Most people are familiar with common conditions linked to cognitive impairment in older adults, such as Alzheimer’s disease and dementia.
But up to half of older patients undergoing surgery face a lesser-known but similarly formidable cognitive challenge: postoperative delirium, a condition triggered by a surgery that requires anesthesia and whose trademarks are confusion, disturbed mental faculties, loss of orientation and anxiety. In the worst cases, postoperative delirium leads to extended hospital stays, admission to long-term care facilities, long-term impairment in function and cognition, and even death.
Despite these seismic health impacts — and the fact that postoperative delirium costs the U.S. health care system more than $164 billion per year — little is known about the precise biological mechanisms that trigger the condition. Though clinicians are attuned to some risk factors, such as advanced age, pre-existing cognitive challenges and use of certain medications, there is no systematic method for predicting and mitigating the condition’s impacts.
A pair of University of Nebraska–Lincoln researchers, in collaboration with scientists at Beth Israel Deaconess Medical Center, are hoping that will eventually change. In a recently published paper in Scientific Reports, the group identified 90 metabolites that were altered in blood samples from people who experienced postoperative delirium when compared to samples from people who did not. This difference, particularly in the samples taken before surgery, indicates that postoperative delirium may have reliable biomarkers that would enable clinicians to predict and treat the condition.
“Longer term, we’re looking for a way to be able to draw blood and be able to say (that) if X, Y and Z are elevated, there is a higher risk that after surgery, this person could have delirium,” said Bridget Tripp, the paper’s lead author and a Husker doctoral candidate in complex biosystems. “Right now, the only way to tell if someone is delirious is if they actually are delirious.”
The study is part of the research group’s larger effort to identify what it calls a “multi-omics signature of delirium.” That signature would comprise a group of molecules — metabolites, lipids, proteins and more — that is altered in people with postoperative delirium, laying the groundwork for researchers to pinpoint the condition’s biomarkers. The signature molecules would be identified using various branches of the “omics” technologies, each of which pertains to a different area of biology. Proteomics, for example, examines the complete composition of proteins found in a system. Similarly, lipidomics focuses on molecules of lipids.
The group’s most recent study used metabolomics: the large-scale study of molecules known as metabolites, the substances that result when the body processes foods or drugs.
“If you think about the biological processes within a system, one of the final outputs is a metabolite,” Tripp said. “By studying metabolomics, we get an almost instant snapshot into the system, and we can also see the tail end of what is happening.”
The research team analyzed blood samples from 104 patients, half of which were delirium cases, the other half controls. They used a technique called mass spectrometry, which separates the different molecules in a sample by mass and records their abundance. Because mass spectrometry is an inherently variable process, Tripp devised a set of internal standards and quality control measures to ensure consistency across the study. These analytical techniques were one of the most innovative aspects of the study.
“Though these components are out there and have been applied to these types of research projects before, there was some novelty in how we chose the preprocessing approaches and how we controlled for different types of variability,” she said.
That high level of quality assurance lends more credibility to the team’s finding that there are 37 metabolites associated with delirium in blood samples taken preoperatively, and 53 metabolites tied to delirium postoperatively. In the pre-surgery samples, the most striking change was seen in the valine, leucine and isoleucine pathway. Those three substances are essential nutrients that humans cannot produce internally — they must be acquired from food — and are key players in energy metabolism.
Another pathway vital to energy metabolism, the citrate cycle, was altered in post-surgery samples. That pathway facilitates the transformation of nutrients into energy. Tripp said the similarities between affected pathways at the two time points suggests that dysregulation in energy metabolism may be a driver of postoperative delirium, a finding that breathes new life into a line of research from roughly 20 years ago.
“Our results support a previous chain of thinking that it was dysregulation of alternative energy sources that are associated with delirium,” she said. “That line of research had died off, but recently, our team and other labs are starting to see those results again. We dusted off the cobwebs on some of the older papers.”
The team’s findings may also shed light on the mechanisms driving other presentations of delirium, which can be linked to use of medication and drugs, changes in metabolism and severe or chronic disease. Delirium has recently been in the spotlight as a symptom of COVID-19: According to one study, it’s the sixth most common presenting symptom in older adults with the coronavirus. A clearer understanding of delirium’s physiological triggers may open the door to effective treatments in contexts beyond surgery.
Hasan Otu, professor of electrical and computer engineering and Tripp’s adviser, was also an author on the paper. The research was funded by the National Institutes of Health, the Alzheimer’s Association and the Beth Israel Deaconess Medical Center Capital Equipment Fund.
