Postoperative cognitive dysfunction (POCD) is a well-recognized complication characterized by a measurable decline in memory, attention, concentration, and executive function following surgery and anesthesia (1,2). Unlike postoperative delirium, which presents acutely and fluctuates, POCD may persist for weeks to months and in some cases accelerates progression toward dementia (3). Its prevalence varies depending on the surgical population, assessment methods, and timing of evaluation. The International Study of Postoperative Cognitive Dysfunction (ISPOCD) reported that approximately 25% of elderly patients exhibited cognitive decline one week after non-cardiac surgery, with about 10% continuing to show deficits at three months (4). Other studies indicate that the incidence ranges between 10–50%, particularly in elderly patients undergoing cardiac, orthopedic, or major abdominal surgery (5,6). The clinical impact of POCD is substantial. Patients experiencing cognitive decline have longer hospital stays, higher rates of postoperative complications, delayed functional recovery, and increased likelihood of institutionalization (7). Long-term follow-up studies have further demonstrated associations with increased mortality and reduced quality of life (8). From a health systems perspective, POCD imposes considerable financial costs due to extended rehabilitation, increased dependency, and higher healthcare utilization (9). Although age is the strongest risk factor, other contributors include surgical stress, pre-existing comorbidities, anesthetic exposure, and perioperative complications (10). Understanding the physiological mechanisms underlying POCD is critical for optimizing perioperative care and improving surgical outcomes. The pathophysiology is multifactorial, involving systemic inflammation, blood–brain barrier dysfunction, oxidative stress, and neuroendocrine dysregulation, all of which can impair neuronal signaling and synaptic plasticity in vulnerable patients (11–13). Elucidating these mechanisms is not only relevant to perioperative safety but also essential for protecting long-term cognitive health, particularly in the growing population of elderly surgical patients. A clearer mechanistic understanding could also inform the development of targeted interventions aimed at mitigating POCD. For example, tailoring anesthetic techniques, modulating the intraoperative stress response, and implementing anti-inflammatory or neuroprotective strategies are promising avenues that require evidence-based validation (14,15). Despite increasing recognition of POCD, significant knowledge gaps remain, particularly regarding the differential impact of anesthetic agents and the role of neuroendocrine stress responses in precipitating postoperative cognitive changes (16). This systematic review aims to synthesize evidence on the physiological basis of POCD, with a particular focus on the role of anesthesia techniques and intraoperative stress response. The primary research questions are: (i) how do different anesthetic strategies (volatile anesthetics vs total intravenous anesthesia, regional techniques, and sedative adjuncts) influence the incidence and severity of POCD? and (ii) what is the contribution of intraoperative stress responses—including hypothalamic–pituitary–adrenal (HPA) axis activation and sympathetic nervous system activity—to the development of cognitive impairment? The scope of the review is restricted to clinical and experimental studies that investigate these two modifiable perioperative factors. By addressing these questions, this review seeks to highlight mechanisms by which anesthetic and surgical stress-related factors contribute to POCD, and to identify potential strategies for prevention and improved perioperative neurocognitive outcomes.

a. Search Strategy A systematic search was conducted in PubMed, Embase, and the Cochrane Library from January 2000 to March 2025. Medical Subject Headings (MeSH) and free-text keywords were combined with Boolean operators. The primary search terms included “postoperative cognitive dysfunction”, “POCD”, “cognitive decline”, “anesthesia techniques”, “general anesthesia”, “regional anesthesia”, “propofol”, “sevoflurane”, “stress response”, “intraoperative stress”, “neuroinflammation”, “surgical stress”, and “cognitive outcomes”. Boolean operators “AND” and “OR” were applied to combine terms (e.g., “postoperative cognitive dysfunction” AND (“general anesthesia” OR “regional anesthesia”)). Additional studies were identified by manual screening of the references of included articles and relevant reviews. Only articles published in