Coronavirus disease is new, but does that mean we toss out decades of research showing better ways to keep ICU patients safe?

Dr. Wes Ely returns to school us. Here’s our previous episode on ICU delirium. Here’s the website and resources he references.

Reach out to Dr. Ely on Twitter.

– Hey, what’s up, Z-Pac? It’s Dr. Z. All right, today I have back on the show somebody who just kicked so much butt last time that I wanted to have ’em back to finish this conversation because it’s so important. Dr. Wes Ely, is a critical care doc, professor at Vanderbilt University and is an expert in how we manage patients in the ICU, to keep them safe and sound not just in the ICU but beyond. We started this conversation before and now I wanna follow up on ventilator management and sedation and how we can prevent complications and improve outcomes, especially when so many patients are in our ICUs. Wes, welcome back to the show, brother.

– Hey, thank you. Thank you, Zubin. It’s really great to be here. I do think we have some unfinished business. So for the audience here, I hope this builds on the first show.

– I think it will and it’s interesting ’cause since the first show, it kind of blew up and all these people were like, “Oh my gosh, this guy needs to come back,” and all that. And so you and I were talking and I’m like, “Wes, everyone’s tweeting at you. “Where are you? “You’re not on Twitter.” And I said, “Get a Twitter account.” And you said, “But I have a life “and I wanna actually maintain my sanity.” And so you came up with a way to actually start, what is it, @WesElyMD. It’s E-L-Y-M-D. You started that, and you immediately got like 1,000 plus followers, but you have a way of dealing with Twitter that’s actually quite enlightened. What is that? How do you deal with it?

– Yeah, I mean, so I created this thing @WesElyMD and I just do it in the morning, in the evening. And I have decided that I’m gonna stay focused on it so that I can really work at the bedside of my patients on this research that we’re doing here at the CIBS Center, C-I-B-S Center, which is Critical Illness, Brain Dysfunction and Survivorship. And I’ve found that my Twitter, I’m loving it, but it’s also not completely controlling my life. So thank you for your teaching points and for getting me started on Twitter.

– Yeah, so you’re able to just chest check it twice a day or something like I actually put some parameters around, right?

– Yeah, you know what’s really funny, Zubin, in that funny/useful, I found in the three days after I got on Twitter, some Spanish investigators and COVID doctors from Valencia and Madrid emailed me, Rafa Vaitonis and Gabby Harris and said, “Look, we wanna study delirium with you, Dr. Wes. “And we had 80% delirium in our patients. “How can we do that?” So actually I said, “Well, hey, I’m on Twitter. “Why don’t I tweet out an invitation for people around the world to join a research project called COVID D,” which we created COVID, the D for delirium. And do you know we closed enrollment yesterday after just 96 hours and we have 140 sites in 28 countries who are gonna participate in this COVID D studies. So I already see the value of Twitter in a big way.

– Man, that’s awesome. Well, I’m gonna take full credit for your social media awakening, Wes. That’s great because actually, I’m a huge believer in this. We had Eric Topol on the show talking about recruiting for a trial. They’re doing it scripts with COVID and healthcare professionals and that sort of thing. So it’s really important. So last time, Wes, you and I were talking about how this sort of body of knowledge that’s accumulated over the years of how to keep patients in the ICU safer with better long-term outcomes and you can hear someone hammering next door. That’s a function of living in the Bay Area where everyone’s socially isolated and decides they wanna put up paintings during my show. So during that talk, we talked about how lightening sedation, doing these spontaneous awakening trials, spontaneous breathing trials, where we let up off the ventilator, how this could actually liberate people from some of the complications of ICU, including cognitive dysfunction that well out lasts their stay in the unit and PTSD and other things that can happen. And so I want to follow up now and really get into that because you have a lot more to teach us about how to keep our patients safe. Give us some–

– Sure, thanks. I love to take us down a little bit of a journey here and for the audience, whether you’re in medicine or non medicine, I think it’s a critical feature of our decision making that we base it on history and knowledge and evidence. And so I’m gonna have fun here going through a little pathology of the disease of COVID and then a bit of physiology and then we’ll get into pharmacology. So there’s three Ps, path, physio and pharmacology. And I’m gonna keep this at a digestible level for everybody. You tell me if I don’t, Zubin. And the end goal here is to make sure that we’re all keeping people as safe as we can keep them. And they were making the decisions, that are well versed in the literature. So let’s just start with when a person gets infected with COVID, that virus comes in through the mouth, goes down into the respiratory tract, and the first thing it does pathologically is that it attacks the respiratory epithelium. So epithelium is the lining of the lung. And that was our really big initial knowledge of what the COVID virus, the coronavirus was doing was destroying this epithelium. But now we’re learning something so fascinating. It’s attacking now the endothelium, which is the blood vessel lining, okay? So now we have been hearing these stories of people getting strokes and having all these blood clots DBTs, PEs. Well, that really speaks to the second injury of the coronavirus, which is endothelium and then, excuse me, epithelium and then endothelium. And that’s very relevant to us because it creates in the lung what we call either a shunt or a VQ mismatch and a tremendous drop on our pulse ox. And I think all the audience here has been hearing about the role of pulse oximeters and we’re seeing this oxygen level just plummet and it’s scaring me, but GBs out of us and making us put all these people on ventilators, right?

– Yeah, exactly.

