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 NIVEN: Welcome to the Mayo Clinic Critical Care Insights-- COVID Edition. My name is Alex Niven. 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 Multispecialty 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 have been providing it are frequently less than rigorously peer-reviewed.

In response, Mayo Clinic has developed and AskMayoExpert COVID-19 Task Force that have collected and curated the available contents into a free public website under the Mayo Clinic AskMayoExpert 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 this information is continuously informed by rapid literature scoping reviews performed by the Kern 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 AskMayoExpert 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 to infection control considerations, in this challenging population.

We hope that you enjoy this work. This information 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.

[INTERPOSING VOICES]

ALEX NIVEN: Welcome to Critical Care Grand Rounds on this Thursday. My name my name is Alex Niven. The topic that we are discussing today is a case-based approach to venous thromboembolism prophylaxis in COVID-19 patients. And we have a fantastic panel here with lots of data and recommendations hot off the press. So this is a really controversial topic, and so looking forward to a great conversation.

So with that, I'll just have my panel members introduce themselves here, going around the room.

ROB MCBANE: So my name's Rob McBane. I work in the Vascular Center and also have a joint appointment in Hematology, where I participate with the Coagulation Disease-Oriented Group, so I come at this from a venous thrombosis perspective.

DAMON HOUGHTON: I'm Damon Houghton. Also work in the Vascular Center. I work with Dr. McBane. Have a little bit of a background in hematology as well, in addition to the thrombosis and anticoagulation.

JOHN CHARNIN: I'm John Charnin. I'm an intensivist, and I come at this from an intensivist, trying to make sure that everybody's ready and patients get all of the details right to try and optimize their outcome. It's so easy to get focused on the big details that the small details get lost. And so that's how my interest in this got started.

ANDREA NEI: I'm Andrea Nei. I am an ICU pharmacist that works primarily in medical and trauma ICUs.

ALEX NIVEN: Perfect. And we have tried to socially distance as much as we can in this space. I'll just say as a reminder to everybody, including myself, to try to speak loudly and distinctly over these masks so that we can make sure that our points are made.

And we're talking about venous thromboembolism prophylaxis. And the algorithm that we're discussing is literally hot off the press because we just finished an enterprise call making some modifications on this this morning. I've already seen a few little edits that still need to be done with that, but as usual, we are providing you with this information as quickly as possible, recognizing that those updates will be ongoing.

Something else that I just want to spend a minute before we get started here. So as many of you know, Ask Mayo Expert has put together a tremendous amount of COVID-relevant content, basically collecting the material from our COVID Corner along with other areas of the practice, synthesizing it, and putting it together into a public site.

If you want to see the results of our work so far, you can go to any web browser and just type in AskMayoExpert COVID Navigator and click on the Inpatient link. And you will see our content in addition to a large variety of other content that has been generated by other stakeholder groups that have been most significantly impacted by COVID-19 in our practice.

So John, I want to start with you, because it was really you six weeks or so ago that said, listen, we need to have a DVT prophylaxis section in the COVID Corner. How come?

JOHN CHARNIN: It doesn't take a lot of imagination to think that a thoughtful approach to DVT prophylaxis might have other benefits for our COVID patients. We are in the phase of medical literature where different areas of the world have an intense exposure of COVID patients for a period of time and then a body of medical literature, a perspective, a take on practices evolving from those areas.

And there may be subgroups of the virus that lead to actual differences in how the virus is affecting patients in different areas. And it's very easy for the medical system to get overwhelmed. When you have all of the beds in an ICU filled, every order you write becomes particularly important, because if you don't have the nurses, if you don't have the supply, if you don't have the lab techs to run whatever you wanted to do, it might not be helpful and productive.

So what I was attempting to do at the start is to come up with our best guess for the most bang for the least buck. And as an intensivist, all of the people in the ICU are screened for risk of needing DVT chemoprophylaxis, risk of bleeding, risk of clotting. And this is part of what is considered good practice in the ICU. Not everybody gets DVT prophylaxis, but it should be considered for everybody.

And if we didn't start with a unified approach, if we didn't have a place to begin, then that decision would be weighing on the minds of all of our practitioners who are trying to deal with COVID patients, potentially coming up with various ways forward that might be in agreement or not in agreement. And watching Twitter and talking to my colleagues from around the country, I'd say that across the country there is not currently consensus on the best practice for DVT chemoprophylaxis. And I think this is an area that will continue to evolve.

