Lung injury remains one of the major complications of mechanical ventilation in the ICU. This injury could result from an altered host immune response after mechanical stretch [3]. Using statin therapy to protect patients with lung injury could therefore be a reasonable strategy, as these drugs could abate the host inflammatory response to infection [21], especially within the lungs [6]. This study revealed that statin use was associated with improved 28-day survival and in-hospital survival. All kinds of statins showed reduced HRs. This evidence might indicate the protective effect of statins in ventilation patients. In the subgroup analyses, we found that statins had a protective effect in most of the subgroups but not in the septicemia, acute respiratory failure or pneumonia subgroups. All these results might explain the protective effect of statins.
In addition to lowering cholesterol, statins exert pleiotropic effects [6–9] such as anti-inflammatory, antioxidant, and immunomodulatory effects, especially in the context of pulmonary disorders [22]. Statins may reduce COPD exacerbation [23]. Statins have also been suggested to be effective in patients with acute lung injury or acute respiratory distress syndrome in some observational studies [24, 25]. These clinical effects may be mediated by a reduction in pulmonary and systemic inflammation. Simvastatin decreased bronchoalveolar lavage IL-8 by 2.5-fold (P = 0.04) [26]. Statins also showed a protective effect against sepsis. When compared with nonusers, simvastatin (HR, 0.72; 95% CI, 0.58–0.90) and atorvastatin (HR, 0.78; 95% CI, 0.68–0.90) users had improved 30-day survival [13]. The current study examined the anti-inflammatory effect of statins from a ventilation patient cohort, which has not been previously reported. A recent study showed that infections in older adults were associated with prolonged, impaired neutrophil migration. Simvastatin improves neutrophil migration in vivo in healthy individuals and in vitro in milder infective events but not in severe sepsis, supporting its potential utility as an early intervention during pulmonary infections [27, 28].
Animal models may have further explained the protective effect of statins against lung injury. Statins increase glucocorticoid receptor expression in alveolar macrophages and downregulate NF-κB activation associated with the increased number of alveolar macrophages [15]. Two other animal models of lung injury induced by mechanical ventilation also support these findings [16, 17]. The protective effect may be due to the anti-inflammatory effect of statins. Prior statin use was associated with a lower baseline IL-6 concentration, and continuation of atorvastatin treatment in this cohort was associated with improved survival [29]. Statins have been shown to reduce vascular leakage and inflammation in animal models of lung injury [30]. Statins may also attenuate lung injury by downregulating the expression of inflammatory cytokines [31, 32]. Our previous study revealed the lung-protective effect of statins caused by the reduction of inflammatory cell infiltration [33]. Additionally, statins may have direct antibacterial effects and modulate bacterial virulence [34–36]. Sarah et al. showed that prior exposure to physiological nanomolar serum concentrations of simvastatin confers significant cellular resistance to the cytotoxicity of pneumolysin, which revealed how statins contribute to the reduced pathology observed in the context of pneumonia and other bacterial infections [37].
The subgroup analyses showed that statins had no efficacy in the context of pneumonia, septicemia or acute respiratory failure. However, this difference might be explained by the fact that statins may exert an inflammatory protective effect only for mild-to-moderate pulmonary infectious disease. From this point of view, the subgroup analyses explained why evidence of the efficacy of statins against sepsis and ARDS is controversial. In a randomized controlled trial (RCT) with a follow-up of over one year, there was no significant difference in cumulative survival between the rosuvastatin and placebo groups (58% vs 61%; p = 0.377) [38]. Simvastatin therapy was not significantly associated with the difference between the study groups in mortality at 28 days (22.0% and 26.8%; P = 0.23) among patients with ARDS [39]. However, the effect of statins on ventilation-induced lung injury was minimal. Recently, a group of “hyperinflammatory” ARDS patients showed a benefit from statin treatment [40]. Sapey stated that statins may improve neutrophil migration and may have protective effects in milder infective events but not in severe sepsis or ARDS [27]. The underlying reason for this controversial evidence might be that statins may have immune modulatory effects in only milder diseases instead of in intensive inflammatory diseases such as ARDS. However, we might need new RCTs exploring the effects on mild infectious diseases such as ventilation-induced lung injury to prove this hypothesis.
Several limitations must be disclosed in the current study. The main limitation of this study was that the observational nature without randomization precludes a definite conclusion regarding statin benefits. However, a randomized controlled trial on the effect of long-term statin treatment on the outcome of patients on ventilation would require many participants. To explore the effect of statins on patients on ventilation, observational data may currently remain the best available evidence. Second, because of the retrospective design of this study, patient selection bias may be inevitable. Third, the missing data of potential confounders was a limitation that could not be overcome. Our findings should thus be interpreted with caution. Additionally, only white blood cell (WBC) measurements were analyzed for inflammation assessment. Regarding the host response, the assessment of inflammatory cytokines might provide different insights. The relationships of the dose and treatment duration of statins with survival were not analyzed here because we included different types of statins, and the doses of the different statins were not comparable. Finally, we included ventilation patients with different diagnoses. Even with subgroup analyses, we cannot conclude that statins are specifically effective in a specific population.