– So the question is, do all these people need to be on the ventilator and what’s the decision making process to put them on that ventilator? By the way, interestingly, of the autopsy studies that have been done thus far on these COVID patients, we’re seeing a big time neutrophilic alveolitis and hemorrhagic alveoli. So that means bleeding and an infiltrate of these troops of the body. Kind of different than what you might see with a flu. So it’s not exactly the same as the flu. But the end result of this is that it looks like ARDS. We call it diffuse alveolar damage. And that is the ultimate thing that we’re seeing here is ARDS. What were you gonna ask?

– Yeah, so it’s interesting. So a lot of people have talked about this idea of bleeding into the lungs and there’s a lot of like, kind of quacky reports online of like, Oh, this is a heme problem and dissociation of oxygen from heme and this kind of thing, but that’s not necessarily the conclusion you draw from that pathology, correct?

– That’s not the conclusion. I think there was way too much attention given to that whole heme thing at the beginning. I’m not saying there’s nothing there, but really, what we’re seeing here is a very clear cut injury inside the lung to both the lining of the lungs’ air sacs, and then to the blood vessels themselves. And what that means is when you inhale oxygen, that oxygen can’t get across the membrane which used to be thin and is now, it’s gone from thin to thick. And it used to not be filled with edema or swelling fluid or bleeding and now we’re seeing that the air sacs filled up with those two things, which is the essence of DAD, or diffuse alveolar damage, and that’s basically ARDS.

– Exactly, exactly, so that’s the pathological–

– Another message open is that there’s these different types of lung disease and it’s not all ARDS. I mean, yeah, some people come in with more flexible lungs and more elastic lungs, and other people come in with the lungs are already stiff. But this is essentially a disease of ARDS. We’re gonna call this ARDS. And it’s untrue that COVID has created a new lung disease that wasn’t included in the previous ARDS studies. That’s not true.

– So this is important because a lot of people are saying, “Well this is absolutely different. “We need a brand new way of thinking. “It’s high compliance, it’s not your typical ARDS, “it’s more like high altitude pulmonary edema.” And so on and so forth. And you’re saying, but no, no, the end stage of this, actually looking at the pathology and looking at the way it behaves, it’s still in, it’s compatible with our body of knowledge around ARDS.

– And the crucial thing of what you just said is that if that is true, what you just said, and I’ll come back to it, then that means that we should primarily go with treatment things that have been determined over the last 20 years from large scale, definitive randomized trials and not Chuck that stuff out. And that’s one of my take home points. Let’s stick to the basics of what we know. Let’s stick to the basic arts and protocols, let’s stick to the basics of sedation, the ABCDS and all of that will keep our patients much safer than if we go cowboy this and just start over and think we can do whatever we want.

– Awesome, and that’s very important because that data has been 20 years plus of a growing body, that has been working on quality and safety and it applies to these patients. But one thing I wanna back up and make sure we clarify, because again, I’ve had guests on the show talking about this, what getting on the ventilator in the first place is a decision point, right? So once we’re on the ventilator, that’s one thing. But even like should we be intubating as many people as we are because of the number, the hypoxemic number that we’re trying to treat? What are your thoughts on that?

– Let’s hit on that. So you were basically saying, do these people require mechanical ventilation? Very few people ever require a mechanical ventilator. It’s a physician judgment, okay? Who would require it? Well, if you’re in a cardiopulmonary arrest, clearly arresting, yeah, you clearly require a ventilator. But otherwise there is a judgment involved and the judgment is often driven by fear. It’s not inappropriate fear, it’s fear of, I am afraid that you as a patient are about to go down a road of increasing lack of oxygen to the point you’re gonna get organ injury, okay? Now, let’s think about that for a second. First off, if you see a pulse ox dropping like crazy, like going from 95% sat to 90 to 85 to 80 to 70, yes, that means that they are having less oxygen delivered from the atmosphere and lung to the rest of the body. But what does the body do when you get less oxygen delivery or so-called a drop in your D.02? Physiologically, now we’re onto the physio, I said we’re gonna go path, physio, firm, now we’re under physio. Physiologically, what that means is that your oxygen delivery is down. So what does your body do? It increases oxygen extraction. It says, “Okay, I will now suck more oxygen. “You’re giving me less, “I’m just gonna suck more, extract more.” And guess what happens to oxygen consumption? It stays the same. So it actually, Tobin wrote a great paper last week in the Blue Journal about this. If you wanna pull up Martin Tobin’s paper, and he pointed this out beautifully and he’s one of the masters of physiology in the whole world right now, and he points out that you actually don’t get a critical problem with oxygen consumption until you get a problem down to around 25% of oxygen delivery. That is not happening in the vast majority of these people. So what we have to recognize is that when the sats are dropping and we’re giving, we need to give supplemental oxygen, high flow and or BiPAP in different circumstances. People are making different decisions about when those are safe to use based on negative pressure rooms, et cetera. But just keep in mind that you are making a judgment about whether or not to put that person on the ventilator. And if you’re only thinking of the lung in making that decision, then we’re all way off as clinicians and healthcare professionals because the instance that you put that person on the ventilator, your lens has to get much broader to consider all of the potential complications that are now going to develop. Remember this, the ventilator does not heal the body. The ventilator actually creates extra injury to the lung usually if we blow the lung up too much and then you immobilize and sedate people and they start developing clots, ulcers, delirium and toxic effects of drugs. So it’s a humongous decision you’re making, and I just want us to be careful about who to put on and who to manage noninvasively.

