Microglia, the resident immune cells of the CNS, play a crucial role in maintaining CNS homeostasis. Similar to peripheral macrophages, microglia are responsible for clearing cellular debris and promoting neuronal survival (19). However, in the elderly, microglia often undergo age-related changes, including a shift towards a pro-inflammatory phenotype. This imbalance in the production of pro- and anti-inflammatory cytokines creates a neurotoxic environment within the CNS, contributing to neuronal damage and dysfunction (20). Further research is needed to understand the specific microglial alterations that contribute to PND and to identify potential therapeutic targets to modulate microglial activation.

Astrocytes, the most abundant glial cells in the CNS, are essential for maintaining neuronal health and function. They play a vital role in transporting essential nutrients, such as glucose and lactate, to neurons and regulating the extracellular environment by controlling glutamate levels (21). As brain ages, astrocytic functions deteriorate, leading to disruptions in energy metabolism and an accumulation of neurotoxic glutamate (22). This disruption in astrocytic function can further contribute to the neuroinflammatory processes implicated in PND. Investigating the specific mechanisms by which aging affects astrocytes and their contribution to PND is a crucial area for future research.

A key area of investigation focuses on the differential effects of GA versus non-GA (regional or local anesthesia) on PND. GA agents cross the BBB and suppress CNS activity, potentially contributing to neurocognitive decline. However, the extent and duration of these effects remain debated.

A meta-analysis by Gao et al. (27) examined seven randomized controlled trials (RCTs) involving 1,031 patients (526 in the GA group and 505 in the non-GA group) to assess the impact of anesthesia type on PND. The results showed that PND incidence was significantly higher in GA patients in the early postoperative period. On postoperative day one, three studies reported a nearly fourfold increase in PND risk in GA patients. By day three, two studies confirmed an increased risk, with GA patients experiencing twice the likelihood of PND. However, by day seven, five studies found no significant difference between groups, and at 3 months, two studies reported comparable PND incidence. These findings suggest that GA-related cognitive impairment is primarily transient, affecting patients in the immediate postoperative period but resolving over time.

Another area of focus involves comparing the effects of propofol-based total intravenous anesthesia (TIVA) versus inhalational anesthetics such as sevoflurane or isoflurane on PND in elderly patients. Pang et al. (28) conducted a meta-analysis of 15 RCTs involving 1,854 elderly patients undergoing non-cardiac surgery, evaluating PND incidence and postoperative cognitive status at different time points.

Their findings suggested that propofol anesthesia was associated with a lower risk of early PND. Between postoperative days 2 and 6, patients receiving propofol had a significantly lower incidence of PND compared to those receiving inhalational anesthesia. Additionally, Mini-Mental State Examination (MMSE) scores were higher in the propofol group, suggesting better postoperative cognitive function. The analysis also showed that propofol anesthesia was linked to lower levels of systemic inflammation, with reduced Interleukin-6 (IL-6) and Tumor Necrosis Factor-alpha (TNF-α) compared to inhalational agents.

Depth of anesthesia (DoA), the level of unconsciousness during GA, is achieved through anesthetic agents that suppress CNS activity, reducing responsiveness to stimuli. Traditionally, DoA assessment relied on subjective methods such as monitoring vital signs and patient movement, which are prone to bias and inaccuracy, sometimes leading to intraoperative awareness and psychological distress, including Posttraumatic stress disorder (48). This underscores the need for objective and precise monitoring, particularly in elderly patients, who are more sensitive to anesthetics and require lower doses to achieve the same level of unconsciousness. The development of EEG-based monitoring, such as the BIS monitor, has significantly improved anesthesia precision and safety by providing a numerical value (0–100) that correlates with anesthesia depth (49, 50). Maintaining an optimal BIS range of 40–60 during surgery balances anesthesia with reduced intraoperative and postoperative complications, including a lower risk of awareness (51), attenuated inflammatory responses (52) and a decreased incidence of PND.

Numerous studies suggest that excessive anesthesia depth is more strongly associated with PND than insufficient anesthesia. A sub-analysis of the BALANCED study (53) found that light anesthesia (BIS 50) resulted in a lower incidence of POD (19% vs. 28%) compared to deep anesthesia (BIS 35). This is particularly significant in elderly patients, as deeper anesthesia has been linked to greater neurocognitive impairment due to increased anesthetic sensitivity. Similarly, a Cochrane review (54) and a meta-analysis (55) support BIS-guided light anesthesia as a strategy to reduce POD, reinforcing its neuroprotective role in the elderly.

