POD is a serious postoperative complication among the elderly, characterized by disturbances in cognitive function, attention, and consciousness. It is strongly correlated with high morbidity, mortality, longer hospital stays, elevated medical costs, and decreased cognitive and physical functions (1). In contrast with a typical general surgical patient cohort, where the incidence of POD ranges from 2.5 to 3% (2, 3), elderly patients have higher rates, approximately 20 to 45% (4). In addition, up to 20–50% of older adults develop postoperative cognitive dysfunction 3 months after undergoing cardiac surgery (4). Due to its high prevalence and poor outcomes, effective management and objective assessment of POD are critically important, with evidence supporting the reduction of perioperative risks as an important method of prevention (5).

Esketamine, the S-enantiomer derivative of ketamine, was granted regulatory approval by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) in 2019 (6). It gained interest as an emergent POD (postoperative delirium) therapeutic intervention because its N-methyl-D-aspartate (NMDA) receptors have superior affinity and strong, non-competitive antagonist activity (7, 8). Its increased receptor interaction allows esketamine to produce strong anesthetic and analgesic effects at lower doses than racemic ketamine, thereby reducing psychotomimetic symptoms and adverse effects (8, 9). Esketamine also shows increased clearance and a favorable safety profile (8). Owing to these properties, it is widely used in a variety of patient populations, such as pediatric, obstetric, adult, and geriatric patients. Its clinical applications include treatment-resistant depression, sedation and analgesia in perioperative settings, anxiety reduction, potential prevention of POD, and enhancement of postoperative recovery quality (10–14).

Given the favorable pharmacological profile of esketamine and the high clinical priority of POD in older surgical patients, the present meta-analysis aimed to systematically evaluate the preventive efficacy and safety of esketamine for POD prevention specifically in elderly surgical patients. Notably, this review focuses solely on the prevention (not the treatment) of POD. The use of esketamine for other indications, such as depression or analgesia unrelated to POD prevention, is not addressed, and comparisons with other pharmacological agents for POD prevention are not included. Furthermore, the analysis is limited to elderly patients; thus, the findings might not be generalizable to younger cohorts. The results are expected to provide evidence-based insights to guide clinical decision-making in the context of POD prevention.

This meta-analysis was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (15). The protocol was prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO) (16), available at https://www.crd.york.ac.uk/PROSPERO/view/CRD420251151647 (registration number: CRD420251151647).

This meta-analysis, encompassing 13 RCTs involving 1,581 elderly patients, suggests a potential association between perioperative esketamine administration and reduced POD incidence. Notably, after excluding one outlying study (Y. (30)), which identified surgical timing as a significant confounder, heterogeneity disappeared (I² = 0%), indicating remarkable consistency among the remaining studies. According to Zhang et al., heterogeneity primarily increased from differences in surgical timing; afternoon surgeries independently reduced POD risk, irrespective of esketamine use. The other studies did not specifically control for surgical timing. Although variability in POD diagnostic tools might contribute to heterogeneity, 11 of the 13 included trials used the Confusion Assessment Method (CAM or CAM-ICU), the accepted criterion standard. Two studies (19, 21) did not specify their diagnostic instruments. Sensitivity analysis excluding studies with unspecified tools reinforced the robustness of the primary association. Future perioperative studies should consistently use and explicitly report standardized diagnostic tools such as CAM to improve comparability. Han et al. (32) reviewed previous studies examining esketamine’s effect on postoperative cognitive dysfunction in elderly patients, concluding that esketamine delayed neurocognitive recovery (dNCR) at 30 days postoperatively, despite improvements in early cognitive function. Another meta-analysis (33) indicated no clear preventive effect of perioperative esketamine on POD or postoperative neurocognitive disorder (POND), but considerable heterogeneity was present. Cognitive function differences across elderly surgical patients (aged 60–80 years) may partly explain this inconsistency. Although sensitivity analysis excluding age-related studies did not fundamentally alter conclusions, detailed subgroup analyses based on age should be pursued to enhance clinical applicability. The current literature regarding esketamine and neurocognitive outcomes remains inconclusive, with some reviews indicating no preventive effects or even potential risks. Our analysis, while consistently showing a beneficial direction, contributes to this evolving and uncertain evidence base. Therefore, further investigation into esketamine’s effect on POD in high-risk populations using standardized methodologies is necessary. Future studies are required to confirm potential benefits and determine optimal dosing and timing strategies.