– This is the most important thing we can say actually, because you said this, the ventilator doesn’t heal you, it actually creates a whole set of complications. You use it because you are, like you said, afraid that without it you’re gonna go down a path of a lot of problems relating to either oxygenation or ventilation, removing CO2. And so making that decision is a key thing. So anything else you wanna say on making the decision before we go into, okay, you’ve made the decision and now how do we keep the patient as safe as possible from all those complications?

– Yeah, sure. I used to be, I’m a transplant pulmonologist too and I used to ask patients, “Do you want to get a transplant?” And they would say, “Dr. Ely, tell me what it means “for me to get a transplant.” And I would always tell them some version of this, “We’re gonna take an end-stage lung problem “that you have right now “and we’re gonna replace your lung with a transplant “and you’re exchanging one set of problems “for an entirely new set of problems. “You’re gonna go from two or three drugs a day “and a lot of oxygen and shortness of breath “to no oxygen and well-working lungs and now 25, “20, 25 medicines and immunosuppression. “So we’re building you a new set of issues to deal with.” And that’s exactly what happens when you put somebody on a ventilator. You’re exchanging one set of issues for another set, but don’t think that the next set isn’t a big deal because it is potentially massively life-changing for this person that you might keep on the ventilator, sedated and immobilized for three weeks. Like my patient last week, we took this person off the ventilator and this person who had COVID and was on the ventilator for double digit days when he came off, he could not lift a fork, couldn’t lift a fork, couldn’t read, couldn’t talk to his wife, couldn’t remember names. And this was extremely distressing for this former Marine and very energetic and go get ’em kind of guy. So part of that came about because of our decision of what to do now, did he require the ventilator? Did he not? I wasn’t there the day that decision was made, but I’m just trying to get everybody to realize that we have to have a wide angle lens when we’re making these choices.

– Yeah, that makes perfect sense. And I think it bears repeating, especially for younger residents, fellows who are trying to make these decisions in the middle of the night when a patient comes in and the oxygen saturation is 85 and you’re concerned. And Scott Weingart and I spoke about this on the show as well, how do you make those decisions? The so-called happy hypoxemics versus someone who’s an unhappy hypoxemic. Any thoughts on that?

– Yeah, and I saw your show with Scott Weingart, it was excellent. And you brought up something at the end of the show regarding end of life. And I’d like to end on that when we get to it. So try and remind me.

– Yes, yes.

– Weingart was brilliant. These happy hypoxemics or some people say that the COVID patients some are coming in hot and some are coming in just like talking on their phone. Gattinoni and others, in the pulmonary literature, including an article by Marini and Gattinoni last week in JAMA, we’re urging people to early intubate, and they were doing that because of a very relevant physiological principle, which is if you’re doing this, that sort of situation. They’re worried about wide swings in intrathoracic pressure and that that would create some lung injury. That’s a hypothesis, okay? That is a hypothesis. What if we took those patients though and gave them some form of a sedation approach? Now, we’re inching into pharmacology here about the third piece and gave them something that wasn’t suppressing their respiratory drive, ’cause that the coronavirus can hit the respiratory center in the midbrain or in the ponds. So we don’t want to suppress the respiratory drive with like a benzo or a propofol or a narcotic. But what about like an alpha-2 agonist, clonidine, dexmedetomidine or even an antipsychotic such as haldol or an atypical antipsychotic. These things can sedate and calm somebody in a way that doesn’t suppress their respiratory drive and might actually help them to reduce this whole serious hyperventilation circumstance and calm them down to avoid intubation altogether. So that’s a major thing that I proposed on the front end here is a pharmacological chill effect on the patient to see if they can maintain their breathing and their oxygenation without having to go on the ventilator. Does that make sense at all?

– It does, let me re-understand this so that you can rephrase it again because I think it’s so important. So somebody coming in with what Scott Weingart called the dog panting respirations where they’re just . So there is a component of anxiety, there’s a component of hyperventilation which is a response to the fact that they’re hypoxemic and they’re trying to oxygenate and so they’re increasing their respirations. You’re saying that you can use medications to actually take some of the edge off that without actually damaging the respiratory drive that would then put them in serious trouble, that would then lead to intubation almost inevitably if you do depress that. And you gave a list of a few meds that we might use. Can you again repeat that list again and explain why that’s important?

– Imagine two columns of drugs, and one column is standard things, you put people on when they’re on the ventilator. Propofol, fentanyl and even nowadays there was just a paper last week on neurological complications in COVID and 86% of this French co-work was on benzodiazepines. This is very scary to me and we’re gonna have to move into that in a second here. But these are drugs that we use to deeply sedate somebody on a ventilator, propofol, narcotics, benzos. The second column of drugs is things like alpha-2 agonist and anti-psychotics that I use on the front end of mechanical ventilation or before I intubate somebody, because they allow the patient to be calmer, tolerate perhaps BiPAP, high flow, not get claustrophobic and yet do not contribute to suppressing their respiratory drive at all. That second list is also the same drugs that I transition somebody to on the back end of mechanical ventilation. So either early before or late at the end, same list, non respiratory suppressant drugs, which can help you a tremendous amount on the front end, the back end of the ventilator.

– So this makes perfect sense. So you start using those drugs to try to see, well, can you first of all avoid ventilation, mechanical ventilation? If you can’t, at least you know that’s a shot that you tried. Then they go to the propofol, the heavier sedatives while they’re ventilated for a period, and then as you’re bringing them out, you would then switch back to that approach because it allows the anxiolysis, breaking that anxiety without affecting the respiratory drive as much or the level of consciousness.

