol becoming on shortage, [INAUDIBLE] as light sedation if able, which we certainly can and should continue to do. But just remember that [INAUDIBLE] does not provide true anesthetic effect. And so we should not be paralyzing patients if required [INAUDIBLE] sedation.

Phenobarb is another thing that we've been trying, as Dr. [INAUDIBLE] said, about 5 mgs per kg. The times that I've used it so far, it's been maybe a dose every three or four days, depending how the patient's doing. If you're using it so infrequently, there's not really a reason to check levels. I think that's all I have about that.

MALE SPEAKER: Yeah. It is going to be really fall half 10 than 15 days at least. So I mean, if, you know, once you're at the tail end of this sedation and if you find that your patient isn't waking up. I mean, you know, one of the reasons for that could be phenobarbital because it could hang around for days and days.

MODERATOR: Important to consider since we don't use it that often.

MALE SPEAKER: Yeah, we don't use that often. And really, it's going to hang around for a long time and you have to, you know-- because at that point, you'd run into this issue of are they waking up? Have they suffered anoxic damage? And so on and so forth, head CT. Can we have CT somebody who's COVID positive? What are the issues to consider with transport in a COVID-positive patient. All those things come up.

MODERATOR: Sure.

MALE SPEAKER: But the thing to keep in mind is that maybe consider that the phenobarb is going to hang around for a very long time.

FEMALE SPEAKER: And to piggyback on that as well, just remember that the midazolam, especially in larger patients, is lipophilic and will also form a depot in fat tissues and also take a very long time to come off once the patients are off the actual infusion, particularly if there's renal dysfunction.

Then, again, fentanyl's contact sensitive half-life, and the fact that the longer somebody is on a higher infusion the longer it'll take to wake up from it.

MODERATOR: And those are all for COVID and non-COVID patients.

FEMALE SPEAKER: Yeah.

MALE SPEAKER: Right.

MODERATOR: This is all what we know what we do as intensive and critical care units. Excellent. Let's talk about drug-on-drug interactions in this patient, and any other specific considerations that we should have.

FEMALE SPEAKER: Yeah, there's some unique things. Especially with the study drugs. So remdesivir and when we were using some Kaletra in some patients as well, there's drug interactions that we have to consider. They're all CYP3 and 4 inhibitors. So it can increase concentrations of other agents that we're using.

We do have some nice references that your pharmacist can refer you to as well, if you're concerned about anything. But keep in mind, specifically if we are using the midaz drips on these patients, we have to be extra careful with that CYP interaction, specifically with some of the study agents as well. Yeah.

FEMALE SPEAKER: From another common ICU medication standpoint, our pressers and inotropes aren't really affected by the potential novel agents that we're looking at. Agents we like to rely on for delirium, like haloperidol and thiopene, do you have an increased risk of QTc prolongation across the board? That's if we're using hydroxychloroquine or the [INAUDIBLE] combination?

In terms of rate control agents for AFib, amiodarone has an increased risk of toxicity, digoxin as well. And so does diltiazem. So it's not that you can't use these agents. It's just that we need to be on the lookout for potential adverse effects. And if we're continuing them longer than a day or two, we need to re-evaluate what we're doing at that point.

MODERATOR: OK. Any other considerations from drug interactions that we want to discuss at this moment, or experience?

FEMALE SPEAKER: Again, it's just important to re-emphasize that with these study agents, they're still very unfamiliar. So just making sure that you're having your pharmacist run those drug interactions for any of the other agents that we're using.

MODERATOR: We're basically learning as we go, with the care of this patient.

FEMALE SPEAKER: Yeah.

FEMALE SPEAKER: One other [INAUDIBLE] that I want to bring up. If the patients are being prescribed the Kaletra combination by infectious disease and we're giving them steroids, it will decrease your steroid metabolism and increase overall exposure of the patient. So methylprednazalone, for example, will have a decreased metabolism, about 60%. So it's important to modify doses when you're giving it to those patients. Dexamethasone, as well, will have increased exposure.

FEMALE SPEAKER: Excellent. What about anticoagulation? Anything that we've learned already? And what do we need to change our practice?

FEMALE SPEAKER: I can speak some to this. We had a patient this week that came in with the elevated D-Dimer, I think probably one of the highest we've seen so far, and has gone up, even today. I know this is an interesting thing we're seeing with these patients, is this elevated D-dimer. But I think we just need to remember our critical care practice.

