Corticosteroids for Treating Sepsis in Adult Patients: A Systematic Review and Meta-Analysis

Objective Corticosteroids are a common option used in sepsis treatment. However, the efficacy and potential risk of corticosteroids in septic patients have not been well assessed. This review was performed to assess the efficacy and safety of corticosteroids in patients with sepsis. Methods PubMed, Embase, and Cochrane library databases were searched from inception to March 2021. Randomized controlled trials (RCTs) that evaluated the effect of corticosteroids on patients with sepsis were included. The quality of outcomes in the included articles was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation methodology. The data were pooled by using risk ratio (RR) and mean difference (MD). The random-effects model was used to evaluate the pooled MD or RR and 95% confidence intervals (CIs). Results Fifty RCTs that included 12,304 patients with sepsis were identified. Corticosteroids were not associated with the mortality in 28-day (RR, 0.94; 95% CI, 0.87–1.02; evidence rank, moderate) and long-term mortality (>60 days) (RR, 0.96; 95% CI, 0.88–1.05) in patients with sepsis (evidence rank, low). However, corticosteroids may exert a significant effect on the mortality in the intensive care unit (ICU) (RR, 0.9; 95% CI, 0.83–0.97), in-hospital (RR, 0.9; 95% CI, 0.82–0.99; evidence rank, moderate) in patients with sepsis or septic shock (evidence rank, low). Furthermore, corticosteroids probably achieved a tiny reduction in the length of hospital stay and ICU. Corticosteroids were associated with a higher risk of hypernatremia and hyperglycemia; furthermore, they appear to have no significant effect on superinfection and gastroduodenal bleeding. Conclusions Corticosteroids had no significant effect on the 28-day and long-term mortality; however, they decreased the ICU and hospital mortality. The findings suggest that the clinical corticosteroids may be an effective therapy for patients with sepsis during the short time. Systematic Review Registration https://inplasy.com/wp-content/uploads/2021/05/INPLASY-Protocol-1074-4.pdf


INTRODUCTION
Sepsis is a life-threatening organ dysfunction, which is caused by a dysregulated host response to infection (1,2) that culminates in systematic hypoperfusion and considerable organ dysfunction. The main therapies to treat sepsis in the early phase are antibiotic administration and perfusion restoration (3). Early and aggressive treatment is associated with a mortality rate of 30%-50% in critically ill patients admitted to the intensive care unit (ICU) and induces more than 5 million deaths each year across the world (3,4). Therefore, further investigation for the treatment of sepsis is crucial.
The pathology of sepsis is marked by a dysregulated host response to infection; therefore, immunomodulatory therapies have been used in sepsis treatment that may be effective (5). Doctors have started using corticosteroids as an adjuvant therapy for sepsis since the middle of the twentieth century (3). Corticosteroids were used to treat sepsis, especially the septic shock therapy; numerous randomized clinical trials (RCTs) were performed to evaluate the safety and efficacy of corticosteroids. However, the results of these RCTs varied. Thus, many systematic reviews have been performed to assess the safety and efficacy of corticosteroids in patients with sepsis. However, the results of the most recent reviews remain controversial (6,7). Subsequently, several studies have further assessed whether the combination of corticosteroids, vitamin C, and thiamine as compared with corticosteroids or placebo improved the survival duration, increased the vasopressor-free time over 7 days, and reduced organ injury (8,9). These results suggest that the use of corticosteroids in combination with other drugs did not affect the safety and efficacy of corticosteroids in patients with sepsis. Hence, resolution of this controversy regarding the latest reviews that have assessed the efficacy of corticosteroids in patients with sepsis is currently the primary problem in sepsis treatment. Therefore, this systematic review and meta-analysis were performed based on the latest reviews to reintegrate the relevant data to evaluate the effects and safety of corticosteroids in patients with sepsis.

METHODS
The protocol of this systematic review and meta-analysis was registered on INPLASY (ID: INPLASY2020110122). The methodology of this study was according to items of the Cochrane Collaboration, and each outcome was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guidelines (10).

Study Searches
This meta-analysis was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) criteria. Moreover, the PRISMA 2020 checklist is shown in Supplemental Table 1. PubMed, Embase, and Cochrane library databases were searched for relevant data from inception to March 2021, update to 5 July 2021, to identify RCTs that have evaluated the effect of corticosteroids on patients with sepsis. The MeSH/Emtree and title/ abstract keyword combination were used to identify the eligible articles; the keyword search terms used for the English literature included the words corticosteroids and sepsis (detailed search strategy in Supplemental Table 2). It is noteworthy that we also conducted a manual search for the references of the relevant articles (study search flowchart in Figure 1).

