Does midazolam increase delirium risk during general anesthesia?
It is often recommended to avoid using benzodiazepines, including midazolam, in older adults to reduce the risk of delirium. Benzodiazepines are included in the Beers Criteria—a list of medications to avoid in individuals age 65 and older due to increased adverse events such as delirium, cognitive impairment, and falls. However, when it comes to general anesthesia, does avoiding midazolam reduce the risk of delirium?
All general anesthetic agents have the potential to cause delirium.1 This risk is higher with sevoflurane maintenance compared with total intravenous anesthesia (TIVA) using propofol, and it is higher in both pediatrics and older adults. The important question is, does premedicating a patient with midazolam increase the risk of delirium beyond what would occur during general anesthesia alone?
Researchers examined this question by conducting a retrospective cohort study in patients ≥ 70 years old undergoing non-cardiac surgery under general anesthesia. Patients were divided into two groups based on whether they received midazolam premedication or not. The primary outcome was delirium determined by one of several standardized methods performed routinely in the PACU and following admission. Exclusion criteria included patients with dementia, surgeries lasting < 30 minutes, craniotomies, direct postoperative admission to the ICU, and postoperative mechanical ventilation.
A total of 1,973 patients were included with a median age of 75 years. Forty percent of the patients received midazolam. The overall incidence of postoperative delirium was 15.3% (n = 302). Midazolam was not associated with an increased risk of delirium adjusted odds ratio 1.09 (95% CI 0.82-1.45; p = 0.538).2 This persisted in subgroup analysis looking at patients older than 80 years, patients with preoperative cognitive impairment, and those undergoing high-risk surgeries.
The study is notably limited by its retrospective nature with potential for confounding. Those receiving midazolam were more likely to be younger and have lower ASA scores, yet were more likely to undergo high-risk surgeries. These differences could have affected the results even though the authors attempted to control for them. The exclusion criteria of surgeries < 30 minutes leads one to wonder if midazolam could increase delirium risk in short cases where it may not be worn off by the time of emergence. Additionally, stratification by the agents used to maintain anesthesia could have been informative. Perhaps midazolam does not increase the risk of delirium with volatile agents but does with TIVA.
Despite its limitations, this study adds to prior research which has shown similar results. Given this, if I have a patient who may benefit from preoperative anxiolysis, I do not consider age as an absolute contraindication to midazolam use.
Ketamine, while having a known side effect of delirium, has been shown in studies to reduce the risk of delirium under general anesthesia. This is a topic we will explore in more detail in the future.
Longer duration of anesthesia (aOR 1.24; 95% CI 1.14–1.34 p < 0.001), higher risk surgery (aOR 2.03; 95% CI 1.49–2.78; p < 0.001), age (aOR 1.05 per year above 70; 95% CI 1.02–1.07; p < 0.001), and preoperative cognitive impairment (aOR 3.06; 95% CI 2.30–4.07; p < 0.001) were identified as independent risk factors for delirium.