Journal of Clinical Medicine Research, ISSN 1918-3003 print, 1918-3011 online, Open Access
Article copyright, the authors; Journal compilation copyright, J Clin Med Res and Elmer Press Inc
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Original Article

Volume 18, Number 10, October 2026, pages 704-720

Comparative Efficacy and Safety of Corticosteroids vs. No Corticosteroids in Septic Shock Intensive Care Unit Patients: A Systematic Review and Meta-Analysis

Figures

↓  Figure 1. PRISMA 2020 flow diagram.
Figure 1.
↓  Figure 2. Risk of Bias 2 (RoB 2) traffic-light plot displaying per-domain (D1–D5) and overall judgements for each of the 11 included trials. Green (+) denotes “low risk of bias,” amber (?) denotes “some concerns,” and red (–) denotes “high risk of bias.”
Figure 2.
↓  Figure 3. Weighted summary of Risk of Bias 2 judgements across the five domains and the overall rating. Each horizontal bar shows the percentage of included trials adjudicated as “low,” “some concerns,” or “high” in the corresponding domain.
Figure 3.
↓  Figure 4. Forest plot of pooled risk ratios for 28-day all-cause mortality (random-effects model with REML estimator and Hartung–Knapp–Sidik–Jonkman adjustment). Square markers represent individual trial estimates with their 95% confidence intervals, sized by inverse-variance weight; the diamond denotes the pooled estimate; the orange band represents the 95% prediction interval. REML: restricted maximum likelihood.
Figure 4.
↓  Figure 5. Leave-one-out sensitivity analysis for the 28-day mortality meta-analysis. Each row shows the pooled risk ratio re-estimated after sequential omission of one trial. The pooled estimate remained statistically significant in all 11 iterations.
Figure 5.
↓  Figure 6. Contour-enhanced funnel plot for 28-day mortality. Shaded contours represent statistical-significance regions for the log-risk-ratio (white, P > 0.10; light gray, 0.05 < P < 0.10; mid-gray, 0.01 < P < 0.05; dark gray, P < 0.01). The visually symmetric distribution and Egger’s test (P = 0.972) provided no evidence of small-study effects.
Figure 6.
↓  Figure 7. Funnel plot following the Duval and Tweedie trim-and-fill procedure for 28-day mortality. No missing trials were imputed, and the pooled estimate remained unchanged at RR 0.91 (95% CI 0.86–0.97). CI: confidence interval; RR: risk ratio.
Figure 7.
↓  Figure 8. Bubble plot of the univariable random-effects meta-regression of log-risk-ratio for 28-day mortality on hydrocortisone-equivalent daily dose (mg/day). Bubble area is proportional to the inverse-variance weight of each trial. The regression slope was non-significant (β = 0.0021; P = 0.135).
Figure 8.
↓  Figure 9. Forest plots of secondary efficacy endpoints: shock reversal incidence (binary, RR scale; k = 5). All estimates from the random-effects REML/HKSJ model. HKSJ: Hartung–Knapp–Sidik–Jonkman; REML: restricted maximum likelihood; RR: risk ratio.
Figure 9.
↓  Figure 10. Forest plots of secondary efficacy endpoints: Time to shock reversal (mean difference in days; k = 5). All estimates from the random-effects REML/HKSJ model. HKSJ: Hartung–Knapp–Sidik–Jonkman; REML: restricted maximum likelihood.
Figure 10.
↓  Figure 11. Forest plot of ICU length of stay (mean difference in days; k = 4). Substantial between-study heterogeneity (I2 = 76.2%) was driven by divergent point estimates between ADRENAL and Sprung 2008 (CORTICUS). ICU: intensive care unit.
Figure 11.
↓  Figure 12. Forest plot of hyperglycemia incidence as an adverse event (k = 3). Each contributing trial individually showed a statistically significant excess; pooled RR was elevated but not significant under HKSJ adjustment owing to between-trial variability in operational thresholds. HKSJ: Hartung–Knapp–Sidik–Jonkman; RR: risk ratio.
Figure 12.
↓  Figure 13. GRADE summary of pooled effects with certainty color-coding. Risk-ratio outcomes (left panel; log scale, null = 1) and mean-difference outcomes (right panel; linear scale, null = 0) are plotted with marker color mapped to GRADE certainty (dark green = high; light green = moderate; amber = low; red = very low). The certainty stamp (filled/empty circles) is annotated beside each estimate. GRADE: Grading of Recommendations, Assessment, Development, and Evaluation.
Figure 13.