Study Selection
Before the potential articles were searched and screened, the eligibility criteria and exclusion criteria were identified. Articles may be eligible according to the inclusion criteria in this study if they meet all of the following conditions: (1) adult patients diagnosed with sepsis, severe sepsis, or septic shock, as per the inclusion criteria during the study (11)(12)(13) [studies reporting adult patients with acute respiratory distress syndrome (ARDS) and sepsis were included]; (2) the study compared the use of corticosteroids (including hydrocortisone, methylprednisolone, betamethasone, fludrocortisone, and dexamethasone) with no use of corticosteroids; (3) the study measured and reported the outcomes in terms of 28-day and long-term mortality (>60 days), ICU mortality, in-hospital mortality, length of stay in hospital and ICU, vasopressor-free days, ventilation-free time, shock reversal at days 7 and 28, time for resolution of shock, Sequential Organ Failure Assessment (SOFA) scores at day 7, hypernatremia, hyperglycemia, superinfection, and gastroduodenal bleeding; (4) the study was an RCT or abstract and was published in English. Furthermore, the study design including case reports, case series, and observational studies or the previous unpublished studies that required the author to be contacted were excluded. All the available articles were searched by two searchers, respectively, and when disagreements occurred during the process, the third investigator should resolve these disagreements. Reviewers performed reviews in pairs to screen all relevant citations and references as per the search strategy, and the screening process included the following two stages: initial evaluation of titles and abstracts and skimming of the full text to identify the eligible studies. disagreements, the third reviewer resolved the issue. Relevant data, including the study title, first author, study type, study period, the therapy in treatment and control groups, reported outcomes, sepsis definition, and so forth were collected. The data only for the studies that we searched including the previous review (6) were abstracted. The risk of bias for this meta-analysis was assessed by two investigators independently for every abstracted data of each article based on the Cochrane Collaboration (14) and domains including allocation concealment, blinding of participants and staff, blinding of outcome assessors, incomplete outcome data, selective outcome reporting, and other biases. Additionally, the GRADE framework was used to evaluate the overall evidence rank for every outcome (15). The studies with more than six, four, to six and fewer than six items were considered high, fair, and poor quality, respectively. Importantly, the GRADE was used to assess the evidence rank of mortality and adverse events. According to the risk of bias, inconsistency, indirectness, imprecision, and publication bias, the studies were evaluated as low, moderate, or high quality.

Statistical Analyses
Mantel-Haenszel (M-H) or DerSimonian Laird (DL) methods with random-effects meta-analyses were conducted for the eligible RCTs. All the relevant data were assessed using the Review Manager (RevMan), version 5.3 (Cochrane Collaboration), STATA 16.0 (StataCorp, College Station, TX, USA). Risk ratio (RR) and mean difference (MD) were used to present the dichotomous and continuous outcomes, with 95% CI. Moreover, a Funnel plot was used to examine the potential for some small effects if the outcome included more than 10 trials, and the possibility of publication bias was assessed using the Funnel plot and Egger regression test (16). The chi-square test, I 2 , and visual inspection of the forest plots were used to evaluate heterogeneity among the eligible studies; when I 2 was >50%, the heterogeneity was considered substantial. In addition, we performed the subgroup analyses based on the following variables: sepsis subtype [sepsis, septic shock, sepsis and ARDS, sepsis and community-acquired pneumonia (CAP), and severe COVID-19], type of corticosteroids (hydrocortisone or hydrocortisone plus fludrocortisone or methylprednisolone or prednisone or betamethasone or dexamethasone), and type of ICU [surgical, medical (internal) or surgical/medical ICU], searching the source of heterogeneity. Additionally, as the unit dose of the corticosteroids varied, relevant included studies about the use of corticosteroids were collected based on catecholamine use for qualitative analysis.
The results of sensitivity analysis showed that the models of the 28-day mortality, in-hospital mortality, and ICU mortality were credible ( Supplementary Figures 4-6). Furthermore, L'Abbeṕ lot reported that the mortality in the placebo group increased significantly than the corticosteroids group, suggesting the potential effects of corticosteroids in patients with sepsis ( Supplementary Figures 7-9).