In this study, esketamine primarily reduced the incidence of early POD in elderly patients, supported by relevant mechanistic evidence. Earlier research has revealed that esketamine decreases plasma levels of S100 calcium-binding protein β (S100β), a widely recognized biomarker for brain injury (34). Numerous perioperative factors, including surgical stress, anesthetic effects, blood–brain barrier dysfunction, and epigenetic modifications, can induce neuroinflammation, a critical mechanism underlying POD pathogenesis (35). Esketamine has also been shown to suppress neuroinflammation and neuronal apoptosis by reducing S100β expression (6). Animal studies have indicated that esketamine significantly attenuates neuroinflammation, thereby potentially preventing delirium (36). Thus, the association suggested by our meta-analysis is biologically plausible, as mechanistic studies indicate that esketamine may reduce neuroinflammation and brain injury markers, both implicated in POD pathogenesis. These findings offer a supportive rationale for the clinical hypothesis generated by our statistical analyses. Furthermore, this study provides clinically practical absolute effect measures. An NNT of 16 (95% CI: 16–29) indicates moderate clinical utility of esketamine for POD prevention. Importantly, this NNT is calculated based on an overall baseline POD risk of 13%. In high-risk populations (baseline risk ≥30%), the NNT would decrease to approximately 10, enhancing the value of this intervention, whereas its utility diminishes among lower-risk patients. This supports the rationale for targeted interventions in high-risk individuals.

Contrary to previous reports, this meta-analysis did not find a significant analgesic benefit from the administration of esketamine. Previous research often showed esketamine’s effectiveness in providing short-term post-surgical analgesia (37, 38). Esketamine’s analgesic effect primarily relies on its NMDA receptor antagonism and prevention of nociceptive signaling at the dorsal horn of the spinal cord. In addition, esketamine can deliver analgesic effects through peripheral NMDA receptor modulation (39). The inconsistent analgesic findings in the current analysis could be due to varied pain perception thresholds in geriatric populations. In one previous study (6), no significant differences in postoperative pain scores were reported between older adults and younger adults when assessed at rest and during mobilization in the first 48 post-surgical h.

Our findings must be interpreted within the broader context of multi-component delirium prevention strategies. Dexmedetomidine, a widely recognized pharmacologic agent, effectively reduces POD incidence but has not consistently demonstrated superiority regarding critical outcomes such as in-hospital mortality, long-term mortality, delirium duration, or mechanical ventilation duration (40, 41). Within this context, esketamine’s opioid-sparing effect potentially mitigates opioid-associated adverse effects such as respiratory depression, which may contribute to delirium. However, these potential benefits must be balanced against esketamine’s adverse effect profile, notably increased risks of hypertension and dizziness, limiting its application among vulnerable populations. Lee et al. (42) have also indicated that combination therapies appear more effective in preventing POD, underscoring the importance of determining optimal pharmacological approaches. Importantly, multidisciplinary strategies integrating both pharmacological and non-pharmacological interventions have shown superior efficacy in preventing and managing POD among older adults (43). Thus, esketamine should be considered not as a standalone intervention but as a potential pharmacological adjunct within comprehensive delirium prevention strategies.

An interesting finding of this research was that esketamine administration at induction affected remifentanil usage. Studies conducted by Yuan et al. (44) have shown that continuous administration at the rate of 0.250 mg·kg⁻¹·h⁻¹ decreased opioid consumption. Stress responses in geriatric patients are alleviated by esketamine, serving as a primary mechanism for reducing opioid use (38). Due to differences in surgical stress across operative phases, administering esketamine at induction may facilitate more comprehensive control of perioperative stress and optimize opioid usage. However, the lack of clear clinical recommendations, such as specific dosing ranges or clearly defined indications and contraindications, limits its direct clinical application. Therefore, future studies should focus on establishing evidence-based protocols for optimal dosing, timing, and patient selection in perioperative esketamine administration.

Esketamine administration did not significantly improve MMSE scores, nor did it reduce postoperative hallucinations, dizziness, or perioperative nightmares, aligning with the majority of previous studies (45, 46). Dizziness in elderly patients may pose significant risks, particularly by increasing the likelihood of falls, fractures, and delayed postoperative mobilization, thereby adversely affecting overall recovery (47). Nevertheless, owing to its unique pharmacology compared to classical ketamine, esketamine significantly reduced postoperative nausea and vomiting (8, 48). This finding, considering the susceptibility of the older population, stands out among the main points in need of clinical improvement.

