Effect of Remimazolam on Postoperative Delirium in Elderly Surgical Patients: A Critical Review of Pharmacological Mechanisms and Clinical Evidence

Abstract

Background

Postoperative delirium (POD) affects 4–53% of elderly surgical patients, and is linked to prolonged hospitalization, functional decline, and elevated mortality. Traditional benzodiazepines are confirmed POD risk factors due to accumulation of long-acting metabolites. Remimazolam, an ultra-short-acting benzodiazepine metabolized by tissue esterases, is a promising alternative. However, existing reviews pool heterogeneous surgical populations, and overlook procedure-specific pathophysiology as well as the confounding effect of flumazenil reversal on delirium assessment.

Methods

We performed a focused literature search of PubMed/MEDLINE, Embase, and the Cochrane Library to June 2026, using terms including remimazolam, postoperative delirium, elderly, and surgery. Randomized controlled trials (RCTs), cohort studies, meta-analyses, and mechanistic studies were included, with reference lists hand-searched. Data were synthesized narratively, with emphasis on orthopedic surgery, frailty stratification, and mechanistic plausibility.

Results

Recent RCTs in frail elderly surgery patients show remimazolam does not significantly raise POD incidence compared with propofol, consistent with pooled meta-analytic findings. Remimazolam reduces intraoperative hypotension and vasopressor requirements, which are independent POD risk factors. Its potential neuroprotective mechanisms include attenuated systemic inflammation, microglial M2 polarization, preserved cerebral perfusion, and maintained sleep architecture. Routine flumazenil reversal in multiple trials is a key methodological confounder that may mask early emergence delirium. Remimazolam retains class-related risks such as respiratory depression, with limited long-term ICU data and unproven cost-effectiveness.

Conclusion

Remimazolam does not increase POD in elderly surgical patients versus propofol or dexmedetomidine, while offering better hemodynamic stability. It serves as a valuable option for frail patients with cardiovascular comorbidities undergoing high-risk orthopedic procedures. Future RCTs should standardize frailty assessment, apply flumazenil-free delirium screening windows, enroll cognitively vulnerable populations, and evaluate long-term cognitive and cost outcomes.

Introduction

Postoperative delirium (POD) is defined as an acute, fluctuating disturbance of attention and awareness accompanied by cognitive dysfunction, representing one of the most common neurological complications following surgery in elderly patients.1 The incidence of POD varies significantly depending on the surgical population, ranging from 4% to 53% in patients undergoing orthopedic procedures such as hip fracture repair and joint replacement.2 Advanced age, pre-existing cognitive impairment, frailty, and the physiological stress associated with trauma and surgery contribute to this elevated risk.3

The consequences of POD extend beyond the immediate postoperative period. This complication is associated with prolonged hospitalization, increased healthcare costs, delayed functional recovery, and elevated mortality rates.4 Furthermore, POD has been identified as an independent risk factor for long-term cognitive decline and dementia.5 Consequently, identifying modifiable risk factors and implementing preventive strategies constitute essential components of perioperative care for elderly patients.

Several recent systematic reviews and meta-analyses, including those by Arias et al,6 Huang et al7 and D’Amico et al,8 have synthesized evidence on remimazolam and cognitive outcomes. However, these publications reveal several unresolved controversies and knowledge gaps. First, the potential confounding effect of flumazenil reversal on early delirium detection has not been systematically addressed. Second, the specific impact of remimazolam on different surgical subspecialties and frailty subgroups requires further clarification. Third, the biological mechanisms underlying any potential neuroprotective effects remain incompletely elucidated. The present narrative review was undertaken to provide a comprehensive, clinically oriented synthesis that addresses these specific gaps, with particular emphasis on the implications for anesthesia practice in elderly surgical populations.

