Hydrocortisone Compared with Placebo in Patients with Septic Shock Satisfying the Sepsis-3 Diagnostic Criteria and APROCCHSS Study Inclusion Criteria

Abstract

Background: Two recent randomized controlled trials (Adjunctive Glucocorticoid Therapy in Patients with Septic Shock [ADRENAL] and Activated Protein C and Corticosteroids for Human Septic Shock [APROCCHSS]) of corticosteroids in patients with septic shock reported different treatment effects on 90-day mortality. Both trials enrolled patients who met the criteria for septic shock using the second international consensus definitions for sepsis and septic shock (Sepsis-2), but the APROCCHSS trial mandated a greater severity of shock as an inclusion criterion. Methods: The authors conducted post hoc sensitivity analyses of the ADRENAL trial to determine the effects of hydrocortisone versus placebo in subgroups selected using third international consensus definitions for sepsis and septic shock (Sepsis-3) diagnostic criteria or APROCCHSS inclusion criteria. results: There were 1,950 subjects (973 hydrocortisone and 977 placebo) who met the Sepsis-3 criteria (ADRENAL-Sepsis-3 cohort) and 905 patients (455 hydrocortisone and 450 placebo) who met the APROCCHSS criteria (ADRENAL-APROCCHSS cohort). At 90 days after randomization, in the ADRENAL-Sepsis-3 cohort, 312 of 963 (32.4%) and 337 of 958 (35.2%) patients assigned to hydrocortisone and placebo, respectively, had died (odds ratio, 0.86; 95% CI, 0.70 to 1.06; P = 0.166). The corresponding figures for the ADRENAL-APROCCHSS cohorts were 187 of 453 (41.3%) and 200 of 445 (44.9%), respectively (odds ratio, 0.84; 95% CI, 0.60 to 1.17; P = 0.303). There was no statistically significant difference in the time to death between the groups during the 90 days after randomization (hazard ratio = 0.87; 95% CI, 0.75 to 1.02; P = 0.082 for ADRENAL-Sepsis-3; and hazard ratio = 0.86; 95% CI, 0.71 to 1.06; P = 0.156 for ADRENAL-APROCCHSS cohorts). In both cohorts, patients assigned to hydrocortisone had faster resolution of shock. In the ADRENAL-Sepsis-3 cohort, patients assigned to hydrocortisone had an increase in the number of days alive and free of mechanical ventilation (57.0 ± 37.2 vs. 53.7 ± 38.2 days; 95% CI, 0.40 to 7.04; P = 0.028) and the number of days alive and free of the intensive care unit (54.3 ± 36.0 vs. 51.0 ± 37.1; 95% CI, 0.82 to 7.24; P = 0.014). Conclusions: In a post hoc analysis of the ADRENAL trial participants who fulfilled either the Sepsis-3 or the APROCCHSS inclusion criteria, a continuous infusion of hydrocortisone did not result in a lower 90-day mortality than placebo in septic shock.

Intravenous corticosteroid treatment in adult patients with sepsis defined by the Sepsis-3 criteria: a systematic review and meta-analysis

“…However, our findings should be taken with caution because the disease severity (sepsis vs septic shock or high vs low SOFA score) seemed to modify the association between corticosteroid treatments and the 28-day mortality in the Sepsis-3 cohort. Although our analysis showed that corticosteroids were not associated with reduced 28-day mortality, the post hoc analysis of the ADRENAL trial 16 showed that intravenous corticosteroid significantly reduced the 28-day mortality in patients who fulfilled the Sepsis-3 criteria for septic shock (odds ratio, 0.80; 95% CI, 0.64 to 0.99, p=0.04). In addition, the APROCCHSS trial, 2 which included patients with mean baseline SOFA score of 12—much higher than the SOFA score≥2 required by the Sepsis-3 criteria for sepsis—showed that corticosteroids were associated with reduced 90-day mortality (RR, 0.88; 95% CI, 0.78 to 0.99, p=0.03).…”

“…11 Thus, the Sepsis-3 definitions were increasingly adopted by researchers and clinicians to ensure consistency in clinical studies and daily practice. 11 13-15 After the Sepsis-3 definitions were proposed, to the best of our knowledge, only one post-hoc analysis of the ADRENAL trial has applied the Sepsis-3 criteria for septic shock, 16 but the association between intravenous corticosteroids and mortality in patients with sepsis defined by the Sepsis-3 criteria has not yet been summarized. Thus, we aimed to conduct this systematic review and meta-analysis to summarize the efficacy of corticosteroids in patients with sepsis defined by the Sepsis-3 criteria.…”

Adjunctive treatments for the management of septic shock – a narrative review of the current evidence

“…trial using the inclusion criteria for the trial by Annane et al. showed no effect of corticosteroids on 90‐day mortality [70]. The mortality benefit observed by Annane et al.…”

Staging and Personalized Intervention for Infection and Sepsis

“…Glucocorticoids are natural steroid hormones with pleotropic effects, including the upregulation of anti-inflammatory protein expression and downregulation of proinflammatory protein expression through binding of the transcription factor glucocorticoid receptor (GR). Since the first trial conducted in the 1960s, 24 randomized placebocontrolled trials have been published with conflicting results [59][60][61][62][63]. Factors affecting the response of a patient with sepsis to glucocorticoid treatment may have accounted for the conflicting results of the trials, including the time to treatment, dose and dosing strategy, type of glucocorticoid, other drugs administered, as well as patient comorbidities and genetic polymorphisms [64,65].…”