– Yes, and it is the overall exposure to these GABA-urgent drugs and the amount of time somebody is in delirium and a coma is the strongest predictor of the acquisition of this PICS Dementia. So I’m thinking to myself, I’ve got this big camera lens in my head as a doctor, I’m thinking, I need to protect this patient from too much exposure, i.e, many days of delirium and drug exposure and so on the front end I will try and avoid the ventilator, which begets those drugs by using these safer approaches if I can. And if that doesn’t work, then fine. I tried it, it didn’t work. Now I’m gonna intubate the patient. And then every single day the sun comes up I’m gonna ask myself a question again with SATs and SBTs spontaneous awakening trials and spontaneous breathing trials, can I turn these things off and make that transition? So that’s a general movement that we use. And that’s basically the A-F bundle in a nutshell and it’s also one of the things I think that we have kind of ditched 20 years of data in three months, which is something we all have to kind of regroup and get back to some basics.

– Okay, incredibly important. And I wanna clarify one thing. PICS is Post Intensive Care Syndrome, this cognitive dysfunction, correct?

– Right, it is. And so Post Intensive Care Syndrome, PICS, you could read about that on our website if anybody wants to, we’re not selling you anything there, but That’s the website for our center, the CIBS or CIBS Center. And we got a whole section for patients and families on PICS. One more thing before we leave the ventilator and the types of lung injury, this idea of having a low, a high compliance, low elasticity, the L type of lung, those patients were included in ARDSNet high, low tidal volume studies, et cetera. It’s not as if this is a new disease that was never included in the prior studies, and that’s why I’m saying that we should stick to what we know and don’t act as though this new talking on your phone hypoxemia is something totally new. They were always included in other trials but we don’t know the breakdown of that, but they were there from the get go.

– Okay, so a lot here and that’s very important. Number one is that there are people who argue this is so different that we have to throw all this stuff out and go with just by flying by the seat of our pants and learn as we go. But what you’re saying is, no, actually this same type of patient was included in the trials that show that our current approach is once you’re ventilated, still apply and to throw out all that learning is a mistake. Especially when we’re stressed and we’re overwhelmed and we’re afraid, which I think is a piece of it. And the other thing I wanna make sure that we point out that you said that was very important is the area under the curve, in other words, the total amount of benzodiazepines and sedation that you’re giving actually has a direct correlation to outcomes for these patients. It’s almost the way I would think about it from what you told me, and tell me if I’m wrong, is it’s almost like radiation. If you’re living outside of Chernobyl, the longer you’re there exposed to whatever it is that’s dangerous, the worse your outcome’s gonna be. And that could be the same with sedation?

– Yes, I love the way you put that. And there’s gotta be somebody watching this right now saying, “Ely, that nobody’s talking about, “the degree of hypoxemia we’re seeing “is out of proportion to prior.” And I want to completely affirm that situation. There’s no question that they’re two huge differences that we are seeing about this, and they are the general degree of hypoxemia and the duration of this respiratory illness is much longer and greater. What I’m saying is even acknowledging that, degree of hypoxemia and the duration is to say that that does not mean that we throw out all that we knew over the past 20 years. So I’m acknowledging the differences, but saying that they are not qualitatively different as much as quantitatively different insight. Therefore, we keep our evidence-based intact.

– It makes sense. And we’ll definitely talk more about that ’cause I think it’s important. And these are broad strokes, Wes. So many people are getting into the weeds of this. So how do we do? And there’s so much misinformation floating around. There’s a lot of anecdote, but you’re saying, look, we have a body of actual peer reviewed evidence that applies to this even in the setting of, okay it’s severe hypoxemia and the duration is long and all of that. So now walk me through, so what’s your thinking now? How do we go about this?

– Okay, so let’s get into some this, let’s get into some of this pharmacology. Let’s talk a little history, and I think for the audience, you’ll see me put on my nerd glasses here, ’cause I’ve got something typed out here to go through with you. I want to talk about two things. One is the Law of the Gift and I’m gonna tell you what I mean by that. And the second is what that means for us in terms of clinicians. The Law of the Gift is a more human than medical, but the Law of the Gift is that a true gift like love, the more we give love, the more we get love. Love is one of these paradoxical things that the more we give of ourselves to other people, the bigger our heart gets. It’s kind of like that Grinch thing when he finally learns to care about other people and his heart grows like crazy at the end of The Grinch, right? Well, as a clinician, as a healthcare provider, part of the way I think at the bedside is, you know what? This is not easy. What I’m talking about doing, waking people up, getting them out of a bed, walking them. This whole A-F bundle thing, it requires a lot of us and it requires a lot of attention to the patient, a lot of energy on our part and it would be way easier to sedate the person, keep them in a coma. It was a disaster yesterday, today seems calm. The sats are finally 92, I’m gonna leave it as is. No question, but if you go back to the Law of the Gift, I’ve got to give of myself as a clinician and I’m gonna have to really use our whole team to let this patient try and wake up and to try and get them out of the bed and to stop these sedatives. And in order for you to buy in on that, to think, “Okay, well that’s a hell of a lot more work “than keeping them sedated.” Then you have to know the evidence base. So I’d like to take the audience through the evidence base on this real briefly and just let everybody try and digest. If you want to go look this up, go look it up, but I’ll give you the nutshell on what we learned between 2005 all the way to 2012 and I’m gonna do it with just a few studies, is that okay?

