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COVID-19 survivors who experience severe critical illness are at risk even when they leave the ICU. Long COVID is becoming recognized as a widespread problem, resulting in lower quality of life and productivity. Ludwig H. Lin, MD, is joined by E. Wesley Ely, MD, MHP, MCCM, to discuss the range of symptoms encompassing long COVID, as well as the latest research and treatment. Dr. Ely is a subspecialist in pulmonary and critical care medicine who conducts patient-oriented health services research as a professor of medicine in the Division of Allergy, Pulmonary, and Critical Care Medicine at Vanderbilt University Medical Center in Nashville, Tennessee, USA. He is a practicing intensivist and the author of Every Deep-Drawn Breath: A Critical Care Doctor on Healing, Recovery, and Transforming Medicine in the ICU. As associate director for research for the VA Tennessee Valley Geriatric Research Education and Clinical Center, his focus is on geriatric ICU care.
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Dr. Lin: Hello, and welcome to the Society of Critical Care Medicine Podcast. I’m your host, Dr. Ludwig Lin. Today, I’ll be speaking with Dr. Wes Ely and we’ll be talking about long COVID. Dr. Ely is the Liddle Endowed Chair in Medicine, a physician-scientist, and tenured professor at Vanderbilt University Medical Center. He is the associate director of aging research for the Tennessee Valley Veterans Affairs GRECC in Nashville, Tennessee. He is the founder and codirector of the Critical Illness, Brain Dysfunction, and Survivorship (CIBS) Center, and a pioneer in the investigation of delirium and long-term cognitive outcomes, including dementia in survivors of critical illness. Dr. Ely is the author of Every Deep-Drawn Breath, from which he is donating 100% of the net proceeds to help COVID survivors and family members rebuild their lives. I would like to, first of all, thank Dr. Ely and welcome him, and make sure that we discuss any disclosures. Dr. Ely?
Dr. Ely: Fantastic. Dr. Lin, thanks for having me, and everybody, thanks for taking time out of your busy day. I think we’re going to have a very interesting discussion. I do not have any disclosures with regard to companies that make drugs for long COVID, etc. I did do a research project that designed and ran the original COV-BARRIER study of baricitinib for acute COVID, which is now FDA approved. But I did not take any money for that project. I have no consultancies with Eli Lilly and don’t have any stock in the company, etc., so I have no financial conflicts with that topic.
Dr. Lin: Great. Thank you for stating that. Let’s get the show on the road. I know that there are lots of people out there who are interested, and this is going to be a great, educational, and enlightening conversation. Let’s just start with the basics. Let’s talk about nomenclature and definition. I read somewhere that maybe we should call long COVID PASC now, post-acute sequelae of COVID. Let me ask you what you prefer, what you think of as long COVID, and we’ll go from there.
Dr. Ely: Sure. Fantastic. I think of long COVID as a syndrome, I’m going to give you kind of a double answer here, a syndrome that occurs in people three months or longer after the acute illness, which is multifactorial, multiorgan system involved. We’ll get into that in a minute. I think of the name better as long COVID than PASC. The post-acute sequelae of COVID, PASC, is more of a research term. The NIH and others have come up with this term, PASC. I think that we need to, as part of our social consciousness and the justice approach of addressing this as a public health issue and letting the patients have a voice, they came up with this term long COVID. I think it fits great with common parlance, so I call it long COVID all the time, and I try to avoid calling it PASC actually.
Dr. Lin: Oh, that’s really good to know. Your experience is that our patients feel more comfortable with that term.
Dr. Ely: That’s what I’m saying. I think that the patients and the advocacy groups strongly, strongly prefer the term long COVID. They’ve made it very, very clear. It’s just a more universal term because people aren’t used to using acronyms like that out in the regular world. Doctors and scientists are, but people who are not in medicine are not. The words long COVID make a lot of sense to people because it’s a long version of COVID. It’s going on in their life, and it’s just self-explanatory. I use that even in my grants, my scientific grants. I’m writing an NIH grant right now, and at the very beginning, I mentioned PASC. And I say, “From now on in this grant, we’re calling this long COVID.”
Dr. Lin: Got it. What would you consider are the diagnostic criteria fulfilling long COVID?
