Sepsis—life-threatening organ dysfunction caused by a dysregulated host immune response to infection (1)—can result in systemic hypoperfusion and end-organ dysfunction, and is associated with frequent morbidity and mortality in the ICU (2). The mainstays of treatment are early antibiotics and restoration of perfusion (IV fluids and vasopressor therapy) (3); despite early and aggressive therapy, mortality in septic shock remains as high as 30–40% (4).
Because the pathology of sepsis is characterized by a maladaptive host response to infection, experts have hypothesized that immunomodulatory therapies may provide effective treatment (5). Exogenous glucocorticoids are an attractive candidate given their widespread availability, relatively low cost, and their demonstrated ability to dampen the inflammatory cascade (5). In combination with mineralocorticoids, they may also address the relative deficiency of cortisol that can occur in states of extreme stress (5).
Despite the physiologic rationale, clinical data examining the effect of corticosteroids in sepsis have remained inconsistent, leading to substantial variation in clinical practice worldwide. The most recent Cochrane meta-analysis suggested that corticosteroids may reduce 28-day mortality in sepsis (relative risk [RR], 0.87; 95% CI, 0.76–1.00), although there was only low certainty in the evidence, limited by imprecision, inconsistency, and the potential for publication bias (6). Results from this review suggested that patients with septic shock and those treated with a low dose and a long course of corticosteroids had the highest likelihood of benefit. Another review showed a similar point estimate, but wider CI, and concluded no effect of corticosteroids in those with sepsis (RR, 0.87; trial sequential analysis adjusted 95% CI, 0.74–1.08) (7). Since these reviews, a number of large randomized controlled trials (RCTs) addressing the topic have been published (8 , 9), establishing the need for an updated systematic review.
This systematic review is part of the Rapid Recommendations project, a collaborative effort from the Making GRADE the Irresistible Choice (MAGIC) research and innovation program (www.magicproject.org) (10). The aim of the project is to respond to new potentially practice-changing evidence and provide trustworthy practice guidelines in a timely manner. In light of the two recently published large RCTs of 5,042 critically ill patients with sepsis (11 , 12), we updated the previous systematic review and meta-analysis (6) in order to inform a parallel clinical practice guideline (http://www.magicapp.org/public/guideline/EZ1w8n).
The protocol for this systematic review was registered on PROSPERO (CRD42017058537) and published in full (13). Substantive deviations from the published protocol are highlighted with an accompanying explanation.
Rapid Recommendation Guideline Panel
According to the Rapid Recommendations process, the guideline panel provided critical oversight and identified populations, subgroups, and outcomes of interest for this review (14). The panel included content experts, methodologists, and patients or caregivers of patients with lived experience of sepsis. Patients received personal training and support to optimize contributions throughout the guideline development process. The patients on the panel led the interpretation of the results based on what they expected the typical patient values and preferences to be, as well as the variation between patients. The four patients who were full members of the guideline panel contributed to the selection and prioritization of outcomes, values and preferences assessments, and critical feedback to the protocol for the systematic review.
Data Sources and Searches
We performed a comprehensive search of MEDLINE, EMBASE, CENTRAL, and LILACS for RCTs from December 1, 2014, to January 10, 2018. As this was an updated systematic review, to ensure adequate overlap, we searched from 3 months before the last review (6) (supplemental electronic material 1, Supplemental Digital Content 1, http://links.lww.com/CCM/D757, presents the MEDLINE search strategy). Keyword search terms included corticosteroids, sepsis, and septic shock in a search that did not apply any language restrictions. We searched conference proceedings and abstracts from the last 3 years (2014–2017) from the following societal meetings: The Society of Critical Care Medicine Congress, The American Thoracic Society, and The European Society of Intensive Care Medicine.
We performed all screening in duplicate with disagreements resolved by discussion and third party adjudication as required. After implementation of the search strategy, reviewers worked in pairs to screen all potentially relevant citations and references. Reviewers performed screening in two stages, initially assessing titles and abstracts, and then full articles for those possibly eligible. We captured reasons for exclusion at the full article review stage.