– That’s brilliant and I wanna say that Law of the Gift is such a beautiful way to frame this and this idea that the more you give, the more you get, right? Now, if only the administration would hear that when it comes to supporting clinicians and nurses and respiratory therapists and dieticians and those on the front, I think they will get it after this ’cause they’re gonna hear us loud, please continue.

– I hope so.

– Yeah.

– Okay, so let’s go to 2006. A paper came out from our group by Pratik Pandharipande. Pratik came to me, he’s a professor now, and Pratik is now one of the co-directors of our center with me. The two of us do it together. And he was green behind the gills. He didn’t know how to do research, and he’ll laugh when he sees this, but the dean, Dean Bolzer sent him to me and said, “Wes, can you mentor this young researcher?” And so I did, and I said, “Pratik, I have this hypothesis “that if we can get people away from GABA-urgent drugs, “that we will do a better job for our patients.” So how are we gonna do that? I said, “Well, we got to have “to set up randomized controlled trials “to look at alternatives to things like benzodiazepines.” So the first paper we published in 2006 is always shown at big meetings. It was a paper in anesthesiology about the risk of lorazepam leading to delirium. And there’s this famous graph showing that more lorazepam skyrockets in delirium, those response. And everybody should say, “Duh, we know benzos create delirium.” But it just hadn’t been shown quantitatively. So we showed it, it’s the graph always show in 2006. Meanwhile, we were doing a randomized trial called the MENDS study, M-E-N-D-S, like mending the brain. So in 2007, we published the MENDS study, M-E-N-D-S in JAMA, first randomized trial ever to use delirium as a primary outcome. And what we did was we randomized to an alpha-2 agonist versus the benzodiazepine, lorazepam. And I actually didn’t think that the alpha-2 approach was gonna be as good at keeping our patients as safe as keeping the patients on the benzo because I didn’t think we could get them deep enough. By the way, this is not an advertisement for any specific drug, and I have received honorary in the past, I’ll acknowledge that, from the companies that used to make decks, it’s generic now, but you’ll see where I’m gonna go with this. I’m not giving you a commercial for any one drug, okay? And in the end I’ll prove that by a statement. But anyway, in this study we proved that the alpha-2 plus fentanyl approach got us more accurately at the level of sedation we wanted, than did the benzo-fentanyl approach. And it’s critical, Zubin, that we make this point ’cause I got some questions to me on Twitter this week, “Can you adequately get somebody deeply sedated “with an alpha-2 approach or an antipsychotic?” And my answer was, if you use a narcotic along with it, this combo gets you where you wanna go, but true enough, if you need them to be deeper like arras minus three or something, then you absolutely have to have a combination. Any questions from you about that sort of thing so far?

– No, that makes sense because when I was running ICU patients years ago, it was fentanyl-Versed. That was the combo. And I saw the delirium and I saw the outcomes of that. And people were talking about decks, but it was still like, “Wow, can you really do that?” So this is really interesting.

– So in the ’90s, there were ads in all of our journals that said, infused Versed, increased calm, or keep the patient calm, comfortable, asleep, et cetera. A, it’s not sleep.

– Yeah.

– These drugs do not create restful sleep. They create micro arousals and no slow wave sleep. They actually suppress your slow wave sleep. So, two nights ago I was up multiple nights in a row. We were getting brains donated from COVID patients for our research, and that was an amazing journey with these deceased patients. We can talk about that at the end as well, but I was super tired until last night and I finally got eight hours sleep last night and I feel like a completely different person. Imagine though, if you were in the unit sick and going for multiple days in a row on these drugs, having your slow wave sleep suppressed, how hard that would be for your body, right?

– Yeah, yeah. Again, we don’t necessarily have that at the top of our mind because we’re just busy with everything else and trying to, like you said, it’s, very much easier to have someone on a dose of Versed that keeps them calm and easy to care for, than having to put in that extra work to allow different levels of arousal and spontaneous awakening.

– I wanted to say that linking back to the pathology, so as a physician, somebody comes in with this ARDS pathology, diffuse alveolar damage, my initial thought is, oh, I’ve got a clavicle to diaphragm problem. It’s a lung issue, I need to focus on the lung. What I’m asking the audience to do is to say to yourself, This is not just a lung issue. This is a total body disease and if I’m gonna care for this human being, using the Law of the Gift, then I’ve got to give up myself to pay attention to the muscles, the nerves, the brain, all of the other pieces, and I can not just stay focused on the ventilator and the lung or else I’m doing a disservice to this human being.

– Again, it bears repeating and repeating and repeating. And I think a lot of people will go back into the unit after seeing this with a different mindset, and hopefully it lasts. It’s very hard because human beings tend to fatigue which is why you need protocols and processes and the things that people love to–

– So let’s keep going with the literature then. So in 2006, anesthesia increased risk from benzos, 2007, MENDS, JAMA, better with an approach that avoided benzos, 2008, our paper in the Lancet ABC trial. In that study, we proved that using a daily shutoff of these drugs, in very sick people, these were people with APACHE II scores of 27. For the lay audience, that’s sick as crap on the ventilator shock, et cetera, death store. In those sick people, we shut these drugs off every single day, just like the COVID patients are that sick, and we improve survival at the end of one year instead of being a 50% death rate, there was only a 35% death rate and the only thing we did differently between the two groups was they got half the amount of sedation, propofol and benzos as the other group did and 15% more likely to live at the end of the year. That’s huge.