Dr. Ely: I think the diagnostic criteria fulfilling long COVID are that, about 90 days or longer after your acute event, you are having intermittent and or consistent problems, mainly with your brain, the way you’re thinking, cardiovascular and autonomic problems, meaning rapid heart rate, problems with dizziness, extreme fatigue (“fatigue” doesn’t really do it justice). These patients experience something that is so far beyond that they get completely zapped of any ability to carry on a normal daily life. They refer to it as PEM, post-exertional malaise.
But post-exertional malaise is not just a physical catastrophe for them, it’s a mental catastrophe too. The brain and the body get so exhausted that they really can’t function in their daily life, their jobs, their interactions with human beings. Those are the main things that go on with long COVID. But there are over 200 symptoms, so we can’t get into the whole list here. But mainly brain, cardiovascular, dysautonomia, dizziness, GI problems, that’s what long COVID looks like to people on a regular basis.
Dr. Lin: Do you have an archetypical patient presentation that you think of when you think of long COVID?
Dr. Ely: Yeah. I’ll give you an example. I wrote a piece last week in STAT News called “The Haunting Brain Science of Long COVID.” Here is a 24-year-old man. He’s an engineer. He used to work for Tesla, and I think he’s a classic case of long COVID. He got COVID last May. He did not have any problems for about a month or so, and then in June, July, and August, he started having ridiculous problems with headaches and inability to think at work. As an engineer, he couldn’t go back in the lab anymore. If he did go back to the lab, it would knock him out for four or five days in terms of just cognition. He couldn’t come up with words. He was having a tremendous problem communicating and doing the science that he normally was able to do all the time. This is a person who had no previous disability at all and, in addition, he was a great athlete. He used to ride bikes two or three thousand feet in elevation for two or three hours at a time; he can barely even go up a hill at this point. Even just to wash his car knocks him out for two days. We’re already now in February, March, and he’s still not over this.
He is a real classic case of long COVID. He’s really scared. He doesn’t know what the rest of his life is going to look like, and I’m hoping for him that he can rest his way through this. He’s used to working his way through it, but people can’t rehab their way through this, they have to rest. That’s because we think it’s a mitochondrial disease as well as an autonomic nervous system disease and an endovascular disease. We don’t really know how to help these people yet. There are no proven medical treatments. But this patient is a very classic case.
Dr. Lin: That sounds quite intense. I think a lot of us in critical care like to be systematic and organizing the way we think about some things. I’m going to try this one on you. Could you go through the different organ systems and tell us what tends to affect them in terms of long COVID? So, neuro, cardiac, pulmonary, GI, endocrine, renal.
Dr. Ely: Yeah. Let’s start with neuro, let’s start with the brain. I’m going to read a paragraph of a patient here and I just want the listeners to listen to this man’s story. This is a man in his early 50s. This is out of Every Deep-Drawn Breath. This is in a chapter called “Spreading the Word.” Listen to this paragraph and think about making a differential diagnosis. He ended up taking a two-year disability leave to get the medical support he needed after his acute illness. Toward the end of that time, when he was preparing to return to his job, he began to feel encouraged. His wife’s voice lifted. He went from feeling total despair to finding hope again.
She recalled the day the family went to Chicago to shop for some work clothes. Walking through the department store, he got sidetracked, as was common by this time, and decided to buy a 15-foot long stainless steel countertop that they didn’t need. His wife remembered her confusion. He bought the racket straps to tie it to the top of the car, then struggled. This is a guy she said who grew up on a farm, a mechanical engineer, and he couldn’t figure out how to work the straps. Her voice sank. It caused him a lot of irritation. I guess that happened a lot back then. I wasn’t sure if the countertop ever made it home with him. It wasn’t the point of the story, but I imagine it in the parking lot, heaved off the car and discarded, just one more reminder of a life gone askew.
The reason I read that story to you and for the listeners to hear is that he has another form of acute, rapidly acquired dementia called PICS, post-intensive care syndrome. He had necrotizing fasciitis of his elbow, a perfectly healthy man before that, and ended up with brain dysfunction after a month-long illness. Now, long COVID patients have the exact same thing happen to them except instead of the ICU, it’s just this viral illness of COVID. So what’s going on?