And there is no evidence, at this point, for treating with therapeutic anticoagulation, unless they have another indication. I know that's practice elsewhere. But elsewhere they are, in some places, starting heparin, therapeutic heparin. But at this time, there is no evidence for doing so. And we're need to continue to treat our patients like we would.

MALE SPEAKER: I heard that people are using [INAUDIBLE] and things like that.

FEMALE SPEAKER: Yes.

MALE SPEAKER: But I think we ought to focus on usual care.

FEMALE SPEAKER: OK.

MALE SPEAKER: And do it the best way we can do it. And try not to use non-evidence-based treatments, except if it's part of a clinical trial.

FEMALE SPEAKER: Heparin DVT chemoprophylaxis is that still the recommendation? Right?

MALE SPEAKER: The usual DVT prophylaxis. Enoxaparin, if you can use enoxaparin, or unfractionated heparin, for people with renal dysfunction, or so on. Or based on BMI and those issues. Where otherwise I haven't used it. And I don't think it's a good idea to use it, unless some new study or data comes around.

MODERATOR: Only particular information for that patient that may [INAUDIBLE]

FEMALE SPEAKER: Exactly.

FEMALE SPEAKER: [INAUDIBLE] it.

FEMALE SPEAKER: Yeah. And certainly with the reports that we're seeing, certainly out of China, the data suggested that patients that had mortality had a much higher D-dimer than other patients. But that's across-the-board truth for any critically-ill patient.

MALE SPEAKER: Exactly.

FEMALE SPEAKER: Same with the instance of DIC. I think reacting to those numbers is something that is inappropriate to do, particularly without other collaborative data on the patients. And when you're ordering the DVT prophylaxis, in an effort to get nursing to not have to go under as many times, like Dr. [INAUDIBLE] said, if we can do enoxaparin, barring renal dysfunction, please do.

Just to avoid the excessive use of PPE. Then, from a drug-interaction standpoint, none of the novel agents they were using Interact with any of our intravenous anticoagulants or enoxaparin. But if the patient is apixaban or rivaroxaban at baseline, they can have increased exposure of these agents if they're on that Kaletra combination again.

MODERATOR: What about patients that are going also in liver failure, kidney failure, any specific considerations from a drugs perspective, that we need to again, consider with the COVID patients?

FEMALE SPEAKER: Many of the trial drugs that the patients are being enrolled in for the studies, they are disqualified if they have liver or renal dysfunction at baseline. So that is something, that idea is nicely following along and deciding whether these patients are eligible to be enrolled in a trial, based on their liver and kidney function.

But as usual, I think with our critically-ill patients, we titrate many of our agents to effect. So just keep that in mind with your agents as well.

MODERATOR: OK. So you mentioned clinical trials. So what are the clinical trials here at Mayo? What we, as intensivists, should be aware of? Who do we call? How do we figure it out, if can my patient be part of a clinical trial here at Mayo?

MALE SPEAKER: I think the people who are running the trials are monitoring patients coming in. And we have a liaison group which consists of infectious disease and critical care. So the COVID research panel, treatment panel.

And they would liaise with the clinician team, to check who's going to be eligible. Or you know, check if there are any concerns or questions about who's going to be eligible, and you know, which treatment? Which trials might this patient be eligible for?

MODERATOR: Excellent.

MALE SPEAKER: And then they will work on the research. And with the research, the idea is to try to match that.

MODERATOR: Perfect.

MALE SPEAKER: I don't think we, as clinicians, we don't make that decision.

MODERATOR: Perfect. So there is somebody in the background that is that is over pharma, reviewing the patients.

FEMALE SPEAKER: Yeah.

MALE SPEAKER: We usually get contacted by the panel.

MODERATOR: Excellent.

MALE SPEAKER: Yeah.

FEMALE SPEAKER: Then, in terms of the trials that are most relevant to the ICU, we are a sight for the front of remdesivir study. So you may see patients that are receiving remdesivir. We are also a site for a placebo-controlled sarilumab trial. And a gluctose sarilumab is either already started or may be starting.

Obviously, you've heard in the news, about all the convalescent plasma. I haven't seen that the protocol is active yet. But in theory, there will also be a site for that, as that gets up and rolling.

MALE SPEAKER: So that's an expanded use. So I think it's not a placebo-controlled trial.

FEMALE SPEAKER: Right.

MALE SPEAKER: Yeah. OK.