– I mean that’s massive. And it tells you, again, that there’s an iatrogenic, caused by us, component to this, and getting back to the Law of the Gift, now it’s almost like a do no harm, hippocratic oath issue. If we know this, which your data is saying that we’re starting to know this, then it is really incumbent on us to not only recognize it, but train people to make sure they understand how to deal with that.

– Exactly, now let’s keep moving along. So then that’s 2006, seven, eight. 2009, JAMA published the publication called SEDCOM, S-E-D-C-O-M, Rich Riker, first author, much larger trial than our original men’s study showing once again that this time Versed versus the alpha-2 approach and the avoidance of benzos. I’m not saying pro alpha-2, I’m saying avoidance of benzos. Avoiding the benzo last time on the vent, better communication, better overall brain function, et cetera. So we found out through these trials that less sedation, avoidance of benzos was a safer approach for patients. And actually right after this study, SEDCOM, I was asked to do a pro-con for chest in the journal and I actually looked the literature up and at that time, around 2010, there had been 30 trials, 30 randomized controlled trials of a benzo versus something else. And I was actually stunned to find out, guess how many times in those 30 comparisons the benzo was as good or better than the comparison?

– I’m gonna suspect by the way you’re framing it, zero?

– Good say.

– Yeah.

– Not one time, even statistically you’d ask yourself, statistically 30 times by chance alone, you have the benzo winning at once or twice. Not once did the benzo win. So that’s when I began to get very convinced that we had been doing our patients something wrong to give them these benzos over the years.

– Well, real quick question, why are we so attached to benzos? What is seductive about them? Just so people can understand.

– Well, what’s seductive is that it’s super easy to get somebody calm and quiet and minding their manners in their bed to keep the sheet nicely tucked around the human being and to have a tidy circumstance in the unit where somebody is not able to pull out their lines and tubes. That’s very appealing, I mean, it is all the surface. That’s an appealing thing. In fact, many nurses have told me, “I went into ICU medicine “so that I could have a comatose patient.”

– Yeah, yeah, yeah. So then let me ask a related question. In the studies that you’ve done on benzos versus other things, do the other things lead to more self extubation, more lines pulled out, more of that other drama?

– I love that you asked that. In the ABC trial, I’ll keep my answers evidence-based, not my opinion. In the ABC trial, we did see an increase in the self extubations once we had these people’s drugs stopped every day. But guess what? We did not see an increase in reintubation.

– What!

– So the patients were right. The patients basically said, “Screw you, I’m ready. “You don’t know I’m ready. “So I’m pulling this thing out.” And there was an increase in that, but not an increase in reintubations, which means it was our problem.

– Oh my God! It doesn’t surprise me at all because every time one of my patients would self extubate, they didn’t get reintubated because they were like, “You don’t know,” and they were right. Okay, this is a humbling piece of wisdom, Wes. So keep going, sorry.

– Okay, so just for the audience, in the literature, self extubations usually equate to about a 50% reintubation rate. So it’s kind of a coin toss when you remove. So in COVID right now when you’re thinking, I gotta get my PPE on, I gotta get in the room, whatever, for self extubation, one of the things we were worried if they’re outside the room and they’re thinking, “If I lighten the sedation, they might self extubate “and if they self extubate, “I remember what it was like for John three days ago “when he was crashing and burning, “and I don’t want him to go through that again.” I mean, let’s call it a spade a spade. We are trying to be benevolent, okay? But benevolence is different from beneficence. Benevolence is the desire to do good and beneficence is the actual doing good. So your desire to do good by keeping this person on sedation and prevent reintubation isn’t necessarily doing them good if they’re prolonged sedation is creating more PICS, muscle nerve disease and brain disease. I can’t tell you what to do at the bedside. I can just arm you with literature so that you can make your own best decisions.

– So let me ask a related question to that, how many haters do you have about this? So this is your passion, this is your life’s work. How many people come at you, “Wes, no, you’re wrong for these reasons. “This is dangerous thinking, “you need to stop talking about this.”

– Yeah, across the years I’ve had a ton of people say that that was wrong, et cetera. But after a while, when you take MENDS and ADC and SEDCOM and then I didn’t even get to the 2010 NONSEDA study by Strum, that was published in Lancet, come back to it in a second, and then 2012 was PRODEX, MIDEX. All these studies, this is now thousands of people and randomized controlled trials, which all said the same thing. Lightening it up as you move along in the ventilator management is safer for the patient. It does not mean that the day you intubate them, and the day they’re crashing, that you don’t get them deep and control the circumstance. What it means is that if this is the arch of critical illness and you’re getting sicker, sicker, sicker, it means as soon as you get the person calm down and they’re getting things stabilized right then is when you have to start removing things and saying, “Is it okay to remove it?” If the patient proves to you that it’s not safe, fine, add it back. But you have to ask the question by removing it to see if it is still required. And that is the essence of ICU liberation.

– That makes perfect sense. That makes perfect sense.

– Now, there’s something interesting that happened. So after 2012 and PRODEX, MIDEX and all of that, that’s when the bundle was born and we went into the ABCDEFs, we went all over and study 25,000 people and we showed that better compliance with the bundle translated into just like in the individual trials, better survival, less time on the vent, less time in the ICU, less ICU readmissions, et cetera, okay? Now, when that happened, the overall amount of sedation globally kind of reduced. We kind of started using generally lighter sedative approach, more mobilization, more out of the bed, even on the vent. And that’s what happened. So just recently somebody out there is saying, “Ely, you’re not being honest with us ’cause in 2019 “we had the SPICE III study and the NONSEDA study “by Shehabi and Olsen.” These are two new England journal papers, okay? In both of those new England papers, we did not see a difference between the light sedation group and the, between the non sedation group and these usual care. So I need to explain this, Zubin, okay?