What’s happening is that the blood vessels in the brain are having endothelial damage, and we know in COVID that endothelium has ACE2 receptors. The virus is attacking those ACE2 receptors, and then we’re having a leaky blood-brain barrier. It’s not as much that the virus is getting in and attacking the neurons, but the virus gets in and attacks the glial cells, astrocytes, microglia, etc. Those glial cells are what support the neurons. When the neurons don’t have this support structure, think of it as the nurturing environment to keep the neurons healthy and happy, then they go south, they have a tremendous problem. So the person starts having issues with memory, executive dysfunction, processing speed, all kinds of neurocognitive deficits, exactly the same kind that this patient had after post-intensive care syndrome.
The end of my answer here is that what’s happening in the brain across different types of rapidly acquired dementias, which we refer to as ADRD, Alzheimer disease and related dementias. ADRD is NIH’s term to allow diseases that cause rapidly acquired brain dysfunction into the camp of dementia. Regardless of what the original inciting event was, the downstream phenotype looks like these two patients.
Dr. Lin: Let me ask you a question about this glial cell destruction. Is it reversible?
Dr. Ely: Yeah. I love this topic. I was actually very ignorant about this when I first started doing long-term brain dysfunction research after the ICU. When I was doing my basic science research, I did neutrophil priming. Neutrophils get primed quickly; they dump their azurophilic and basophilic granules quickly and the whole thing’s over with in a couple of hours. The microglia and the brain are completely different beasts. They can get primed and stay primed for eight weeks, 12 weeks, not a day. When these microglia and astrocytes get primed, they start getting extremely overactive, laying down all kinds of scar tissue, if you want to think about it like that; imagine the highways and byways of the brain, and if the cars, the electrical signals, need to get from one place to another, they can’t get there because of downstream axonal injury laid down during this priming process.
So the answer is yes, this is reversible and, even after months of this priming and injury, we can see the brain go through a process of neuroplasticity and heal itself, which is very encouraging because even years after the ICU experience or years after COVID, we think that the neuroscience that we have out there will tell us that the brain can be gotten back again. That’s why we are going to enroll long COVID patients, for example, even from the first wave, into our studies of Paxlovid and immunomodulators, different approaches we’re taking pharmacologically, and we’re not going to exclude people who’ve had it for two years.
Dr. Lin: That sounds great. Do you tend to see cognitive and personality changes? Do you see motor difficulties, coordination? What is the mixture that you see?
Dr. Ely: Patients absolutely experience an array of problems. Cognition I want to address first. Cognition is a big problem because somebody’s trying to exercise their memory and their executive function at work, organize themselves on a computer, get the list accomplished at Costco, they’re trying to do things that will help them be the matriarchs and patriarchs of their family, manage their finances, get directions in a car, and they can’t do any of these things because their organizational abilities are extremely thwarted, and that’s because of frontal lobe problems. They’re also having hippocampal problems, which is memory. We think that the memory and executive dysfunction are tied together very intricately.
Then those things bleed over into the mental health problems that long COVID patients experience, which are basically profound depression and PTSD. Lots of our patients have intractable depression, and some of them are trying all kinds of things, ketamine infusions, transmagnetic cranial stimulation, they’re really just having to grasp at straws here because they feel scared and frustrated and they don’t have immediate answers. So there’s really a cross-class of problems from a CNS perspective, but you also asked about muscles and peripheral nerves, and there’s no doubt that people are experiencing neuropathies. Guillain-Barré is a problem that people experience down the line, and motor and sensory neuropathy is absolutely part of long COVID as well.
Dr. Lin: Okay. What about cardiac? That’s a big topic of discussion.
Dr. Ely: It really is. Just to start with this, we now have at least four different cohorts, and consistency in medicine is one of our linchpins, when we start seeing the same thing over and over again, four cohorts showing that there is this dramatic rise in the likelihood months after COVID of myocardial infarctions, myositis, and also strokes. This endothelialitis, this endothelial dysfunction, microclots, it’s undeniable, it’s absolutely happening, and we’re seeing the odds ratios and hazard ratios in the neighborhood of 1.6, 1.7, so 60% to 70% increase in risk of cardiovascular and cerebrovascular problems.