Secondary Outcomes
Supplementary Figures 10-22  The Funnel plot and Egger test showed no publication bias in the length of stay in hospital (p = 0.99), SOFA scores at day 7 (p = 0.86), hyperglycemia (p = 0.98), the shock reversal at day 7 (p = 0.285), length of stay in ICU (p = 0.334), superinfection (p = 0.231), gastroduodenal bleeding (p = 0.867), and shock reversal at day 28 (p = 0.414) ( Supplementary Figures 23-30). The results of the sensitivity analysis showed that the models of the abovementioned outcomes, including length of stay in hospital, SOFA scores at day 7, hyperglycemia, shock reversal at day 7, length of stay in ICU, superinfection, gastroduodenal bleeding, and shock reversal at day 28 were credible ( Supplementary Figures 31-38).
Importantly, the risk of bias was reported in the first plot of each outcome, and the evidence rank is shown in Table 2.

Subgroup Analysis
We performed subgroup analysis based on the sepsis subtype or type of corticosteroids used for the primary outcomes or I 2 >75% in the secondary outcomes with more than 10 trials for each outcome. The results of the subgroup analysis showed no effect on the 28-day mortality; however, the in-hospital and ICU mortality were significantly improved in the hydrocortisone plus fludrocortisone treatment and in the patients with septic shock, sepsis, and community-acquired pneumonia ( Supplementary Figures 39-44). Moreover, the result of the subgroup in SOFA scores at day 7 represented that the main original heterogeneity may be from the trials with smaller samples who were given hydrocortisone treatment or trials on patients with sepsis shock (Supplementary Figures 45 and 46).
Additionally, the subgroup based on the patients that were recruited into the surgical, medical, or surgical/medical ICU showed that corticosteroids were not associated with a 28-day mortality, SOFA scores at day 7, and in-hospital mortality but were related to lower ICU mortality in surgical/medical ICU patients (Supplementary Table 3). Importantly, the subgroup in   (21) study showed that corticosteroids may be associated with the lower ICU mortality. Furthermore, three RCTs (25,27,28) showed that the corticosteroids dose was more than 200 mg/day; corticosteroids was not associated with the ICU mortality. However, two RCTs (21,23) showed that corticosteroids dose of 200 mg/day or 50 mg every 6 h may reduce the time of vasopressors use.