Anesthetic management significantly influences the incidence of POD. While benzodiazepines have traditionally been associated with increased POD risk due to their long elimination half-lives, active metabolites, and accumulation in elderly patients,9 the introduction of remimazolam has challenged this paradigm. Remimazolam is a novel, ultra-short-acting benzodiazepine receptor agonist that was approved for general anesthesia.10 Unlike traditional benzodiazepines, remimazolam undergoes rapid metabolism by tissue esterases (primarily carboxylesterase-1) to an inactive metabolite, resulting in a context-sensitive half-time of approximately 5–10 minutes and minimal accumulation even during prolonged infusions.11

The pharmacological profile of remimazolam suggests potential advantages for elderly patients, including rapid recovery, minimal organ-dependent metabolism, superior hemodynamic stability compared to propofol, and specific reversibility with flumazenil.12 However, given its classification as a γ-aminobutyric acid type A (GABA-A) receptor agonist, concerns regarding its potential to precipitate or exacerbate POD persist.13 This review examines the current evidence regarding the effects of remimazolam on POD in elderly patients undergoing surgery, with particular emphasis on recent randomized controlled trials (RCTs) and cohort studies, potential mechanisms of action, and implications for anesthesia practice.

For this review, we systematically searched PubMed/MEDLINE, Embase, Web of Science, and Cochrane Library databases to June 2026 for studies investigating remimazolam and postoperative delirium in elderly surgical patients. We prioritized randomized controlled trials and prospective cohort studies but also included retrospective analyses and meta-analyses where they provided relevant data. This review specifically focuses on patients aged 60 years and older undergoing surgical procedures, with particular attention to orthopedic, abdominal, and emergency surgery populations. The following sections present the pharmacological characteristics of remimazolam, the pathophysiology of POD, a critical synthesis of clinical evidence from RCTs and observational studies (summarized in Table 1), potential neuroprotective mechanisms (Figure 1), and a balanced discussion of current limitations and future research directions.

Table 1.

Summary of Key Randomized Controlled Trials Investigating Remimazolam and Postoperative Delirium in Elderly Surgical Patients

Study (Year)	Design	Population	Surgery Type	Intervention	Comparison	Primary Outcome	Key Findings
Cai et al (2025)14	RCT, single-center	n=136, frail elderly (Reported Edmonton Frail Scale Score ≥ 6)	Hip surgery	Remimazolam tosilate	Propofol	POD incidence (3 days)	Comparable POD (4.4% vs. 17.6%; P = 0.0143)
Yang et al (2023)15	RCT, single-center	n=320, age >60 years	Orthopedic surgery	Remimazolam	Propofol	POD incidence (CAM, 3 days)	No difference in POD (15.6% vs. 12.4%); lower hypotension (17.1% vs. 43.0%; P<0.05)
Zhong et al (2025)16	RCT	n=405	Hip fracture surgery	Remimazolam infusion	No remimazolam treatment	POD incidence (Confusion Assessment Method-Chinese Revision at 1–7 days)	Reduced POD incidence and severity vs. control
Xu et al (2026)17	RCT	n=60, elderly colorectal cancer	Laparoscopic radical resection patients	Remimazolam	Midazolam, or no sedative	POD incidence (CAM,7 days)	Reduced POD incidence
Ren et al (2026)18	RCT	N=90, elderly patients	Laparoscopic-assisted gastrointestinal surgery	Remimazolam	Sevoflurane or remimazolam combined with sevoflurane	POD incidence	No difference in POD
Yuan et al (2026)19	RCT	N=80	Thoracoscopic partial lung resection	Remimazolam	Propofol	PND and POD incidence	No difference in early PNDs or POD
Sim et al (2025)20	RCT, non-inferiority	n=432, aged ≥ 65 year	Gastrectomy	Remimazolam	Propofol	POD and recovery quality	Non-inferior for POD
Zhang et al (2025)21	RCT	n=370, Elderly patients	Major abdominal surgery	Remimazolam	Propofol	POD incidence (CAM, 5 days)	Comparable delirium

Figure 1.

Neuroprotective Mechanisms of Remimazolam. ↓ (In the box): It indicates reduction or lowering. ↓(In the flowchart): It is a part of the process or will lead to something.

Pharmacological Characteristics of Remimazolam

Remimazolam represents a structural modification of midazolam, incorporating a carboxylic ester moiety that renders it susceptible to rapid hydrolysis by tissue esterases.22 This design results in an elimination half-life of approximately 0.75–1.0 hours, with a rapid onset of action (1–2 minutes) and recovery time (10–40 minutes) following cessation of administration.23 Importantly, remimazolam demonstrates a stable context-sensitive half-time independent of infusion duration, contrasting with the accumulation observed with traditional benzodiazepines such as midazolam and diazepam.24

