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Lab Notes | Taming the beast

August 5, 2020

NoneWhen the first COVID-19 cases began arriving at hospitals int he U.S., doctors nicknamed the illness "The Beast" because of the way it attacked the body. Seattle-area doctor Ryan Padgett treated several patients before he himself became infected and nearly died. How can this beast be tamed? Dr. Mukesh Jain and his colleagues, who are part of the AHA-Allen Initiative in Brain Health and Cognitive Impairment, believe they have identified a set of tools that could help save lives and speed recovery times for patients like Dr. Padgett.


PODCAST TRANSCRIPT

Ryan Padgett  
I am a tribute to everyone that stayed up at night taking care of me that went to the ends of experimental thought of how to save my life.

I'm just fortunate recipient of these incredible people. This was not a, "I was strong and made it through." This is I woke up because people are unwilling to say we're done. The muscle aches and the joint aches and the fever and the trouble breathing was just profound. For the first time I understand why they call this 'The Beast.'

Rob Piercy  
I'm Rob Piercy.

Rachel Tompa  
I'm Rachel Tompa.

Rob Piercy  
And this is Lab Notes. Hey, Ryan, how are you?

Ryan Padgett  
I'm doing well, good to meet you!

Rob Piercy  
Likewise! That's Dr. Ryan Padgett. He's an emergency room physician at evergreen health Medical Center in Kirkland, Washington, just east of Seattle. I asked him what a typical day is like in the ER.

Ryan Padgett  
The only thing constant in an emergency department shift is, you're gonna be on your feet for 10 hours straight. You'll probably need to go to the bathroom for two hours before you finally get there. And you better have a granola bar and a bottle of water right there. Because there's no such thing as a coffee break or lunch break. Everything else is completely unpredictable.

Rob Piercy  
So it was with COVID-19. You remember that first case? Or at least what was the first known case at the time?

Rachel Tompa  
Yeah, I feel like it was so long ago. But it was really just a few months. And I remember being not at all surprised that the Seattle area was the first case,

Rob Piercy  
Right. This was a guy who had traveled to visit family and Wu Han China. He was in his 30s came back to Snohomish County, Washington, and he was treated at a hospital just 20 miles from Dr. Padgett's hospital.

Ryan Padgett  
So you had a sense like this was gonna hit us somehow. But you never predict that you're going to be the epicenter and that somehow it infiltrated this group of the most fragile people you can imagine. We had our first positive test results on the 29th of February, which came back from a patient that had passed the day before.

Rob Piercy  
That patient was the first reported U.S. coronavirus, death. It was a patient from a nursing home called Life Care Center.

Ryan Padgett  
Of course, immediately everyone's eyes open up and say, Wow, so we saw the patient in the ER simply the surgical mask. We ran up to a code to put a breathing tube in this patient, unprotected, all sudden, people are getting really scared. It didn't take long for us to go well, that patient came from that nursing facility. We have like 10 plus patients in the hospital from that same place. And you just felt like this wave is about to crash on you.

Rachel Tompa  
Yeah, it's so weird to think that we're just you know, we were just right across the lake from Kirkland, reading about this stuff in the news. And this is what it was like and in the hospital over there for Dr. Padgett.

Rob Piercy  
Yeah, in many ways, it felt like it was, you know, still completely a world away even though it's just on the other side of Lake Washington.

Rachel Tompa  
Like, everyone suddenly knew what Kirkland, Washington was.

Rob Piercy  
And you have to remember to this was really early on in the outbreak and well before most of us knew much of anything about Coronavirus.

Ryan Padgett  
There's this huge unknown, you're pretty fearful that something's coming down that we've never seen before. And then there's that fear of like, not even knowing how it's transmitted. You know, CDC shows up [the] next day. And we expect that there's a plug and play model of how to handle a crisis like this.

Rob Piercy  
There was no plug and play for COVID-19. The hospital turned half the ER into an isolation ward the ICU into a COVID Ward and the staff began wearing spacesuit looking protective gear as the hospital filled with suspected COVID positive patients. The virus was spreading like wildfire.

In more than two decades of clinical medicine, Dr. Padgett had only taken five sick days. And most of those were due to surgeries for old injuries from his days playing college football at Northwestern University. But just a couple of days after the first COVID patients came through the ER doors, Ryan started feeling sick.

