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Research Highlights

Researchers test new approaches to prevent delirium in older adults

Making cognition a vital sign

Delirium — a state of sudden, acute confusion — affects millions of hospitalized older adults each year. It is a common, troubling problem that can lead to many other problems. To protect older adults from this distressing condition, researchers are testing new ways to prevent it and striving to make proven methods more widespread.

Two arms extended across the edge of a hospital bed and the hands are clasped togetherYears of research have revealed a lot about delirium — who is at risk, how long it lasts, and related complications — but much about the condition remains unknown. We don’t truly understand what happens in the brain during delirium, which occurs in 25% or more of hospitalized adults age 65 and older after major surgery or acute illness, and in more than 80% of older patients in the intensive care unit (ICU). We do know that it is associated with serious, sometimes long-lasting cognitive dysfunction.

“Delirium is more likely to happen in patients with dementia and can worsen their cognitive decline. Conversely, delirium in cognitively normal patients may signify their risk for developing cognitive impairment,” said Luci Roberts, Ph.D., a program director in NIA’s Division of Neuroscience.

NIA-supported researchers in recent years have tested interventions that limit sedation during surgery, but these interventions reduced delirium more than usual anesthesia only in relatively healthy older adults. Scientists are now turning to other possible solutions involving drug and nondrug approaches.

Delirium in the Hospital

Hospital-based delirium can occur within a few days of surgery or serious illness and has a range of symptoms, including disorientation and the inability to think clearly or pay attention. While some patients have obvious signs, such as agitation, aggressive behavior, or hallucinations, others are quiet and sleepy — and harder to diagnose.

Hospital sign hanging from the ceiling that says intensive care unit and wards 5-6 with directional arrowExperts note that hospital staff can miss delirium because its symptoms may wax and wane or be overlooked among other complications a patient has. Lack of a universal delirium screening tool and minimal staff training to recognize and document the condition also contribute to under-diagnosis.

Although the fluctuating symptoms of delirium usually disappear within a week or two, its impact may last longer in the form of complications, including hospital readmission within 30 days of discharge, emergency room visits, and discharge to a long-term care facility. Patients with in-hospital delirium also have a higher risk of falls and death than those without delirium.

Among older adults, risk factors for postoperative delirium include preexisting cognitive impairment, certain medications, suboptimally controlled pain, constipation, fever, infection, depression, alcohol use, sleep deprivation, low blood oxygen levels, and not being able to move. Longer surgeries, such as cardiac operations and hip fracture repair, also pose a risk. It is unclear how much anesthesia contributes to delirium. Roberts noted, “In the absence of other risk factors, current evidence indicates that delirium is unlikely to be caused by anesthesia alone.”

Though usually temporary, delirium can affect cognition for months or even years, even after initial recovery from surgery, studies show.

“On average, people who have had delirium have a steeper rate of cognitive decline over subsequent years than people who don’t,” Roberts said.

Long-term postoperative cognitive dysfunction is a murky area, according to researchers, with no common agreement on its definition and prevalence.

Strategies to Prevent Delirium

Two multipronged strategies that provide patients with appropriate medical care, physical and mental engagement, and emotional support have been shown to prevent delirium.

The Hospital Elder Life Program (HELP), developed by Sharon Inouye, M.D., a professor at Harvard Medical School and director of the Aging Brain Center at Hebrew SeniorLife’s Marcus Institute for Aging Research, Boston, has been shown to lower the incidence of delirium by 40% in hospitalized older adults and reduce the likelihood of cognitive and functional decline, as well as to reduce hospital length of stay and reduce falls. The ABCDEF Bundle, developed by E. Wesley Ely, M.D., a professor at Vanderbilt University School of Medicine, Nashville, has been found to significantly lower the incidence of delirium, increase survival, and reduce ICU readmission, among other outcomes.

No part of HELP works better than another, according to Inouye. “It’s really the whole package. What’s been shown to be effective is multicomponent strategies that address multiple risk factors at the same time,” she said.

Developed with NIA support, both HELP and the ABCDEF Bundle emphasize coordinated care by the surgical team, postoperative nurses, and patients’ family members to help prevent delirium or, if it occurs, to minimize symptoms. The interventions include having a volunteer, staff, or family member present during recovery to help orient and talk to a patient, making sure a patient has glasses and hearing aids if needed, allowing uninterrupted sleep, and getting a patient moving as quickly as possible. After surgery, the care team assesses patients for delirium, manages their pain, and tries to avoid certain medications, such as antipsychotics and benzodiazepines, which raise risk for delirium. One study, in ICU patients with delirium, showed that the antipsychotics haloperidol and ziprasidone did not significantly reduce the duration of delirium, coma, or ventilator use in the ICU or hospital compared to a placebo.

Barriers to Implementation

Making systemwide changes in complex procedures and staffing arrangements to implement programs like HELP and the ABCDEF Bundle is not easy, experts said, and insurance policies are needed to further incentivize delirium prevention.

“There’s a lot of variation across hospitals in their awareness of the specific needs of older adults,” Roberts said.

For example, to prevent falls, some hospitals may keep patients in bed after surgery, even though getting them up and about with the help of a nurse or physical therapist helps recovery and can reduce delirium. Inouye noted that delirium is a leading risk factor for falls, so “preventing delirium is a key way to prevent falls in the hospital.”

Hospitals can take steps to evaluate older patients for cognitive impairment before surgery and for delirium after surgery, and teach caregivers how to recognize the condition as the patient recovers at home.

“It’s a work in progress. It’s always difficult to implement change,” said Babar Khan, M.D., a researcher at Indiana University’s Regenstrief Institute and president of the American Delirium Society. “It requires a champion.”

