“Mrs. Croft, I truly regret that I’m calling you about a covid-19 research program only an hour after your husband, John, died of his coronavirus infection. None of us know what you are feeling, and we want you to know how immensely sorry we are for all that you and your family are going through. It’s just that the whole world is trying to grapple with this pandemic, and we are trying to understand what the virus is doing to the brain, since so many people are presenting with an inability to smell, confusion and strokes. I am calling to see if you might consider a priceless gift to the world so we can learn and hopefully help others: We are studying the brain in those who die of covid, and I’d like to talk with you about the possibility of donating John’s brain to our NIH-funded scientific research program.”

As a physician-scientist, I have spent 30 years at the bedside of my patients and their families. There is no place I’d rather be, but I wouldn’t have stayed here for so long without the research part. Alongside 90 others in Vanderbilt’s Critical Illness, Brain Dysfunction and Survivorship (CIBS) Center, I now study covid-19, the disease caused by the novel coronavirus. The pandemic is different: tough, inspiring and exasperating all at once. Answering questions to help reduce human suffering is what we do. Attempts to flatten the curve have shuttered our existing projects and catapulted us into new work and international collaborations in what seemed like one day. And then almost as quickly this month, we were immersed in disparities. The pandemic has amplified elements of the everyday disadvantages that millions face, and it’s obvious to all of us that it’s not fair or just.

Every covid-19 doctor has patients we will never forget, especially those of us who work in the ICU and specialize in mechanical ventilation. In my mind’s eye, I see faces of triumph and tragedy. Julio, a young agricultural laborer, represents both. He’d come in with horrendous shortness of breath that got worse fast. Despite this, he always greeted me with a smile, “Hola Doctor! Buenos días y gracias por cuidarme y ayudarme a recuperarme.” (Hi, Doctor. Good day, and thank you for taking care of me and helping me recover.) After 10 days on the ventilator, he seemed to be getting better. One morning, he was extubated and just on nasal cannula oxygen. I sat at Julio’s bedside celebrating with him, talking in my “poquito” Spanish. He stuck out his arms and gave me a hug over my personal protective equipment — a huge, strong bear hug I can still feel. That night, though, he got quiet — too quiet. Within hours, he’d suffered a massive stroke, as too many covid-19 patients do. Cayce Strength, one of our most experienced ICU research nurses, called his wife, whom none of us had met in person since she wasn’t allowed to visit, and got a consent through tears to receive Julio’s brain into our BRAIN-ICU-2 research program. I’m devastated, yet thankful at the same time. It feels weird and right. How can that be?

Doing our best to provide great clinical care is getting us through the days, but it will only be through great research that we get through the years. Why did Julio have that stroke when everything else about his infection was getting better, while he was safely on prophylactic blood thinners and as markers of his blood flow indicated steady improvement?

Yet just at the time we need our best research, we are seeing deviations in our approach as a scientific community that make me nervous. First, we heard early news that hydroxychloroquine was going to be a saving grace, then we heard that prominent journals had embarrassingly retracted erroneous science, leaving the country with stockpiles of pills that will probably expire and be tossed into waste bins someday. Earlier this month, we heard through a news release, rather than a fully vetted peer-reviewed publication, that steroids were the next savior in the pandemic. That “steroids will save the day” is a familiar line that I have seen come and go dozens of times over the decades.

Recently I faced another uncertainty in the ICU with John, a 77-year-old patient suffering from a protracted case of covid-19 pneumonia. On the ventilator for a week, he’d been off just a day as I prepared to see him again. Thirty minutes earlier, his O2 sats — which tell us how well his blood is saturated with oxygen — were only 84 percent on what we call “HiFlo,” which is like a pipe of air placed under his nose with 100 percent oxygen blowing into his body with every breath. We want those levels to be 90 percent or higher. After a short treatment, his read 97. The only change we’d made was proning him onto his stomach, then angling his bed upward to make his position a bit more comfortable. Will this help John survive?

The truth is we don’t know the answer to these day-to-day questions about covid-19 — yet.

But all over the world, with their prior studies shut down, researchers are rapidly designing new investigations related to the pandemic to help answer important questions that will affect your life and millions of lives. Not just patients and families, but all of us in society. How does this research work, and why?