However, some studies present conflicting findings. The ENGAGES trial (56) recorded only a mild reduction in POD incidence with BIS monitoring (26% vs. 23%). Likewise, a meta-analysis by Wang et al. (57) found no consistent correlation between light anesthesia (BIS 50) and lower POD incidence compared to deeper anesthesia (BIS 35). These discrepancies suggest that while BIS monitoring optimizes anesthesia depth, its direct impact on PND prevention remains debated.

Despite this, BIS monitoring remains particularly valuable in elderly patients, who face a higher risk of PND, intraoperative awareness, and prolonged recovery. Given age-related changes in drug metabolism and anesthetic sensitivity, BIS helps prevent both under-sedation and over-sedation, minimizing neurocognitive complications. Integrating BIS into anesthesia protocols for older adults offers benefits beyond PND prevention, including reduced anesthetic exposure and enhanced postoperative recovery.

Intraoperative hypotension (IOH), defined as a systolic blood pressure (SBP) below 90 mmHg or a mean arterial pressure (MAP) below 60 mmHg, is a common complication during surgical procedures and anesthesia (58). Various factors contribute to IOH, including the effects of anesthetic agents, hypovolemia, and patient positioning (59). IOH significantly compromises perfusion to vital organs, and if left untreated, can lead to serious complications, including myocardial infarction (MI), cerebrovascular events, and acute kidney injury (AKI) (60, 61). Given the age-related decline in cerebrovascular autoregulation, elderly patients are particularly susceptible to the adverse effects of IOH. Reduced vascular elasticity, impaired baroreceptor sensitivity, and pre-existing comorbidities such as hypertension increase their vulnerability to cerebral hypoperfusion, potentially exacerbating postoperative neurocognitive impairment.

Researchers have hypothesized a link between IOH and PND, particularly in elderly patients, where compromised cerebral perfusion may increase POD and long-term cognitive decline (62). Some studies support this association, particularly when IOH episodes are prolonged. For instance, Mohr et al. (63) found that IOH episodes lasting more than 2 min were associated with a higher incidence of POD following cardiac surgery. Additionally, Krzych et al. (64) proposed targeting IOH as a modifiable risk factor for PND, reinforcing the importance of maintaining stable blood pressure during surgery. However, many of these studies are retrospective, limiting their ability to establish causality.

Conversely, other studies have failed to demonstrate a significant correlation between IOH and subsequent neurological dysfunction. Langer et al. (65) compared non-cardiac surgical patients with targeted higher MAP maintenance to a control group without targeted MAP management, finding no significant difference in PND incidence between the two groups. Similarly, a post-hoc analysis of the DECADE trial reported a negative association between IOH and POD (66). These conflicting findings suggest that the relationship between IOH and PND remains complex, potentially influenced by patient-specific factors such as cerebral autoregulation, pre-existing cognitive impairment, and individual susceptibility to hypoperfusion.

While current evidence does not definitively establish a causal link between IOH and PND, maintaining adequate intraoperative blood pressure is particularly critical in elderly patients. Given their reduced physiological reserve, strategies should focus on personalized blood pressure management, avoiding both hypotension, which may exacerbate cerebral ischemia, and excessive hypertension, which could increase the risk of cerebrovascular complications.

Hypothermia, defined as a core body temperature below 36°C, is a common occurrence in surgical patients (67). Several factors contribute to intraoperative hypothermia, including the effects of anesthesia, cool operating room temperatures, and heat loss during surgical procedures (68). Hypothermia is associated with various adverse postoperative outcomes, including coagulopathy, delayed wound healing, and increased risk of surgical site infections (SSIs) (69). These complications highlight the importance of effective perioperative warming strategies, particularly in elderly patients, who are more vulnerable to hypothermia due to impaired thermoregulation, reduced metabolic heat production, and altered vasomotor responses.

Perioperative warming techniques can be broadly categorized as active or passive. Active methods, such as forced-air warming systems and heated intravenous fluids, actively raise core body temperature, while passive methods rely on thermal insulation to minimize heat loss (70). Maintaining normothermia perioperatively has been consistently linked to reduced rates of wound infections, shivering, intraoperative blood loss, and even mortality (71, 72). Given that elderly patients experience greater difficulty in maintaining core body temperature, proactive temperature management is particularly crucial in reducing their perioperative risks.