The metabolic pathway of remimazolam offers distinct advantages for elderly patients. Unlike midazolam, which relies heavily on hepatic cytochrome P450 metabolism and demonstrates prolonged clearance in patients with hepatic impairment or advanced age, remimazolam metabolism remains relatively preserved in mild to moderate hepatic and renal dysfunction.25 The primary metabolite, CNS7054, exhibits negligible pharmacological activity at GABA-A receptors (approximately 300–400-fold less potent than the parent compound), minimizing the risk of residual sedation even with prolonged infusions or in patients with renal impairment who may accumulate this metabolite.26

From a hemodynamic perspective, remimazolam produces less pronounced cardiovascular depression compared to propofol. Randomized trials have consistently demonstrated that remimazolam induction and maintenance are associated with significantly lower incidence of hypotension, reduced requirements for vasopressor support, and greater hemodynamic stability in elderly patients.27 This characteristic is particularly relevant for surgery, where intraoperative hypotension represents a well-established independent risk factor for POD.28

Remimazolam maintains the pharmacodynamic properties of benzodiazepines, including amnesia, anxiolysis, and anticonvulsant effects, mediated through positive allosteric modulation of GABA-A receptors.29 However, its effects can be rapidly reversed by flumazenil, a selective benzodiazepine receptor antagonist, facilitating immediate recovery and enabling prompt postoperative neurological assessment.30

Postoperative Delirium: Pathophysiology and Risk Factors in Surgery

The pathophysiology of POD is multifactorial, involving neuroinflammation, neurotransmitter imbalances, disruption of the sleep-wake cycle, and cerebrovascular dysfunction.31 Surgical trauma triggers systemic inflammatory responses characterized by elevated circulating cytokines including interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and C-reactive protein (CRP).32 These inflammatory mediators can compromise the blood-brain barrier, activate microglia, and induce neuronal dysfunction in susceptible brain regions including the prefrontal cortex and hippocampus.33

Neurotransmitter alterations represent another critical mechanism. Cholinergic deficiency and dopaminergic excess have been implicated in delirium pathogenesis.34 Additionally, disruption of melatonin secretion and circadian rhythm disturbances contribute to sleep fragmentation and delirium development.35 Elderly patients exhibit particular vulnerability due to age-related reductions in cerebral reserve, diminished neurotransmitter synthesis, impaired cerebral autoregulation, and increased blood-brain barrier permeability.36

Surgical patients present unique risk profiles for POD. Hip fracture patients are typically frail, elderly individuals with multiple comorbidities, often presenting with acute pain, dehydration, and pre-existing cognitive impairment.37 The surgical procedure itself involves significant physiological stress, blood loss, potential fat embolism, and tissue trauma, further increasing delirium risk.38 Frailty, characterized by decreased physiological reserve and increased vulnerability to stressors, has emerged as a particularly important predictor of POD in this population.39

Intraoperative hemodynamic instability constitutes a modifiable risk factor of particular relevance. Studies have demonstrated that intraoperative hypotension (mean arterial pressure <20% below baseline or <65 mmHg) is independently associated with POD incidence and severity.40 The hemodynamic stability offered by remimazolam may therefore confer theoretical advantages in this population. Furthermore, postoperative hyperactive delirium, characterized by agitation and increased motor activity, represents a specific subtype particularly relevant in patients requiring immobilization.41