This also cannot be discussed without talking about postural orthostatic tachycardia syndrome, or POTS, this is a dysautonomia, and that’s obviously part of the cardiovascular problems. The cardiologists are actually getting inundated with these patients. How to handle it, whether it be a beta-blocker or some other way of handling the tachycardia, is very difficult in some patients, and the therapy is not a one-shoe-fits-all; it has to be targeted individually to the patient’s specific needs. The real sad part about the cognitive and the cardiovascular problems is that a lot of long COVID patients don’t read the book on the illnesses, so when they go get tested, they’ll end up just below the thresholds of the abnormalities, for example, on tilt tests, etc.
So when they get just below the threshold, they get looked at by their care provider and they hear, “Um, you’re just kind of abnormal, but you’re not totally abnormal, so I don’t think there’s anything really wrong with you.” Then they leave, feeling very dejected and denied, and there’s a lot of stigma too associated with that because people are acting like they’re making this up. I want to say that they are the experts of their illness. They’re not making it up. It absolutely is real. For many years, we denied ME/CFS and fibromyalgia. I think we’ve just got to acknowledge that we don’t know everything in medicine, and sometimes these people just don’t fit into a tight little diagnostic box.
Dr. Lin: So true. What about the lungs?
Dr. Ely: The lungs are fascinating as well. There are some pretty-well-described xenon studies out of Britain to show that, down the line, weeks and months after COVID, the patients having problems with oxygen transportation. Obviously, the lungs can get destroyed during acute COVID and people can get cryptogenic organizing pneumonitis, or so-called COP, which is like a keloid scar in the lung, if you will. Overabundant, frothy, and loosely formed connective tissue in the lung as a dysregulated healing process that the lung laid down pathologically. That’s one thing. You’ll see that on a chest x-ray, you’ll see it on a CT scan, we treat that with steroids.
But even in the absence of infiltrates, people have these problems with peak Vo2s on cardiopulmonary exercise testing. They’ll have all kinds of problems with this tremendous fatigue and early exhaustion that they used to not have. We’re really starting to think this is maybe a mitochondrial disease. The mitochondria cannot do oxidative phosphorylation, so you’re not getting good oxygen transportation. This is kind of a kissing-cousin disease, if you will, with PICS because we think that post-intensive care syndrome patients have a problem with mitochondria as well. They may have gotten there by a different route, but the downstream issue may have more to do with each other than we knew.
Dr. Lin: What about the GI system? I just saw that Nature Communications published something yesterday about motility issues in long COVID patients.
Dr. Ely: Yeah, the GI tract is absolutely involved. We’ve had lots of patients complaining about anything from irritable bowel syndrome to bloating to profound constipation or diarrhea, either direction. What we know from pathology studies is that there are viral ghosts in the gastrointestinal mucosa. Are those viable viruses that can start proliferating again, that can start reproducing, or are they ghosts creating some sort of delayed or ongoing immunologic response? If you look at the immune mechanism going on with long COVID, it looks like there is ongoing antigenic stimulation, and that antigenic stimulation may very well come from the GI tract, so the GI tract is a key part of the story of long COVID that we do not have adequately worked out just yet.
Dr. Lin: Okay. What about endocrine and renal?
Dr. Ely: No question, the endocrine system can be involved. We see people with anything from like a Hashimoto-type illness, a hypothyroid issue. There are other types of endocrinologic abnormalities and we are seeing autoantibody production. A lot of the rheumatologic diseases have autoantibodies. There was a very nice study looking at lupus-like disease with autoimmunity, I think this was out of Germany, it was a couple of hundred thousand people where there was like a 43% increased risk of new autoimmune diseases in long COVID. A lot of those people end up with endocrine problems. Renal-wise, I can’t cite chapter-and-verse studies saying how the kidneys are involved. They absolutely can be involved, but it’s not been as much of a prominent part of the story as the other things we’ve just been discussing for the past 15 minutes.
Dr. Lin: Thank you so much for that. I think that puts it in a framework that most of us intensivists are used to. Let’s go back and talk about this stigma and this lack of official medical diagnostic validation that patients with long COVID often seem to encounter. What types of confirmatory studies can one do to say, “Okay, we see something”?
Dr. Ely: Let’s start with how we know there’s a stigma. There was a very nice study by Nisreen Alwan out of the UK looking at the prevalence of stigma. It’s absolutely profound, the numbers, over half of people saying that they feel somehow stigmatized, disregarded, denied. This is fascinating too, it’s also with the family members. Family members are dissing the patients as well as friends and professional colleagues. So even within the context of your own family, you might be disbelieved. What we have to first start doing, and this is really about humanism, and that’s one of the things that I really hit on in Every Deep-Drawn Breath, my book that I read from earlier, is that we need to start listening better. We need to start thinking about touch first, technology second.