We included all RCTs comparing the use of corticosteroids (including but not limited to hydrocortisone, methylprednisolone, betamethasone, fludrocortisone, and dexamethasone) with a corticosteroid-free comparator group in critically ill patients with sepsis, excluding case reports, case series, and observational studies. The population of interest included all adults and children, excluding neonates, diagnosed with sepsis, severe sepsis, or septic shock, according to accepted criteria (15–17). We included data from trials enrolling patients with acute respiratory distress syndrome (ARDS) as long as the data from patients with sepsis were reported separately.
We included the following outcomes: short-term mortality up to 31 days, long-term mortality (60 d to 1 yr), shock reversal at day 7 (defined as stable hemodynamic status for > 24 hr after withdrawal of vasopressors), organ dysfunction at day 7 (using total Sequential Organ Failure Assessment [SOFA] score ), ICU length of stay, hospital length of stay, quality of life at 1 year using a validated index, stroke, myocardial infarction, and adverse events including neuromuscular weakness, gastrointestinal bleeding, neuropsychiatric effects (including delirium, confusion, mania, and others), hypernatremia, superinfection, and hyperglycemia. Our published protocol further separated short-term mortality into two separate endpoints, 28–31 days and 90 days. Given that all studies that reported 28- to 31-day mortality also reported 90-day mortality, we deviated slightly from our protocol and included both endpoints from these studies separately in our analysis. The short-term mortality from these studies was grouped with the other studies that also reported this 28- to 31-day endpoint, whereas the longer 90-day mortality data were grouped with the 1-year mortality data. To assess for any difference in long-term mortality between studies reporting at 60–180 days and those that reported at 1 year, we performed subgroup analysis.
Data Extraction and Quality Assessment
Reviewers performed data extraction independently and in duplicate using predefined data abstraction forms. A third reviewer resolved disagreements. Abstracted data included study title, first author, demographic data, details of the intervention and control, primary and secondary outcome data, and risk of bias (RoB) for each study. We performed our own data abstraction only for studies not included in the prior review (6), and for outcomes or subgroups that were not previously reported.
RoB was assessed, independently and in duplicate, for each outcome of individual studies using a modified Cochrane RoB tool (19) that classifies RoB as “low,” “probably low,” “probably high,” or “high” for each of the following domains: sequence generation, allocation sequence concealment, blinding, selective outcome reporting, and other bias. We rated the overall RoB as the highest risk attributed to any criterion. We assessed the overall certainty of evidence for each outcome using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework (20). Disagreements for RoB and GRADE assessments were resolved by discussion. GRADE assessments were also agreed upon with the linked British Medical Journal Rapid Recommendation guideline panel.
We used DerSimonian and Laird random-effects models in Rev-Man 5.3 (The Cochrane Collaboration, Copenhagen, Denmark) to conduct the meta-analyses. Study weights were generated using the inverse of the variance. We present results as RRs for dichotomous outcomes and as mean difference (MD) for continuous outcomes, both with 95% CI. We examined the potential for small study effects using a funnel plot if evidence included more than 10 trials per outcome, using the Egger test to detect funnel plot asymmetry for continuous outcomes (21) and the arcsine test for dichotomous outcomes. Funnel plots and small study effect testing were performed using Stata 15 (StataCorp, College Station, TX).
We assessed for heterogeneity between studies using the chi-square test for homogeneity, the I2 statistic, and visual inspection of the forest plots. We considered the magnitude and direction of heterogeneity when considering whether to rate down our certainty in the evidence for inconsistency. We explored prespecified subgroups with random-effects metaregression using Stata 15 and present interaction p values. Subgroups assessed included the following: high RoB versus low RoB hypothesizing that corticosteroids would be more effective in trials with high RoB; patient subpopulation (sepsis without shock vs septic shock, respiratory [ARDS/community-acquired pneumonia (CAP)] vs no respiratory illness) hypothesizing that corticosteroids would be more effective in those with septic shock and pneumonia/ARDS; dose and duration of corticosteroids (high dose/short course vs low dose/long course) hypothesizing that corticosteroids would be more effective with lower doses and when used for a longer duration; and corticosteroid molecule (hydrocortisone vs hydrocortisone plus fludrocortisone vs methylprednisolone or prednisolone or prednisone vs dexamethasone) hypothesizing that corticosteroids would be more effective using agents with more mineralocorticoid effect. The protocol (13) included these subgroup analyses and a plan for assessment for credible subgroup effect (22).
