General anesthesia is a common anesthetic protocol for abdominal surgery, rendering patients pain-free and providing optimal conditions for surgical procedures. However, due to diminished organ compensatory capacity, reduced physiological reserve, and decreased tolerance in elderly patients, combined with the effects of anesthetic agents themselves, surgical trauma, and stress response, they are prone to a series of postoperative complications, among which Postoperative Cognitive Dysfunction (POCD) is the most prevalent (Kitthanyateerakul et al., 2024; Viderman et al., 2023). The occurrence of POCD not only prolongs the patient’s recovery process and increases medical costs but also reduces their postoperative quality of life, adversely affects prognosis, and imposes a substantial burden on families and society (Suraarunsumrit et al., 2024). Sevoflurane is a modern inhalational anesthetic agent. It produces sedative, hypnotic, and muscle relaxant effects by interfering with signal transduction at the neuromuscular junction, inhibiting the central nervous system and excitatory transmission between nerve cells, thereby reducing the brain’s responsiveness to external stimuli (Xu et al., 2013; Zhu et al., 2023). Owing to its advantages such as rapid induction, fast metabolism, and smooth emergence, sevoflurane is widely used for anesthetic maintenance in elderly patients.

As a significant stressor, postoperative pain can activate the hypothalamic-pituitary-adrenal axis, thereby triggering a rise in cortisol that promotes neuronal atrophy and apoptosis—processes that ultimately impair cognitive function (Cao et al., 2023). Pain sensitivity reflects an individual’s tolerance and response to noxious stimuli and serves as a crucial indicator for assessing anesthetic quality and postoperative outcomes. Studies have confirmed that the perioperative use of agents such as sevoflurane may alter postoperative pain sensitivity by influencing central sensitization processes. Furthermore, changes in pain sensitivity can subsequently impact cognitive function via neuroendocrine stress responses (Zeng et al., 2023). Currently, clinical research quantitatively elucidating the relationship between sevoflurane inhalation concentration and cognitive function and pain sensitivity, particularly in high-risk populations like elderly patients undergoing abdominal surgery, remains insufficient (Laferrière-Langlois et al., 2024). Some studies support the conclusion that sevoflurane inhalation may cause potential damage to the central nervous system through various mechanisms, including inducing neuroinflammation, modulating neurotransmitters, and promoting ββ-amyloid protein deposition (Yang et al., 2024). Conversely, other research indicates that sevoflurane helps maintain cerebral oxygen balance during cardiopulmonary bypass and ameliorates cognitive impairment in a dose-dependent manner (Hu et al., 2014). Therefore, this study aims to analyze the relationship between end-tidal sevoflurane concentration during general anesthesia and postoperative cognitive function and pain sensitivity in elderly patients, with the goal of informing the optimization of sevoflurane anesthesia protocols for this population and reducing the risk of POCD.

POCD primarily manifests as decline in central nervous system functions such as attention, executive function, and memory. Its pathogenesis remains incompletely understood but is considered to be primarily associated with factors such as localized hypoxia, surgical trauma, pain, and imbalances in neurotransmitters (Varpaei et al., 2024). An a large-scale meta-analysis involving 12,921 elderly non-cardiac surgery patients, the incidence of POCD demonstrated a declining trend over time, with rates of 23% at 1 week, 16% at 1 month, and 10% at 3 months postoperatively, the incidence of POCD on day 7 was significantly higher after abdominal surgery compared to orthopedic surgery (β = 0.13, 95% CI: 0.03–0.22, P = 0.01) (Huang et al., 2025). Therefore, perioperative cognitive management in elderly patients undergoing abdominal surgery, as a high-risk population for POCD, has become a significant challenge and a key research focus in the field of perioperative medicine. This study administered sevoflurane to elderly patients undergoing general anesthesia for abdominal surgery, observing the effects of different sevoflurane concentrations on cognitive function and pain sensitivity, aiming to provide targeted evidence-based guidance for clinical anesthetic management.

Sevoflurane is an inhalational anesthetic agent, and its safety profile and impact on cognitive function in elderly patients remain subjects of debate (Zhao et al., 2022). An animal study demonstrated that repeated sevoflurane exposure in rats disrupts the tPA/PAI-1 fibrinolytic system balance, thereby impeding the conversion of proBDNF to mature BDNF, low BDNF expression subsequently inhibits the activation of the downstream tropomyosin-related kinase B (TrkB) signaling pathway and reduces hippocampal synaptic plasticity, thereby inducing POCD (Dong et al., 2020). Another study involving 192 patients undergoing laparoscopic surgery maintained anesthesia with inhaled sevoflurane combined with remifentanil. The results showed that on the day of surgery, the mean MMSE score in Group II (40 < BIS ≤ 50) was 29.00 ± 0.89, significantly higher than the 28.336 ± 1.42 in Group I (30 < BIS ≤ 40), indicating that a relatively deeper level of anesthesia had a milder impact on postoperative cognitive function (Shu et al., 2015). The present study found that while the high-concentration group had longer emergence time, time to orientation recovery, spontaneous breathing recovery time, and extubation time compared to the low-concentration group, they also exhibited higher MMSE scores on postoperative days 1 and 3, and a lower incidence of POCD. This suggests that a higher concentration of sevoflurane, despite prolonging recovery times, can mitigate the suppressive effect of general anesthesia on cognitive function and reduce the occurrence of POCD. Serum levels of NSE and ApoJ increased and NGF decreased on postoperative day 1 in both groups compared to their preoperative baselines. However, the high-concentration group demonstrated lower postoperative serum NSE and ApoJ levels, and higher NGF levels, than the low-concentration group. This indicates that while general anesthesia for abdominal surgery causes some degree of neurological impairment, a higher concentration of sevoflurane plays a positive role in alleviating neuronal damage and promoting neural repair. The potential reasons are hypothesized as follows: (1) Sevoflurane pretreatment or exposure might upregulate the expression of superoxide dismutase and glutathione peroxidase by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, thereby enhancing antioxidant enzyme activity, mitigating oxidative stress induced by surgical trauma or the anesthetic itself, providing neuronal protection, and consequently reducing the risk of POCD (Varpaei et al., 2024; Zhou et al., 2016). (2) Sevoflurane can inhibit the activation of nuclear factor kappa B (NF-κB), downregulate the expression of NF-κB-dependent inflammatory genes, suppress the release of inflammatory mediators, and thus alleviate inflammation-related neurological damage (Peipei et al., 2022). Pearson correlation analysis in this study revealed that the end-tidal sevoflurane concentration was positively correlated with the MMSE score and NGF levels, and negatively correlated with NSE and ApoJ levels on postoperative day 1. Furthermore, a high sevoflurane concentration [OR: 0.182 (95% CI: 0.056–0.590)] was identified as a protective factor against POCD in elderly patients undergoing abdominal surgery under general anesthesia. This further confirms the close relationship between sevoflurane concentration and postoperative cognitive function, suggesting that appropriately increasing the sevoflurane concentration might be a feasible neuroprotective strategy. In this study, remifentanil dosage in both groups was adjusted based on BIS and MAP fluctuations, and a standardized PCIA regimen was used postoperatively. Statistical analysis confirmed no significant difference in remifentanil consumption between the groups. Furthermore, patients using benzodiazepines, ketamine, or similar medications preoperatively were excluded, and these drugs were not administered intraoperatively. This suggests that differences in analgesic medication use were not the primary factor contributing to the observed POCD differences between the groups.