Clinical Evidence: Randomized Controlled Trials in Frail Populations

Recent high-quality RCTs have specifically investigated remimazolam’s impact on POD in elderly surgical populations. Cai et al14 compare remimazolam tosilate versus propofol in 136 frail elderly patients (Reported Edmonton Frail Scale Score ≥ 6) undergoing hip surgery. Using the 3D Confusion Assessment Method (3D-CAM) for frailty assessment, the study found comparable delirium rates between groups (4.4% vs. 17.6%; P= 0.0143), with remimazolam recipients reporting superior postoperative pain control and higher patient satisfaction scores. This study is particularly significant as it focused specifically on the frail elderly population most vulnerable to POD. Yang et al15 conducted a single-center RCT comparing remimazolam (n=158) versus propofol (n=162) in patients >60 years undergoing surgery. The primary finding indicated no statistically significant difference in POD incidence assessed by the Confusion Assessment Method (CAM) during the first 3 postoperative days (15.6% vs. 12.4%).33 However, the remimazolam group demonstrated significantly lower incidence of intraoperative hypotension (17.1% vs. 43.0%) and reduced vasopressor requirements. Zhong et al16 investigated the clinical effectiveness of intraoperative continuous pump infusion of remimazolam on POD in elderly patients with hip fractures. Xu et al compared remimazolam, midazolam and no sedation in 60 elderly patients undergoing laparoscopic colorectal cancer surgery. Remimazolam notably cut the incidence of postoperative delirium, relieved inflammation, preserved cognitive function and shortened recovery time, performing better than midazolam with milder advantages over the control group. The results prove remimazolam is a favorable sedative option and needs further multicenter research for verification.17 Ren et al compared remimazolam, sevoflurane and their combination in 90 elderly patients undergoing gastrointestinal surgery, focusing on postoperative delirium (POD) and cognitive function. The three regimens showed no obvious differences in POD incidence and early cognitive recovery, while remimazolam alone brought better circulatory stability.18 Yuan et al compared remimazolam and propofol combined with esketamine in patients undergoing thoracoscopic partial lung resection. The two regimens showed no obvious differences in the incidence of early perioperative neurocognitive disorders and postoperative delirium, but remimazolam led to better hemodynamic stability, shorter hospital stays and fewer adverse reactions.19 Their study demonstrated that remimazolam infusion significantly reduced the incidence and severity of POD compared to control groups, suggesting a protective effect when used as part of the anesthetic maintenance strategy in this high-risk population.

Clinical Evidence: Cohort Studies and Special Populations

Recent cohort studies have expanded the evidence base beyond randomized trials. Tang et al enrolled 1123 hyperlipidemic patients confirmed remimazolam significantly reduces the incidence and severity of postoperative delirium and improves six-month cognitive function, likely by modulating neuroinflammation. A dose-response relationship exists, with protective effects observed at total doses ≥10.29 mg or maintenance rates ≥0.51 mg/kg/h.42 Yang et al39 conducted a prospective controlled cohort study examining the effect of remimazolam versus conventional anesthesia on POD in frail patients. Their findings suggested that remimazolam was associated with reduced POD incidence in this vulnerable population, supporting its use in frail elderly patients undergoing major surgery. Kim et al41 performed a retrospective observational study specifically examining the effects of remimazolam versus inhalational anesthetics on the incidence of postoperative hyperactive delirium in geriatric patients undergoing hip or femur surgery. Their results indicated that remimazolam-based anesthesia was associated with a lower incidence of hyperactive delirium compared to inhalational agents, which is clinically significant given the challenges of managing agitated delirium in postoperative surgery patients with weight-bearing restrictions. Lee et al43 investigated the relationship between remimazolam-based anesthesia, systemic inflammatory biomarkers, and POD in elderly patients. Their retrospective cohort study found that remimazolam was associated with lower levels of postoperative inflammatory markers (IL-6, CRP) and reduced POD incidence, suggesting a potential mechanistic link between the anti-inflammatory properties of remimazolam and cognitive protection.

Critical Appraisal: Confounding Variables and Methodological Considerations

A balanced interpretation of the current evidence requires careful consideration of several confounding variables and potential sources of bias. First, the use of flumazenil for reversal of remimazolam sedation represents a significant confounding factor that has not been adequately addressed in most published studies. Flumazenil, a selective benzodiazepine receptor antagonist, may transiently improve alertness and mask early symptoms of delirium during the immediate postoperative period. If delirium assessment occurs shortly after flumazenil administration, the true incidence of POD may be underestimated in remimazolam-treated patients. This pharmacological interaction warrants explicit consideration in future study designs, with standardized timing of delirium assessments that account for flumazenil’s duration of action (approximately 1–2 hours).

Second, patient selection criteria across studies have introduced potential selection bias. Most RCTs excluded patients with pre-existing dementia, severe cognitive impairment, or psychiatric disorders—precisely the populations at highest baseline risk for POD. The favorable safety profile observed in relatively healthy elderly patients may not generalize to those with established neurodegenerative disease or significant frailty. Additionally, the predominance of single-center studies conducted in Asian populations raises questions about generalizability to Western healthcare systems, where patient demographics, surgical practices, and perioperative care pathways may differ substantially.