Think about eye contact, touch, listening to somebody’s story. Instead of saying, “Here’s what’s the matter with you,” I think about switching the preposition to saying, “What matters to you?” Switching “that” with to “to.” So instead of me telling you, “Here’s what’s the matter with you,” or “You don’t have anything wrong with you because you didn’t pass this test, this tilt table test,” or whatever, “Tell me what matters to you.” And they say then, “I can’t play with my grandchildren anymore,” “I can’t do my job,” “I can’t manage my finances,” “I can’t drive a car,” “I’m getting lost,” “I had a wreck.” Then we start realizing, “Oh, this person has a life disability now.” Whether or not they have an abnormality on their CBC or their chem-7, I know there’s something wrong with this person because I heard their story, I took their HPI and their past medical history, and I see that their past medical history does not line up with the way their life is now. Temporally, it all started happening in the weeks and months after COVID. They have a new disease, period. I think that’s where we start.
Then, in the future, we’ll be looking for biomarker panels and other diagnostic tests. But Dr. Lin, we’ve got to start acknowledging that we don’t know everything. It’s a new disease, but it’s a disease that fits in with the pattern over the past century of acknowledging other postviral illnesses. There was postviral illness after the 1918 flu. There’s postviral illnesses after polio. There’s postviral illnesses after Lyme and Borrelia, that’s not a virus, but long Lyme is there and we denied that for a long time. This is a pattern of society and the government doing a very bad job of creating a disability process for people to process Social Security disabilities, disability from their work, etc., and whether it be the medical profession or society, I think we owe it to these people to do a better job this time.
Dr. Lin: I think that’s a call to action that we need to follow, yes. Thank you so much for stating that. I think that’s so important to think about, rather than asking and listing the various confirmatory studies to justify that because the biggest thing is, how are these people feeling when they come to us with a plea for help?
Dr. Ely: I love that you said that. Exactly. It gets down to, Who is the person in front of you? You have to say to yourself, “This is an entire person. I want to serve this person, mind, body, and spirit, all of them.” When we actually look at who the person is and listen to them and hear their story, we cannot deny that their life has been derailed by this problem. We don’t do a good enough job with this because we think, when the diagnostic test doesn’t support it, the science isn’t there. Well, the humanism has to be what we do first.
Dr. Lin: You are talking about something like slow medicine. We talk about slow cooking and slow this, slow farming. You’re talking about actually taking the time and listening to patients. That’s almost revolutionary, I have to say. How do you feel about that?
Dr. Ely: I believe it’s what we have to do. I remember a patient during COVID; he was an inmate, he was a prisoner, and he came in my unit. He was footcuffed to the bed with huge, big shackles. He didn’t even have COVID, he had ARDS and sepsis, but it was during COVID, so no family visitation, etc., which was anti-medicine and wrong. We never can go back to that. I was obsessed with getting those cuffs off him. So, while caring for the antibiotics and the ventilator management and making sure his I:E ratio was right and all of that business, I just kept calling the warden at the prison and making sure that we got these cuffs off. By about four or five hours later, we took the cuffs off, and he lifted his legs up in the bed, pulled his knees up to his chest, and looked at me and nodded. I’ll never forget the look on his face of, “You paid attention to me and I have dignity. I’m a human being.”
What we need to do for long COVID patients is respect their dignity and pay attention to who they are as an entire human being. When we start doing that, we’re going to feel more sense of purpose as physicians, as nurses, as ICU doctors, as people, and our burnout will recede. Right now, we’re burned out because we have these frustrations that we don’t think we know enough. Forget about that. Look at the person. Do the slow medicine, as you just put it, and you’ll find the meaning and the purpose at the bedside that keeps us coming back.
Dr. Lin: I like it. I feel like there are huge chunks that I really need more time to explore, such as potential management strategies, urban myths. But I would like to actually finish up this conversation with this question: What is your priority list of what to do next in terms of how we help people with long COVID? What are the things that you absolutely want to get done?