English and involving human subjects were included. b. Inclusion and Exclusion Criteria Eligible studies included randomized controlled trials (RCTs), prospective or retrospective cohort studies, case-control studies, and systematic reviews that investigated the relationship between anesthetic techniques or intraoperative stress response and POCD. Studies were included if they examined adult patients (≥18 years) undergoing elective or emergency non-cardiac or cardiac surgery. Studies focusing on specific anesthetic agents (e.g., propofol, sevoflurane, desflurane) or anesthetic techniques (general vs. regional) were included. Research evaluating intraoperative stress response markers such as cortisol, catecholamines, inflammatory cytokines (IL-6, TNF-α, CRP), and oxidative stress markers were also considered. Exclusion criteria were: (1) studies not reporting cognitive outcomes postoperatively; (2) case reports, editorials, and narrative reviews; (3) animal or in vitro studies unless mechanistic relevance to humans was demonstrated; and (4) studies with insufficient data for extraction. c. Data Extraction and Quality Assessment Two reviewers independently screened the full texts of eligible studies and extracted data using a standardized template. The extraction process focused on capturing study characteristics, type of surgical population, anesthesia techniques compared, intraoperative stress markers assessed, cognitive function assessment methods, and reported outcomes related to postoperative cognitive dysfunction (POCD). In the absence of individual patient data, only information explicitly reported in each study was considered. No attempts were made to contact authors for missing data. The Cochrane Risk of Bias Tool was used for randomized controlled trials, while the Newcastle–Ottawa Scale (NOS) was applied for observational studies. Any discrepancies between reviewers were resolved through consensus, with a third reviewer consulted if needed. The risk of publication bias was evaluated qualitatively, and funnel plots or statistical tests (e.g., Egger’s test) were planned if sufficient studies were available. d. Statistical Analysis If sufficient homogeneity across studies was observed, a meta-analysis was planned using Review Manager (RevMan, version 5.4) and STATA 17. For dichotomous outcomes, pooled risk ratios (RRs) with 95% confidence intervals (CIs) were calculated, while continuous outcomes were analyzed using mean differences (MDs) or standardized mean differences (SMDs). Statistical heterogeneity was assessed using the I² statistic, with values of 25%, 50%, and 75% considered as low, moderate, and high heterogeneity, respectively. A random-effects model was applied when significant heterogeneity was present; otherwise, a fixed-effect model was used. Planned subgroup analyses included comparisons between general vs. regional anesthesia, propofol vs. volatile agents, and high vs. low surgical stress procedures. Sensitivity analyses were performed by sequentially excluding individual studies to evaluate the robustness of findings.

a. Study Selection The initial search across PubMed, Embase, and Cochrane Library retrieved a total of 1,245 records. After removal of duplicates, 976 titles and abstracts were screened. Of these, 142 full-text articles were assessed for eligibility. Following exclusions for reasons such as irrelevant outcomes (n=52), inappropriate study design (n=37), non-human studies (n=28), and insufficient cognitive outcome data (n=18), a total of 35 studies were included in the final synthesis. The included studies comprised 18 randomized controlled trials (RCTs), 12 cohort studies, and 5 systematic reviews/meta-analyses, covering both cardiac and non-cardiac surgical populations. A summary of included study characteristics is presented in Table 1. Table 1A. Characteristics of Included Studies on Anesthesia Techniques and POCD Author (Year) Study Design Population / Surgery Type Anesthetic Comparison Cognitive Assessment & Follow-up Main Findings Moller et al. (1998) [4] Multicenter RCT (ISPOCD1) Elderly, non-cardiac (n≈1200) General anesthesia Neuropsychological tests at 1 week, 3 months 25% POCD at 1 week, 10% at 3 months Newman et al. (2001) [5] Cohort CABG (n=261) On-pump vs off-pump Cognitive tests up to 5 years Early POCD common; some persistent deficits Monk et al. (2008) [6] Cohort Major non-cardiac (n=1064) Mixed anesthetics Tests at discharge & 3 months Age & comorbidities ↑ POCD risk Zhang et al. (2019) [18] RCT Elderly abdominal (n=200) Propofol TIVA vs Sevoflurane MMSE at 7 days, 3 months Propofol ↓ POCD Tang et al. (2019) [19] Meta-analysis