Third, several intrinsic pharmacological limitations of remimazolam deserve acknowledgment. As a GABA-A receptor agonist, remimazolam shares the same fundamental mechanism of action as traditional benzodiazepines, which are well-established risk factors for delirium. While its ultra-short-acting profile minimizes accumulation, the theoretical risk of GABA-mediated neurotransmitter imbalance persists. Furthermore, remimazolam’s efficacy for prolonged sedation in critically ill ICU populations has been questioned, with recent trials demonstrating higher treatment failure rates compared to propofol.44,45 Cost-effectiveness analyses remain limited, and the drug’s higher acquisition cost compared to generic propofol or midazolam may represent a significant barrier to widespread adoption in resource-constrained settings. Finally, the long-term cognitive outcomes beyond 7 days postoperatively remain largely unexplored, leaving open the question of whether remimazolam’s short-term delirium rates translate into durable cognitive protection.

Clinical Evidence: Evidence From Non-Orthopedic Surgery

The studies included in this review encompass three broad surgical categories: (1) orthopedic surgery, primarily hip fracture repair and total hip arthroplasty, which represents the largest evidence base and the highest-risk population for POD due to advanced patient age, frailty, and emergency presentation; (2) abdominal surgery, including gastrectomy and major abdominal procedures, which involves distinct physiological stressors such as visceral manipulation, fluid shifts, and potential for postoperative ileus that may independently affect delirium risk; and (3) other non-cardiac surgery requiring postoperative ICU admission, which captures higher-acuity patients with greater physiological derangement. The heterogeneity of surgical populations and procedures necessitates cautious interpretation of pooled findings, as the pathophysiological stressors and inflammatory responses differ substantially across these categories.

While the focus of this review is surgery. Sim et al20 and Wang et al46 conducted randomized non-inferiority studies comparing remimazolam versus propofol in older patients undergoing gastrectomy. Both studies found that remimazolam was non-inferior to propofol regarding POD incidence while offering better hemodynamic stability and faster recovery profiles. Zhang et al21 reported similar findings in patients undergoing major abdominal surgery, with remimazolam showing comparable delirium rates but improved recovery quality compared to propofol. These findings support the generalizability of remimazolam’s safety profile across surgical specialties. Zhu et al47 conducted a retrospective propensity score-matched study examining remimazolam’s impact on POD in elderly non-cardiac surgery patients admitted to the ICU. Their analysis revealed that remimazolam use was not significantly associated with POD incidence (aOR = 0.810, 95% CI = 0.588–1.113, P = 0.196). The incidence of POD was 9.32% in the remimazolam group and 11.26% in the non-remimazolam group (P = 0.225).

Clinical Evidence: Meta-Analyses and Systematic Reviews

Recent meta-analyses have synthesized available evidence regarding remimazolam and cognitive outcomes. In an umbrella review of meta-analyses encompassing 114 systematic reviews and meta-analyses with data from 250,777 patients, Amico et al demonstrated that remimazolam was associated with reduced postoperative neurocognitive complications.48 Zhu et al analysis included 30 relevant studies consisting of 25 RCTs, 4 retrospective studies and a prospective cohort study, to explore the link between remimazolam and postoperative as well as emergence delirium. Overall, remimazolam did not significantly change the total delirium risk (11.4% (312/2734) vs 15.2% (429/2827)), though it cut delirium risk for general anesthesia patients and raised the incidence of postoperative nausea and vomiting.49 Arias et al6 published a comprehensive systematic review and meta-analysis of 23 RCTs (n=3598) examining remimazolam’s association with delirium and cognitive function. The pooled analysis revealed no significant increase in delirium risk with remimazolam compared to propofol or dexmedetomidine (OR 1.20; 95% CI 0.76–1.91, P=0.378843). Notably, remimazolam was associated with significantly better Mini-Mental State Examination (MMSE) scores on postoperative day 7 (mean difference 0.53; 95% CI 0.30–0.75, P<0.0001). Huang et al7 analyzed 8 RCTs comprising 2013 elderly surgical patients and found no significant difference in POD incidence between remimazolam and propofol (RR 0.67; 95% CI 0.45–1.01). However, remimazolam significantly reduced the risk of intraoperative hypotension (RR 0.48; 95% CI 0.29–0.80) and requirement for vasopressor support, factors particularly relevant to surgery where hemodynamic stability is crucial for cerebral perfusion. D’Amico et al8 conducted an umbrella review of meta-analyses of randomized controlled trials examining interventions to prevent postoperative neurocognitive complications. Remimazolam was compared with propofol and dexmedetomidine via two meta-analyses across clinical and ICU sedation scenarios. It has similar postoperative delirium risk and recovery quality to propofol but causes less intraoperative hypotension, and takes less time to reach target sedation than dexmedetomidine.50 Their analysis concluded that current evidence supports the non-inferiority of remimazolam regarding POD risk while highlighting its favorable hemodynamic profile compared to alternative agents.

