Midazolam Premedication Immediately Before Surgery Is Not Associated With Early Postoperative Delirium

Man-Ling Wang, MD; Jie Min, MS; Laura P. Sands, PhD; Jacqueline M. Leung, MD, MPH


Anesth Analg. 2021;133(3):765-771. 

In This Article

Abstract and Introduction


Background: Postoperative delirium is common among older surgical patients and may be associated with anesthetic management during the perioperative period. The aim of this study is to assess whether intravenous midazolam, a short-acting benzodiazepine used frequently as premedication, increased the incidence of postoperative delirium.

Methods: Analyses of existing data were conducted using a database created from 3 prospective studies in patients aged 65 years or older who underwent elective major noncardiac surgery. Postoperative delirium occurring on the first postoperative day was measured using the confusion assessment method. We assessed the association between the use or nonuse of premedication with midazolam and postoperative delirium using a χ 2 test, using propensity scores to match up with 3 midazolam patients for each control patient who did not receive midazolam.

Results: A total of 1266 patients were included in this study. Intravenous midazolam was administered as premedication in 909 patients (72%), and 357 patients did not receive midazolam. Those who did and did not receive midazolam significantly differed in age, Charlson comorbidity scores, preoperative cognitive status, preoperative use of benzodiazepines, type of surgery, and year of surgery. Propensity score matching for these variables and American Society of Anesthesiology physical status scores resulted in propensity score–matched samples with 1–3 patients who used midazolam (N = 749) for each patient who did not receive midazolam (N = 357). After propensity score matching, all standardized differences in preoperative patient characteristics ranged from –0.07 to 0.06, indicating good balance on baseline variables between the 2 exposure groups. No association was found between premedication with midazolam and incident delirium on the morning of the first postoperative day in the matched dataset, with odds ratio (95% confidence interval) of 0.91 (0.65–1.29), P = .67.

Conclusions: Premedication using midazolam was not associated with higher incidence of delirium on the first postoperative day in older patients undergoing major noncardiac surgery.


Benzodiazepines are frequently used clinically to relieve anxiety and insomnia, but may also cause delirium in susceptible population, such as older adults after major surgery. Postoperative delirium is a common geriatric syndrome that occurs in older patients after surgery.[1,2] Delirium in hospitalized patients is associated with the increased length of stay and hospital costs.[3,4] In a prior study of patients >50 years undergoing elective noncardiac surgeries, the postoperative use of long-acting benzodiazepine (chlordiazepoxide, diazepam, and flurazepam) was shown to be associated with higher risk of postoperative delirium than short-acting agents (oxazepam, lorazepam, triazolam, midazolam, and temazepam).[5] Midazolam, a short-acting benzodiazepine with an elimination half-life of 1.5–2.5 hours, is commonly used as a premedication.[6,7] However, the half-life of midazolam can be doubled in older adults.[8] An important clinical question is whether premedication with midazolam is associated with postoperative delirium and whether its use should be limited in older patients at risk for postoperative delirium.

Benzodiazepines such as midazolam are commonly administered as a premedication immediately before surgery to serve as an anxiolytic. However, whether the use of a single dose of short-acting benzodiazepine is associated with delirium in older patients particularly in those aged ≥65 years is a clinical area that has not been clarified. One prior study suggested that the preoperative chronic use of benzodiazepines was associated with postoperative confusion.[9] Others found that the new use of lorazepam in critically ill patients was associated with delirium.[10] In mechanically ventilated patients in an intensive care unit, midazolam-treated patients experienced more delirium than patients treated with dexmedetomidine.[11] The aforementioned studies referred to patients who were already at risk for delirium due to the long-term use of benzodiazepine or who were critically ill and mechanically ventilated. However, whether premedication with a short-acting benzodiazepine such as midazolam has similar adverse cognitive effects in older surgical patients who do not have these predisposing risks for postoperative delirium is unknown.

A recent meta-analysis reported that there are few high-quality studies quantifying the direct association between preoperative medication use and postoperative delirium.[12] Accordingly, the aim of this study is to assess the effect of intravenous midazolam as a premedication on the incidence of postoperative delirium in older adults. We hypothesize that the use of midazolam as a premedication is not associated with postoperative delirium in older patients undergoing elective surgical procedures. We combined 3 prospective studies to investigate whether premedication with midazolam is associated with postoperative delirium and adjusted for confounding using propensity score matching.