This study found that the high-concentration group exhibited lower PSQ scores, smaller medial arm and incisional mechanical hypersensitivity areas, and higher medial arm and incisional mechanical hypersensitivity thresholds on postoperative day 1 compared to the low-concentration group. Furthermore, the end-tidal sevoflurane concentration was significantly correlated with the PSQ score, mechanical hypersensitivity thresholds, and mechanical hypersensitivity areas. These results indicate that a higher concentration of sevoflurane helps reduce postoperative pain sensitivity and mechanical hypersensitivity areas while elevating pain thresholds in patients, suggesting it plays an important role in inhibiting hyperalgesia and central sensitization. The underlying mechanisms may involve the following aspects: On one hand, sevoflurane can act directly on the central nervous system, modulating N-methyl-D-aspartate (NMDA) receptor activity and interfering with pain signal transmission (Guo et al., 2024; Xie et al., 2024). On the other hand, data from this study demonstrate that a higher concentration of sevoflurane suppresses the postoperative release of pain mediators (PGE2, 5-HT), thereby alleviating pain sensitivity.

Painful stress promotes excessive activation of the hypothalamic-pituitary-adrenal (HPA) axis, leading to elevated cortisol levels. Excessively high cortisol levels exert toxic effects on hippocampal neurons, thereby impairing learning ability and spatial memory (Cao et al., 2024). Furthermore, pain promotes overactivation of central nervous cells and the release of large quantities of inflammatory factors, exacerbates sympathetic nerve excitability, and impairs the capacity for information exchange between brain cells. This consequently leads to cerebral hypoxia-ischemia and disruption of the cerebral microcirculation (Irvine and Clark, 2018). The multivariate logistic regression model established in this study identified elevated preoperative day 1 levels of PGE2 and 5-HT as risk factors for POCD in elderly patients after general anesthesia, supporting the aforementioned theory. Additionally, a domestic study reported that the PSQ score correlates with postoperative pain intensity, and pain sensitivity can effectively predict the occurrence of chronic postoperative pain and neuropathic pain (Wu et al., 2023). This demonstrates that pain sensitivity indirectly influences patients’ cognitive function. In this study, the high sevoflurane concentration reduced pain sensitivity and mechanical hypersensitivity in elderly patients undergoing abdominal surgery under general anesthesia, thereby interrupting the pathological process of “pain-stress-cognitive impairment” and consequently exerting a neuroprotective function after general anesthesia.

The concentration of sevoflurane during general anesthesia in elderly patients is closely associated with postoperative cognitive function and pain sensitivity. A higher sevoflurane concentration can reduce pain sensitivity, inhibit the expression of pain mediators and neurological damage markers, alleviate cognitive impairment, and serves as a protective factor against the development of POCD. Several limitations must be acknowledged. Firstly, the single-center observational design and limited sample size may introduce confounding biases. Consequently, our results require confirmation from future multi-center, large-sample randomized controlled trials. This study did not include other inhalational or intravenous anesthetics as controls, making it difficult to entirely exclude the potential for cross-drug interactions. Furthermore, the incidence of POCD was only recorded up to postoperative day 3; it is recommended that future studies extend the follow-up period to observe the medium- and long-term effects of sevoflurane on cognitive function in elderly patients after general anesthesia. Additionally, as an observational association study, while correlations were established, causality cannot be definitively determined. ASA III elderly patients are common in clinical practice. However, due to their reduced organ functional reserve and higher burden of comorbidities, their anesthesia tolerance and postoperative recovery characteristics differ from those of ASA I-II patients. The impact of sevoflurane concentration on POCD and pain sensitivity in this specific population remains unclear, which may limit the generalizability of our findings. Future studies specifically targeting ASA III elderly patients are needed to further validate the clinical application value of sevoflurane concentration. The specific mechanisms through which sevoflurane influences cognitive function and pain sensitivity were not thoroughly investigated; future studies incorporating basic science experiments are needed to further elucidate the precise mechanisms of action at the signaling pathway and molecular levels.