Ryan Padgett  
The first symptoms were on seventh and eighth, which is that Saturday and Sunday, this add headache like I never had before, not terrible and type. But I just don't get headaches and feel and kind of run down and take take a nap person and you keep going. Then that Monday, Tuesday, Wednesday is when the traditional stuff showed up. So the fevers the drenching sweats, dry cough. And so probably that Tuesday is when they finally let it seep into my mind that that's what it could be. And then Wednesday started feeling shorter breath. Thursday got worse. And then about five in the morning on Friday, I was on the ventilator.

Rachel Tompa  
I can't believe it was that fast. That's crazy.

Rob Piercy  
It just goes to show that even in people who are outwardly healthy, just how quickly this can cut them down at the knees.

Rachel Tompa  
Yeah, that's terrifying to think you could be just feeling a little sick early in the week. And then by the end of the week, you're on a ventilator.

Rob Piercy  
Everything doctor Padgett knows about the next 17 days is what he's been told by his doctors, his friends and his family. Because he was unconscious the whole time. He developed what's called a cytokine storm.

Rachel Tompa  
I feel like we've probably all heard the phrase cytokine storm in news reports, or at least maybe more than we had six months ago. But what is the cytokine storm?

Rob Piercy  
In the most basic sense, it's an overreaction of our own immune system. You know, imagine our immune system is this silent sentinel that's just sitting there waiting to pounce and attack whenever there's a foreign invader. In a cytokine storm. It keeps attacking even after that foreign invader is wiped out, and it starts attacking our own tissues. In Ryan's case that led to multiple organ failure.

Ryan Padgett  
[The] big four for me was my lungs sign up with ARDS, acute respiratory distress syndrome, essentially, these very inflexible, scarred lungs that can't there aren't elastic to allow you to get the proper oxygen. My heart was only functioning at a third of normal, my kidneys, it failed. So I was on dialysis. And then my liver was failing as well.

Rob Piercy  
Having tried everything to save him, including drugs that suppressed his immune system, Dr. Padgett's care team decided to try what's called ECMO extracorporeal membrane oxygenation. The ventilator just wasn't giving his body the oxygen he needed to survive.

Ryan Padgett  
Even with maximal settings with maximum oxygen being put into my lungs with maximum pressure to force the oxygen through the lung tissue on the red blood cells. Even on those maximum measures, you can't do it.

Rob Piercy  
Put simply ECMO siphons out your blood oxygenates it and then pumps it back into your body.

Ryan Padgett  
I was on ECMO for about a week, it finally allowed my body to get the appropriate oxygen, keep my blood pressure up, and also give your body a rest. So much of the healing needs to be your body having that extra energy and ability. And so the machine you know allowed my body to rest a bit.

Rob Piercy  
While Dr. Ryan Padgett was resting. The world was changing. During the 17 days he was unconscious and fighting for his life. States issued stay at home directives...

Rachel Tompa  
Schools closed travel was restricted. We all tried to find that last half bottle of pure oil we knew we had in the cabinet somewhere

Rob Piercy  
Life as we knew it came to a standstill.

Finally, in late March more than two weeks after doctors put him on a ventilator, the beast, let Ryan Padgett go.

Ryan Padgett  
This is incredible group of people saved my life.

Rob Piercy  
He woke up to a whole new world

Ryan Padgett  
It was incredible. You turn on the TV, you're realizing this world it stopped. Like you don't think that anything can do that. And you see these pictures of downtown Seattle and no cars at noon, you see that the whole world is shut down. is incredible the outpouring of support of people and people that are hurting if people that didn't have a job now and yet the support of health care providers the support of each other is really incredible. I it I thought it was very helpful because it you saw this well of desire and ability for us to help our fellow man and woman.

Mukesh Jain  
COVID constitutes the greatest health challenge in 100 years.

Rachel Tompa  
Among those trying to help is Dr. Mukesh Jain, a cardiovascular researcher at University Hospitals Cleveland Medical Center in Ohio.

Mukesh Jain  
This is remarkable in its scope, I mean, this literally brought the world to a stop.

Rachel Tompa  
Dr. Jain is also the team lead on a project supported by the American Heart Association Allen initiative in brain health and cognitive impairment. His work in this four year project is to explore how red blood cells and the inner lining of blood vessels, which is called the endothelium work together to drive brain health and age related cognitive diseases like Alzheimer's and other dementias.