Meet one such champion: Catherine Price, Ph.D., a neuropsychologist at the University of Florida College of Public Health and Health Professions, Gainesville.

Assessing Delirium Risk Before Surgery

Years ago, as an NIA-supported postdoctoral researcher, Price recalled, “I was blown away by the number of people with mild cognitive impairment who were coming in for surgery.” Even today, she said, not enough hospitals follow guidelines to assess the cognitive function of patients age 65 and older before elective surgery, even though lots of other vital signs — including blood pressure, heart rate, and respiratory rate — are monitored. A cognitive assessment can identify who is at risk for delirium so actions can be taken to prevent or at least minimize it.

How can hospitals add one more requirement to a busy, complex setting? Price and her colleagues found a way: the Perioperative Cognitive Anesthesia Network (PeCAN), which has performed brain checks in about 3,000 patients since it was launched in 2017.

Before elective surgery, patients age 65 and older visit University of Florida Health’s preoperative anesthesia clinic, which includes a quick cognitive screening as part of its assessment. If there is a concern, patients are referred to PeCAN staff, who conduct a neurobehavioral evaluation of memory, attention, executive function, and other aspects of cognition. Family members fill out a questionnaire about their perceptions of the patient’s thinking and behavior.

The results provide a baseline cognitive status — valuable information Price and other experts say is too often missing from a patient’s preoperative chart. About 20% of older adults coming in for surgery are “cognitively compromised,” which can contribute to delirium, said Price, who co-directs PeCAN.

Knowing a patient’s cognitive status can help both patients and the surgical team make changes before surgery or, in some cases, avoid surgery. For example, a patient could be told to stop certain medicines, reduce alcohol intake or smoking, or increase hydration.

“If we knew someone had Alzheimer’s disease, that would change some of the medical management,” Price said.

To pass on cognitive information to surgeons and anesthesiologists, PeCAN staff act as the “squeaky wheel” by inserting notes in a patient’s electronic medical record, with brain health recommendations, Price added. As a result, doctors might adjust medications or ask a geriatrician to assess a patient for delirium after surgery. Nurses can follow HELP or similar strategies for the patient’s recovery. PeCAN also loops in a patient’s primary care doctor and caregivers to be on the lookout for cognitive dysfunction after discharge.

For now, PeCAN remains within the confines of the University of Florida. Price is hopeful that the approach can be expanded to other hospitals after her team publishes evidence of its cost-effectiveness. “A team-based approach is leading to better [clinical] outcomes,” including delirium prevention and shorter hospital stays, she said.

Investigating Drugs to Prevent Delirium

While scientists like Price focus on hospital systems, others are investigating drugs to prevent delirium. NIA supports a clinical trial of intravenous acetaminophen given after surgery to see if it can reduce the frequency, severity, and duration of delirium in patients age 60 and older undergoing cardiac surgery, an especially vulnerable group. Investigators will also examine the pain reliever’s effect on the use of opioids after surgery — which are linked to delirium risk — length of ICU and hospital stay, and cognitive dysfunction up to one year after surgery. The four-year trial, which launched in early 2020, is recruiting 900 patients at the Beth Israel Deaconess Medical Center, Boston, and other U.S. sites.

An earlier study showed that 10% of ICU patients who received acetaminophen every six hours for 48 hours developed delirium, compared with 28% of those who received a placebo. They also did not need as much opioid analgesia for initial pain control and had shorter ICU stays.

“There are two possible mechanisms. One is that acetaminophen enables a reduction in opioids in the first 48 hours after surgery, which is when the most intense pain is felt. The other is that it may prevent brain inflammation,” said principal investigator Balachundhar Subramaniam, M.D., associate professor of anesthesiology at Harvard Medical School and director of Beth Israel’s Center for Anesthesia Research Excellence.

If acetaminophen works, it is likely to work best with nondrug approaches, he added. “I strongly believe a combination will be beneficial. The HELP checklist … and common-sense use of drugs — like taking pain medications and possibly acetaminophen and avoiding certain drugs — will help prevent [delirium].”

What About Nondrug Approaches?

Several nondrug interventions to prevent delirium are being examined, including better sleep habits, cognitive training, physical activity before or after surgery, and combined cognitive and physical activity for discharged ICU patients.

Could music do the trick? Khan, of Indiana University, is leading a clinical trial, begun in March, in 160 patients age 50 and older receiving mechanical ventilation in the ICU. The trial will compare the effects of listening to slow, relaxing music versus listening to silence through headphones. Patients will listen for one hour, twice a day, for up to a week.

At least half of patients in the ICU on a ventilator typically develop delirium. In a pilot trial of 52 ICU patients at an Indianapolis hospital, listening to music was shown to decrease sedation, anxiety, and pain in this critically ill group of patients and reduce the length and severity of delirium.

“Music is such a complex holistic stimulus that engages many parts of the brain. It reduces pain and anxiety. I think we can control some of the risk of delirium” by affecting multiple brain pathways, Khan said.

The trial will show if listening to slow-tempo music can lower the number of days in delirium or coma, delirium severity, pain intensity, anxiety, and depression, compared to listening to silence. Cognition will be measured three months after hospital discharge. Results are expected in 2024.

Time will tell if music listening or other interventions can prevent delirium. Researchers say that while new interventions should be tested, those known to work should be more widely adopted. Other areas to research include delirium assessment in the emergency room, the nature of delirium in people with preexisting cognitive impairment, and delirium’s underlying mechanism and brain changes, which can potentially reveal new treatments to test.

“As researchers and clinicians, we should strive to find effective and scalable interventions that can be implemented in real-world practice,” Khan said.

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