Sepsis-associated encephalopathy (SAE), a common complication of sepsis, is characterized by cognitive dysfunction, changes in mental status, and delirium (1, 2). The prevalence of SAE in septic patients ranges from 8 to 70%, depending on the criteria used to define SAE (2, 3). SAE denotes alterations in consciousness that lack direct proof of infection in the central nervous system. Compared with sepsis patients without SAE, SAE patients are associated with elevated mortality, increased utilization of intensive care unit (ICU) resources, and prolonged hospitalization (4). Furthermore, mortality increases with the severity of SAE and is almost 70% in severe SAE patients (5). Identifying modifiable factors that affect mortality in SAE is important for improving the prognosis of SAE and lessening the disease burden.

An essential aspect of SAE treatment is the appropriate management of systemic infections, sepsis, and systemic inflammatory response syndrome (6). Plausible mechanisms of SAE include neuroinflammation, disruption of the blood–brain barrier, alteration of cerebral microcirculation, and oxidative stress (7). Owing to the favorable anti-inflammatory, antioxidative, and immunomodulatory effects of statins, they have been investigated as a cost-effective and feasible alternative or adjunctive host-directed therapy for infectious diseases (8). In animal models, atorvastatin exerted anti-inflammatory and antioxidant effects in the cerebral cortex (9). Simvastatin, by exerting a neuroprotective role, effectively mitigates long-term cognitive impairments in rats that survived sepsis (10). Lee et al. (11) reported the administration of either atorvastatin or simvastatin before sepsis showed an association with enhanced survival rates at the 30-day survival. Rosuvastatin also was protective against SAE (12). In another study, statin use was associated with lower odds of 30-day and 90-day mortality in patients hospitalized with sepsis (13). In early sepsis, statin use in the ICU was associated with reduced delirium, with delirium being a performance indicator of SAE (14).

Statins have been recommended as a treatment for SAE; however, the effect of statins on the prognosis of SAE remains unexplored. We aimed to investigate the relationship between statin use and 30-day mortality in SAE patients and further explore the effects of different types of statins.

We investigated the association between statin use and 30-day mortality among patients with SAE. Our findings indicated that statin use was associated with a lower 30-day mortality risk in all SAE patients. Furthermore, when compared to patients who received atorvastatin treatment, rosuvastatin treatment was associated with higher odds of 30-day mortality in SAE patients who received statin treatment. An association between statin use and a lower risk of 30-day mortality was also found in SAE patients aged <65 years old and SIRS <3. Furthermore, the findings revealed a relationship between rosuvastatin treatment and a higher risk of 30-day mortality in specific patient groups, including those aged ≥65 years old, male, SOFA ≥8, SAPS II ≥44, and SIRS ≥3.

In the SAE population, our findings revealed a potential benefit associated with statin use. The findings were consistent with some existing studies that suggested that statins, through their pleiotropic effects beyond lipid-lowering, may have potential immunomodulatory and anti-inflammatory properties that could be beneficial in sepsis (20–22). In the case of sepsis patients admitted to the medical ICU, the usage of statins before ICU admission was causally linked to a reduction in both 30-day ICU mortality and 30-day in-hospital mortality, compared to non-use (22). Pienkos et al. also reported that in sepsis-related acute respiratory distress syndrome, simvastatin therapy seems safe and could reduce mortality (23). However, it is crucial to note that the studies on the overall impact of statins in sepsis are mixed, with some studies reporting no significant survival benefit (24). Azkarate et al. reported that the administration of statin therapy before hospitalization did not significantly influence the manifestation of sepsis or its outcomes (24). A meta-analysis also found that statin therapy for the indication of sepsis is not recommended (25). Further research is required to confirm the role of statins in SAE patients. Careful consideration should be given when choosing a specific statin.

Rosuvastatin was associated with a higher 30-day mortality rate in certain subgroups, including older patients (aged 65 years and older), males, and those with higher SOFA scores ≥8, SAPS II scores ≥44, and SIRS scores ≥3. The finding emphasizes the need for more nuanced, individualized treatment strategies in critically ill patients, particularly in those with higher comorbidity and severity of disease. In older patients, age-related changes in pharmacokinetics and pharmacodynamics, as well as altered immune responses, may amplify the adverse effects of statins, including their potential to increase systemic inflammation or interfere with mitochondrial function in neuronal tissue, which could worsen outcomes in SAE. In males, hormonal differences could influence statin metabolism and its impact on immune modulation. The interplay between the sex-specific immune response and statin therapy may further contribute to adverse outcomes, but further targeted research is required to elucidate these mechanisms fully. For patients with higher SOFA and SAPS II scores, which indicate greater organ dysfunction and physiological derangement, the potential for statin-induced immunosuppression or mitochondrial toxicity could be more pronounced, further compounding the already heightened risk of mortality. This suggests that in patients with severe sepsis or septic shock, rosuvastatin may exacerbate organ dysfunction and inflammatory imbalance. To mitigate these risks, clinicians may consider tailoring statin therapy based on patient age, sex, and severity of illness, carefully considering the potential benefits of statin use in SAE against the risks of worsening outcomes in vulnerable subgroups. Alternative therapeutic strategies or dose adjustments may be warranted for high-risk patients, alongside close monitoring for adverse effects.