The thing that I think makes it particularly interesting for DVT prophylaxis is some of the patients with COVID have severe hypoxemia but initially early lung compliance. And severe V/Q mismatch is one of the mechanisms for their hypoxemia, and the thought is that there are microthrombi as one of the potential mechanisms for causing this V/Q mismatch and the severe hypoxemia.

So if we are treating DVT prophylaxis, preventing DVTs as best we can, and there might also be some benefit in treating the hypoxemia with preventing the propagation of microthrombi, that's in the best interest of everybody. And the interest in proning for treating severe hypoxemia may potentially lead to a lot of immobile patients with limbs not moving for a long period of time, elevating the risk of DVT in these patients who are already prone for clotting.

I didn't come up with the first version on my own. I was in close contact with Dr. Ariela Marshall, and we were trying to minimize the number of administrations that we gave, minimize the amount of testing that was done. And I think as the algorithm has gone on, I'm less concerned that our resources will be totally strapped, and we are currently prone to more testing and more administrations, and I'm all for that if we can. But I think it's great to give people a standardized approach, take one thing off your mind so that we can focus on other things to begin with. And that's what I think the first version was hoping to do.

ALEX NIVEN: Yeah, absolutely. And if you don't mind, I'll just-- I'll summarize and highlight a couple of your points in terms of the importance of maintaining consistent best practices for preventive and supportive care, regardless of the setting that we're in. And we we've all struggled a lot with the cognitive load of a new disease with a lot of pretty scary ramifications that have very rapidly changed our practice. The challenge is out there in terms of the deluge of information when it comes to risk of thrombosis and how to prevent it, and in a real high-risk population.

And I don't know about you, but when I see a patient who's got hypoxic respiratory failure with gas exchange abnormalities that seem out of proportion of lung compliance and perhaps radiographic abnormalities, I'm awfully worried about venous thromboembolism in that setting. And so I think being responsible, consistent, and delivering the best evidence-based practice informed by our opinion is what we need to do in this situation to make sure we're taking good care of our patients.

So Rob, you've been scouring the literature for about three weeks. And so we've got a lot of data out there from different practice experiences, really across the world. What have we learned since the start of this conversation when John put out some initial recommendations in terms of the risk of venous thromboembolism and other clotting and bleeding issues in COVID patients?

ROB MCBANE: Yeah. Thanks, and thank you for the opportunity to participate in this forum. As this COVID pandemic unraveled, one thing that I think many people recognized was that there was a striking risk of venous thromboembolism and coagulopathy associated with the infection.

But what was interesting to me as I was reviewing the literature is just the rapidity of the reports. And the reports that came in the form of letters. They came in the form of pre-peer-reviewed literature. And I must say that in my years, I've never heard of a pre-peer-review publication that's published but hasn't been-- hasn't seen any formal peer review.

But nonetheless, albeit as it may, a number of reports came out suggesting a coagulopathy. And then, the call was for, if there is a coagulopathy, are the events clotting or bleeding? And so following the initial identification of the coagulopathy, which, by the way, is similar to the original SARS outbreak in 2002 in China and also somewhat similar to the Middle Eastern outbreak in 2012, and these were all coronaviral epidemics, not pandemics, but so perhaps shared some similarities.

But nonetheless, as the coagulopathy became apparent, people quickly went to publish their experience with VT, venous thromboembolism. And so very rapidly, a number of pre-peer-reviewed series came out. And the event rates were quite a bit higher than one might anticipate for an ICU setting.

And so when looking at these pre-peer-reviewed and some peer-reviewed series, the first thing that's important is to understand how the data was collected. So there are groups who have mandated ultrasound imaging for patients who are coming into the intensive care unit. And there are other groups who are simply reporting clinically driven ultrasound evaluation strategies. And it's important to make this distinction because of the event rates are markedly different.

So if you look at the patient groups where a mandatory ultrasound was performed at baseline, and some have advocated serial ultrasound, DVT rates can be anywhere from 25% to 50%. If, on the other hand, you look at series where the evaluation was driven purely based on clinical assessment, the risks are more-- or the event rates are more in the single-digit, 1 and 1/2%, 2%, 3%, 4% range. And so the first thing that becomes apparent when you're looking at this is you have to understand how the events were driven.

