Background: An increase in the frequency of surgeries among older individuals is observed in some countries. Hypotension is common and exaggerated in older patients and can lead to increased morbidity and mortality. Total intravenous anesthesia is commonly administered with propofol, while remimazolam has been suggested as an alternative to propofol because of advantages such as a more stable hemodynamic profile and less respiratory suppression. We conducted a single-blind, parallel-group randomized controlled trial to compare the incidence of intraoperative hypotension between patients administered with remimazolam and propofol. Methods: A total of 132 patients, aged between 65 to 80 years and undergoing laparoscopic cholecystectomy or transurethral resection of bladder tumors were randomly assigned to the propofol or remimazolam group with a permuted block system while being blinded to the hypnotic agent. Remifentanil was administered via target-controlled infusion in both groups, with an initial effect-site concentration of 3.0 ng/mL and titration range of 1.5 to 4.0 ng/mL intraoperatively. The primary outcome of this study was the overall incidence of hypotension during general anesthesia. Results: Patients in the propofol group experienced higher intraoperative hypotension than those in the remimazolam group (59.7% vs 33.3%, P = .006). Multivariate logistic regression analysis showed that remimazolam administration was associated with reduced hypotension (adjusted odds ratio, 0.34; 95% CI, 0.16–0.73). Secondary outcomes such as recovery time, delirium, and postoperative nausea and vomiting were comparable in both groups. Conclusion: Total intravenous anesthesia with remimazolam was associated with less intraoperative hypotension than propofol in older patients, with a comparable recovery profile.

Incidence of intraoperative hypotension in older patients undergoing total intravenous anesthesia by remimazolam versus propofol: A randomized controlled trial

A recent systematic review and meta-analysis by Wang and colleagues in the British Journal of Anaesthesia calls into question the concept that perioperative benzodiazepine administration is associated with development of postoperative delirium in older individuals after anaesthesia and surgery. This editorial focuses on potential bias within the systematic review and addresses major concerns surrounding benzodiazepine use in the older perioperative population. 

Benzodiazepines and postoperative delirium: should we be as cautious as we are?

BACKGROUND We compared the effect of remimazolam and propofol intravenous anesthesia on postoperative delirium in elderly patients undergoing laparoscopic radical resection of colon cancer. MATERIAL AND METHODS One hundred patients undergoing elective radical operation of colon cancer under general anesthesia were divided into a remimazolam group (group R) and propofol group (group P) by a random number table method. During anesthesia induction and maintenance, group R was intravenously injected with remimazolam to exert sedation; however, in group P, propofol was injected instead of remimazolam. The occurrence of postoperative delirium was assessed with the Confusion Assessment Method for the Intensive Care Unit scale and postoperative pain was assessed with the visual analogue score (VAS). The primary outcome measures were the incidence and duration of delirium within 7 days following surgery. Secondary outcome measures included postoperative VAS scores, intraoperative anesthetic drug dosage, and adverse reactions, including nausea and vomiting, hypoxemia, and respiratory depression. RESULTS There was no significant difference in baseline data between the 2 groups (P>0.05). There was no statistically significant difference in the incidence and duration of postoperative delirium between the 2 groups (P>0.05). There were no significant differences in VAS scores, remifentanil consumption, and adverse reactions, including nausea and vomiting, hypoxemia, and respiratory depression between the 2 groups (P>0.05). CONCLUSIONS In elderly patients undergoing radical colon cancer surgery, remimazolam administration did not improve or aggravate the incidence and duration of delirium, compared with propofol.

Comparison of Remimazolam and Propofol on Postoperative Delirium in Elderly Patients Undergoing Radical Resection of Colon Cancer: A Single-Center Prospective Randomized Controlled Study

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 (POD) in older patients undergoing non-cardiac surgery. Methods This study included patients aged ≥ 65 years who received general anaesthesia between April 2020 and April 2022 in multiple hospitals across China. POD occurring within 7 days was assessed using the 3-minute Diagnostic Interview for Confusion Assessment Method (3D-CAM). Univariable and multivariable logistic regression models based on the random effects were used to determine the association between midazolam administration and the occurrence of POD, presented as risk ratio (RR) and 95% confidence intervals (CI). Kaplan–Meier cumulative incidence curve was plotted to compare the distribution of time to POD 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 POD. Results In all, 5,663 patients were included, of whom 723 (12.8%) developed POD. Univariate and multivariable logistic regression analyses based on random effects of different hospitals showed no significant association between midazolam medication and POD among older population (unadjusted RR=0.96, 95% CI: 0.90–1.30, P=0.38; adjusted RR=1.09, 95% CI: 0.91–1.33, P=0.35). Kaplan–Meier curve showed no difference in the distribution of time to POD onset (Hazard ratio [HR]=1.02, 95%CI: 0.88-1.18, P=0.82). The results of subgroup analyses found that intraoperative midazolam treatment was not associated with POD in the specific subgroups of patients. Conclusions Intraoperative administration of midazolam may not be associated with an increased risk of POD in older patients undergoing non-cardiac surgery. 

The effect of intraoperative midazolam on postoperative delirium in older surgical patients: a prospective, multicentre cohort study

OBJECTIVE
To evaluate the association between the intraoperative administration of midazolam and the incidence of postoperative delirium in patients undergoing cardiac surgery.


DESIGN
Retrospective observational cohort study.


SETTING
The Japanese Diagnosis Procedure Combination database.


PARTICIPANTS
Patients aged 65 years and older who underwent cardiovascular surgery (excluding transcatheter surgeries, multiple surgeries per admission, and preoperative delirium) between April 1, 2015, and October 31, 2019.