Tables

↓  Table 1. Baseline Characteristics of Included Studies
 
StudyAuthor, yearCountryPopulation/settingIntervention (drug, dose, duration)ComparatorTotal N (intervention/control)
aADRENAL [34] randomized 1,853 intervention/1,860 control (total 3,713); 1,841/1,840 were analyzed for 28-day mortality. ACTH: adrenocorticotropic hormone; ICU: intensive care unit; IV: intravenous.
[24]Agarwal, 2022IndiaGeriatric patients (> 60 years) with septic shock in ICUHydrocortisone: 200 mg/day IV in four divided doses, tapered after shock reversalStandard therapy120 (61/59)
[25]Annane, 2002FranceAdults with septic shock (ACTH non-responders & responders)Hydrocortisone 50 mg IV q6h + fludrocortisone 50 µg/day enteral for 7 daysPlacebo299 (150/149)
[26]Annane, 2018FranceAdults with septic shock (APROCCHSS trial)Hydrocortisone 50 mg IV q6h + fludrocortisone 50 µg/day enteral for 7 daysPlacebo1241 (614/627)
[27]Cicarelli, 2007BrazilAdults with septic shockDexamethasone: 0.2 mg/kg IV, three doses at 36 h intervalsPlacebo29 (14/15)
[28]Gordon, 2014UKAdults with septic shock (VANISH pilot)Vasopressin + hydrocortisone 50 mg IV q6hVasopressin + placebo61 (31/30)
[29]Lv, 2017ChinaAdults with septic shock (within 6 h of onset)Hydrocortisone: 200 mg/day continuous infusion for 6 days, then taperedPlacebo118 (58/60)
[30]Meersseman, 2025EuropeCirrhotic patients with septic shockHydrocortisone: 100 mg bolus + 200 mg/day continuous infusion for ≥ 3 daysPlacebo83 (40/43)
[31]Oppert, 2005GermanyAdults with early hyperdynamic septic shockHydrocortisone: 50 mg bolus + 0.18 mg/kg/h continuous infusion, then taperedPlacebo41 (18/23)
[32]Sprung, 2008Int'lAdults with septic shock (CORTICUS trial)Hydrocortisone: 50 mg IV q6h for 5 days, then taperedPlacebo499 (251/248)
[33]Talebi Doluee, 2018IranAdults with refractory septic shockHydrocortisone: 50 mg IV q6h for 7 daysPlacebo160 (80/80)
[34]Venkatesh, 2018Int'lAdults with septic shock on mechanical ventilation (ADRENAL)Hydrocortisone: 200 mg/day continuous infusion for 7 daysPlacebo3,713 (1,853/1,860)a

 

↓  Table 2. Pre-Specified Subgroup Analyses for 28-Day All-Cause Mortality
 
SubgroupkPooled RR (95% CI)I2/τ2QbetweenP
The em-dash (—) denotes a parameter not estimable owing to k = 1. aThe early-initiation subgroup (k = 2) [29, 31] yields an uninformative estimate: the 95% CI (0.09–14.00) spans two orders of magnitude owing to the extreme between-study standard error and should be regarded as hypothesis-generating only, not as evidence of equivalence. k: number of trials within subgroup; CI: confidence interval; I2: inconsistency statistic; Qbetween: Cochran’s Q test for subgroup differences; RR: risk ratio; τ2: between-study variance.
Regimen6.410.041
  Hydrocortisone alone80.93 (0.86–1.01)0.0%/0——
  Hydrocortisone + fludrocortisone20.88 (0.72–1.07)0.0%/0——
  Dexamethasone10.63 (0.35–1.12)———
Population0.140.986
  General adult ICU80.91 (0.85–0.99)0.0%/0——
  Geriatric (> 60 years)10.85 (0.54–1.33)———
  Cirrhotic10.89 (0.51–1.55)———
  Refractory shock10.93 (0.76–1.14)———
Immune status0.010.911
  Immunocompetent100.91 (0.86–0.97)0.0%/0——
  Immunocompromised10.89 (0.51–1.55)———
Timing of initiation0.830.362
  Standard/unspecified90.91 (0.86–0.96)0.0%/0——
  Early (< 6 h or hyperdynamic)21.09 (0.09–14.00)a0.0%/0——

 

↓  Table 3. GRADE Summary of Findings
 
OutcomeStudies (patients)Pooled effect (95% CI)Absolute effectCertainty (GRADE)
aImprecision: although the 95% CI excluded the null, the absolute risk reduction did not meet the optimal information size threshold for a high-certainty conclusion. bRisk of bias: substantial contribution from trials at high or some-concerns RoB on a process-of-care outcome susceptible to clinician unblinding. cNo serious concerns; SMD sensitivity analysis confirmed scale-robust effect (SMD −0.41, 95% CI −0.51 to −0.32; I2 = 10.8%). dInconsistency (I2 = 76.2%) and indirectness (ICU discharge influenced by step-down logistics). eInconsistency (varied operational definitions of hyperglycemia across trials) and indirectness (biochemical surrogate for patient-centered metabolic harm). CI: confidence interval; ICU: intensive care unit; MD: mean difference; OIS: optimal information size; PI: prediction interval; RCTs: randomized controlled trials; RR: risk ratio; SMD: standardized mean difference.
28-day all-cause mortality11 RCTs (6,332)RR 0.91 (0.86–0.97)27 fewer deaths per 1,000 (10 to 44 fewer)⊕⊕⊕◯ Moderatea
Shock reversal (incidence)5 RCTs (980)RR 1.08 (0.99–1.19)51 more per 1,000 (10 fewer to 117 more)⊕⊕⊕◯ Moderateb
Time to shock reversal5 RCTs (3,952)MD −1.25 days (−2.09 to −0.41)1.25 fewer days on vasopressors⊕⊕⊕⊕ Highc
ICU length of stay4 RCTs (4,381)MD −2.07 days (−6.50 to 2.36)2.07 fewer days in the ICU (95% CI crosses null)⊕⊕◯◯ Lowd
Hyperglycemia (adverse event)3 RCTs (1,787)RR 1.26 (0.63–2.50)Wide PI (0.38–4.11); each contributing trial individually showed excess⊕⊕◯◯ Lowe