However, taking all of that those caveats into account, if you compare that with what one might anticipate in an ICU setting pre-COVID, these numbers are quite a bit higher. So for example, the PROTECT trial, which was published a few years ago, a randomized trial of unfractionated heparin versus low-molecular-weight heparin, where patients had a mandatory serial duplex ultrasound imaging of their lower extremities, the event rate is about 5%. So if you compare that to the currently reported 25% to 50% rate, you can see that there's a marked difference.

The second issue is that the pulmonary embolism rates from the current series can be anywhere from 15% to 25%, which would be quite a bit higher than we would anticipate in a non-COVID patient population.

So I think in summary, if you had to summarize it all very quickly, it appears that the VTE rate is about three-fold higher than one would anticipate in a non-COVID comparator. And with that, we said, well, gee, we're just-- I'm not sure we're seeing these event rates. And so I asked Dr. Houghton to look at the event rates that we've seen in the Mayo enterprise to ascertain whether those are similar to our current experience.

ALEX NIVEN: So Damon, what did you find so far?

DAMON HOUGHTON: Let me make a couple comments on what you said, Dr. McBane. And so as we think about the rates of events, there are a couple, also, things that I think are a little bit important. Sometimes we say a DVT, but that may mean different things depending on which part of the country we are in.

So whereas DVT may involve a calf DVT in one location, there are countries and hospital systems that may not think that a calf DVT is quite as important, and so that may be some discrepancy in some of the rates that we're looking at here, in addition to all of the other components that you mentioned. So for the purposes of the data that I've been pulling here, DVT would apply to both a distal DVT and to a proximal DVT.

The way that I was able to look at the data that we have currently available is by looking at the Epic Reports. With this tool, you can pull out patients who have had testing for COVID-19, and you can pull out the patients who have positive testing. And then I looked at patients who had completed hospitalizations.

So the data that I'll talk about here, it does not apply to any of the patients that you may still have in the hospital service who are being treated, so if things don't look exactly right to you based off of what I said, that could be some component of the differences. These are discharged patients, whether that's discharged alive or discharged deceased.

So in doing that, looking back over the past four months, throughout the Mayo Clinic enterprise, we have 101 patients who have had completed hospital admissions and were COVID-positive by testing in one location or another. The average age of those individuals was 61 years old. 56% were male. The average length of stay was about nine days. And almost half, 47%, had an ICU component to their hospitalization. Within those numbers, Rochester had 41 of those patients.

Looking then at the hospital diagnoses codes-- so these would be codes that would be put in by providers that would be associated with this hospital admission, and then search those for thrombotic events. And so in doing that, that would capture anyone who presented with a pulmonary emboli or had a pulmonary emboli within their hospitalization. In been doing that, I found no cases of COVID-positive patients that were diagnosed with a PE.

Similar for deep vein thrombosis. I did not find any cases of DVT. I am aware of one patient that did have a DVT that was not added to the encounter diagnoses. It was a calf DVT. So that would indicate to some extent that this is not a precise mechanism, and without the reporting of this, if it's just located in an ultrasound, we wouldn't be able to capture by this methodology.

I also looked at some of the other macrovascular things that could occur, both stroke and myocardial infarction. I did not find any patients that had a stroke. And I found one patient that had a myocardial infarction, which was listed as an NSTEMI.

There were two patients that had myocarditis. And there was one patient that had hemorrhagic shock. Among the 101 patients that were admitted, there were eight deaths. So that's the current state of our records as of this morning based off of the most recent Epic data.

ALEX NIVEN: So I guess I just want to highlight, since you're providing data with such granular detail, that we want to be careful not to basically feed into the same pre-publication bias that I think we're worried about with other entities. But I think one of the reasons why we wanted to at least talk about some preliminary results there is to point to the fact that there is likely still some degree of clinical equipoise here and a lot more than we need to learn.

And so, you know, John, you were talking about your Twitter feed and talking to friends across the country. You and I probably follow similar people. You know, I've seen lots of practices quoted in terms of prophylactic systemic anticoagulation, you know, even low-dose continuous thrombolytic infusions and things along those lines.