Ongoing Research

Wang et al51 reported a protocol for a prospective, multicenter, randomized controlled trial comparing remimazolam tosilate versus sevoflurane on the incidence of POD in older patients undergoing total hip arthroplasty. This registered protocol aims to provide definitive evidence on the comparative efficacy of these agents in a homogeneous surgery population, addressing current gaps in the literature regarding specific procedures.

Potential Mechanisms Underlying Remimazolam’s Cognitive Profile

Anti-Inflammatory and Neuroprotective Effects

Emerging experimental and clinical evidence suggests remimazolam may exert neuroprotective effects independent of its sedative properties. Zhou et al52 demonstrated in a lipopolysaccharide-induced neuroinflammation model that remimazolam attenuates microglial activation and reduces expression of pro-inflammatory cytokines including IL-6, TNF-α, and interleukin-1β (IL-1β) in the hippocampus. These anti-inflammatory effects were associated with improved cognitive performance in behavioral testing. Lee et al43 provided clinical translational evidence that remimazolam is associated with attenuated postoperative inflammatory responses, as evidenced by lower serum levels of IL-6 and CRP compared to propofol anesthesia. This anti-inflammatory effect may represent a key mechanism by which remimazolam reduces POD risk in vulnerable elderly patients. Wen et al53 reported that remimazolam inhibits postoperative cognitive impairment following cardiopulmonary bypass by promoting microglial M2 polarization (anti-inflammatory phenotype) and suppressing nuclear factor-kappa B (NF-κB) signaling pathways. Additionally, remimazolam has been shown to reduce serum levels of the astrocytic protein S100β and neuron-specific enolase (NSE), markers of neuronal injury, in surgical patients.54

Hemodynamic Stability and Cerebral Perfusion

The superior hemodynamic stability associated with remimazolam may contribute to preserved cognitive function through maintenance of adequate cerebral perfusion. Propofol-induced hypotension can result in cerebral hypoperfusion, particularly in elderly patients with impaired cerebral autoregulation or significant cerebrovascular disease.55 By maintaining mean arterial pressure within physiological ranges, remimazolam may prevent ischemia-reperfusion injury and hypoxic-ischemic encephalopathy.56 Liu et al57 conducted a systematic review and meta-analysis confirming that remimazolam significantly reduces the incidence of hypotension during anesthesia induction and maintenance in elderly patients compared to propofol, which may translate to reduced cerebral hypoperfusion events and subsequent delirium.

Sleep Architecture Preservation

Sleep disruption represents a major contributing factor to POD. Unlike propofol, which alters sleep architecture and may delay circadian rhythm re-establishment, remimazolam’s rapid elimination may facilitate natural sleep-wake cycle restoration.58 Yaqiu et al59 demonstrated that remimazolam-based anesthesia in elderly patients undergoing spinal surgery was associated with improved postoperative sleep quality, higher melatonin levels, and reduced sleep fragmentation compared to propofol anesthesia, potentially translating to reduced delirium incidence.

Limitations of Current Evidence

Several limitations characterize the current literature regarding remimazolam and POD in surgery. First, while recent RCTs such as Cai et al14 have specifically examined frail elderly patients undergoing hip surgery, many studies remain limited by single-center designs and relatively short follow-up periods (≤7 days), precluding assessment of long-term cognitive trajectories or persistent postoperative cognitive dysfunction.60

Second, heterogeneity exists in delirium assessment tools, timing of evaluation (ranging from immediate emergence to 7 days postoperatively), and diagnostic criteria across studies.61 The lack of standardized frailty assessment in earlier studies may have obscured differential effects in the most vulnerable populations, though recent studies have begun addressing this gap.14

Third, most trials excluded patients with pre-existing dementia or severe cognitive impairment, precisely the population at highest risk for POD and most relevant to clinical practice.62 The generalizability of findings to patients with established neurodegenerative disease remains uncertain.