Primum non nocere. First, do no harm. This is a code taken from the Hippocratic corpus that drives us as clinicians. It’s an oath I took when graduating from medical school. I take it very seriously, and it’s a guiding principle of my life as a doctor and a researcher. You might not imagine a boring researcher getting sweaty palms, but I still remember how nervous I was designing my first study as a young ICU doctor. I knew I could help people, but what if I killed them?

Harm comes in many shapes and sizes.

What about extreme social isolation during the pandemic? We hypothesize that it’s hurting not only patients, but also families, friends and health-care professionals. We know about PTSD and depression after critical illness, but is post-intensive care syndrome (PICS) going to be worse in the covid-19 era? In the past week, our center pondered these questions, gathered ourselves together, recruited other national experts and designed a study about it. We’ll get some answers quickly using a national registry and figure out the best way to mitigate harm.

What about the acute brain problems we are seeing in covid-19 patients? Doctors in Spain running the Humanizing-the-ICU project wrote to me that 75 percent of their coronavirus patients have delirium. They asked, “Can we study this with you and determine risk factors for brain injury in covid and how to treat patients better?” You bet. In less than a week, we had worked with investigators throughout the world to launch a study, enrolling more than 2,000 coronavirus-infected ICU patients in a dozen countries over two weeks via my new Twitter feed. We are analyzing the data now.

Will covid-19 delirium leave survivors with an acquired dementia? We already know that delirium duration is the most robust predictor of a prolonged Alzheimer’s-like dementia after critical illness. We designed an investigation to measure the long-term neuropsychological outcomes of covid-19 survivors from across the United States, and it’s going to help you learn if that confusion you saw during your wife’s coronavirus infection will leave her with memory problems that cause her trouble going back to work and organizing daily life, or shame in forgetting friends’ names at long-awaited post-pandemic parties. (If so, we will enroll her into an existing cognitive rehabilitation study for ICU survivors using computer games to rebuild brain power.)

Like I saw in Julio, there are reports about even young people suffering strokes and other brain problems that the virus can cause, so we joined forces with the National Institute on Aging and Rush Alzheimer’s Disease Center to modify our BRAIN-2 investigation into a covid-19 brain study. A few weeks ago, my phone rang at 6 p.m. Dan Ford, a Vanderbilt ICU nurse practitioner, told me that another covid-19 patient had just died. “Her family wants to talk to you about donating her brain to science,” he said. The patient’s dutiful son explained why: “We want something good to come out of all this. I woke up and thought, ‘Ugh, Mom died of covid at 92. I had her for 70 years, and now she and our family can give back to others.’” The son in another family, after deliberation, explained, “My father had to die without my mom at his side. They both felt isolated. So, yes, study his brain and give value to their suffering.”

But that first principle — do no harm — is essential throughout. For decades before covid-19, we ICU doctors tweaked knobs on your ventilators with the goal of raising the O2 saturations for millions of people suffering pneumonia. Now we know definitively, through research studies, that some of the things we did to humans to see a better number on the pulse oximeter were killing them by blowing their lungs up too large or keeping them on sedation too long. Armed with that information, we changed our approach globally to use a lower “dose” of air and daily sedation holidays. Until covid-19, that is. Now people are taking to Twitter and questioning even the basics, perhaps perilously, in my opinion. For those urging us to “just give this medicine” or “try this idea,” realize the danger of such an approach for you and for society. Careful and properly designed research is our best path to success here.

The same goes for my patient John. In full protective gear, I went up to John’s bed recently, where his cranked-to-the-right head was jammed into the mattress with the HiFlo oxygen pipe crammed under his nose. It didn’t look comfortable, and he implored, “How much longer? This doesn’t feel good.” Proning is one of many approaches to get the oxygen levels higher. We know a lot about proning when you are on the ventilator, and highly selected patients survive more often if maintained that way for 16 hours a day. But does proning a covid-19 patient when he’s not even on the ventilator help save his life? I sure hope so, but to avoid opinion and conjecture, rest assured, it’s actively being studied.

It has been nearly 100 years since Sinclair Lewis’s classic portrayal of the physician-scientist in “Arrowsmith.” More than ever before in my career, the pandemic has me thinking about Martin Arrowsmith and his enduring conflict: How am I best to serve others? I think the answer is through compassionate bedside care of sick patients as their physician, and through obsessive analytical science as an investigator trying to improve the lives of people I will never meet. It is this mind-set that keeps me going. We’re trying to get to the truth.

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