– Yeah.

– All right. When you change the culture of ICU to lighter sedation, then let’s say this is heavy sedation and this is light sedation. When you take the previous 2006, seven, eight, nine, 10 studies, and you lower the overall usual care to lighter, so now your control group is light here and your intervention group, there’s not as much of a difference between the two groups. You follow me?

– Yeah, yeah.

– You don’t see a change. It’s like, I’ll give you two other examples. Six versus 12 CCs per kg tidal volume, okay? When Roy Brower and the ARDSNet designed that study, they didn’t choose six versus eight. They didn’t choose six versus nine. They chose six versus 12 and you can see a difference, okay? And we know that six is better. It’s been proven over and over. If you now redid ARDSNet and compared six versus eight, you probably wouldn’t see a difference, okay? So when you redo these sedation studies, before it was heavy sedation, light sedation, this was the treatment group, now it’s heavy versus moderate. So these recent SPICE III and NONSEDA studies are technically negative, but I don’t think it does anything to debunk all that we learned between 2006 and 2012.

– So you’re saying these culture changes in ICU that have changed the thresholds for what you’re comparing actually, make it harder to detect a difference because the treatment group and the control group were actually closer together.

– And I’ll give you another great example. I gave you ARDSNet, but let’s give the audience something they can really hang their hat on here. Go back to 2001 when Manny Rivers designed the Early Goal-Directed Therapy Study, EGDT, where they took people in the ED who had sepsis and they randomized them into two groups. One they got very aggressive resuscitation and one they got usual care, which at the time in 2001 was crap for resuscitation, okay? A leader or something. You double or triple the amount of resuscitation, and Manny saw a huge difference in survival with early goal-directed therapy. That changed globally, the aggressivity with which we resuscitate our sepsis patients. So that 15 years later when Derek Angus redid that study, it’s now called the study called Process published in the new England, that was in, what year was that? I guess it was 2014, so 15 years later, or 13 years later, Process was negative. They didn’t see a difference. And what we know is that, was Manny wrong originally? Or have we revamped the way we resuscitate people so that now we don’t see a difference in these intervention groups? And many people believe that Process was a neutral study because of this changing culture that took place over a decade and that’s the only reason I think that SPICE III, and as a main reason, I think SPICE III and NONSEDA we’re neutral here in the New England last year.

– I can think of an analogy here when you look at antidepressants like SSRI, is if you run those trials now versus placebo, they will not be better than placebo. And the reason may not be that the drugs have changed, the reason is that the expectation of placebo is so much higher that placebo has gotten stronger, the effect has gotten stronger, and this has actually been documented. So it’s really interesting and these are the subtleties of evidence-based medicine that you have to talk about if you’re gonna understand really what this trial data means.

– That’s really interesting. So yeah, I hope that the audience can hear that there are ways forward here. So when you’re thinking about putting somebody on the ventilator, maybe you can use noninvasive, a high flow or a mask and give them non respiratory suppressant sedative approaches to see if they can avoid going on the blower. If that fails and you put somebody on the ventilator, deeply sedate them for a moment in time, it could be 12 hours, it could be a day. Every time the sun comes up, let’s try and transition them to either non-sedation or to something that is not as respiratory suppressive, using that category of drugs, the alpha-2s, clonidine, dexmedetomidine or even antipsychotics. I do not think that inherently that, for example, I told you I wasn’t giving you a drug advertisement earlier. I do not think inherently that dexmedetomidine, for example, is safer than propofol. I don’t. I think that if you use these drugs for a short period of time and constrain the overall exposure of the patient, I think they’re safe. These are all safe approaches. What is dangerous is when we give these drugs for too long and we give the drugs that build up and expand their half-life. Propofol does not keep a short half-life once you’re on it for three or four days. And there’s obviously the risk for lipid-laden plasma and serum, i.e, propofol infusion syndrome. So let’s just be careful how we use these very, very potent agents in these patients.

– That makes sense, and again, I think everything that you’ve told us and taken us on this ride is gonna be very important to understand where we are now with dealing with sedation in the ICU, keeping people safe, even the decision to ventilate. We’ve gone through all that. Now, one thing I wanna see, if there’s anything else you wanna talk about with that, but then I promised you and the audience that we’d come back to end of life too because I think that’s important.

– Sure, let’s close on two last topics and we’ll wrap it up in the next couple of minutes. One, I want people to know that we are absolutely committed as investigators, as physician scientists, to studying COVID and on our website we actually have a COVID website that shows you these research projects we built. So just real quickly, the CIBS Center is now doing this COVID D study. I told you using that @WesElyMD handle, we got 140 something sites, 25 countries, et cetera. We’re also doing a study where we’re gonna learn what the virus does to the brain of humans. And so some extremely generous patients and families are helping us create a repository. This is called our BRAIN-2 study. We have a study called Isolate ICU, where we’re actually trying to study Mina Nordness. Mina Nordness is a surgeon here, and she’s setting up a study of the effect of isolation during this COVID pandemic on healthcare workers, families, and patients as well. The person doing BRAIN-2 is a surgeon here too named Mayur Patel, he’s an amazing trauma surgeon and investigator with the CIBS Center. We have another study called Orchid Bud. Orchid is the randomized trial that the Pedal Network is doing of hydroxychloroquine versus placebo. And the Bud part was led by Jen Han and we’re doing longterm cognitive outcomes of COVID patients to see, does COVID create this acquired dementia that we know exist after critical illness? And those are the main things we’re doing. I hope that that’s of interest to people and let us know if we can be of any help to anybody out there.

