In Search of the Cause of Postoperative Delirium

    Why do some patients, especially older patients, develop postoperative delirium?

    Recently published studies investigated two suspected causes of postoperative delirium in orthopaedic patients – general anesthesia and preoperative use of central nervous system-acting drugs – and found that one of them is not an issue, while the other one is.

    General vs. Regional Anesthesia

    In the first study, 950 older patients who were undergoing hip fracture fixation in hospitals across China participated in a multicenter, open-label, randomized clinical trial that compared postoperative delirium in those who received general anesthesia versus those who received regional anesthesia. General anesthesia is thought to be more likely than regional anesthesia to cause postoperative delirium.

    The study authors, from the University of Birmingham in the UK and Wenzhou Medical University Second Affiliated Hospital in China, found that the type of anesthesia made no difference: 6.2% of the general anesthesia patients and 5.1% of the regional anesthesia patients developed delirium following hip fracture fixation.

    A similar multicenter study in the US and Canada came to the same conclusion, although more patients developed delirium in that study: Postoperative delirium occurred in 20.5% of hip fracture patients who received spinal anesthesia patients and 19.7% of hip fracture patients who received general anesthesia. [1]

    Findings of the study conducted in China were published by JAMA. A detailed explanation of the study methodology is available here.

    An Unlikely Cause of Delirium

    “The causes of delirium remain poorly understood, but our trial highlights that factors such as general anesthetic agents, [which] we thought may be associated with delirium, are in fact unlikely to cause delirium,” said the study’s chief investigator, Professor Fang Gao from the University of Birmingham.

    “Our trial has also provided clinical evidence on the safety of [regional anesthesia and general anesthesia] in older patients for hip fracture surgery, helping anesthetists in selecting appropriate anesthesia for these patients – particularly those at high risk of [postoperative delirium].”

    RELATED: Assessing the Safety of General Anesthesia in Hip Fracture Patients

    Hip fractures are a growing global health problem, making it important for physicians to understand why so many patients develop delirium after fracture fixation surgery and how they can prevent the problem.

    “To date, we have no treatments … to shorten or stop delirium when it develops,” said study co-author Thomas Jackson, BSc, MBBS, MRCP(Geriatrics), PhD, from the University of Birmingham. He is also a member of the board of the European Delirium Association. 

    “This trial is an important step forward in our understanding of how people develop delirium after an operation. Demonstrating that a general anesthetic is not a probable cause of delirium will allow researchers to further study other areas, such as the bodies inflammatory response to the surgery itself, and how this carries over into the brain.”

    Impact of Drugs Affecting the CNS

    In the second study – a matched case-control study – researchers from the University of South Australia used data from the Australian Government Department of Veterans’ Affairs to evaluate the effect preoperative use of various central nervous system-acting drugs had on development of delirium after hip or knee arthroplasty.

    Of the 10,456 patients in the database who were age 65 years and older and who had undergone primary or revision hip or knee arthroplasty in the past 20 years, 2614 had experienced delirium after surgery. They were matched with 7842 patients from the database who did not develop postoperative delirium. The researchers then reviewed and compared patients’ medication usage prior to surgery, including use of anxiolytics, sedatives, hypnotics, opioid analgesics, and antidepressants.

    Patients who were taking nitrazepam, a benzodiazepine used to treat anxiety and insomnia, and certain antidepressants were found to be twice as likely to develop postoperative delirium after hip and knee arthroplasty. This prompted the researchers to recommend that older patients temporarily cease these medications or change to safer alternatives prior to surgery. (Note: Nitrazepam is not approved for marketing in the US.)

    The study was published in the journal Drug Safety.

    Risky Medications

    Besides nitrazepam, 5 selective serotonin reuptake inhibitor antidepressants – sertraline, mirtazapine, venlafaxine, citalopram, and fluvoxamine – were also associated with postoperative delirium in this study population, although not to the same extent. No link was seen between opioids and delirium.

    “Our findings show that different classes of medicine are riskier than others when it comes to causing delirium after surgery, and [that] the older the patients are, the greater the risk,” said lead researcher Gizat Kassie, BPharm, MSc, PhD.

    Smoking, alcohol use, multiple health conditions, polypharmacy, use of psychoactive drugs, and impaired cognition also put people at risk. “Many of these factors can’t be altered, but we can do something about medications,” Dr Kassie said.

    The study from the University of South Australia is the first to investigate the link between specific medications and postoperative delirium. Previous studies have been broader in scope, considering a range of factors predisposing older patients to delirium.

    The researchers hope that evidence-based recommendations can be implemented into clinical practice so that delirium risk by medication type can be determined.

    “In people undergoing elective procedures, it should be practical to taper specific medications well in advance,” Dr. Kassie said. “It’s important that people are weaned off these riskier drugs well before surgery because abrupt withdrawal can have even worse consequences.”


    Li T, Li J, Yuan L, et al. Effect of regional vs general anesthesia on incidence of postoperative delirium in older patients undergoing hip fracture surgery: the RAGA randomized trial. JAMA. 2022 Jan 4;327(1):50-58. doi: 10.1001/jama.2021.22647.

    Kassie GM, Roughhead EE, Nguyen TA, Pratt NL, Kalisch Ellett LM. The risk of preoperative central nervous system-acting medications on delirium following hip or knee surgery: a matched case-control study. Drug Saf. 2022 Jan;45(1):75-82. doi: 10.1007/s40264-021-01136-1.


    1. Neuman MD, Feng R, Carson JL, and the REGAIN Investigators. Spinal anesthesia or general anesthesia for hip surgery in older adults. 2021 Nov 25;385(22):2025-2035. doi: 10.1056/NEJMoa2113514. Epub 2021 Oct 9.