Working Backwards: From Bedside to Bench to Bedside

Medical College of Wisconsin physician-researcher Julie Freed, MD ’11, PhD ’08, GME ’16, FEL ’17 assistant professor of anesthesiology, is improving experts’ understanding of vascular dysfunction by working backwards. “The way research typically works is investigators go from bench to bedside, where we make discoveries in a lab that we apply to patient care,” she explains. But for her current research on blood pressure during surgery, she already had the treatment for patients; doctors just didn’t understand why it worked.

Dr. Freed is a member of the MCW Cardiovascular Center vascular biology group, which focuses on the tiny arteries that control blood pressure. As one of the few labs in the country that studies arterial dysfunction using human vessels, Dr. Freed’s team is uniquely positioned to investigate diseases affecting blood circulation, and her task was to learn why a certain treatment was effective for certain surgery patients.

“There’s a rare but troubling occurrence we see in patients in the operating room for procedures like transplant or cardiac surgeries when substances are released into the blood, causing blood pressure to drop precipitously low,” Dr. Freed explains. “What my colleagues have observed is that giving these patients vitamin B12 intravenously can bring their blood pressure back up to normal levels. We just did not know exactly why or how it worked.”

So Dr. Freed and her team had to do things in reverse – work from bedside to bench. Her team struggled for months to find answers, but eventually they learned more about how vitamin B12 binds up compounds in the blood that cause a patient’s blood pressure to drop.

To fund her project, Dr. Freed received the 2018 Steve Cullen Healthy Heart Scholar Award as well as a grant awarded to the Cardiovascular Center by the Research Education Program Fund, a component of the Advancing a Healthier Wisconsin Endowment at MCW. Established in 2015, the Steve Cullen Healthy Heart Scholar Award is a competitive annual research grant for cardiovascular research within the Cardiovascular Center. The $25,000 award comes from the Cullen Family Healthy Heart Research Program and honors the memory of former Milwaukee Alderman Steve Cullen, who died of a heart attack at age 40. Proceeds from the annual Steve Cullen Healthy Heart Club Run & Walk help fund important research initiatives like Dr. Freed’s.

“The funds from the Cullen program were extremely important for our vascular studies, and now we are ready to publish our findings,” she says. “But they also helped lead us to another exciting finding that will potentially save even more lives.”

Through her partnership with two MCW physicians, Rodney Willoughby, MD, professor of pediatrics who specializes in infectious diseases, and Jayshil Patel, MD, associate professor of medicine who works in the Froedtert Hospital Medical Intensive Care Unit (MICU), Dr. Freed’s team is now working on a clinical trial investigating the effect of vitamin B12 on patients with sepsis. Sepsis is a life-threatening condition caused by the body’s dysregulated response to an infection; it’s a common cause of death in both pediatric and adult intensive care units for patients who have bacteria in their blood.

“With Dr. Willoughby, we found that when bacteria are present in blood vessels, the body is no longer able to maintain normal blood pressure, a phenomenon called vasoplegia,” Dr. Freed explains. “But we found vitamin B12 could reverse this.” This finding led her team to a new, surprising question.

“We wondered, ‘Can vitamin B12 also help patients with sepsis, in addition to surgery patients?’ If it could, that would deserve its own study,” she shares.

Dr. Patel, who treats patients with sepsis in the ICU and researches ways nutrition can improve outcomes, approached Dr. Freed about collaborating to establish a randomized, control clinical trial that is the first of its kind with patients with septic shock.

“Patients with sepsis, if inadequately treated, can progress to septic shock and death,” Dr. Patel explains. “Sepsis is one of the most common and burdensome problems in hospitals worldwide and accounts for significant ICU morbidity and mortality. If sepsis progresses to septic shock, which is hallmarked by low blood pressure, mortality rates can increase to an alarming 50 percent.”

Short of timely and appropriate antibiotics and supportive care measures, there is very little doctors can do, Dr. Patel says, which is why he finds this study researching vitamin B12 as a potential treatment so exciting. A novel, inexpensive, easy to administer, and nontoxic therapy like B12 could change morbidity and mortality rates for patients with sepsis. Dr. Patel and Dr. Freed designed the double-blind pilot study enrolling 26 patients over the course of a year. Patients are given vitamin B12 or a placebo and are monitored to detect whether their blood-pressure-elevating medication can be reduced.

“The study’s goal is to see whether vitamin B12 can get patients off blood pressure elevating medications, as compared to placebo,” Dr. Patel says. “Our question is, ‘Will this ultimately save lives?’ That’s what doctors, patients and their families care about most.”

Dr. Freed agrees that this kind of translational, life-saving research is what inspires her to work in her role as a physician-researcher. “I need to see and know that what I am doing in the lab will affect patients for the better,” she says. “That is ultimately why I chose to do my training here at MCW with physicians like David Gutterman, MD, working on human vascular trials. Because I am a physician and regularly see patients, it is important to me to work in translational research.”