FEMALE SPEAKER: But we have given that, I know, to a few of our patients.

FEMALE SPEAKER: OK. So the CCP then, it's active.

FEMALE SPEAKER: Yeah.

FEMALE SPEAKER: And ongoing.

MALE SPEAKER: There is the trial for health care-- which is slightly different from this-- but health care providers who may have exposure. We're also eligible for the University of Minnesota trial, on the hydroxychloroquine, For post-exposure prophylaxis. So that's ongoing. Then there's a steroid trial that's ongoing. I saw on Slido, there was one of the questions that has come up about steroid dosing in these people.

MODERATOR: OK.

MALE SPEAKER: I think we are not doing it as a standard treatment, outside of a clinical trial. There's a clinical trial that's ongoing with that as well.

MODERATOR: Here at Mayo?

MALE SPEAKER: At Mayo, yeah.

MODERATOR: OK.

MALE SPEAKER: So they are using CRB to guide how much steroid somebody gets, against standard of care.

MODERATOR: OK. So the standard of care, as of now, we're going to use steroids as any other septic patient. Is that what we're doing? Right?

MALE SPEAKER: Yeah. So the role for steroids would be if they have septic shock on two pressers or more, or so on. You know, the usual way that we use steroids.

MODERATOR: The assessive guideline that we follow.

MALE SPEAKER: Yeah. Or for COPD exacerbation, any other indication for using steroids. If someone has a severe inflammatory condition like a vasculitis, or are they have something else that needs steroids, asthma exacerbations, COPD exacerbation, things like that.

MODERATOR: Correct. OK.

MALE SPEAKER: Just limiting steroid use.

MODERATOR: Well, let's talk a little bit, then, about other medications. More of that controversial medications. Antibiotics, anything that is causing some controversy out there. You're going to start.

[LAUGHTER]

FEMALE SPEAKER: I think we all have something about this one.

MALE SPEAKER: I would say for antibiotics, use them like you would if a patient had an actual bacterial infection. There's no evidence that antibiotics are helping at all with specifically SARS-COV-2. At this point, just treat if there's a concern for superinfection with your patient, and an actual bacterial infection and no evidence outside of that.

MODERATOR: So we should be getting cultures as we always do.

FEMALE SPEAKER: Right.

MODERATOR: Nothing specific. OK.

FEMALE SPEAKER: There are reports of bacterial superinfection in other sites, and coming out of China in Europe, as well. IB did put out a statement, preferentially saying if someone's coming from the community, they have severe COVID and there is concern for bacterial superinfection, it's reasonable to do a five-day course ceftriaxone and doxycycline, which we do that for our influenza patients as well, that are also at higher risk. I would say it's reasonable to consider. Then, just keeping in mind, if we don't grow anything on culture like as we normally would do, put in a reasonable end point of five days. And then reassess at that point.

MODERATOR: Yeah, I was going to ask if the COVID patient needs to be treated for a longer period of time when they develop other pneumonias or other conditions. The answer is no?

FEMALE SPEAKER: At this point, we don't have any evidence to say that a longer duration of treatment is beneficial. So I would say stick to your standard duration that we follow for other illnesses.

MODERATOR: Stewardship of the antibiotic, that's so important. Any other medications that we should be aware, the COVID patients?

MALE SPEAKER: Let me just comment about testing. You know it's April. It should be towards the end of flu season. Typically this is the time when we start to move away from flu testing.

But I don't know, I guess that's something that strikes me on the back of my mind too. Whether should we be checking people or not? Because activity is reported as leaders, it will be. But I guess it's getting to the point where flu season should be coming to an end.

MODERATOR: OK.

MALE SPEAKER: But at least in March, I was seeing myself asking, especially outside-referring institutions, sure, you checked for COVID. But did you check for the flu? Don't forget the usual stuff that we do and the usual treatment that we would do for people, in the absence of this pandemic.

But I think that shouldn't be such a big issue now. Because I think flu season should be pretty much over.

FEMALE SPEAKER: And if this extends into the next flu season, which hopefully it won't, but if it's here to stay, important to remember that oseltamivir does not have any activity against coronavirus. However, if somebody does have influenza treat them with oseltamivir. Especially if you're in ICU. Then there's no reason to do a prolonged duration if they also have COVID.

MODERATOR: So the question about steroids. I think part of it we've discussed already. But any experience with low dose or pulses with the steroids? What's the data. Are there any recommendations based on data right now?