However, the relationship between perioperative temperature and neurocognitive outcomes remains complex, particularly in the elderly. While normothermia is generally preferred, some studies suggest that mild hypothermia (34–35°C) may have neuroprotective effects in certain high-risk surgical contexts. RCTs have indicated that inducing mild hypothermia can reduce brain injury following aortic dissection repair and improve cognitive outcomes after cardiopulmonary bypass (CPB) (73, 74). These findings suggest that targeted temperature modulation could potentially benefit older adults undergoing specific high-risk procedures. Conversely, other studies have demonstrated a positive correlation between intraoperative hypothermia and the development of POD (75–77).

Elderly patients are already at increased risk for PND, and intraoperative hypothermia may exacerbate neurocognitive dysfunction by impairing cerebral autoregulation and reducing metabolic activity in the brain. However, inconsistencies in the literature regarding the impact of hypothermia on PND may be due to variations in surgical procedures, patient demographics, and differences in PND diagnostic criteria.

An Enriched Environment (EE) consists of cognitive, sensory, and social stimuli that enhance brain function. EE has been shown to improve memory, learning, attention, mood, and overall cognitive resilience (8, 78). The mechanisms underlying EE’s benefits include increased neuroplasticity, synaptogenesis, and neurogenesis, which may be particularly valuable in mitigating age-related cognitive decline and neurodegenerative diseases.

Numerous animal studies highlight EE’s cognitive benefits in aging. Speisman et al. (79) demonstrated that aged rats housed in EE exhibited better cognitive functions potentially via enhanced hippocampal neurogenesis and modulating neuroimmune cytokine signaling. Similarly, Mate et al. (80) found that EE reduced tau pathology and neurodegeneration, suggesting a potential neuroprotective role against age-related cognitive impairment. Speisman et al. (81) reported that EE improved synaptic plasticity and reduced oxidative stress in aging rodents, reinforcing its role in preserving cognitive function. These findings suggest that EE may slow cognitive decline and could be particularly relevant for elderly populations at risk of PND, dementia, or postoperative cognitive dysfunction.

While much of the clinical research on EE has focused on early development (82, 83), an increasing number of studies suggest its potential cognitive benefits in aging. For instance, one meta-analysis found that virtual reality-based exergames, an enriched and interactive form of cognitive and physical stimulation, significantly improve overall cognitive function, memory, and depressive outcomes in older adults, with greater effects observed in interventions of longer duration (84). Similarly, a randomized trial showed physical, cognitive, and combined training enhance cognition differently—physical training sustained concentration gains, cognitive training improved cognitive speed over time, and combined training had immediate and lasting benefits (85). These findings highlight the diverse yet complementary effects of enriched interventions in aging.

In older adults, these mechanisms could be particularly beneficial in mitigating PND and long-term postoperative cognitive dysfunction. However, clinical trials specifically targeting EE interventions in the elderly remain limited. While the evidence for EE’s cognitive benefits is compelling, further research is needed to optimize EE protocols for elderly individuals and assess their long-term effects on postoperative cognitive function.

Acupuncture, a therapeutic modality originating from Traditional Chinese Medicine (TCM), involves the insertion of thin needles into specific points on the body. While its precise mechanisms remain under investigation, recent studies suggest that acupuncture modulates neuronal activity, connective tissue, and muscle fibers (86, 87). These effects may influence neurotransmission, inflammation, and cerebral blood flow, factors that are particularly relevant to cognitive health in elderly patients, who are more susceptible to neuroinflammation and vascular impairment.

Beyond its well-established role in pain management (88, 89) and treatment of various medical conditions (90, 91), acupuncture has gained interest as a potential non-pharmacological intervention for cognitive enhancement. Emerging research suggests that acupuncture may positively influence memory, attention, and executive function, with applications in neurodegenerative and vascular conditions such as Alzheimer’s disease (92), Parkinson’s disease (93), post-stroke cognitive impairment (94), and vascular dementia (95). Given the age-related decline in cognitive function and increased risk of PND in the elderly, acupuncture could serve as a potential adjunct therapy to mitigate cognitive impairment following surgery.