QoR-15 scores suggested that esketamine could enhance postoperative sleep quality, consistent with the majority of peer-reviewed studies (49, 50). However, significant heterogeneity in this meta-analysis must be interpreted with caution. Future high-standard studies are needed to confirm these results, thereby enhancing the evidentiary base for clinical practice decisions.

Esketamine showed benefits in the control of intraoperative hypotension but increased the risk of hypertension. Intraoperative hypotension analysis revealed heterogeneity due to an unusual study design adopted by the Qiuping Ye (28) team. Their experimental group used an opioid-free regimen with esketamine alone, which deviated from other studies. Compared to ketamine, esketamine more effectively sustains perioperative hemodynamic stability (51), which can be explained by its mechanism of action (52). Esketamine likely blocks sodium channels at brainstem parasympathetic neurons, inhibits parasympathetic cardiac nerve activity, raises cardiac output, inhibits neuronal norepinephrine uptake, and increases systemic norepinephrine levels. Such mechanisms elevate sympathetic excitability and peripheral vascular resistance, resulting in stable hemodynamics. Compared to the control group, patients receiving esketamine experienced a 2.40-fold increased risk of intraoperative hypertension. For elderly surgical patients, who frequently have underlying hypertension, atherosclerosis, or cardiovascular comorbidities (e.g., coronary heart disease, heart failure, or stroke history), acute intraoperative hypertension is a well-established risk factor for severe perioperative complications, including myocardial ischemia, arrhythmias, acute heart failure, stroke, and intracranial hemorrhage (53). Therefore, when administering esketamine, clinicians should carefully balance its analgesic and anti-delirium benefits against the associated risks of hemodynamic instability. We recommend rigorous real-time blood pressure monitoring and readiness for immediate antihypertensive intervention in these patients.

Several limitations must be acknowledged when interpreting these results. First, substantial variability was observed across studies concerning esketamine dosing (ranging from 0.2 to 1.0 mg/kg), timing of administration (e.g., induction vs. postoperative analgesia), administration methods, and concomitant analgesic use. Such variability, although reflective of ongoing clinical exploration, inevitably reduces the comparability of pooled data and complicates definitive conclusions regarding optimal perioperative protocols. Second, in this current study, the incidence of POD was evaluated only on the first postoperative day. Future studies should include multiple postoperative time points for comparison. Third, although the clinical advantages of esketamine are evident, studies are required to determine optimal dosing regimens. Variability in physiological state, degree of stress, and therapeutic needs across perioperative periods (induction, maintenance, and postoperative analgesia) can influence esketamine efficacy, dosing, and safety. Finally, the majority of studies included were from China, which may limit generalizability due to ethnic differences. However, we suggest that while our findings remain robust within the studied context, this meta-analysis provides foundational insights into the clinical use of esketamine. Therefore, these results should be interpreted as indicative of general trends and safety profiles of esketamine across various clinical practices rather than as evidence supporting a specific protocol.

This meta-analysis indicates a potential net benefit of esketamine in perioperative care for elderly patients, demonstrating improvements in several key recovery domains. However, due to notable heterogeneity in some analyses (e.g., pain scores and QoR-15), the certainty of evidence is moderate, and findings should be interpreted cautiously. Esketamine administration was associated with reductions in POD, nausea, and vomiting. Additionally, it showed potential in stabilizing perioperative hemodynamics by mitigating hypotension, although it may concurrently increase the risk of hypertension and dizziness. Benefits in postoperative sleep quality were also observed. Moreover, esketamine administered at induction reduced intraoperative opioid consumption, suggesting a role in optimizing perioperative analgesia. Given its multifaceted and variable effect profile, the overall risk–benefit ratio of esketamine should be evaluated individually, supporting personalized strategies for optimizing perioperative analgesia.

Future studies should concentrate on identifying optimal timing and regimens for esketamine administration to maximize therapeutic benefits and minimize risks, particularly hemodynamic instability. Extended follow-up is also essential to assess long-term impacts on cognitive trajectories, functional independence, and quality of life. Such evidence is critical for guiding precise and individualized perioperative management strategies in elderly surgical patients.