We conducted the current systematic review and meta-analysis to evaluate the effects of dual corticosteroid treatment in terms of clinical outcomes in patients with septic shock. While previous systematic reviews had shown conflicting results, we found a reduced mortality with high certainty: 28-day, in-hospital, and long-term (later than 90 days) mortalities were reduced by the treatment with both hydrocortisone and fludrocortisone.
The main difference between the current study and other meta-analyses is the fact that we examined only the effects of the dual corticosteroid treatment for septic shock. The idea behind the addition of fludrocortisone to hydrocortisone, used as glucocorticoid replacement therapy in patients with adrenal insufficiency, is to enhance the mineralocorticoid activity [35–37]. The biological activity of mineralocorticoids is mediated by the mineralocorticoid receptor (MR) [35, 47], which exists in various organs, such as the kidneys, cardiovascular, immune, and central nervous systems [48, 49]. Animal studies found an association between sepsis and the downregulation of the MR in endothelial cells [50], and mineralocorticoid supplementation lowered IL-6 levels, hastened shock reversal, and improved survival [51, 52]. Some clinical studies also revealed inappropriately low aldosterone levels in patients with septic shock, suggesting an impaired adrenal synthesis of aldosterone, that might be associated with increased mortality [41, 53]. Although the direct effect of mineralocorticoids in septic patients has not been fully elucidated, our results support a recommendation for the dual administration of hydrocortisone and fludrocortisone to patients with septic shock.
The meta-analyses on the secondary outcomes found that the incidence of AEs was not increased by the dual corticosteroid treatment, except that for hyperglycemia, which is consistent with the results of a systematic review examining all types of corticosteroid therapies for sepsis [5]. In that study, the risks for hyperglycemia, hypernatremia, and neuromuscular weakness were similarly increased by the corticosteroid administration, while the incidence of superinfections, GI bleeding, and psychiatric disorders remained similar to those in control patients. Although there may be additional adverse event risks by adding fludrocortisone on hydrocortisone, our sensitivity analysis comparing the dual corticosteroid treatment with hydrocortisone-only therapy identified only higher superinfection rates in the dual corticosteroid treatment group. Considering that MRs are expressed in monocytes and macrophages that undergo a pro-inflammatory polarization in response to mineralocorticoids [54, 55], pathophysiological immunomodulatory changes by the additional mineralocorticoid administration should be further examined.
The recommendation of fludrocortisone use in a previous version of the Surviving Sepsis Campaign guidelines was an optional addition to low-dose hydrocortisone [56], and it got removed from the most recent guidelines in 2016 [28]. Two recent systematic reviews analyzed the dual administration of hydrocortisone and fludrocortisone in subgroup analyses that evaluated heterogenicity in types of corticosteroid treatments, and did not find a credible effect of the specific type of corticosteroid treatment [5, 8]. However, these analyses did not examine the direct association between the dual corticosteroid treatment and clinical outcomes, and based on our results the dual corticosteroid treatment (adding fludrocortisone to hydrocortisone) should be considered more than just an adjunctive therapy.
The results in this study must be interpreted within the context of the study design. We found only four eligible studies and included only two in the meta-analysis for the primary outcome [15, 27], in part because the additional fludrocortisone has not been extensively examined and because we considered only RCTs. However, our search strategy used a wide variety of search terms and the eligibility criteria were wide enough to capture an article by Laviolle et al [46] that was not included in the recent systematic reviews [5–8]. Also, the primary outcome had no heterogenicity and we evaluated the RoBs of the studies included as “low” using the Cochrane risk of bias assessment tool.
Another limitation of this study is the fact that the control group in the meta-analyses consisted of both corticosteroid-free and hydrocortisone-only populations, which may hamper the interpretation of our results. Although some secondary outcomes such as in-hospital and long-term mortalities and superinfection differed in the sensitivity analyses according to the definitions of the comparator group, the reduced 28-day mortality by the dual corticosteroid therapy resulted only from the comparison with placebo administration. Considering that the current study aimed to find beneficial effects of the dual administration of hydrocortisone and fludrocortisone (rather than effects directly related to only fludrocortisone), we believe that this specific corticosteroid therapy can be recommended for patients with septic shock with high quality of evidence.
Moreover, all eligible studies used the same intervention protocol in terms of type, dose, and duration of the corticosteroid therapy. Although different doses of hydrocortisone and/or fludrocortisone might affect the results, the doses used were those standardly used in the replacement therapy for primary adrenal insufficiency [40, 57]. Given that a study on different hydrocortisone-only treatment durations for septic shock revealed no differences in outcomes between 3-day and 7-day regimens [58], a shorter regimen of the dual corticosteroid treatment may be effective and should be investigated.