Trial Seeks to Understand the Molecular Basis of Post-Operative Delirium in the Elderly
DURHAM, N.C. -- A new clinical trial at Duke University Medical Center hopes to unravel the genetic and molecular basis for delirium, a common complication afflicting elderly patients after major surgery.
Delirium, which can prolong the recovery of elderly surgical patients, is a mental state characterized by impaired cognitive function, fluctuating levels of consciousness, disturbed sleep-wake cycles and agitation. Although difficult to measure, the incidence of delirium has been reported to be as high as 60 percent, with the elderly at the highest risk, the researchers said.
"The proportion of elderly surgical patients is increasing, so we feel it is important to gain a better understanding of this condition," said Duke pharmacologist Madan Kwatra, PhD, principal investigator of the study. "This is the first such study looking at the role of genetics in the development of delirium."
The trial is support by a $2.57 million grant from the National Institute on Aging, part of the National Institutes of Health. This month, Duke researchers will begin enrolling 250 patients over the age of 65 who are undergoing either knee or hip joint replacement procedures.
The joint replacement surgeries will be performed by orthopedic surgeon T. Parker Vail, M.D., director of Duke's Total Joint Replacement Center.
The researchers point out that delirium is almost always a transient condition, and although it usually dissipates with time, over the short-term it has been associated with complications, delayed recovery, longer hospital stays and even death. They estimated that post-operative delirium annually costs the U.S. health care system between $8 billion and $10 billion.
Kwatra said that there are many hypotheses for the cause of post-operative delirium, and it is likely that there are numerous factors involved. One theory the Duke team is exploring holds that reduced levels of oxygen in the brain during surgery can lead to a decline in the levels of certain neurotransmittors such as acetylcoline, that one nerve cell uses to signal its neighbor to trigger a nerve impulse.
Since the researchers do not have access to actual nerve cells in the brain, they are studying molecular changes in circulating red blood lymphocytes, which share many of the same responses to neurotransmittors as nerve cells.
"Preliminary data has shown that the act of surgery alone causes a twofold or greater increase in the expression of 466 individual genes, as measured in red blood cells," Kwatra explained. "The magnitude of this surgery-inducing change in gene expression is unprecedented and raises the probability that some of these genes may cause or contribute to post-operative delirium."
Using a comprehensive battery of cognitive and psychological tests before and after surgery, the researchers will first identify those patients who become delirious. Blood samples will also be taken before and after surgery.
The researchers then plan to employ "DNA microarray" (also known as the gene chip) technology to measure the activity of more than 12,000 known human genes in lymphocytes. This analysis will help identify delirium-associated genes, Kwatra said. In addition, the team will use protein chip technology and 2D-gel electrophoresis to determine delirium-associated proteins.
"Identification of genes associated with post-operative delirium could lead to new insights that could help us better identify patients at high risk for developing delirium or even develop a potential drug for treating it," Kwatra said.
"The average age of a patient undergoing joint replacement surgery is about 68 years," Vail said. "Patients with delirium often have longer hospital stays and more difficult recoveries. The results of this study should help us get a handle on how even subtle changes in mental status can adversely impact a patients ability to recovery smoothly from surgery."
Vail said that current strategies to prevent or reduce delirium are varied.
"During surgery, we try to maintain optimal oxygenation of the blood, to keep blood pressure as normal as possible and to target the anesthesia to the patient," Vail said. "Where possible, for example, we try to use regional anesthesia as a way of avoiding the possible adverse effects of general anesthesia."
After the surgery, Vail explained, the care team tries to make the recovery period as stress- and pain-free as possible.
"What is optimal for the benefit of the patient's recovery is paying close attention to the whole continuum of care, from the preoperative screening to the actual surgery to the time in the recovery unit," Vail said. "We hope the results of this study will help us improve the outcomes for these patients."
The multidisciplinary team includes researchers from geriatrics, psychology, nursing, psychiatry, anesthesiology, bioinformatics and molecular pharmacology. Patients interested in more information about enrolling in the study should contact Grace Falcone at 919-684-3996.