Epinephrine Disrupts Brain Oxygen Levels in Mice

Physicians, experimental neuroscientists, and biomedical engineers at Duke University and the University of Texas Southwestern Medical Center (UT-SMC) have demonstrated that epinephrine can alter oxygen delivery and constrict small blood vessels in the brains of mice. The findings could help researchers better understand how epinephrine affects the brain when it’s used after significant cardiac events, like a heart attack.

This work appeared in the journal Anesthesiology and was highlighted as the ‘Paper of the Month’ by the editorial team.

Epinephrine is the standard drug physicians use to treat patients that are suffering from heart attacks. As a synthetic form of adrenaline, it can narrow large blood vessels and increase blood pressure, ensuring that organs receive enough blood and oxygen to function if the heart isn’t beating properly.

While epinephrine has proven to be an effective tool for treating cardiac events, clinical data has also shown that some heart attack patients who received doses of epinephrine had poor neurological recovery afterward.

“Indeed, epinephrine is the life-saving drug of choice for acute care after cardiac arrest,” said Wei Yang, director of the Multidisciplinary Brain Protection Program in Duke Anesthesiology Department. “However, mounting evidence suggests that the potential harmful consequences of its effects on brain blood flow cannot be ignored.”

“Many of our imaging tools only allow us to see overall blood flow, but what really matters is what’s going on in the microcirculation, which are the tiny blood vessels in different organs,” said Ulrike Hoffmann, division chief of neural anesthesia at UT-SMC, who was an assistant professor of anesthesiology at the Duke University School of Medicine (DUSM) at the time of the study. “There is a concern that we’re actually doing more harm than good to the microcirculation of the brain by using this drug.”

Looking into this potential problem is difficult, however, because standard imaging tools aren’t sensitive enough to visualize the brain’s microvasculature. To address this challenge, Hoffman and Wei Yang, teamed up with Junjie Yao, associate professor of biomedical engineering at Duke, to use an imaging tool known as photoacoustic microscopy (PAM).

PAM uses the properties of light and sound to capture detailed images of organs, tissues and cells throughout the body. The technique uses a laser to send light into a targeted tissue or cell. When the laser hits target tissue, it slightly heats up and expands instantaneously, creating an ultrasonic wave that travels back to a sensor. Researchers then use this data to make highly detailed biomedical images.

“Photoacoustic imaging is naturally sensitive to blood pumping through deep tissue, so it’s a useful tool for tracking blood flow and oxygen levels in the brain,” said Yao. “There was a perfect overlap between our technology and the questions behind this medical problem. Our technology may provide the critical clue to this important clinical question and thus lead to the necessary changes to the standard patient care practice”

The team tested epinephrine in healthy young and old mice that hadn’t had any previous heart issues to explore how the young and aging brain reacts to epinephrine. They gave the mice either one dose of epinephrine or three doses with five minutes apart, which is the maximum dosage approved by the American Heart Association for resuscitation after cardiac arrest. They used PAM to track the size of the microvessels and blood-oxygenation levels for the entire duration of the treatment.  

The team found that after each dose of epinephrine, the small blood vessels in the brains of healthy young adult mice substantially constricted, even as normal blood pressure was restored. While the vessels in older mice were less reactive to the drug, their vascular constriction persisted longer.

Intuition would suggest that constricting microvessels would lead to lower oxygen levels in the tissue. However, PAM revealed that the opposite happens.

“We saw a surprising amount of oxygen was basically dropped into the tissue as soon as epinephrine was introduced,” said Yao. “This oxygen dump triggered brain hyperoxia, which can also be damaging.”

Hoffmann stresses that these results are limited to mouse models in a very specific research setting. “We still have a great deal to explore surrounding the role of epinephrine and similar drugs, and how we can rethink and develop ways to ensure healthy blood flow and oxygen delivery,” said Hoffmann. “But this research was a critical step toward that goal.”