This is the first systematic review examining the role of premorbid ACEI or ARB exposure on mortality outcomes in patients with sepsis. Patients receiving ACEIs or ARBs prior to developing sepsis were associated with a 6% reduction in 30-day mortality compared with those who did not receive any ACEIs or ARBs. We further conducted subgroup analyses to determine the effect of the geographic area (Asian or non-Asian countries), NOS (7 or 6), and prior exposure (ACEIs, ARBs, and ACEIs/ARBs) in our analyses (Table 2). We obtained a statistically protective effect in the Asian population (OR: 0.94; 95% CI: 0.91–0.98), ACEIs (OR: 0.94; 95% CI: 0.89–0.99), ARBs (OR: 0.84; 95% CI: 0.79–0.88), and a NOS of 6 (OR: 0.88; 95% CI: 0.85–0.91). The results of a meta-regulation test (Figs. 3 and 4) revealed that the geographical area and treatment were associated with 60.62% reduction in heterogeneity across the studies.
One cause of the differences in the outcomes between population may be lifestyle and environmental factors associated with Asian and non-Asian populations [21–23]. Compared with European and American populations, Asian populations have a relatively healthy diet and a lower prevalence of chronic diseases (e.g., diabetes and coronary heart disease) [21–23], which have a substantial impact on the prognosis of sepsis.
ACE inhibitors and ARBs reduce blood pressure by vasodilation, decreasing angiotensin II formation, and kallikrein degradation to reduce sodium and water retention [27]. These effects can also decrease the glomerular filtration rate (GFR) since angiotensin II plays a critical role in the maintenance of GFR, especially during hypovolemia or hypotension [28, 29]. In the guidelines for sepsis treatment, the maintenance of a certain tissue perfusion pressure is necessary; however, the use of ACE inhibitors and ARBs appear to be contrary to the recommended treatment guidelines for sepsis. Moreover, ACE inhibitors and ARBs have not been recommended as a therapeutic drug in previous septic diagnosis and treatment guidelines. In addition to the effect of lowering blood pressure, both ACE inhibitors and ARBs also have anti-inflammatory effects, which can reduce plasma cytokine and nitric oxide concentrations [28, 29]. In septic animal models, although ACE inhibitors have been demonstrated to reduce organ damage through the NF-κB signaling pathway [31], conflicting data exist regarding to whether an angiotensin II blockade improves survival in animal models [32, 33]. Moreover, a clinical study of patients hospitalized with sepsis reported that the prior use of ARBs was associated with improved survival [34].
Our findings have potential clinical implications. Clinical medical providers should be able to identify who is at a high-risk of sepsis as early as possible and guide the course of treatment following the initial screening. Combined with our meta-analysis, the use of ACEIs or ARBs can improve the prognosis of sepsis patients, and the comparison of the effect of ACEIs and ARBs on the prognosis of sepsis is presently not supported by any data. Therefore, if patients treated with ACEIs cannot tolerate their adverse reactions, they can continue to use ARBs. It is recommended that ACEIs or ARBs be abandoned only if the adverse effects are severely intolerable [35, 36].
This study analyzed data from six observational studies and included a larger population and range of trials compared to that previous studies, with the largest number of cases analyzed to date. We conformed to the specifications throughout the entire meta-analysis process and we also simultaneously conducted a publication bias detection. The obtained results are robust and the included analysis was free from obvious publication bias. Moreover, this meta-analysis has a high standard for the quality of the included literature, and thus meets a high quality standard.
There are a few limitations regarding this study that should be noted. First, when selecting appropriate literature, only studies written in English were included; however, a large portion of the articles that were included in our study were performed in Asia, where the official language is not English. Second, it was challenging to predict the effect of misclassification of cohort studies for the results. In addition, the systematic confounding or the risk of bias cannot easily be ruled out in observation studies. Since there was heterogeneity across the studies, we performed a regression analysis to explain the source of such heterogeneity. The observed differences may be due to the differences in the geographical area of the studies. Specifically, differences in the study geographical area and prior treatment (ACEIs, ARBs, and ACEIs/ARBs) may have contributed to the heterogeneity observed in our results (Fig. 4). In this analysis, the comparison between the dose and course of treatment of ACEIs or ARBs and the prognosis of sepsis were not included due to the lack of data provided in the original studies.