MALE SPEAKER: The biggest recommendation would be use only the setting of a clinical trial. And not routine use. The question of steroids in any viral sort of infection or in general, steroids in the whole US, I think, is still a very murky topic. There was evidence of harm in people when this was used for influenza, for example.

FEMALE SPEAKER: And for the first SARS.

MALE SPEAKER: And SARS. And we don't have enough data on this particular COVID infection. The SACM put out guidelines where they said consider the use of steroids. So even they don't make a strong recommendation one way or the other.

I think IDSA went with the same sort of language, which is don't use it routinely. So I think most people are talking about don't use it routinely. Use it, some people would say, case by case. Some people would say, use it only in the setting of a trial. So I think there is no strong recommendation one way or the other. I think most people elect not using steroids.

MODERATOR: OK.

MALE SPEAKER: And speaking with my colleagues, I think most people would recommend not using steroids.

MODERATOR: Actually, there is a clinical trial there. And we're using the steroids, trying different things, that that patient might not be a candidate for a clinical trial. So let's stay with their combinations. That's definitely what we recommend here, from the education standpoint.

FEMALE SPEAKER: In terms of the pulse versus more ongoing lower dose, a lot of the trials that are currently existing use that lower daily dose of steroids. And nothing like a 500 milligram or a gram of methylprednisolone, like we'll do with some other pulmonary conditions. But I think it's also really important to remember that these patients are going to be at higher risk of adverse effects from the steroids, because of the nature of the duration of mechanical ventilation and critical illness.

We're already seeing reports of people that are having higher rates of Pick's after their ICU stay once they've recovered. Which makes sense. We're all wearing masks.

They don't have family there. And the delirium incidence is going to be higher when we're using benzodiazepines. So adding steroids into the mix could potentially make delirium worse in most critical illness with neuropathy.

So I'm very much on the side of we should use it if there's an indication, or in the context of a clinical trial. And not just to try it in patients.

MALE SPEAKER: Yeah, because there's nothing to say that doing something is better than waiting. I think we all have this imperative to do something.

MODERATOR: Do something. For us, so we feel better, right?

MALE SPEAKER: Yeah.

MODERATOR: That's a reality.

MALE SPEAKER: We are faced with an unknown illness. But there's nothing to say that doing something is going to be better than waiting. So I guess you see two camps, where you have the do-something people, and then the waiting people. But I don't know. I'm in the wait camp.

[LAUGHS]

So I think unless some really compelling information comes out that says this has definite benefit, then we'll use it. Otherwise, we stick to doing the usual supportive care. I think supportive care needs a more glamorous name, really. It doesn't sound cool enough.

MODERATOR: But it's very cool. It saves like.

MALE SPEAKER: But it's cool. I mean, it saves lives.

MODERATOR: It saves lives. That's what we do every single day in the unit.

MALE SPEAKER: We go through 11 systems. And we make sure--

MODERATOR: Yes.

MALE SPEAKER: --we try to optimize every single system. We spend a lot of time on it.

MODERATOR: We'll come up with a cooler name.

MALE SPEAKER: Yeah. We need a cooler name, for supportive care. Because I think everything that you see published in the lay presses, there is no cure for this.

People are dying. Yeah, there's no cure. s no specific antiviral cure, or whatever. But it doesn't mean people are dying.

The mortality rate is still 5% or 4%? Or probably lower in the United States, where you have capabilities of good critical care. And certainly lower than that out here, because we obviously haven't seen high numbers like New York.

MODERATOR: Mhm.

MALE SPEAKER: But the mortality rates are not so high. They're not 80%, 90%.

MODERATOR: Correct, yeah.

MALE SPEAKER: Where maybe doing something is--

MODERATOR: --is the only option.

MALE SPEAKER: Is the only option, right.

MODERATOR: Or you've got to try everything.

MALE SPEAKER: If you have an illness which has an 80% or 90% mortality rate, then sure. Try whatever you can try.

MODERATOR: But that has not been the case--

MALE SPEAKER: It's not the case with this.

MODERATOR: --for here, Mayo Clinic, right now.

MALE SPEAKER: Yeah, yeah.

MODERATOR: Excellent. One of the questions was related to the antibiotics. Then, talk about antibiotic conservations for patients with COVID who present in respiratory failure and shock and may have bacterial superinfections. So we touched base a little bit about that.

