CU Surgery Research Fellow Takes First-Place Honors for Method of Preventing Postoperative Delirium in Elderly Patients
For his research into a new way to prevent postoperative delirium in elderly patients, Kenneth Meza Monge, MD, a research fellow in the University of Colorado Department of Surgery, took first place in the New Investigator Competition at the 48th Annual Conference on Shock in Boston earlier in June. It was the first-ever victory for the University of Colorado School of Medicine in the Society’s flagship trainee contest.
“Imagine an older person going through surgery. For many, recovery isn’t just about healing the body — it also involves protecting the brain,” Meza says. “Up to half of older surgical patients experience something called post-operative delirium, a sudden state of confusion and memory problems that can last days or even weeks.”
The condition happens, Meza says, because as we age, our organs become less resilient to stress. In the liver, this is due in part to a decrease in the number of functional liver cells called hepatocytes.
“The blood flow is reduced, and the ability of the liver to detoxify is reduced as well,” he says. “All these different changes caused by aging can predispose older people to more liver damage during this surgical stress.”
How the liver is involved
Working in the lab of Juan-Pablo Idrovo, MD, associate professor of surgery and critical care, Meza looked at the liver as the possible origin site of post-operative delirium, finding that even minor surgery caused a kind of silent or "subclinical" liver injury — not severe enough to show up on standard blood tests but still damaging at a molecular level.
“This subtle liver stress seemed to trigger a domino effect: The surgical stress caused an early liver injury, then toxic molecules built up, weakened the protective barrier between the blood and the brain, and set off inflammation in brain tissue,” Meza says.
Working with animal models, Meza and his mentors looked at the effects of silencing a specific liver protein called MCJ (methylation-controlled J protein), which negatively regulates how mitochondria (the cell’s energy engines) function.
“By turning this protein off just before surgery, we found that aged mice were protected: Their livers didn’t get injured, the toxic molecules were kept in check, the brain’s protective barrier stayed strong, and — most importantly — their attention, awareness, cognition, and behavior state remained normal,” Meza says. “In short, a stressed liver can send dangerous signals to the brain after surgery, but targeting the MCJ protein in the liver might stop that process before it begins.”
Homegrown inhibitor
In their research, Meza and his mentors used a novel MCJ inhibitor developed by Mercedes Rincon, PhD, professor of immunology and microbiology in the CU School of Medicine. Rincon has shown the drug’s ability to improve the efficacy of adoptive T cell therapies in treatment for murine B cell leukemia, and it will be studied in a clinical trial in Spain this fall as a treatment for metabolic dysfunction-associated steatohepatitis (MASH).
Meza foresees a day when elderly patients are given an injection of the MCJ inhibitor 72 hours before surgery to prevent post-operative delirium. More research needs to happen before that becomes widespread, he says, including a clinical trial in humans.
“We’re excited about the potential this has to improve recovery for older patients,” he says. “Our next steps will focus on exploring this liver-brain connection in more detail and seeing whether the biomarkers we tested in the animal models can help us identify patients at risk in real-world hospital settings.”
First-place honor
For Meza, who studied medicine in his home country of Nicaragua before coming to the U.S. for further studies, taking first place at the Shock conference’s New Investigator Competition is one of the great honors of his career thus far, and a tribute to his mentors Idrovo, Akshay Chauhan, MD, associate professor of GI, trauma, and endocrine surgery, and Elizabeth Kovacs, PhD, professor of GI, trauma, and endocrine surgery and vice chair of research in the CU Department of Surgery.
“This achievement wouldn’t have been possible without the amazing support of my mentors,” says Meza, who hopes to complete his surgical residency at the University of Colorado and eventually become a trauma surgeon. “They have believed in me since the day I joined the lab and have pushed me to launch my career as both a scientist and a future surgeon in the United States. We focused on the work to make it understandable for the whole audience, and to show this really complex data in a way that everybody can understand. I think that's the beauty of science, that you can present information in a way that everybody can be part of it.”