In this study comparing SAE incidence in sepsis patients with or without rosuvastatin in a secondary analysis of a prospective RCT, we found that the rosuvastatin group had a statistically significant lower incidence of SAE, although at a statistically significant higher risk of adverse drug effects. Like in the original SAILS study, our study did not show that rosuvastatin was associated with a shortened length of hospital or ICU stay.
In recent years, a series of observational studies and randomized trials showed a beneficial effect of statins on patients suffering from severe infections [19]. A 2006 retrospective study showed that, regardless of infection site, administration of statins at the time of bacteremia diagnosed was associated with a lower all-cause mortality rate in bacteremic patients, and further administration of statis led to even lower mortality [20].
Concerning the severity of sepsis, the protective effect of statin drugs was also recently highlighted [21]. Yaniv Almog and his colleagues conducted a prospective cohort study in 2004, finding that prior therapy with statins was associated with a lower rate of severe sepsis [22]. In the long term, statin also showed a protective effect on bacteremic patients, reducing the 180-day mortality rate in one study [23]. These results were consistent with our findings that found a beneficial effect of statin drugs for SAE patients. Nevertheless, the original study did not perform dose-effect research, which is awaiting further investigation.
Another prospective cohort study with 470 ICU patients illustrated that statin drugs were capable of increasing delirium-free ICU days, although the rate of delirium decrease did not show a significant difference between groups (40% in statin group VS 33% in statin free group) [24]. Like our findings, this other study also reported a decreased SAE rate (32.1% in the statin group vs. 57.1% in the placebo group). Another multicenter prospective cohort study, including 763 ICU patients (263 of which were septic or ARDS patients), showed that in-hospital statin use was associated with a reduced delirium rate while statin use prior to hospitalization did not show a benefit [25].
However, there are also some studies challenging the use of statins for patients with sepsis. A retrospective cohort consisting of 438 septic participants showed worse outcomes in the statin group, with a significantly higher in-hospital mortality rate [26]. Specifically, statins may not attenuate lung injury during sepsis, and the ARDS rate was not significantly reduced in sepsis patients when statins were administered [27]. In our study, we still found that rosuvastatin was protective against SAE, while the mortality rate was not significantly elevated in patients receiving rosuvastatin.
SAE is a central nervous system dysfunction in sepsis caused by an inflammatory cascade [28]. Rosuvastatin is widely used in cardiovascular and cerebral vascular disease patients to lower blood cholesterol levels and rates of disease recurrence [29]. In recent decades, statins such as rosuvastatin were found to possess pleiotropic pharmacologic effects, including anti-inflammatory and immunomodulatory functions [30]. The immunomodulatory effects in particular may contribute to cerebral protection for sepsis patients suffering from an inflammatory cascade.
Up-regulation of IL-1 and IL-6 is associated with reduced inter-endothelial junction proteins [31], leading to BBB disruption, which may also cause SAE in sepsis patients [32]. Statins can reduce the expression of pro-inflammatory factors such as IL-1, IL-6, IL-10, IL-17, IL-18, intracellular adhesion molecule (ICAM) and TNF-α [33], which are closely related to the severity of sepsis in animal models [34]. Similar outcomes were also shown in burn patients treated with statins [35]. Also, statin drugs inhibit the prenylation of Rac and Rho proteins [36], upgrading the expression of endothelium-derived nitric oxide synthetase (eNOS). In turn, eNOS increases NO expression, maintaining endothelial cell function, attenuating BBB damage in sepsis patients [37], thereby reducing the rate of SAE among sepsis patients through an anti-inflammatory pathway. However, the exact pharmacological mechanism of immunomodulation caused by statins has not clearly been demonstrated yet.
Although rare, adverse drug events from statins include myopathy, hepatic function damage and rhabdomyolysis [38]. The original SAILS study selected rosuvastatin due to fewer drug interactions than other statins [39]. Symptoms of statins’ adverse effects include muscle pain, nausea, and vomiting, among others. Unfortunately, in our current study, these symptomatic descriptions were not included in the original data set. We could only assess adverse drug events by comparing the levels of CK, AST and ALT between the rosuvastatin and placebo groups. Our study showed the rosuvastatin group has a statistically significant higher CK level, which may be related to a higher risk of myopathy in the rosuvastatin group than placebo.
Our study still has some limitations. First, bilirubin levels are an important laboratory test for evaluating hepatic function, which may be affected by rosuvastatin. However, bilirubin levels were absent from the SAILS study. Second, regarding baseline drug administration, detailed information such as the type of narcotics and antibiotics was not fully reported in the original study, which could interfere with the SAE outcomes. Statin outcomes may also vary among different types of pathogens.