We performed two additional metaregression subgroup analyses that were not predefined but were requested by the linked Rapid Recommendations panel: impact of the mortality rate in the control group and year of study publication (as a continuous variable) on the effect of corticosteroids on mortality. The panel hypothesized that corticosteroids would be more effective in trials with a higher mortality rate in the control group and in older studies. Although we planned for subgroup analysis based on age of patients (adults vs children) and presence of critical illness–related corticosteroid insufficiency, there was insufficient evidence examining these subgroups for metaregression. We also performed three additional sensitivity analyses at the request of peer reviewers: we examined the effect of corticosteroids on short-term mortality in those only treated with long-course and low-dose corticosteroids, the effect of short-term mortality only in the last two published RCTs (11 , 12), and the effect of corticosteroids in only studies at low or probably low RoB. Absolute effects were calculated using the pooled baseline prevalence from the control arm of included studies.
Description of Eligible Studies
The 2015 Cochrane review contributed 30 eligible studies (n = 3,623) (23–52). Of the 7,202 citations identified in our updated search, we reviewed the full text of 33, of which 12 new RCTs ultimately proved eligible (7–9 , 11 , 53–60) for a total of 42 RCTs (Fig. 1).
Supplementary Table 1 (Supplemental Digital Content 2, http://links.lww.com/CCM/D758) presents a detailed description of eligible trials, 20 of which were multicenter (7–9 , 11 , 23 , 24 , 26 , 27 , 31–33 , 37 , 38 , 42 , 44 , 46 , 49 , 54 , 57) and the remainder single center. Twenty-four of the RCTs examined patients with septic shock (8 , 9 , 11 , 24–26 , 28–30 , 32–34 , 39 , 43 , 46–48 , 50 , 53–58); five included patients with both CAP and sepsis (28 , 35 , 39 , 42 , 46) and four enrolled patients with the ARDS and sepsis (32 , 34 , 37 , 57). Three of the included studies enrolled only children (41 , 47 , 55) and one enrolled both adult and children, but reported the two groups separately (33).
The majority of studies used hydrocortisone (n = 27; 6,922 patients) (7–9 , 11 , 25 , 26 , 28 , 29 , 31–35 , 39 , 41 , 42 , 47 , 48 , 50 , 53–60); others used methylprednisolone (n = 6; 859 patients) (23 , 27 , 36 , 37 , 40 , 49), prednisolone (n = 3; 308 patients) (45 , 51 , 52), or dexamethasone (n = 3; 333 patients) (30 , 38 , 44). Two studies used hydrocortisone in addition to fludrocortisone (1,541 patients) (11 , 24), and two studies included both dexamethasone and methylprednisolone groups (231 patients) (43 , 47). The dose of corticosteroid administered varied, although most (n = 37; 9,283 patients) used what we defined as low dose (< 400 mg/d of hydrocortisone or equivalent) and used them over a short course of therapy (< 3 d) (7–9 , 11 , 24–26 , 28–35 , 37–42 , 45 , 46 , 48–53 , 55–60).
Supplemental material 2 (Supplemental Digital Content 1, http://links.lww.com/CCM/D757) presents individual study RoB. Approximately half of the included studies were judged to be at low (n = 10) (7–9 , 11 , 24 , 38 , 46 , 49 , 57 , 59) or probably low RoB (n = 11) (23 , 25 , 27 , 28 , 32 , 35 , 37 , 45 , 51 , 52 , 60).
Table 1 shows summary of findings for all outcomes, based on the meta-analysis of identified trials, and includes the certainty of the evidence and the reasons for rating down certainty. Interactive tables summarizing the findings are available at http://www.magicapp.org/public/guideline/EZ1w8n. Figures 2 and 3 and supplemental material 3–18 (Supplemental Digital Content 1, http://links.lww.com/CCM/D757) present forest plots, metaregression results, and funnel plots for all outcomes including sensitivity analysis.