The choices of statin in clinical practice are influenced by various factors, including drug cost, the patient’s comorbid conditions, and the severity of the disease. Cost considerations are particularly relevant in resource-limited settings where the price disparity between atorvastatin and rosuvastatin could impact treatment choices (26). Additionally, patients with multiple underlying conditions may require a statin with a more favorable side effect profile, potentially influencing the choice of rosuvastatin despite its higher cost (27). In the context of SAE, where patients often present with severe systemic inflammation and multi-organ dysfunction, the choice of statin may need to account for its anti-inflammatory effects and ability to penetrate the blood–brain barrier. The differential outcomes associated with lipophilic (simvastatin) and hydrophilic (rosuvastatin) statins may be explained by their ability to penetrate the blood–brain barrier and modulate neuroinflammation, which are critical factors in SAE pathophysiology. Atorvastatin’s tissue penetration may offer additional benefits in such severe conditions compared to rosuvastatin, which could explain the observed differences in mortality (28).

Compared with atorvastatin use in SAE patients, the association of pravastatin or simvastatin with 30-day mortality was not statistically different. It is noteworthy that the association between rosuvastatin and higher odds of 30-day mortality was observed in statin users. This finding indicated caution against the use of rosuvastatin. Lee et al. (11) also demonstrated that compared with atorvastatin and simvastatin, rosuvastatin had an inferior effectiveness in reducing mortality. Pienkos et al. (23) also found that rosuvastatin was associated with an increased mortality in low-cholesterol patients. The observed differences may be attributed to variations in the population studied and differences in statin dosages. Furthermore, differences in pharmacokinetic and pharmacodynamic properties between statins contribute to variations in outcomes. The hydrophilic nature of rosuvastatin may influence its distribution and tissue penetration, compared to the more lipophilic atorvastatin, potentially impacting their respective efficacy in SAE (29). The underlying reasons for the potential differential effects of statins require further investigation in SAE, particularly considering the complexity of the underlying pathophysiology.

The pathophysiological factors of SAE included mainly neuroinflammation, impairment of the blood–brain barrier, disorders of brain perfusion, changes in neurotransmitters, and alterations in neuroanatomy (3). Statins may exert beneficial effects through their pleiotropic properties, including anti-inflammatory and immune-modulatory effects (30, 31). Statin has been shown to suppress pro-inflammatory cytokines such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor-α, and these three cytokines are theorized to play important roles in SAE initiation (32, 33). Furthermore, statins have been shown to exert neuroprotective effects through their ability to modulate neuronal apoptosis, reduce oxidative stress, and improve cerebral blood flow (34).

The finding that statin treatments were associated with lower 30-day mortality compared in SAE patients without statin treatments has implications for clinical practice. Therefore, using statins with caution needs to be considered in the assessment and management of SAE patients to improve patients’ prognosis. Rosuvastatin should be avoided in SAP patients of those aged ≥65 years, males, SOFA ≥8, SAPS II ≥44, and SIRS ≥3. Furthermore, it is imperative to conduct randomized trials or prospective studies and delve into the underlying mechanisms to confirm and provide a better understanding of these findings.

The study is subject to certain limitations. First, this study was conducted solely at a single medical facility, which may present limitations in terms of generalizability. Future investigations encompassing multiple centers and larger patient cohorts should be undertaken to validate the results. Second, our study did not assess all types of statin use, as only atorvastatin, pravastatin, rosuvastatin, and simvastatin were used. The lack of dosage and duration data limits actionable clinical insights. It remains unclear whether high doses or longer courses of simvastatin or atorvastatin amplify benefits, or if dose adjustments could mitigate rosuvastatin-associated risks. The absence of comprehensive blood lipid levels data before and after treatment limits further analysis. Finally, the covariates utilized for analysis were solely those available within the database, and there may exist certain unmeasured confounders. Therefore, we emphasize the importance of future studies incorporating an expanded set of covariates to enhance the comprehensiveness of the analysis and strengthen the overall scientific validity of the study.

Our study found an association between statin use and a lower risk of 30-day mortality in SAE patients. Caution should be exercised in the choice of statin, as rosuvastatin was associated with higher odds of 30-day mortality compared to SAE patients with atorvastatin treatment. Furthermore, it is imperative to conduct prospective studies and delve into the underlying mechanisms to confirm and provide a better understanding of these findings.