– And so we’ll include the links to your to your site and everything that’ll have all that.

– Sure, sure. Okay, now I have this sentence, I want to read it to you. The question about end of life and the use of ventilators is not, what’s the value of a particular person’s life? We’re talking about instead, what’s the value of a treatment for an infinitely valuable human being in their particular circumstances? So a lot of people are wondering, how do we ration the ventilator? And is there ever a role for reallocating a ventilator from one patient that we don’t think is benefiting, to another patient? And what about withdrawal of life and withdrawal support, end of life care? I just wanted to say that I thought that what you and Weingart touched on was beautiful, and I thought that we all as a community should acknowledge that never are we trying to say that any amount of disease reduces the infinite value of a human being and a human life, no. Every single person has the same inestimable in priceless value and worth. But as a society, we are having to make some decisions about resource use and allocation. And that’s why I think it’s very good that there are triage teams. If I’m at the bedside, I don’t wanna be the one choosing between two patients on the ventilator. I think an independent triage team can make these decisions and there will be subjective differences between our institutions on how those triage teams and guidelines are put into place. But all of them, I think, are doing their best to acknowledge this humanity, the infinite value of a human being and weigh out the societal value and situations that we’re faced with these days. So those are a couple of initial comments. What are your thoughts?

– Yeah, I’m with you. And I think it gets to this thing that I talk about a lot, which is empathy versus compassion. So empathy is a narrow spotlight on the infinite worth of an individual human being and saying, “I feel you, I feel your suffering, “I feel your family’s suffering.” And it’s a beautiful way to connect with people. It’s a great way to connect with your family, but it may not be the best approach for a broader problem where you have limited resources and you have to think about a group of people or a society of people. And that’s when compassion, which is rational love in the face of suffering. And saying, “Okay, yes, you are worth a lot. “But looking at the broader picture, “what is your quality of life gonna be? “What is your chance of surviving gonna be?” And could it be that those resources may be better deployed to save somebody who is more likely to benefit from those resources instead of trying to throw the same solution at everybody?

– That’s really interesting. I love the way you put that. Compassion, com-passio, suffer with. And so what you’re saying is that we are all suffering as a community, as a society, and so that compassion means to suffer with all of us together. I think that makes a lot of sense and it is what’s behind some of these protocols. The word mercy comes to mind here, and mercy is diving into the chaos of another person’s life and then providing lifting and healing. And what we have to remember here is that we can provide lifting and healing even when we can’t cure. And so with my patients, with our patients who are suffering from COVID, I can’t give them a cure ’cause I have no antiviral that’s been proven to do that with this coronavirus, but I can provide a heck of a lot of lifting and healing depending on the way that I make these different decisions, are you going in a ventilator, are you not, et cetera. I will leave you with one final thing about this ventilator situation, which is this, when I enter into a contract with a patient and it is a patient-physician, I’ll say covenant. When I enter into a covenant with a patient, they are then my primary concern and I do not think that I would ever make a decision to reallocate for my individual patient, the ventilator to another human being. Once I’ve committed to this person and I think that the ventilator is appropriate an ordinary care for that human being, I will then make the decision about whether or not to remove that life support based upon what I think the risk and the benefit is, the proportionate, disproportionate worth of that, for that individual person. I would not say, “Betty over there deserves the ventilator more than John. “So John, I’m taking the ventilator from you “to reallocate it to Betty.” No, instead I’m saying, “John, I am with you. “I’m with you,” that’s empathy. “I’m with you, I have compassion and love for you and mercy. “I wanna lift and heal you. “At this time, John and family, “I no longer think the ventilator is of value. “I no longer think this ventilator is prolonging his life in a meaningful way.” And therefore, we can make a decision based on his own thoughts and values, whether or not this life support should be removed at this time. But notice I’m dealing with an individual person and his values and preferences at that moment.

– It brings to mind a mentor of mine, Norman Rizk at Stanford, who’s director of critical care there, and really good guy. He used to tell patients, “At this point, I feel that we’re doing things “to your loved one rather than for your loved one.” And I think it’s time we really did things for your loved one. And so, again, Wes, that was a beautiful way to wrap this up. I wish we had more recording space on our card or I go even longer because I’ve learned so much and it’s a true honor to be in the presence of someone who is not just, knows his stuff, has done the primary research, but is truly passionate and committed to fellow human beings from both compassion and empathy and mercy. And that’s why it’s such a joy to talk to you. And I’m so thrilled you could come back. Will you come back again and talk more about this stuff?”

– If I have any way to help, maybe so, but people are probably tired of hearing me at this point, so you let me know when you think there’s value in it.

– We will definitely do that, and people will let us know in the comments. Z-PAC, please do me a favor, share this episode, we will put links in to Wes’s resources. This is so important, actually at this time when we’re taking care of these very sick patients in the ICU and beyond, that we continue to rely on what we’ve learned over the years through hard work and research of real pioneers in this space, like Wes and others who, and his team that have really done this work. Okay, guys? So do me a favor, subscribe to the show, do all that other stuff. But really more importantly, share this episode and we out, peace.

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