And I think, to me, you know, knowing the wide discrepancy of data and the methods or rigor that we still need to go through to better clarify this wide range of events and potential clinical sequelae, being overly aggressive kind of gives me a little bit of pause. I don't know if you have any thoughts for or to the contrary.

JOHN CHARNIN: Yeah, what's kind of funny is people tell me I have a really young-looking face, but I feel like I'm really old on the inside.

[LAUGHTER]

And I tend to run pretty conservative. And I don't think it's unreasonable to try things, and I don't think it's unreasonable to advance science, but when practices like tPA infusions are started, I cringe because it only takes one patient who might have gotten better anyway for it to become the new norm, a very expensive protocol that may not help anybody's outcome.

And so I note that there are some amazing pictures on Twitter of ultrasounds with clots in transit and so on and so forth.

[BEEPING]

And I have heard stories of people who have survived with a PE with a massive dose of tPA. But I think we really need to discuss making science before we make real recommendations. And in the interim, before we have real science, we need to be conservative, do no harm, create cost-efficient care, and try and represent as best we can for our patients without creating publications based on small data that may or may not actually represent good science.

ALEX NIVEN: Yeah. Yeah. And I mean, we also know, both from anecdote, even the popular press, how challenging it has been to practice in many ICUs who have been overwhelmed with large volumes of COVID patients.

We already know that there is a commonly cited practice gap between what we know is best evidence and what's actually delivered at the bedside, and you can imagine the potential variation in best practices in terms of DVT prophylaxis in an overwhelmed setting with lots of patients who are intubated early, aggressively sedated, potentially proned, and then remain on mechanical ventilation for a long period of time due to concerns of premature extubation and respiratory failure, and then the risks that go along with airway manipulation in those sorts of settings. So I think there's lots of questions here, and I think we have to disclose upfront that the recommendations that we're putting together here are basically-- are measured recognizing the many questions that still need to be answered as our clinical experience with this grows.

So with that-- so I've heard lots of different things in terms of the marked proinflammatory markers that you can see with COVID, and certainly that's been the case in many of the patients that we've taken care of so far. So you know, what we've seen from a coagulation standpoint is very high inflammatory markers, often very high ferritin levels, very high levels of D-dimer, suggesting, you know, an overall activation of the clotting cascade, but as a knuckle-dragging intensivist, I'm going to get myself into trouble pretty quickly if I start talking about those things. So I'm going to pass it over to the vascular medicine folks to explain to me what all that stuff means, what I should be checking on a regular basis, and what the potential mechanisms here are that predispose COVID patients to clots.

ROB MCBANE: So the first point is that I think that the mechanism underlying the coagulation abnormalities are largely in their infancy with respect to potential hypotheses. So that has to be the first disclaimer. But having looked through the literature and some of the pathology reports and the wonderful hypotheses that have been driven, it seems to me that there are really three good hypotheses. And the answer in the end is probably that all three of these are playing a role.

So the first one, which I thought was absolutely intriguing, is the notion that this was all complement-driven. And as an individual who's spent a couple of decades now thinking about coagulation--

[BEEPING]

--the idea that complement would be driving a thrombotic process, to me, is novel. But the idea is that the infection has a predilection for endothelial cells and epithelial cells. The epithelial cells or endothelial cells then trigger complement activation, either through the classical pathway or an alternative or lectin pathway. The complement, then, once activated, goes through its stages of development to the point that it then develops a membrane attack complex, which then destroys the endothelium and sets up a small vessel coagulopathy.

And the reason why this is intriguing-- first of all, it's, again, an idea somewhat in its infancy, but one group have done immunohistochemistry of pathology samples, and they found membrane attack complexes and signals of complement activation that is rather widespread, including skin biopsies-- including skin biopsies of otherwise clinically normally appearing skin. So this suggests, at least in this hypothesis, that there's widespread complement activation.

And it turns out that there are a number of microvascular thrombotic processes that potentially could be driven by a complement pathway. A couple of examples are patients with catastrophic antiphospholipid syndrome or atypical hemolytic uremic syndrome. So while I think that this needs further investigation, a complement-driven process is very intriguing.