DISCUSSION
This meta-analysis included 50 RCTs (12,304 patients) and demonstrated that corticosteroids failed to improve the 28-day and long-term mortality; however, there was a small reduction in the in-hospital mortality and ICU mortality. To our knowledge, this systematic review and meta-analysis is the most comprehensive review of many new RCTs; the precision of the pooled effect estimates how sepsis could be increased substantially.
We found that the corticosteroids therapy for sepsis increased the incidence of the vasopressor-free days, ventilation-free time, shock reversal at days 7 and 28, and adverse events, such as hyperglycemia and hypernatremia. Corticosteroids were associated with a decreased risk of the time for shock resolution and length of stay in the hospital. However, our study failed to report a decreased risk of corticosteroids on the length of ICU stay and adverse events, such as superinfection and gastroduodenal bleeding. Ascertainment of the adverse events in the eligible trials was also vulnerable, which may induce the evidence rank to be low. Moreover, a quantitative analysis for the effect of the time of corticosteroids administration on septic patients was made. The effect of the different time of corticosteroid administration on septic patients cannot be compared because the time of corticosteroid administration was indistinct in the included studies. Therefore, further clinical studies should explore the time of corticosteroid administration for septic patients and ensure whether it is the same as antibiotics, which is the earlier the better.
Subgroup analyses in this review showed that the results did not identify any credible effect of modification in sepsis subtype and type of corticosteroids used. Much evidence comes from the trials with hydrocortisone or methylprednisolone treatment. Our subgroup analysis results showed that the efficacy of corticosteroids on in-hospital, ICU, and short-time mortality was mainly due to the hydrocortisone plus fludrocortisone.
Mechanistically, corticosteroids could inhibit the nuclear factor kappa B (NF-kB) activation and the extensive inflammatory factors release, finally improving the inflammatory response of sepsis or pneumonia. Our previous studies reported that corticosteroids were associated with a decreased risk of ARDS and length of the disease in patients with CAP (67). Previous reviews have assessed the efficacy and safety of corticosteroids in patients with sepsis. Unfortunately, the conclusions were contradictory owing to the small number of trials included. One meta-analysis included 20 RCTs and showed no reduction in the 28-day mortality, hospital mortality, and ICU mortality in patients with severe sepsis and sepsis shock on corticosteroids treatment (68). Subsequently, a Cochrane systematic review further conducted to search the effect of corticosteroids on mortality of patients with sepsis, including a total of 33 RCTs, found a small reduction in 28-day mortality on the corticosteroids treatment (69). Simultaneously, another study included 35 RCTs and showed a converse result that corticosteroids failed to decrease the mortality (70). In 2018, Rochwerg et al. The results of this meta-analysis showed that corticosteroids treatment failed to improve the 28-day mortality, in contrast with results from the previous meta-analysis. The difference in part may be due to the result reported by Annane et al. (6), in which corticosteroids therapy showed an increased risk of 28-day mortality, while the CI contained the null effect line, suggesting that corticosteroids had no effect on sepsis based on the statistics. More importantly, we included four RCTs about severe COVID-19 and showed that there was no significant difference in 28-day mortality with corticosteroids use. The data were extracted from the latest RCTs and may have helped in reinforcing the conclusions, decreasing the heterogeneity among the studies, and improving the precision with more comprehensive assessment for the therapeutic effects of corticosteroids treatment.
In this meta-analysis, the result of the qualitative analysis showed that 200 mg/day or less may have a clinical benefit, such as increasing the vasopressor-free time, improving tissue oxygen supply, and restoring circulatory homeostasis in catecholaminedependent septic shock (21,23,37). More importantly, the earlier study (25) reported that supraphysiological doses of hydrocortisone could improve hemodynamics and enhance the vascular sensitivity to catecholamines, thereby reducing the dose of catecholamine (dopamine >10 µg/kg/min) in the patients with septic shock. The subsequent studies (40) also showed that under the dose of dopamine ≥6 µg/kg/min, low-dose hydrocortisone could be a better maintenance of hemodynamics by increasing vascular sensitivity to catecholamines. Furthermore, Ibarra-Estrada et al. (72) suggested that compared with bolus infusion of hydrocortisone, continuous infusion may restore the vascular sensitivity to catecholamines better. Similarly, an experimental study (73) found that fludrocortisone combined with hydrocortisone therapy dose dependently increased phenylephrine with cumulative increasing concentrations, which caused concentration-dependent contraction of isolated mesenteric arteries from septic rats. Contrarily, a prospective cohort study (74) showed that after hydrocortisone therapy, there was a significant reduction in norepinephrine in survivors, whereas higher catecholamine dosages were required for the non-survivors. However, a latest retrospective cohort study (75) showed that higher norepinephrine (24.6 mcg/min) in early hydrocortisone therapy could improve reduction in ICU mortality compared with the late hydrocortisone therapy with norepinephrine (21.3 mcg/min) in patients with sepsis shock. Based on the abovementioned results, the potential mechanisms of corticosteroids restoring the vascular sensitivity to catecholamines have been reported as follows: (1) in the septic shock, as the excess production of nitric oxide causes host catecholamine resistance (76,77), corticosteroids could inhibit inducible NOS formation and production restoring the vascular sensitivity to catecholamines; (2) desensitization and/or downregulation of b-adrenergic receptors (78) and possibly aadrenergic receptors (79) maybe due to the