The majority of available studies originated from single-center experiences in Asian populations, potentially limiting generalizability to Western healthcare systems or diverse ethnic groups.63 Additionally, cost-effectiveness analyses specific to surgery populations are currently lacking, representing an important consideration for resource allocation.64

Furthermore, several intrinsic pharmacological limitations of remimazolam must be acknowledged. As a GABA-A receptor agonist, remimazolam shares the same fundamental mechanism of action as traditional benzodiazepines, which are well-established risk factors for delirium through GABA-mediated neurotransmitter imbalance. While its organ-independent metabolism and rapid clearance theoretically minimize this risk, the possibility of transient GABAergic effects during administration cannot be excluded. The widespread use of flumazenil reversal in remimazolam protocols introduces an additional confounding variable, as it may transiently improve alertness and potentially mask early delirium symptoms during the immediate postoperative assessment window. The drug’s higher acquisition cost compared to generic propofol or midazolam may limit accessibility in resource-constrained healthcare settings. Additionally, recent concerns regarding remimazolam’s efficacy in critically ill ICU populations, where higher treatment failure rates have been reported compared to propofol,44,45 warrant caution when extrapolating findings from surgical populations to broader critical care contexts. Finally, the lack of cost-effectiveness analyses specific to surgical populations represents an important gap that limits informed decision-making for healthcare systems considering adoption of this agent.

The predominance of evidence from Asian populations also represents a notable limitation. Cultural differences in perioperative care, baseline genetic polymorphisms affecting drug metabolism (particularly carboxylesterase-1 variants), and variations in surgical and anesthetic practices may limit the generalizability of these findings to Western populations. Future multicenter trials incorporating diverse ethnic and geographic populations are essential to establish the broader applicability of remimazolam’s cognitive safety profile.

To address the remaining knowledge gaps, we recommend that future clinical trials incorporate the following design elements: (1) standardized delirium assessment protocols using validated tools (eg, CAM, CAM-ICU, 4AT) with predefined timing that accounts for the potential masking effect of flumazenil reversal; (2) explicit documentation and stratified analysis of flumazenil use as a potential confounding variable; (3) inclusion of patients with pre-existing cognitive impairment and dementia, who represent the highest-risk population; (4) multicenter designs with diverse geographic and ethnic representation to enhance generalizability; (5) extended follow-up periods of at least 30–90 days to assess persistent postoperative cognitive dysfunction and long-term functional outcomes; (6) incorporation of standardized frailty indices (eg, FRAIL scale, Clinical Frailty Scale) to enable subgroup analysis of the most vulnerable patients; (7) cost-effectiveness analyses comparing remimazolam to standard anesthetic agents within specific surgical populations; and (8) mechanistic studies exploring the relationship between remimazolam’s anti-inflammatory effects, sleep architecture preservation, and cognitive outcomes using biomarker panels and polysomnography. Such rigorously designed studies will provide the evidence necessary to definitively position remimazolam within perioperative delirium prevention protocols.

Conclusion

Remimazolam represents a significant pharmacological advancement in the anesthesia management of elderly surgical patients. Contrary to traditional benzodiazepines, current clinical evidence, including recent high-quality RCTs in frail elderly hip surgery patients, suggests that remimazolam does not increase the incidence of postoperative delirium when compared to propofol or dexmedetomidine. The hemodynamic stability conferred by remimazolam, combined with its organ-independent metabolism and rapid reversibility, makes it an attractive option for elderly patients with cardiovascular comorbidities or frailty undergoing high-risk surgery procedures.

While the exact mechanisms underlying remimazolam’s favorable cognitive profile require further elucidation, evidence points toward anti-inflammatory effects, preservation of cerebral perfusion through hemodynamic stability, and minimal disruption of sleep architecture as contributory factors. As experience with this agent accumulates and longer-term outcome data become available, remimazolam is positioned to become a valuable component of preventive strategies for postoperative delirium in the growing population of elderly surgical patients. However, careful patient selection and monitoring remain essential, particularly given the recent concerns regarding its efficacy in critically ill ICU populations.

Funding Statement

No external funding was received for the preparation of this manuscript.

Data Sharing Statement

Not applicable. This article is a review and does not report or analyze original data.

Disclosure

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.