The pooled point estimates suggest that corticosteroids may result in a small reduction or no reduction in short-term mortality (RR, 0.93; 95% CI, 0.84–1.03; 1.8% absolute risk reduction; 95% CI, 4.1% reduction to 0.8% increase, low certainty) (Fig. 2 and Table 1) and possibly a small reduction in long-term mortality (RR, 0.94; 95% CI, 0.89–1.00; 2.2% absolute risk reduction; 95% CI, 4.1% reduction to no effect, moderate certainty) (Fig. 3 and Table 1).
Pooled estimates suggest that corticosteroids probably result in small reductions in ICU length of stay (MD, –0.73 d; 95% CI, –1.78 to 0.31; 12.40 vs 13.13 d, moderate certainty) and hospital length of stay (MD, –0.73 d; 95% CI, –2.06 to 0.60; 31.30 vs 32.03 d, moderate certainty). Patients randomized to receive corticosteroids had higher rates of shock reversal at day 7 (RR, 1.26; 95% CI, 1.12–1.42; 12.1% absolute risk increase; 95% CI, 5.6–19.5% increase, high certainty) and lower SOFA scores at day 7 (MD, –1.39 points; 95% CI, –1.88 to –0.89; 6.22 vs 7.61 points, high certainty). None of the studies reported quality of life outcomes.
Corticosteroids likely increase the rates of hypernatremia (RR, 1.64; 95% CI, 1.32–2.03; 2.3% absolute risk increase; 95% CI, 1.2–3.7% increase, moderate certainty) and hyperglycemia (RR, 1.16; 95% CI, 1.08–1.24; 2.9% absolute risk increase; 95% CI, 1.4–4.3% increase, moderate certainty). Corticosteroids may increase the risk of neuromuscular weakness (RR, 1.21; 95% CI, 1.01–1.52; 5.3% absolute risk increase; 95% CI, 0.3–13.0% increase, low certainty). Results did not demonstrate a convincing effect on other adverse effects including gastrointestinal bleeding (RR, 1.09; 95% CI, 0.86–1.38; 0.3% absolute risk increase; 95% CI, 0.5% decrease to 1.3% increase, low certainty), superinfection (RR, 1.02; 95% CI, 0.89–1.18; 0.3% absolute risk increase; 95% CI, 1.8% decrease to 2.9% increase, low certainty), and neuropsychiatric outcomes (RR, 0.58; 95% CI, 0.33–1.03; 2.5% absolute risk reduction; 95% CI, 4.0% fewer to 0.2% more, low certainty). We are very uncertain about the effect of steroids on stroke (RR, 2.07; 95% CI, 0.45–9.61; 0.5% absolute risk increase; 95% CI, 0.3–4.3% increase, very low certainty) or myocardial infarction (RR, 0.91; 95% CI, 0.45–1.82; 0.3% absolute risk reduction; 95% CI, 1.6% decrease to 2.5% increase; very low certainty) (Table 1).
Subgroup analyses did not demonstrate a credible effect for any of the predefined subgroups and on any of the outcomes of interest (p > 0.05 for all outcomes) (Supplementary Material 19, Supplemental Digital Content 1, http://links.lww.com/CCM/D757). Metaregression examining the effect of control group mortality on short-term mortality did not demonstrate a credible subgroup effect (p = 0.26). There was also no effect based on year of study publication (p = 0.89). Although we had planned for subgroup analysis examining the effect of corticosteroids on adults when compared with children, insufficient data precluded this analysis for any of the outcomes of interest.
Our systematic review demonstrates that the use of corticosteroids in sepsis may result in a small absolute reduction in mortality of approximately 2%. In this most comprehensive review to date, including several new large trials, the precision of the pooled point effect estimates has increased substantially (6 , 7 , 61). The CI around the pooled effect on mortality over the short, but not the long term, includes a small risk of harm (moderate quality for the latter because the upper boundary of the CI is 1.0) (Table 1).
