Effect of Intraoperative Midazolam on Postoperative Delirium in Older Surgical Patients: A Prospective, Multicenter Cohort Study

The Takeaway

Conventional wisdom suggests that benzodiazepines increase delirium risk in the elderly. Although they remain on the Beer’s list as a high risk prescription medication, this recent study suggests that perioperative use might not increase risk of postoperative delirium.

Following the study promoting the need to intentionally and thoroughly assess preoperative anxiety, we can feel better providing midazolam to our elderly patients.

Key Points

• Cohort study on whether intraoperative administration of midazolam versus no midazolam was associated with the development of postoperative delirium in the first 7 days after surgery
• The authors found no significant association between intraoperative administration of midazolam and the development of postoperative delirium in the first 7 days after surgery in older patients
• Study included 5,663 patients > 65 years old receiving general anesthesia For non-cardiac elective surgery
• 12.8% of patients experienced delirium after surgery.
• The timing of delirium onset was similar, whether or not midazolam was used.

Physiology Refresh

Postoperative delirium (POD) is linked to disruptions in the blood-brain barrier (BBB) and neuroinflammation. Surgical trauma increases BBB permeability, allowing inflammatory markers such as interleukin-6, C-reactive protein, and macrophages to infiltrate the brain, triggering neuroinflammation and neuronal dysfunction.

These processes impair hippocampal function, affecting memory and cognition. Aging and preexisting cognitive decline exacerbate this vulnerability, aligning with a "two-hit" model: predisposing factors (e.g., impaired cognition) combined with postoperative BBB dysfunction.

Elevated inflammatory indices post-surgery correlate strongly with delirium incidence, highlighting inflammation as a key driver of POD.

Excerpts

Postoperative delirium is a state of acute but temporary neurocognitive disorder that typically manifests within 1 week after surgery and is characterized by symptoms such as inattention, fluctuating consciousness, and an acute change in cognitive status

A study involving 30 hospitals and greater than 20,000 older surgical patients revealed an overall incidence rate of 12.0% for postoperative delirium, ranging from 13.7 to 57.3% after cardiac surgery

Despite its transient nature, postoperative delirium has been linked to long-term cognitive impairment, resulting in adverse outcomes such as extended hospital stays, increased readmission rates, and high mortality rates

current clinical guidelines advise against the use of benzodiazepines in older patients during the perioperative phase, because previous studies have suggested an increased risk of postoperative delirium

Assessments were done twice daily for 7 days or until hospital discharge. The 3-min Diagnostic Interview for Confusion Assessment Method questionnaire was administered in person by research nurses who were centrally trained in a unified lecture.

Midazolam was administered among 3,110 patients (54.9%; median [interquartile range] dose, 2 [1 to 2] mg), and 2,553 patients (45.1%) were not given medication.

Delirium is a serious complication among older patients after surgery, with incidence rates ranging from 15 to 25% in major elective surgery and up to 50% in high-risk surgeries such as hip fracture repair and cardiac procedures

Abstract

Background: Midazolam is a short-acting benzodiazepine frequently used in the perioperative setting. This study aimed to investigate the potential impact of intraoperative midazolam on postoperative delirium in older patients undergoing noncardiac surgery.

Methods: This study included patients aged 65 yr and older who received general anesthesia between April 2020 and April 2022 in multiple hospitals across China. Postoperative delirium occurring within 7 days was assessed using the 3-min Diagnostic Interview for Confusion Assessment Method. Univariable and multivariable logistic regression models based on the random effects were used to determine the association between midazolam administration and the occurrence of postoperative delirium, presented as the risk ratio and 95% CI. A Kaplan-Meier cumulative incidence curve was plotted to compare the distribution of time to postoperative delirium onset between patients who received midazolam and those who did not. Subgroup analyses based on specific populations were performed to explore the relationship between midazolam and postoperative delirium.

Results: In all, 5,663 patients were included, of whom 723 (12.8%) developed postoperative delirium. Univariate and multivariable logistic regression analyses based on random effects of different hospitals showed no significant association between midazolam medication and postoperative delirium among older population (unadjusted risk ratio, 0.96; 95% CI, 0.90 to 1.30; P = 0.38; and adjusted risk ratio, 1.09; 95% CI, 0.91 to 1.33; P = 0.35). The Kaplan-Meier curve showed no difference in the distribution of time to postoperative delirium onset (hazard ratio, 1.02; 95% CI, 0.88 to 1.18; P = 0.82). The results of subgroup analyses found that intraoperative midazolam treatment was not associated with postoperative delirium in the specific subgroups of patients.

Conclusions: Intraoperative administration of midazolam may not be associated with an increased risk of postoperative delirium in older patients undergoing noncardiac surgery.

Citation

Li H, Liu C, Yang Y, Wu QP, Xu JM, Wang DF, Sun JJ, Mao MM, Lou JS, Liu YH, Cao JB, Duan CY, Mi WD. Effect of Intraoperative Midazolam on Postoperative Delirium in Older Surgical Patients: A Prospective, Multicenter Cohort Study. Anesthesiology. 2025 Feb 1;142(2):268-277. doi: 10.1097/ALN.0000000000005276. Epub 2024 Oct 29. PMID: 39470760; PMCID: PMC11723499.

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