downregulation by endogenous catecholamine production in septic shock, whereas the corticosteroids may reverse receptor desensitization (80) and further allow reduced catecholamine dosage (25). Given that the evidence of the relationship between catecholamines and corticosteroids is currently inconsistent, future clinical studies should be conducted to further research the dependence of catecholamine administration on the effect of cortisone administration. Additionally, to explore which septic patients were more responsive to the corticosteroids therapy, the ICU subgroup analysis after the type of disease and corticosteroids subgroup was conducted. The results showed that with corticosteroids use, there was no difference in the 28-day mortality, in-hospital mortality, and SOFA scores at day 7 among the surgical ICU, medical ICU, and surgical/medical ICU, but there was lower ICU mortality in patients with sepsis from surgical/medical ICU. The results of the subgroup analysis may not provide useful information mainly because ICU description is too vague in the included studies. Thus, details cannot be determined. Therefore, future clinical research should distinguish patients based on ICU type (e.g., surgical or medical ICU) to explore which sepsis primary cause is the corticosteroids therapy effective.
Corticosteroids have already been used for adjuvant therapy in sepsis for more than half a century. However, credible evidence is still lacking to guide the choice of patients, the time of corticosteroids administration, or the dose of corticosteroids for catecholamine-dependent patients. With the definition of sepsis that varies from sepsis-1.0 to sepsis-3.0, the accuracy of sepsis diagnosis has significantly improved. However, corticosteroids use also varied from sepsis-1.0 to sepsis-3.0. Specifi cally, only patients with septic shock used corticosteroids and suggested the use of flumetasone (50 µg/ day) in sepsis-1.0 (81). The use of hydrocortisone was suggested only in children with suspected or confirmed absolute adrenal insufficiency, which was a more stringent use of corticosteroids compared with sepsis-1, in sepsis-2.0 (82), and the use of hydrocortisone (200 mg/day) was suggested only in patients with refractory septic shock wherein appropriate fluid resuscitation and vasopressor therapy cannot restore hemodynamic stability in sepsis-3.0 (3), The proposals from sepsis-1.0, sepsis-2.0, and sepsis-3.0 lack credible evidence to support the clinical use of corticosteroids. Analysis of all relevant data from available RCTs showed that the effect of corticosteroids therapy for septic patients was not consistent. However, the latest studies showed that corticosteroids may not reduce mortality in septic patients compared with the control group. Importantly, this study suggests that corticosteroids administration may not reduce the 28-day mortality, long-term mortality, and length of ICU stay but may be associated with ICU mortality, in-hospital mortality, length of hospital stay, SOFA scores at day 7, and time to shock resolution, and increased shock reversal at days 7 and 28 and vasopressor-and ventilationfree days. Furthermore, this study suggested that corticosteroids may be an effective therapy with a low dose and longterm course. However, future studies need to appropriately study the time of corticosteroids administration, the primary infection source, and dose of corticosteroids use for septic shock patients who are dependent on catecholamine in the treatment of sepsis.
This meta-analysis has several strengths. First, this study is the most comprehensive trial to assess the efficacy of corticosteroids treatment on patients with sepsis to date. Second, we performed a thorough literature search including unpublished sources, using the GRADE methodology, to evaluate the evidence rank in overall RR, a predefined illustration of potential effect variables including direction of effect and subsequent subgroup analysis to search the effect variables, and illustration including the relative and absolute effects. Third, the primary outcomes showed low or no heterogeneity among the studies, suggesting that the results were not variable. Furthermore, the heterogeneity of SOFA scores on day 7 was high, and the subgroup analysis showed that the source of heterogeneity may be the inclusion of trials with small size on patients who were given hydrocortisone treatment. Finally, the results of the sensitivity analysis for this study suggested that these conclusions were robust and reliable.
However, this meta-analysis also has certain limitations, including the significant methodological or clinical heterogeneity among the included studies, especially with respect to the SOFA score on day 7. All the included RCTs enrolled patients with sepsis as per the previous sepsis definition criteria; however, we do not know whether the efficacy and safety of corticosteroids would change using the Sepsis-3 definition criteria. Hence, the defined mortality may be essential, but the certainty is limited due to the imprecision of the included studies.

CONCLUSIONS
This is the most comprehensive systematic review and metaanalysis to describe the efficacy and safety of corticosteroids in patients with sepsis. The findings demonstrate that corticosteroids failed to reduce the 28-day, 90-day, and longterm mortalities; however, they could reduce the in-hospital and ICU mortalities. Importantly, our subgroup analyses results indicated that this efficacy of corticosteroids in patients with sepsis may be associated with the hydrocortisone plus fludrocortisone treatment. Therefore, the results suggest that corticosteroids could not improve the 28-day mortality in adult patients with sepsis.

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding authors.

AUTHOR CONTRIBUTIONS
All the authors contributed equally to the work presented in this article. TS, HuL conceived the idea of this study. XD, HoL, and GS contributed to the data extraction. SH, RZ, and XD computed and evaluated the pooled outcomes. HuL and SH contributed to the study protocol and wrote the article. QK and TS revised the article. QK and TS had full access to all of the data, and the final responsibility for the decision to submit this article for publication. All authors contributed to the article and approved the submitted version.