And is there any antibiotic? What is the first one I should think about if I'm thinking above that bacterial? For how many days? What would be the initial recommendation?

FEMALE SPEAKER: The initial recommendation, consistent with how we would handle anyone coming in with a viral pneumonia with a concern for bacterial superinfection would be those community-acquired pneumonia antibiotics, ceftriaxone and doxycycline.

MODERATOR: OK.

FEMALE SPEAKER: It's not unreasonable to check an MRSA swab. Especially if the patient is one who's at risk. We know staph infections are common post viral pneumonia. And especially if you're seeing some of those characteristic imaging findings of an MRSA pneumonia.

I hesitate to say everyone in shock gets vanco/Zosyn. Because I think that's a little bit of an overreach. Especially if they otherwise don't have those exposures.

If it's a patient that we would otherwise normally treat with Zosyn and vancomycin, I think it's very reasonable to start with and then peel off and deescalate. But if it's a normal, community-dwelling patient who has bacterial pneumonia, potentially on top of COVID, I would start with ceftriaxone or doxycycline, outside of another reasonable sustainer.

MODERATOR: So even if it's COVID. Even if it's in shock, respiratory failure, if it's considered a community-acquired pneumonia, we're going to treat it the same way. Right?

MALE SPEAKER: I think so. Then, I think these people will probably be intubated for a long time. So say they're intubated. And they're determined only on case by case.

You do the course and stop. Then see what happens. If they start to develop things like purulent sputum, worsening oxygenation, increased PIP, all of those things that might lead you to think that there's something more happening on top of the idle process.

Because let's assume, with a 5 to 7-day course of bacterial coverage we treated any passenger bacterial infection that was going on. Then, after that, if something new happens, like you have new purulent sputum or something, changes in hemodynamics and so on, then do a new culture. And then try to approach it as though it's a ventilator-associated pneumonia.

MODERATOR: OK Excellent.

MALE SPEAKER: I don't think routinely covering for vanco should be indicated in this infection.

MODERATOR: OK. There's another question. This one is related to thromboembolic events. So it says here, a number of studies have reported high rates of thromboembolic events with COVID.

That's what we were discussing before. So we know that's a fact. Though we're not currently doing systemic anti-population as we spoke, we are doing our standard DVT chemoprophylaxis, depending on each patient.

The question is, is there any benefit, in types of prophylaxis, Lovenox or [INAUDIBLE], fraction or fractioning. And then, what about the monitoring of this population? The coagulation parameters, which parameters should we be following, if any, to make sure, are these patients at a high risk or not? I think this is still a concept that it's so new to us, the thromboembolics. So what are the thoughts regarding medication and the population parameters?

FEMALE SPEAKER: Yeah, I think similar to what we were saying before, there's no evidence, at this point, that Lovenox versus heparin, there's no great studies on that as of yet, in the specific COVID population. But like we were emphasizing, for most patients we should try to prefer Lovenox, if they have the renal function to tolerate it. Because of the once-daily injection, versus sub-cu heparin, where we're doing it multiple times a day.

MODERATOR: OK.

FEMALE SPEAKER: As far as monitoring, there actually is some evidence that APTTs might not correlate well in these patients where they might have supra or sub-therapeutic APTTs. So anti-Xa, I would say, is our preferred. And if we need to do both, I think that's reasonable to give both an APPT and anti-Xa, to have more than one coagulation parameter that we're assessing in these patients. But there is some evidence that APTTs are not accurate in these patients. So an anti-Xa is what I would recommend at this point, for monitoring, if we're going to do any type of therapeutic anticoagulation.

FEMALE SPEAKER: Then, to add to that, it's not standard practice in China, for them to have VTE prophylaxis in the hospitals. So it's hard to say, for the data coming out of China, if their high rate of thromboembolics is because of their baseline standard of care for the disease state itself. And we are certainly hearing rates of high thromboembolic events in centers in New York, centers in Boston. Potentially with a DIC. But again, at this point, outside of an indication in the patients to consider VTE and to fully anticoagulate, the risk and benefit isn't necessarily there.

MODERATOR: What about monitoring? Are we doing an ultrasound of the legs in all of these patients who diagnosed EVT? Are we monitoring the ICD parameters? Is there anything that we can do, medically, to identify if this patient is more prone to thromboembolic effects or not? I'm not aware of anything. I don't know if you've seen anything.

MALE SPEAKER: In general, even with pharmacologic venous thromboembolism prophylaxis, these people will get clots.