Rob Piercy  
Now, I know right now, people are probably asking themselves, "Okay, what does this have to do with COVID?" We'll get there in a moment, I promise.

Mukesh Jain  
Looking at tissues of people that have passed away from dementia, they often have these little lesions all over the place, almost like little blood vessels that collapsed. And as a consequence, a handful of brain cells succumbed. My father had this and so it's very personal. He died from dementia, and from a form where small blood vessels get knocked off over time, called Binswangers Disease. And I remember the progression very well from forgetfulness, to eventually watching someone lose their identity and not know who they were not recognize his spouse or his kids. And, frankly, and mercifully passed away in 2005.

Rachel Tompa  
It was a personal tragedy that has driven Dr. Jain to get to the bottom of this, what causes these blood vessels in the brain to collapse and if there's a way to intervene before that happens?

Mukesh Jain  
The blood is complicated. You have the blood vessel, you have blood cells, and then you have the liquid component of blood

Rachel Tompa  
To uncomplicate it, Dr. Jain explains the circulatory system like this:

Mukesh Jain  
The blood vessel is literally a highway, it's a large highway that then breaks up into smaller, smaller highways, till you get to the driveway to each house. It's almost like the little small blood vessel that supplies itself. It really has two major functions. It's to deliver energy in the form of oxygen and nutrients, and to deliver defense.

Rachel Tompa  
Defense meaning the immune response. The failure to do either one of those and cells begin to die, as they do in many forms of dementia.

Rob Piercy  
So how do you keep the highways open and the blood delivering cargo?

Rachel Tompa  
Dr. Jain and his colleagues have been working on a few different approaches.

Rob Piercy  
One of them involves a family of proteins called KLFs, which keep the endothelium healthy, reducing the potential for clots. There's already a drug that augments KLFs called bortezomib. But Dr. Jain's team is also studying a compound called P7C3, which in addition to enhancing KLFs, helps with energy production in the blood.

Rachel Tompa  
Finally, they're also studying another compound called ethyl nitrite. Or, ENO, for short, you know, is a gas that patients inhale and it allows hemoglobin in your blood to carry more oxygen to your cells.

Rob Piercy  
When Dr Jain and his colleagues began hearing about the complications from COVID-19, they realized the therapies they'd been working on for preventing dementia could help in the pandemic

Mukesh Jain  
We immediately had lab meetings to try to think about what we are doing, and try to get some of these agents into patients with COVID.

Rachel Tompa  
For many patients COVID complications are connected to a lack of oxygen and nutrients, the cargo making it to cells. Others experience clotting issues which can lead to circulation problems or even stroke. bortezomib, P7C3 and ENO could be less invasive alternatives to ventilators and ECMO. And more importantly, they could reduce permanent injuries to patients, lungs, hearts and other organs. These therapies would work in really a coordinated way to one keep the blood vessel and highway open and number to maximize oxygen delivery.

Rob Piercy  
One of the therapies ino which as you'll recall, allows hemoglobin to carry more oxygen to cells has already been tested in people.

James Reynolds  
And it's very effective. We've already done one arm of the study, and I just was our guinea pig.

Rob Piercy  
That's Dr. Jain's colleague, James Reynolds, he's wearing a T-shirt from the post punk band Joy Division, and just a few minutes into our conversation, it's clear, he's exactly the kind of scientist you would expect to volunteer himself.

James Reynolds  
And the main goal of that was not so much. Maybe try to you know, as to be able to get the lab team comfortable with all staff without a volunteer. 

Mukesh Jain  
He wanted to experience what it's like so that he can tell subjects that are going to be exposed to it what it feels like. I think that's incredibly laudable.

Rachel Tompa  
Was this the first time that you've tried out one of your own kind of research treatments? Or is this a regular practice for you to test therapies on yourself?

James Reynolds  
I don't want to sound like a too much of an altruistic idiot, but I felt was important to feel these volunteers to go undergo. So I've done just about every procedure that studying clinically,

Rachel Tompa  
ENO therapy involves wearing this tight fitting mask that covers your whole nose and mouth.

James Reynolds  
I've got a larger than normal head so it fit very tight on me. But it's not too constricting, you just lie there and you can just breathe.

Rachel Tompa  
Some people describe the ino gases having something of a metallic taste. But Reynolds said he didn't notice that.