The second proposed mechanism centers around neutrophil activation. And so if you read through the literature, everybody talks about the cytokine storm. And that's proposed to be a dysregulation in the crosstalk between neutrophils and macrophages. So again, focusing on the idea that there's now, I think, burgeoning evidence that endothelial cells are preferentially infected by the virus, if you then have endothelial activation, one of the first things that happens is that the endothelial cell then starts to express selectins and ICAM, which then activate or recruit neutrophils to the site of infection.

So the neutrophil has three main functions. The first, of course, is phagocytosis, and the second is this oxidative burst that occurs with degranulation. And we're all very aware of these two processes.

The third process is a very interesting process, which is this notion of neutrophil extracellular traps. And this otherwise goes by the term NETosis. And what happens is that the neutrophil becomes activated. It's fascinating. It decondenses the chromatin material from the nucleus, and then it basically sends this deconstructed chromatic material extracellularly in kind of a net or kind of a trap, if you will.

And the idea of NETosis is that it will then provide not only this net for trapping bacteria, fungi, and viruses, but as part of the NETosis process, it also elaborates lots of proteins and can trap platelets. So the idea is, once the neutrophil is activated and then develops this chromatin web, then you can attract and trap platelets, which then initiate the process of microvascular and perhaps even macrovascular thrombosis.

So the second process of uncontrolled or dysregulated neutrophil-macrophage crosstalk with cytokine storm and a rapid--

[BEEPING]

--very aggressive activation of neutrophils is, I think, very intriguing.

And then the third process is a novel process for me, and that's the notion that hypoxia alone can induce coagulation. And so again, very novel, very fascinating process where hypoxia in various organs sets up a process of endothelial activation, turning the endothelium from an anticoagulant property to a procoagulant property through tissue factor, inhibiting tissue factor inhibitor pathway, maybe secreting plasminogen activator inhibitor, and generally becoming prothrombotic. So hypoxia triggers endothelium to change this phenotype.

The other factor is that platelets, when exposed to a hypoxic circumstances, can also become activated and participate in thrombosis. This is all through a nuclear mechanism that focuses on the Irk5 pathway.

And then finally, many cells have this so-called hypoxia-inducible factor, which sets up a pathway which does a phenotype change to the cell itself, which sets up an entire host of responses to the hypoxic environment. And so these three pathways, either in isolation or most likely in tandem, I believe have some relevance to the COVID coagulopathy.

ALEX NIVEN: So I'm going to say it. That's exactly what I was going to say.

[LAUGHTER]

So that's a fantastic summary, Rob, and I know how much time you've spent going through all of the available literature to summarize that, so thank you. I think before we move on to the next point in our conversation, there's a couple of questions, or at least one question, one comment, that came in on Slido.

So I'm going to turn back to Damon here for a minute. So there was a question in terms of the scope of the data that you were discussing before. Was that simply from Rochester, or did that include our other major medical centers in the health system?

DAMON HOUGHTON: Yeah, so this included a search of the Mayo Clinic enterprise. So this includes Rochester, Florida, Arizona, and the Mayo Clinic Health System.

ALEX NIVEN: Yeah. And then there's a comment here about Twitter and the danger of anecdotal medicine, and I think we'll just leave that at that.

ROB MCBANE: Yup. That's really important.

ALEX NIVEN: So, you know, I think-- so we're faced with a dilemma, right? Because certainly, we have some pretty scary numbers, again, based on some of the publications out there, and certainly some plausible mechanisms that predispose these patients to thrombosis. And so we're stuck with a challenge of trying to find the right path forward in terms of protecting these patients from both common and potentially novel pathways for clot with COVID patients, while at the same time being responsible and not doing further harm.

So I think this is where we'll move into the algorithm. And you know, in the interest of keeping things HIPAA compliant, what I've done is I've taken a group of actually five or six different patients that we've had personal experience with here, sort of put that together into a bit of a stylized case that just I think hits some of the important elements. And so let's talk about this sort of virtual patient and march through our recommendations for venous thromboembolism prophylaxis with the setting in mind.

So this patient that I've put together is a middle-aged patient with unclear prior exposure who basically developed what we have become to be very familiar with. This is sort of the viral prodrome that comes along with COVID. So headache, diarrhea, nausea, vomiting, cough, rhinorrhea. There's lots of excitement now about anosmia with it as well, which of course is just stuffy nose, and the impact of that. And about seven days into that course, noted worsening dyspnea, which was the reason why this individual presented to our emergency department.