MODERATOR: Correct.

MODERATOR: In non-COVID patients.

MALE SPEAKER: Even non-COVID patients, right. If you remain in the ICU ventilated for 14 days, the risk of getting clots is high. It's higher than your typical, say, ICU patient who maybe has an ICU stay of maybe under three days or four days, you know?

So they have a higher length of stay. They're immobile. They're maybe paralyzed. They have an inflammatory state going on.

Sure, the risk of generating clots and stuff is going to be higher. But I don't know if there's any test that'll tell you that this person is more likely to get it. Because you know, what the D-dimer, we don't routinely check D-dimers.

MODERATOR: Correct.

MALE SPEAKER: With the RDS.

MODERATOR: They can be elevated for so many other reasons.

MALE SPEAKER: Right, exactly.

MODERATOR: Really, they don't tell you that much information.

MALE SPEAKER: There's a severe inflammatory response, and so on. It's very interesting that you say that China doesn't routinely use VTE prophylaxis. That's fascinating. I didn't know that.

Because that might lead to a lot of clots. I mean, for people who've been in the ICU, of course, we know that these people require a median of 10 to 14 days of ventilator days. So that is much higher.

MODERATOR: So it will be interesting to compare the patients, if possible, that the ones that receive DVT chemoprophylaxis versus none. And was that the reason that they were more prone to complication [INAUDIBLE]?

MALE SPEAKER: Right.

FEMALE SPEAKER: I think it's hard to. Because even in a normal ICU patient, it's very common that we miss doses of VTE prophylaxis during the day, for whatever reason.

And every missed dose is a higher risk of developing an event. Because it's another time period when they weren't prophylaxed. So that logistical piece of this, I think we should consider as well. Then, even if you look at recommendations from the American College of Cardiology, they also talk about we don't have good ground yet, to say that all of these patients need to therapeutic anticoagulation.

As you had earlier mentioned, there are ongoing studies at other institutions, where they're doing things like low-dose tPA in a lot of these patients that have COVID. Outside of the context of the clinical trial, we shouldn't consider therapies like that. And we should really, again, focus on the good, supportive care, as Victoria mentioned, using enoxaparin preferentially and then heparin if they can't tolerate it.

MALE SPEAKER: Do you wonder, how much of the mortality of this disease is related to unproven therapy use? There's going to be no way of testing that. But I mean, it's like shining a flashlight on a dark night. Where you shine the flashlight, that's the only part you see.

MODERATOR: Right.

MALE SPEAKER: And if you see this D-dimer elevated, you infer from that--

MODERATOR: You react to the information.

MALE SPEAKER: You react to that, that oh, this D-dimer elevation is only from a thrombogenic state. And I need to lock that thrombogenic state. You might be doing a lot of harm. Or you may not be reacting to the true process.

I mean, the literature is full of theories like this, where oh, it's because of-- I mean, whatever. The use of things, like widespread use of things. Like hydroxychloroquine, for example. They're put in the same bucket, of reacting to some withdrawal or some sort of preclinical data.

MODERATOR: Yeah. But the [INAUDIBLE] might make sense.

MALE SPEAKER: Right. We may not know the whole picture.

MODERATOR: Correct.

MALE SPEAKER: Yeah.

MODERATOR: But we know that we don't know the whole picture with COVID. That's a known problem that we still have with the disease.

MALE SPEAKER: Right. And what we know and what's been well tested is there are a few interventions that work for people in ARDS. That's what we know. All the other stuff is an unknown.

MODERATOR: We've got to be careful.

MALE SPEAKER: So just do all of the stuff that we know well. And do it well. And do it to the best that you can--

MODERATOR: And learn from the disease as we go.

MALE SPEAKER: And learn as you go, in the form of trials, in the form of nice control trials, where you have a group that didn't receive all the other interventions, and a group that received some intervention. So we know what works and what doesn't work. Because with a lot of these, even some of the convalescent plasma trials or studies that were published, they were not controlled.

The [INAUDIBLE], the heparin, all of these things are going to be case studies where they don't have a control arm. At least, nothing's been published yet.

MODERATOR: Yeah.

MALE SPEAKER: Yeah.

MODERATOR: Interesting. So much that we still need to learn. Another question. Thanks for reviewing the current clinical trials that are ongoing.

What are the side effects that we need just think about when these patients are in this trial medications? I know we touch a little bit about that in drug interactions. But if we can summarize?