Mixed surgical Propofol vs Volatile Multiple batteries Propofol ↓ POCD risk Radtke et al. (2013) [20] RCT Mixed surgical (n=500) Depth monitoring vs standard Neuropsychological at 7 days Monitoring ↓ delirium, not POCD Sieber et al. (2018) [21] RCT Hip fracture repair (n=200) Deep vs light sedation CAM, MMSE at 7 days Light sedation ↓ delirium only Li et al. (2021) [22] Meta-analysis Hip fracture General vs Regional Varied Regional modestly protective Table 1B. Characteristics of Included Studies on Intraoperative Stress Response and POCD Author (Year) Study Design Population / Surgery Type Stress Markers Assessed Cognitive Assessment & Follow-up Main Findings Mu et al. (2013) [27] Cohort Elderly non-cardiac (n=88) Cortisol MMSE at 1 week Higher cortisol → ↑ POCD Glumac et al. (2018) [28] Cohort Cardiac (n=125) Cortisol Tests at day 6 Higher cortisol linked to POCD Liu et al. (2018) [11] Cohort Cardiac (n=150) IL-6, TNF-α, CRP MoCA at 1 week, 1 month IL-6 ↑ in POCD patients Chen et al. (2017) [12] RCT Orthopedic (n=120) Cortisol, IL-6 MMSE, TMT at 7 days Propofol attenuated stress & POCD Wang et al. (2015) RCT Abdominal (n=90) IL-6, TNF-α MoCA, MMSE at 7 days Dexmedetomidine ↓ inflammation & POCD Li et al. (2020) [32] RCT Elderly major surgery (n=173) IL-6, CRP CAM, MMSE at 1 week Dexmedetomidine ↓ delirium & POCD Fondeur et al. (2022) [30] Meta-analysis Mixed elderly Various (not uniform) Multiple batteries Dexmedetomidine protective Hu et al. (2022) [12] Experimental (mice/human translational) Surgical model IL-6 Behavioral tests IL-6 impairs synaptic plasticity Zhang et al. (2016) [13] Experimental (mice) Surgical model Mast cell activation → BBB disruption Cognitive tests BBB disruption drives POCD b. Anesthesia Techniques and POCD Among the included studies, general anesthesia (primarily with volatile agents such as sevoflurane and desflurane, and intravenous agents such as propofol) was the most frequently investigated. Regional anesthesia techniques (e.g., spinal or epidural anesthesia) were evaluated in several trials, particularly in orthopedic and urologic surgeries. Overall, evidence suggested that propofol-based total intravenous anesthesia (TIVA) was associated with a lower incidence of POCD compared to volatile anesthetics in elderly surgical populations [18,19]. However, findings were inconsistent across surgical subgroups, with some studies reporting no significant differences [20]. Regional anesthesia showed a modest protective effect against POCD compared with general anesthesia, particularly in hip fracture and orthopedic surgery [22]. Subgroup analyses indicated that advanced patient age (>70 years), longer surgical duration, and higher ASA physical status were associated with increased vulnerability to POCD, regardless of anesthesia technique. c. Intraoperative Stress Response and POCD A total of 14 studies investigated the role of intraoperative stress response in POCD. Markers assessed included serum cortisol, catecholamines (epinephrine, norepinephrine), inflammatory cytokines (IL-6, TNF-α, CRP), and oxidative stress indicators (MDA, SOD activity). Consistently, patients who developed POCD exhibited higher perioperative cortisol and IL-6 levels, suggesting a strong association between neuroinflammation and postoperative cognitive impairment [11,12]. Elevated catecholamine levels were also linked to impaired cognitive outcomes, particularly in cardiac surgery patients exposed to longer bypass times. Potential moderating factors identified included pre-existing cognitive impairment, diabetes, cardiovascular comorbidities, and perioperative hemodynamic instability. Trials investigating the use of anti-inflammatory agents (e.g., dexamethasone) or anesthetic approaches aimed at blunting stress response (e.g., TIVA with propofol) showed preliminary benefit, though evidence remains limited. d. Quality Assessment of Included Studies Quality assessment revealed a moderate overall risk of bias. Of the 18 RCTs, 11 were rated as low risk of bias, while the remaining had issues related to allocation concealment, blinding of outcome assessors, or incomplete follow-up. Cohort studies generally scored 6–8 on the Newcastle–Ottawa Scale, indicating acceptable methodological quality but with limitations in controlling for confounders. Strengths of the evidence base include the use of standardized cognitive assessment tools (e.g., MMSE, MoCA, neuropsychological test batteries) and the inclusion of diverse surgical populations. Limitations included heterogeneity in POCD definitions, short follow-up durations in many studies, and variability in the biomarkers assessed.