MEASUREMENTS AND MAIN RESULTS
Patients who received midazolam (midazolam group) were compared with those who did not receive midazolam (no midazolam group). The primary outcome was the incidence of postoperative delirium. The secondary outcomes were the incidence of postoperative nausea and vomiting, mortality, and duration of intensive care unit stay and hospitalization. Propensity scores were estimated using logistic regression based on the covariates. The outcomes were compared using stabilized inverse probability of treatment-weighting analyses. Among the 16,185 patients analyzed, 10,633 (65.7%) received midazolam. No significant differences were observed in the incidences of postoperative delirium (odds ratio [OR] 0.95; 95% CI 0.87-1.03; p = 0.21) and hospital mortality (OR 0.92; 95% CI 0.76-1.11; p = 0.39) between the groups; however, the midazolam group had slightly longer durations of intensive care unit stay (3.5 [3.5-3.6] v 3.3 [3.3-3.4] days, p < 0.001) and hospitalization (31.5 [31.1-31.9] v 29.4 [28.8-29.9] days, p < 0.001), and slightly lower incidences of postoperative nausea and vomiting (OR 0.92; 95% CI 0.85-0.99; p = 0.03). The sensitivity analyses supported these results.


CONCLUSIONS
Intraoperative administration of midazolam may not induce postoperative delirium in patients undergoing cardiac surgery.

Association Between the Use of Midazolam During Cardiac Anesthesia and the Incidence of Postoperative Delirium: A Retrospective Cohort Study Using a Nationwide Database.

Benzodiazepine use is associated with delirium, and guidelines recommend avoiding them in older and critically ill patients. Their perioperative use remains common because of perceived benefits.We searched CENTRAL, MEDLINE, CINAHL, PsycInfo, and Web of Science from inception to June 2021. Pairs of reviewers identified randomised controlled trials and prospective observational studies comparing perioperative use of benzodiazepines with other agents or placebo in patients undergoing surgery. Two reviewers independently abstracted data, which we combined using a random-effects model. Our primary outcomes were delirium, intraoperative awareness, and mortality.We included 34 randomised controlled trials (n=4354) and nine observational studies (n=3309). Observational studies were considered separately. Perioperative benzodiazepines did not increase the risk of delirium (n=1352; risk ratio [RR] 1.43; 95% confidence interval [CI]: 0.9-2.27; I2=72%; P=0.13; very low-quality evidence). Use of benzodiazepines instead of dexmedetomidine did, however, increase the risk of delirium (five studies; n=429; RR 1.83; 95% CI: 1.24-2.72; I2=13%; P=0.002). Perioperative benzodiazepine use decreased the risk of intraoperative awareness (n=2245; RR 0.26; 95% CI: 0.12-0.58; I2=35%; P=0.001; very low-quality evidence). When considering non-events, perioperative benzodiazepine use increased the probability of not having intraoperative awareness (RR 1.07; 95% CI: 1.01-1.13; I2=98%; P=0.03; very low-quality evidence). Mortality was reported by one randomised controlled trial (n=800; RR 0.90; 95% CI: 0.20-3.1; P=0.80; very low quality).In this systematic review and meta-analysis, perioperative benzodiazepine use did not increase postoperative delirium and decreased intraoperative awareness. Previously observed relationships of benzodiazepine use with delirium could be explained by comparisons with dexmedetomidine.PROSPERO CRD42019128144. 

Effect of perioperative benzodiazepine use on intraoperative awareness and postoperative delirium: a systematic review and meta-analysis of randomised controlled trials and observational studies.

<h2>Abstract</h2><h3>Background</h3> Despite recent systematic reviews suggesting their benefit for postoperative nausea, vomiting, or both (PONV) prevention, benzodiazepines have not been incorporated into guidelines for PONV prophylaxis because of concerns about possible adverse effects. We conducted an updated meta-analysis to inform future practice guidelines. <h3>Methods</h3> We included randomised controlled trials (RCTs) of all languages comparing benzodiazepines with non-benzodiazepine comparators in adults undergoing inpatient surgery. Our outcomes were postoperative nausea, vomiting, or both. We assessed risk of bias for RCTs using the Cochrane Risk of Bias tool. We pooled data using a random-effects model and assessed the quality of evidence for each outcome using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. <h3>Results</h3> We screened 31 413 abstracts and 950 full texts. We included 119 RCTs; 104 were included in quantitative synthesis. Based on moderate certainty evidence, we found that perioperative benzodiazepine administration reduced the incidence of PONV (52 studies, <i>n</i>=5086, relative risk [RR]: 0.77, 95% confidence interval [CI] 0.66–0.89; number needed to treat [NNT] 16; moderate certainty), postoperative nausea (55 studies, <i>n</i>=5916, RR: 0.72, 95% CI 0.62–0.83; NNT 21; moderate certainty), and postoperative vomiting (52 studies, <i>n</i>=5909, RR: 0.74, 95% CI 0.60–0.91; NNT 55; moderate certainty). <h3>Conclusions</h3> Moderate quality evidence shows that perioperative benzodiazepine administration decreases the incidence of PONV. The results of this systematic review and meta-analysis will inform future clinical practice guidelines. <h3>Systematic Review Protocol</h3> The protocol for this systematic review was pre-registered with PROSPERO International Prospective Register of Systematic Reviews (CRD42022361088) and published in <i>BMJ Open</i> (PMID 31831540). 

The effect of perioperative benzodiazepine administration on postoperative nausea and vomiting: a systematic review and meta-analysis of randomised controlled trials.

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Effect of perioperative benzodiazepine use on intraoperative awareness and postoperative delirium: a systematic review and meta-analysis of randomised controlled trials and observational studies.

The effect of perioperative benzodiazepine administration on postoperative nausea and vomiting: a systematic review and meta-analysis of randomised controlled trials.