Dr. Ely: Okay, I’m making this up on the spot. This is not a prepared question. I think if we could do three things, nobody’s ever asked me this question before, it would be a beautiful new day for long COVID. First off, we’re scientists, right? Let’s start with science. We need well-designed, prospective randomized controlled trials. Right now, people are doing junk out there. They’re trying everything because they’re desperate. It’s a nightmare out there. This anecdotal approach is not going to get us the answers we need. We need NIH-funded, VA-funded, foundational-funded prospective RCTs of the different things that we think are the key factors in the story of long COVID, the pathobiology, which are antivirals for the persistence of virus. We need immunomodulatory agents that will quell the immune activation and the prolonged inflammation. We need better science.
Second, we need a better approach to creating a community for these patients, so that they can talk to one another. At the CIBS Center, our Critical Illness, Brain Dysfunction, and Survivorship Center, listeners can find us at icudelirium.org, every day we have support groups so our patients get on from all over the country and the world onto our COVID, long COVID, spouse COVID, and PICS, if you will too, support groups. They’re on Zoom, Microsoft Teams. We think that it’s saving their lives. They’re telling us, “I would’ve killed myself but now I have a community.” They share with each other, they cry with each other, they yell with each other, and they help each other figure out answers in their lives and make a way forward. I think we’ve got to do that across the nation, across the world, create these communities.
The third thing is that people have to have a way forward financially. When they lose their job, I mean, I can’t tell you how many of our families end up homeless. They first lose their electricity, then they lose their house, and they lose their life flow to their family, which is their income, and they can’t get disability. We have not had a single person in our CIBS Center get approved for disability by our government yet. The ADA, American Disabilities Act, is supposed to support these people, but they get denied over and over and over again, and the younger they are, the more impossible it is for them, like the patient I mentioned who’s 24. Forget it. I mean, his chance of getting approved for disability at the government level, and what I’m talking about, older people trying to get their Social Security can’t even get it. We’ve got to do better scientifically and from a humanistic community perspective and also from a government perspective to support them financially.
Dr. Lin: Okay. Sounds good. I want to actually ask you one more thing. I’ve been a huge fan of your delirium website for the longest time. I thought the patient testimonials on there were so powerful to really drive home the impact of that on everybody involved in ICU care. I know that you’ve established a new page on that for long COVID. I would love to get you to talk to us more about that.
Dr. Ely: Sure. Yeah. We just launched it yesterday. So your timing is perfect, and thank you for bringing this up. We just launched a long COVID page. We’ve worked very hard on it. If anybody wants to go to it, go to icudelirium.org, go to the patient and family page, and you’ll see the long COVID page. It’s right next to the PICS page. We’re going to rearrange the furniture on that to make it more prominent, but that’s where you can find it today. It’s gotten a great response from the long COVID community. I sent it out to a lot of long COVID groups on Twitter, etc., and they gave me a few tweaks here and there, but most of them said, wow, succinct, easy to follow, super helpful clinically, and it’s got links to things like what’s post-exertional malaise, does the vaccine help or hurt with long COVID, what’s this brain disease of long COVID. We have numerous different links to help people get the science, but also the human side of what this disease is all about and helping people find a way forward. I hope that long COVID website is helpful to your listeners.
Dr. Lin: I would encourage all of us to go look this up, tell our patients about it, tell our friends. Is there a way for people to ask your organization questions on that website?
Dr. Ely: There absolutely is. They can get to me. My email, for example, is firstname.lastname@example.org, but also I’m on Twitter @WesElyMD and anybody can direct-message me on Twitter. I use Twitter for just two reasons, science and love. I don’t do politics or anything else on Twitter. I just put out science and messages of humanism. I hope that people can find that at all helpful.
Dr. Lin: That’s a good combination. Well, Dr. Ely, thank you so much for that conversation. I feel like we have so much more to talk about, but this is a very good start. This is going to conclude another edition of the Society of Critical Care Medicine Podcast. Thank you all for joining us. Remember to rate, review, and subscribe. For the Society of Critical Care Medicine Podcast team, I am Dr. Ludwig Lin. Thank you so much for listening.
Ludwig H. Lin, MD, is an intensivist and anesthesiologist at Sutter Hospitals in Northern California, and a consulting professor at Stanford University School of Medicine, where he teaches a seminar on the psychosocial and economic ramifications of critical illness.
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