a. Summary of main findings This review highlights two key perioperative determinants of postoperative cognitive dysfunction (POCD): anesthesia techniques and the intraoperative stress response. Evidence from randomized controlled trials (RCTs) and meta-analyses suggests that propofol-based total intravenous anesthesia (TIVA) may be associated with a lower incidence of early POCD compared to volatile anesthetics, although results are heterogeneous across surgical populations and follow-up durations (18,19). Depth of anesthesia also emerged as an important factor, with excessively deep levels (EEG burst suppression) linked to worse cognitive outcomes irrespective of anesthetic choice (20). The intraoperative stress response, characterized by elevations in cortisol, catecholamines, and inflammatory cytokines, showed a consistent association with POCD. Higher perioperative cortisol and IL-6 levels were observed in patients who developed cognitive decline, particularly following major and cardiac surgeries (27,28). Importantly, interventions that attenuate the stress response—such as the use of dexmedetomidine or optimized multimodal analgesia—showed promising reductions in early cognitive dysfunction (30–32). Taken together, these findings suggest a mechanistic interplay where anesthesia technique not only influences neurotoxicity and oxidative stress but also modulates the surgical stress response, thereby impacting the risk of POCD. b. Physiological mechanisms underlying POCD The pathways linking anesthesia and surgical stress to POCD are multifactorial. Volatile anesthetics have been shown in experimental models to enhance amyloid-beta production, tau phosphorylation, and microglial activation, thereby accelerating neurodegenerative-like processes (14,15). In contrast, propofol demonstrates antioxidant and anti-inflammatory properties, supporting its potential neuroprotective role (18). Neuroinflammation is a central mechanism, with systemic cytokines crossing a compromised blood–brain barrier (BBB) and triggering microglial activation in the hippocampus and prefrontal cortex (11–13). Oxidative stress exacerbates this injury through mitochondrial dysfunction and apoptosis. In addition, stress hormone signaling via the hypothalamic–pituitary–adrenal (HPA) axis plays a major role. Elevated perioperative cortisol impairs hippocampal neurogenesis and long-term potentiation, while catecholamine surges disrupt cerebral autoregulation and neurotransmitter balance (23,29). Emerging evidence also suggests potential genetic and environmental contributions. Polymorphisms in genes regulating inflammation and stress pathways (e.g., IL-6, APOE ε4) may increase susceptibility, while environmental factors such as frailty, educational level, and baseline cognitive reserve modify risk (7,8,10). c. Clinical implications The findings of this review have direct implications for perioperative care. First, careful selection and titration of anesthetic technique is important: while no single agent can be universally recommended, propofol-based TIVA may be preferable in high-risk elderly patients, provided depth of anesthesia is optimized. Second, stress response modulation should be prioritized. This includes multimodal analgesia to blunt nociceptive input, minimizing surgical trauma where possible, and the use of adjuncts such as dexmedetomidine or regional blocks, which can reduce sympathetic activation and inflammatory cascades (30–32). For high-risk populations, such as patients over 70 years, those with pre-existing cognitive impairment, cerebrovascular disease, or prolonged surgical duration, perioperative strategies should include preoperative screening, close intraoperative monitoring of cerebral perfusion and oxygenation, and structured postoperative delirium prevention protocols (9,10). d. Limitations of the review This review has several limitations. First, the existing literature is heterogeneous, with variable definitions of POCD and differing neuropsychological tests, limiting cross-study comparability (7). Second, most trials assess short-term cognitive outcomes, with relatively few evaluating persistence beyond three months. Third, while biomarkers such as cortisol and IL-6 are frequently studied, their measurement timing and thresholds are inconsistent, which may confound associations. Finally, as in all systematic reviews, there is the possibility of publication bias, with smaller negative studies less likely to be published (27).

a. Overall conclusions POCD is a significant perioperative complication with a complex physiological basis involving neuroinflammation, oxidative stress, blood–brain barrier dysfunction, and HPA-axis dysregulation. Both anesthesia techniques and the intraoperative stress response play central roles in modulating these mechanisms. While propofol-based TIVA may offer some neuroprotective benefits compared with volatile agents, and interventions to blunt the stress response show promise, the current evidence does not establish a single superior approach for all patients. b. Future directions Future research should focus on longitudinal trials with standardized cognitive assessments to clarify the long-term impact of anesthetic techniques. Mechanistic studies integrating biomarkers, neuroimaging, and genetic profiling are needed to identify vulnerable patients and therapeutic targets. In addition, trials of stress-modulating interventions—such as pharmacologic anti-inflammatory strategies or structured anesthetic protocols—should be prioritized. Ultimately, the integration of personalized anesthetic care with perioperative cognitive protection strategies holds the potential to reduce the burden of POCD and improve outcomes for the growing elderly surgical population.

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