There, the patient was found to have oxygen saturations that stabilized in the low 90s on low-flow oxygen. Did have infiltrates on chest X-ray, with a little bit more of a peripheral and basilar predominance, which is some of the things that, again, we think perhaps is associated with COVID. And had evidence of lymphopenia, mild acute kidney injury, and a mild transaminitis.

And so due to concerns about respiratory insufficiency, was admitted to our, basically, COVID ward. We have most of our ward patients cohorted here in Saint Marys. And you know, had some additional testing performed, largely as part of stratification for ongoing clinical trials, that demonstrated elevated inflammatory parameters, an elevated fibrinogen level, and a mildly elevated D-dimer.

So this patient arrives on the wards, doesn't really-- so has a PCR that confirms the diagnosis of COVID and doesn't clearly have any contraindications to venous thromboembolism prophylaxis at this point. What do we do? I'll open that up to anybody. Damon? You're on the consult service right now, aren't you?

DAMON HOUGHTON: Yeah. Absolutely. Absolutely. So [INAUDIBLE] We probably won't get to [INAUDIBLE] proposed algorithm [INAUDIBLE].

ALEX NIVEN: Oh, so-- and we're going to use this case, really, to march through that algorithm. So you've got a patient who lands on the wards. You know, what are some of the things that we've been discussing in terms of an approach to venous thromboembolism prophylaxis in that patient with the clinical information I've provided to you so far?

DAMON HOUGHTON: Yeah. So as all sort of decisions are, they're risk-benefit decisions, and someone who does not have a high bleeding risk and who has a hospitalization, many times, the default, even in the absence of COVID, would be to provide this patient with some prophylactic anticoagulation. And I think that's a reasonable-- sort of the place to approach this is from what we may do with a typical patient who's sick and in the hospital that has several different components of hypercoagulability, both with some inflammation and then with the immobility that will come with their hospitalization and recovery. And so I think that's one place to just start and say, well, what might I do normally, and is there any reason that I may do something a little bit different? And at the moment, this patient would not be too atypical for many sick people in the hospital.

ALEX NIVEN: So I do all my practice in the ICU, so I hear these things about Padua scores and other risk stratification tools in ward settings that I truthfully don't commonly employ in the ICU setting. Can you talk a little bit about that, just to make sure that we have a common frame of reference, because I suspect there's others in my situation, and then how you approach this person that's on the ward.

DAMON HOUGHTON: Yeah. So there's a variety of risk stratification tools that are out there for hospital admission. Padua prediction score is one of those scores. It's a little bit more of a cumbersome with multiple different variables involved.

As far as I'm aware, there's no standard approach across Mayo Clinic to use the Padua prediction score. There's a number of other scores that have been out there and are validated, but none of them are, you know, embedded into our medical record like they are in some other institutions. So those scores are out there and can be helpful, especially if there's some uncertainty about the level of risk, but at the moment, those are not part of a standard protocol.

There's a little bit of data out there on COVID and the Padua prediction score at the moment. That data is fairly limited at the moment. It does not appear that that may be the best risk stratification tool. And Dr. McBane might have a little bit more detail from some of his review on that, but there is there's concern that that may not be a discriminating factor in these individuals.

ROB MCBANE: So I think, and all of us at the table have discussed, the issue is, you know, do these Padua scores-- so the Padua score, that improved score, if it's a post-operative patient, the Caprini score. You know, should we be using them?

And just as Damon mentioned, while there are groups who have done Padua scores on patients hospitalized with COVID and they do show that in fact you can differentiate, based on Padua, a high-risk and low-risk group, that there's no clear evidence that using these scores really differentiate high-risk, low-risk COVID patients. While I think they have some utility for non-COVID patients, I think that our default would be to use DVT prophylaxis if the patient has confirmed COVID and is on the floor.

And the things that we thought about for exclusion, three variables. If the patient's actively bleeding, if they have platelet counts of less than 25,000 to 30,000, or if that patient has a known congenital hemophilia. What I mean by that is Von Willebrand disease, hemophilia A or B, hemophilia C, any of those known congenital bleeding disorders, those individuals should probably have sequential compression devices and not pharmacologic DVT prophylaxis.