Subgroup analyses failed to identify credible effect modification in patient population, study RoB, control group mortality (severity of illness), corticosteroid dose, duration, or molecule, or year of publication. Most of the evidence comes from studies that used hydrocortisone with or without fludrocortisone over a long course (> 2 d) and at a low dose (under 400 mg/d of hydrocortisone or equivalent). Results showed that it is likely that corticosteroids result in small reductions in ICU and hospital length of stay (Table 1). Our results fail to demonstrate an impact of corticosteroids on gastrointestinal bleeding, superinfection, neuropsychiatric effects, stroke, or myocardial infarction (Table 1). Based on low certainty evidence, corticosteroids may result in a small increase in the risk of neuromuscular weakness. Corticosteroids did increase the risk of hyperglycemia and hypernatremia although the studies failed to provide information regarding whether these findings required intervention or resulted in patient-important sequelae. Ascertainment of these adverse outcomes in the included studies was also variable, further contributing to the lower certainty in evidence.
Strengths of this review include a comprehensive literature search including unpublished sources, a published protocol to which we adhered (13), application of GRADE methodology to assess certainty in pooled estimates of effect, a priori specification of possible effect modifiers including direction of effect and subsequent metaregression to explore the effect modification, and specification of both relative and absolute effects. Content experts as well as methodologists and patients or caregivers with personal experience with sepsis as part of the Rapid Recommendation process provided critical input to our protocol and assessment of the synthesized evidence.
Limitations include significant clinical heterogeneity over studies conducted over a period of 60 years. Our exploration of subgroup hypotheses, including the era in which the studies were conducted, and the failure to identify any effect modification, markedly diminishes this concern. All included studies enrolled patients based on previous sepsis diagnostic criteria, although we have no reason to believe that using the new Sepsis-3 criteria would change the efficacy or harms of corticosteroids (16).
Although the demonstrated mortality effect may be important, the certainty is limited by imprecision. Our review demonstrates that the use of corticosteroids in septic shock is associated with faster shock reversal and less organ dysfunction at day 7 when compared with those that do not receive corticosteroids. Both outcomes are best viewed as surrogates for mortality and, on the basis of evidence that persistent organ dysfunction and shock may be associated with worse long-term quality of life, for quality of life. Despite previous suggestions that sicker patients might derive greater benefit from corticosteroids in sepsis, we found no support for this hypothesis in our subgroup analyses examining patients with septic shock and study control group mortality rate. Harms associated with the long-term use of corticosteroids (62) are well documented; our review suggests, however, that adverse effects may be minimal with the short-term use of corticosteroids in critically ill patients with sepsis.
The results of this meta-analysis reflect results of the recent large RCTs. The Activated Protein C and Corticosteroids for Human Septic Shock (APROCCHSS) trial enrolled 1,241 patients with septic shock from 34 centers in France and demonstrated a small reduction in 90-day mortality with corticosteroids (RR, 0.88; 95% CI, 0.78–0.99) (11). The Adjunctive Glucocorticoid Therapy in Patients with Septic Shock (ADRENAL) trial enrolled 3,800 patients with septic shock from 69 medical-surgical ICUs, and there was no effect on 90-day mortality (odds ratio, 0.95; 95% CI, 0.82–1.10). The results of both trials are consistent with our pooled estimates of effect and the associated CIs (9).
Based on the results of this review, our best estimates suggest a small absolute reduction in mortality with corticosteroids in sepsis based on low-to-moderate certainty evidence. This absolute reduction in death will be highest in the sickest patients (e.g., those with septic shock); however, the relative effects of corticosteroids appear consistent across all studied subgroups. Previous clinical practice guidelines, before the publication of ADRENAL and APROCCHSS, have made conditional recommendations against corticosteroids in sepsis and conditional recommendations for corticosteroids in the setting of septic shock (3 , 7). The results of this systematic review and meta-analysis will inform a Rapid Recommendation (19) examining the role of corticosteroids in patients with sepsis and septic shock.
The additional recent evidence from large trials has established that if steroids do have on effect on mortality, that effect is small. The most compelling evidence is of a 6% relative reduction in long-term mortality, translating to a 2% absolute risk reduction, but the CI around the estimate includes no effect. Point estimates suggest a reduction in length of stay in hospital and ICU, but these effects are also small—less than a day—and CIs include a possible increase in length of stay. Harms, however, are minimal, and informed individuals may as a result conclude that net benefit is likely.
We would like to express our gratitude to Jean Maragno and Lois Cottrel for their guidance in designing and carrying out our search strategy.
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