In the postoperative period, acupuncture presents a cost-effective and low-risk intervention for reducing PND in older adults, a population particularly vulnerable to surgery-related cognitive decline. A review by Ho et al. (96) examined trials from 2009 to 2018, encompassing both clinical and preclinical studies. While the quality of evidence varied, findings indicated that acupuncture reduced inflammatory biomarkers, including S100β, Neuron-Specific Enolase (NSE), IL-6, and TNF-α, compared to controls. Given that neuroinflammation and oxidative stress play key roles in PND pathogenesis, these findings suggest a potential neuroprotective mechanism for acupuncture in surgical patients, particularly the elderly.

Dexmedetomidine (DEX), a selective alpha-2 adrenergic agonist, is widely used as a sedative and anesthetic adjunct (97). Unlike traditional sedatives, DEX modulates sympathetic outflow, reducing norepinephrine release to induce sedation while preserving respiratory function (98).

Beyond its sedative and analgesic effects, DEX exerts anti-inflammatory properties. Preclinical studies demonstrate its ability to attenuate systemic inflammation. Zhang et al. (30) found that DEX reduced sepsis-induced organ injury by increasing IL-10 and nuclear receptor 77, while suppressing TNF-α and IL-1β. Similarly, Gao et al. (99) reported reduced neuroinflammation and preserved white matter in spinal cord-injured rats, effects reversed by α2-adrenergic receptor antagonism. Clinical evidence supports these findings; a sub-analysis of the DESIRE trial showed significantly lower C-reactive protein (CRP) and procalcitonin levels in DEX-treated sepsis patients (100).

These anti-inflammatory properties have led to investigations into DEX’s role in preventing PND, particularly in elderly surgical patients. Shin et al. (47) compared DEX-based vs. propofol-based sedation in elderly patients undergoing lower limb surgery, reporting a significantly lower incidence of POD in the DEX group, though with lower MAP and heart rate (HR) in the post-anesthesia care unit (PACU). Similarly, Ge et al. (101) found that DEX infusion improved cognitive function post-carotid endarterectomy (CEA), with higher MMSE and MoCA scores and reduced IL-6 and TNF-α levels in the first 72 h. While Brain-Derived Neurotrophic Factor levels were initially similar across groups, only the placebo group returned to baseline after 24 h. Further supporting this, Tang et al. (102) demonstrated that sufentanil plus DEX reduced POD incidence and severity after thoracoscopic-laparoscopic esophagectomy (TLE), accompanied by lower IL-6 and TNF-α, and higher IL-10 at 24 h postoperatively.

DEX’s mechanism, anti-inflammatory properties, and favorable safety profile make it a promising agent for PND prevention, particularly in the elderly and those with pre-existing cognitive impairment. Future research should refine optimal dosing strategies to maximize cognitive benefits while mitigating hemodynamic effects.

Parecoxib sodium, a selective cyclooxygenase-2 (COX-2) inhibitor, is a potent analgesic and anti-inflammatory agent widely used in perioperative care (103). As the only injectable COX-2 inhibitor, it undergoes rapid hepatic metabolism to its active form, valdecoxib, and is typically administered intravenously or intramuscularly for acute pain management. Parecoxib sodium’s COX-2 selectivity provides effective pain relief while minimizing gastrointestinal and renal complications compared to non-selective NSAIDs (104).

Surgical stress-induced systemic inflammation is implicated in PND pathogenesis (105). Given parecoxib sodium’s anti-inflammatory properties, studies have investigated its neuroprotective effects in elderly surgical patients. Mu et al. (106) conducted a multicenter, double-blind RCT in elderly orthopedic patients under spinal anesthesia, finding that PND incidence decreased from 11 to 6.2% when parecoxib sodium was added to a postoperative morphine regimen. Similarly, Zhu et al. (107) examined elderly knee arthroplasty patients, reporting lower PND incidence at 1 week (16.7% vs. 33.9%), improved POP relief within the first 12 h, and reduced IL-1β, IL-6, and TNF-α plasma levels. However, differences in 3-month PND incidence and CRP levels were not statistically significant.

Parecoxib sodium offers potent analgesia, reduced opioid reliance, and a favorable safety profile in the perioperative setting. While its neuroprotective role in PND prevention remains promising, further high-quality trials are needed to establish definitive benefits and optimize perioperative anti-inflammatory strategies for elderly surgical patients at risk of PND.

Dexamethasone, a synthetic glucocorticoid, is widely used in perioperative care due to its anti-inflammatory, immunomodulatory, analgesic, antiemetic, and anti-shivering properties (108–111). These effects contribute to improved postoperative recovery by reducing inflammation, nausea, pain, and thermoregulatory disturbances, making dexamethasone a valuable adjunct in multimodal anesthesia protocols (112).