The one caveat is the patient with the known congenital bleeding disorder. Those individuals, if they're hospitalized for a COVID reason, they should be seen by colleagues in Hematology, because they're are very specific and very complicated group of individuals. So I would agree with everything that Damon has said.

ALEX NIVEN: So I want to move into the ICU realm, because there's lots of questions already starting to come in on this, but just before we finish the ward, so you're really talking about standard DVT prophylaxis in those patients, perhaps not risk stratifying using these other scores. So enoxaparin or low-molecular-weight heparin in typical prophylactic doses-- you know, 40 subcu daily, higher doses, of course, if you've got somebody who has a larger volume of distribution because of a higher BMI, and then thinking about unfractionated heparin in typical BID or TID doses for folks that have a reduced GFR.

ROB MCBANE: Absolutely.

ALEX NIVEN: So let's talk a little bit about--

JONATHAN E. CHARNIN: Before we go on--

ALEX NIVEN: Yeah?

JONATHAN E. CHARNIN: --let me just say, in accordance with our 2030 goal of Bold Forward, I would say some practitioners are more comfortable with subcu heparin. They feel that there's less bleeding risk, there's more familiarity, and maybe my patient will need a procedure or an epidural, and maybe they're going to have renal failure, or they're at the edge of renal failure, and that they would choose unfractionated heparin given the choice. I would say, even for floor patients, consider Bold Foreword, use your low-molecular-weight heparin.

There are two reasons for that. One is it's less doses per day. Less administrations. Fewer things for the nurse to do. Fewer medical waste. And when we're talking about COVID, I think the fewer, the better.

And second, it's in accordance with guidelines from the International Journal of Hemostasis and Thrombosis, who issued some [INAUDIBLE] guidelines. They cite a 449 patient study I think out of China, where unfractionated heparin and low-molecular-weight heparin was reviewed, and it appears overall there was no difference, but when you looked at patients with a higher thrombosis score, patients with a more elevated D-dimer, it appeared that there was a mortality benefit for those patients with a more elevated D-dimer if they had low-molecular-weight heparin versus unfractionated heparin.

So it may actually be that the low-molecular-weight heparin is a better drug for these patients. And for that reason, I would also say err on the side of low-molecular-weight heparin unless you really have a reason not to.

ALEX NIVEN: Thanks very much for that, John. And I--

[INAUDIBLE]

ALEX NIVEN: --recognize there's a spectrum of practice that we still deal with on a regular basis. So let's talk about-- let's take this patient. This is actually, again, based on patients that we've had.

We know that some of these folks, when they come in the hospital, will clinically deteriorate. And so this hypothetical patient that we have, over the course of 36 hours develops progressive worsening respiratory distress, increased oxygen requirements, ends up getting transferred to the intensive care unit, intubated for respiratory failure with progressive infiltrates on chest radiograph.

So you're the receiving critical care physician. What should we be doing in terms of both laboratory risk stratification in this sort of setting, and then you'd mentioned a lot of work that had been done in terms of screening lower extremity Doppler. So let's talk about the rationale behind those recommendations on our algorithm here. Sure.

ROB MCBANE: Sure. All right, so yeah. So the first thing I think that's relevant is that for these individuals, the screening-- we've recommended a screening duplex ultrasound of the length veins when they come into the intensive care unit. And the reason why is that, at least looking at the literature and looking at the event rates for those individuals who had mandatory screening versus those who did not, the event rates are considerably higher, 10-fold higher.

And so if you only do the imaging based on clinical suspicion, my sense is that you're going to miss a number of individuals. And we don't-- and you might say, well, this is more than academic, because that of course would change our strategy from DVT prophylaxis to DVT treatment. But in fact, it might give you suspicion as to the respiratory deterioration for that individual, that they've already suffered a pulmonary embolism. So the first step that we thought about was doing a mandatory duplex ultrasound on admission.

And then I'll just speak briefly to laboratory testing. What seems to be apparent in the literature is that patients who have progressive neutrophilia or progressive lymphopenia or progressive D-dimer elevation, those individuals seem to do worse. So we've thought that at baseline, a CBC with differential, which everybody would get anyway, but then a D-dimer. And the reasons are not just to help risk stratify, but to look for prognostic value down the road. And then in addition, to reiterate, a screening duplex ultrasound.