James Reynolds  
They turned on the ENO, it was a  small dose of only 20 parts per million. And this is gonna sound very anticlimatic, like didn't really feel anything.

Rachel Tompa  
But what they learned helped shape their phase one clinical study in healthy volunteers would reduce how much oxygen

James Reynolds  
They'd inspire, making them hypoxic or reducing the blood oxygen content, and then gave them serial increases in ino. And we're able to find that even with their oxygen availability reduced administration drug was able to improve tissue oxygen delivery, so actually enhanced how the red cells were working normally.

Rob Piercy  
This particular study was funded by DARPA, the Defense Advanced Research Project agency. It's an agency inside the U.S. Department of Defense that funds research projects of strategic interest. Why would the Department of Defense be interested in a gas that allows red blood cells to carry more oxygen? Consider the longest running war in American history. Fought high in the mountains of Afghanistan and the years after 9/11. It can take time for soldiers bodies to adjust to altitude.

James Reynolds  
And that's what we mimicked in the lab where we took them room areas 21% oxygen, we took them down to 12% oxygen, which is equivalent of being on 12,000 foot mountain. We did it fairly rapidly modeling like a helicopter taking off from sea level and then dropping troops off. These are healthy subjects of blood oxygen saturation prior to reducing the amount of oxygen that could inspire was pretty close to 100% saturation. And then we got them down to about 85% saturation. If you are going into high altitude, there are people who don't react well that he can think of those stories of people coming out from adverse to all sudden, like, run an auction and take off all their clothes and and have not a successful outcome. So there is some sort of cerebral dysfunction associated with this reduction option. And actually is relatively easy to think of that same thing happening with covid. And that may be some of that cerebral dysfunction that is being reported, like people are happy and even though they've got low blood oxygen saturations may well be because the brain isn't getting the amount of oxygen that it needs to function properly.

Rob Piercy  
But you believe there's promise here for COVID-19 patients?

James Reynolds  
Yes, I very much do. Because it's a gas, we can run it relatively easy into the ventilator circuit. Subsequent developments, probably we will develop an ambulatory device to that you could just clip on your belt.

Rob Piercy  
Currently, the team is working to get these therapies out of the lab and into patients.

James Reynolds  
Our team members have submitted an application to get FDA approval to use ENO in patients with COVID. Number two, the agent bortezomib that augments KLF levels. We've previously published that bortezomib prevents blood clots from forming. And so we are seeking proper approval both institutionally and at the level of the FDA to use it in patients with COVID.

Rob Piercy  
As public health experts have said, from the beginning, this fall in winter, we will likely have a collision of COVID and flu, which could overwhelm the healthcare system.

Mukesh Jain  
We're gonna have a lot of challenges in meeting the medical demands and the more we can keep people out of the hospital or shorten their stay in the hospital will have a huge impact on our ability to take care of the most the sickest boss who has huge financial implications for health systems across the land.

Rachel Tompa  
Including the hospital where Dr. Ryan Padgett works. New therapies like the ones Dr. Jain and his colleagues are working on would give physicians new early-intervention tools to add to their COVID toolbox.

Ryan Padgett  
If you can avoid intubation and ventilation early, boy that would be an incredible advancement. Nothing harder in medicine, and to see someone sick and realize we have very little offer. To see someone struggling to breathe to to realize, well, I can put a breathing tube in. But beyond that, there's not a direct treatment, that that's really difficult to see suffering. To know that you've trained your whole life, to relieve suffering and to cure illness. And to feel that, that you open that toolbox and it's relatively empty. That's that's a terrible feeling. So it would mean everything for us to to know that there's something to help our patients. And we're all desperate to figure out the combination of this lock.

Rob Piercy  
This fall Dr. Padgett will return to the ER treating patients with a new appreciation for what it means to be one of them.

Ryan Padgett  
You never truly know it until it is you just to truly understand how far the ripple effect is of an illness and to to look at the person sitting next to the patient the bedside and to truly understand the fear and the anguish that they can be going through. I think is the biggest takeaway from it.

Rob Piercy  
I'm Rob Piercy.

Rachel Tompa  
I'm Rachel Tompa. For more Lab Notes episodes and science research news, visit our website at alleninstitute.org.

Rob Piercy  
Thanks for listening.

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