Dexamethasone’s anti-inflammatory and neuroprotective properties have led to increasing interest in its potential role in reducing PND. Inflammation is a key contributor to PND pathogenesis, and glucocorticoids like dexamethasone may mitigate surgery-induced neuroinflammation, thereby improving postoperative cognitive outcomes. Several studies have examined dexamethasone’s impact on PND and POD in elderly surgical patients. Huang et al. (113) found that a single 10 mg dose of dexamethasone significantly reduced POD incidence compared to placebo in elderly patients undergoing intertrochanteric fracture surgery. Similarly, Kluger et al. (114) reported that a 20 mg dose reduced PND severity scores in hip fracture patients, though it did not significantly alter overall PND incidence.

These findings suggest that while dexamethasone may not completely prevent PND, it could help reduce its severity, potentially improving functional recovery and quality of life in elderly surgical patients. The mechanisms underlying dexamethasone’s neuroprotective effects remain an area of active investigation. Proposed pathways include suppression of pro-inflammatory cytokines (IL-6, TNF-α, IL-1β), reduction of blood–brain barrier dysfunction, and attenuation of neuroinflammation-induced oxidative stress (115, 116).

Dexamethasone’s broad-spectrum perioperative benefits, including its anti-inflammatory, analgesic, and antiemetic effects, make it a strong candidate for inclusion in perioperative anesthetic plans. Given its favorable safety profile with short-term use, dexamethasone represents a promising intervention for reducing PND risk. However, future studies should focus on determining the optimal dosage, particularly in elderly patients, to maximize its neuroprotective benefits while minimizing potential side effects.

Melatonin, a pineal gland hormone, regulates the sleep–wake cycle and influences mood, immune function, and cognitive health through its widespread CNS and peripheral receptor distribution including the retina, GIT, and immune cells (117, 118). Exogenous melatonin has demonstrated benefits in insomnia, depression, anxiety, and migraines, with evidence suggesting neuroprotective effects in Alzheimer’s and Parkinson’s disease (119–121).

Sleep disturbances are common in surgical patients, with preoperative insomnia rates up to 79% (122). Melatonin supplementation improves sleep quality, reduces anxiety, and enhances recovery (123, 124). Its antioxidant and anti-inflammatory properties may also protect against PND (125, 126). A meta-analysis indicated melatonin reduces PND incidence, though results vary (127). For Elbakry et al. (128) found that 5 mg oral melatonin preoperatively reduced POD in elderly colorectal surgery patients, whereas Ford et al. (129) observed no effect with 3 mg in cardiac surgery, suggesting dose and surgical context may influence efficacy.

Melatonin shows potential for PND prevention, particularly in elderly patients, by addressing sleep disturbances and reducing neuroinflammation. Further research should optimize dosing and administration timing to enhance its perioperative neuroprotective benefits.

Minocycline, a semisynthetic tetracycline antibiotic, is used for bacterial infections and has shown potential in treating chronic pain, epilepsy, and diabetic neuropathy due to its anti-inflammatory, anti-apoptotic, and immunomodulatory properties (130–132). Its lipophilic nature allows it to cross the BBB, suggesting neuroprotective effects (133, 134).

Animal studies indicate that minocycline regulates microglia, astrocytes, and neurons, inhibiting microglial activation and reducing pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 (135, 136). Li et al. (137) demonstrated that older rats exposed to isoflurane anesthesia exhibited lower neuroinflammatory marker levels with minocycline treatment. However, some studies caution that while minocycline initially inhibits microglial activation, delayed microgliosis may negatively affect the hippocampus, potentially impairing long-term cognitive function (138).

Regarding PND, Liang et al. (139) suggested minocycline may mitigate anesthetic-induced cognitive impairment by protecting against sevoflurane-induced neuroinflammation. However, an RCT conducted by Takazawa et al. (140) in elderly knee arthroplasty patients found no significant difference in PND incidence or postoperative pain between minocycline and control groups. These conflicting results highlight the uncertain clinical efficacy of minocycline in perioperative neuroprotection.

While preclinical studies support minocycline’s neuroprotective and anti-inflammatory properties, clinical evidence remains inconclusive. Further rigorous trials are needed to clarify its efficacy in preventing PND, particularly in elderly surgical patients. Understanding optimal dosing, treatment duration, and patient selection will be essential in determining minocycline’s role in perioperative neuroprotection.