FEMALE SPEAKER: Great question.

FEMALE SPEAKER: That is a great question. So this is another area where we know very little at this point, since this is based on just clinical trials. But remdesivir, the big thing we're seeing with these patients is maybe some GI side effects, some nausea, vomiting.

Then it's kind of unclear with this. We see maybe have hepatotoxicity. But it's unclear if that's related to the underlying process from the virus itself, or if it's related to specifically the study, remdesivir drug. That's remdesivir, as far as side effects.

As far as tocilizumab, at the doses and strength we're using it for many of these things, it's pretty rare to see many side effects. There can be long term immunosuppressants. So you have to consider infections long term, but usually not in the study's doses that we're using, at this point.

FEMALE SPEAKER: Also, since thrombocytopenia is a concern. Then, there are case reports of GI perforation with tocilizumab, as well as sarilumab. So if you've got someone, like an instance of a patient that we took care of was a gentleman that had extremely bad ileus. And we weren't using methylnaltrexone of concern for causing perforation. So in that case, I would be hesitant to the sarilumab or tocilizumab. Just out of the potential for extremely adverse consequences.

For those two drugs as well, people need to have a negative TB, HIV, and hepatitis B/C screen. Because those will reactivate if they receive the medication.

MALE SPEAKER: Does that include latent TB as well? By the TB screen, you mean, does that include latent TB?

FEMALE SPEAKER: Yeah. I mean, if it has been treated and they are no longer active, or they're no longer positive on a [INAUDIBLE], then it would be more reasonable, since they were doing it. But again, with any of those agents, ID is following all these patients. And the trial coordinators know to screen for this and know to look for it.

MALE SPEAKER: You want to speak to the mechanisms of action of these? I don't know, I had to look at all these up.

[LAUGHTER]

MODERATOR: Just refresh. We have time.

MALE SPEAKER: I'm guessing there may be others in the audience who might not have the time?

MODERATOR: Yeah, start with me. Start it with me.

FEMALE SPEAKER: So the tocilizumab and the sarilumab, specifically, the mechanism there is maybe really, the cytokine release storm that we're seeing with these patients. The tocilizumab is something we use in CAR-T toxicities, specifically. And it's an interleukin 6 receptor antagonist, is how it's working. So it's helping to decrease the point of the inflammatory state in these patients.

FEMALE SPEAKER: Other one is here.

MALE SPEAKER: Sarilumab is something similar.

FEMALE SPEAKER: Very similar. A lot of these study guides are related to side effect, at least.

MALE SPEAKER: So those two are targeted to to IL-6.

FEMALE SPEAKER: Exactly.

MALE SPEAKER: There is another one, lenzilumab.

FEMALE SPEAKER: Yep, actually, we are using that with one of our patients this week. And that's actually a GM-CSF inhibitor. But it's, again, related to that cytokine storm, is the thought for the mechanism there, and how it's working.

FEMALE SPEAKER: Are we doing the lenzilumab trial? Yeah? OK.

FEMALE SPEAKER: Well, I think it's compassionate use. But we did give it to a patient this week. But I don't know that's officially a trial, per se, but compassionate use.

FEMALE SPEAKER: The remdesivir works on some of the enzymes, as far as the viral replication cycle. It's specific to single-strand RNA viruses. They looked at it in ebola. And they looked at it with some of the other coronaviruses that we have.

It hasn't really been effective in other trial settings. Gilead has advanced, significantly, the trial enrollment and the availability of the medication to use on an experimental basis. They have changed a little bit of their primary endpoints.

They recently expanded enrollment from 2,000 patients to 6,000 patients. So it'll be interesting to see what we actually get out of that study. I suspect it will be a small effect size, since they had to increase the enrollment so much. But hopefully we'll get something out of it. The hydroxychloroquine, you can talk about that one.

FEMALE SPEAKER: Yeah, it's thought that's maybe--

MODERATOR: The famous one.

[LAUGHTER]

FEMALE SPEAKER: It's thought that maybe has something to do with the viral replication, is the thought there, for its mechanism.

MALE SPEAKER: From what I was reading, it reduces acidification. So it increases the PH of endosomes that are involved in their viral replication. Unfortunately, I don't know more about it than that.

But it's a non-specific effect, is what's the key. So they feel that it's not specific to coronavirus. Many viruses replicate in this way. And by increasing the PH of those endosomes, it hampers viral replication.