ALEX NIVEN: Now, in the algorithm, basically, the way that we risk stratify high- versus is low-risk patients is really using that D-dimer cut off. And so I think it's probably worthwhile talking for a minute or two about why we selected that level and what the evidence is behind it. Rob, I know you've been-- or Damon, yeah.

DAMON HOUGHTON: He might know a little bit more about that specific level of evidence.

ROB MCBANE: Yeah. Yeah, so there's groups that have noted that really elevated D-dimers and the cut off that people have used is six-fold the upper limit of normal. So the upper limit of normal in our institution would be 500 nanograms, so that's why we chose 3,000 nanograms as the differentiation between lower risk and higher risk.

Other people have used other risk stratification tools. And by the way, if you go to MDCalc and simply type in COVID, there's a whole host of very helpful risk stratification tools and scorecards, et cetera that you can-- help with this process.

There are two risk stratification scores that we had contemplated, the SIC score, S-I-C score, and the SOFA score. But in the end, we felt that perhaps a simple D-dimer assessment, very simple, very straightforward, we're getting it on everybody, would probably serve our needs the best. And the data behind this is one study that showed that for those high-risk patients with high D-dimers, if they're given aggressive DVT prophylaxis, that they have a survival advantage.

ALEX NIVEN: So I want to ask this question of the group, because I think it's a fantastic one, which is, how does the incidence of microthrombi and injured lungs and the elevation of D-dimer that we're talking about here compare to non-COVID patients with ARDS? And I'm not sure if I have a good, evidence-informed answer to that, other than the fact that I'm not used to seeing D-dimers in the range that we've been dealing with the COVID patients that we have in my common ICU patients, which, in the MICU, includes a fairly large number of patients with ARDS. I don't know if anybody has other comments on that.

[INAUDIBLE]

ROB MCBANE: So one of the things that can be useful-- and people have said, gee, this is just DIC. But if you also-- again, bookmark MDCalc. You should be-- I mean, I use it every minute of every day. But if you want to ask, is this DIC for my patient, go to the ISTH risk calculator. There are several variables that you plug in, and you can discern DIC versus non-DIC.

And currently, many authors have found that, in fact, this D-dimer elevation is not consistent with DIC for a number of reasons. Number one, the fibrinogen content is high, so that wouldn't be DIC. Number two, the platelet count is modestly elevated, if at all. Number three, the prothrombin time is modestly prolonged, if at all.

So if you go in and you see whether or not this D-dimer elevation is due to DIC, I think you're going to find that you're not going to meet criteria in the vast majority of your patients. And so people are preferring the word sepsis-induced coagulopathy as opposed to disseminated intravascular coagulopathy to distinguish these two processes.

ALEX NIVEN: So there's another question here in terms of, a patient arrives to the intensive care unit in respiratory failure and gets intubated. You do that initial lower extremity Doppler and it's negative. Are you obligated then to do a CT pulmonary angiogram? And here, I'll put my pulmonary hat on and say pretty definitively no, in that setting, unless you have a significant clinical concern for venous thromboembolism in that setting.

So if I see somebody who comes to me who has progressive diffuse infiltrates, you know, who has lung mechanics that are consistent with ARDS and a negative lower extremity Doppler, I'm certainly not going to feel obligated going to the CT scanner for that person. You know, not to mention all the infection control issues that go along with transporting a patient and doing a CT imaging study. I think we've been very reticent when it comes to that.

And I think the biggest challenge that I don't have a good clinical answer for is the compliant patient that we've all heard about out there. So you intubate that person. They've got bad gas exchange abnormalities. Maybe their infiltrates aren't so bad, and they don't have marked reductions in compliance on mechanical ventilation. That's, I think, a real challenging situation I wish I had in answer to. I don't know if you have any bias, John.

JONATHAN E. CHARNIN: You know, my bias is not to overtreat those patients with a specific "it has to be this way or that way." I think the guidelines on AskMayoExpert or how to set up the ventilator for patients in COVID tolerate using a best PEEP tool to help customize the PEEP for the patient so that you're not obligated to follow the high PEEP pathway in the ARDS [INAUDIBLE] hypoxemia so the people with high compliance are getting PEEPs of 25 just because they're severely hypoxemic. And I think our respiratory therapy group has done a great job of making sure that patients get the respiratory care that they need and knows what they don't.