Sunday, August 24, 2025

Corticosteroids in Septic Shock: What We Know, What We Don't, and What Matters

 

Corticosteroids in Septic Shock: What We Know, What We Don't, and What Matters in 2025

Dr Neeraj Manikath, Claude.ai

Abstract

Background: The role of corticosteroids in septic shock remains one of the most debated topics in critical care medicine. Despite decades of research, questions persist regarding optimal agent selection, timing, dosing, and patient selection.

Objective: This review synthesizes current evidence on corticosteroid use in septic shock, with particular focus on recent landmark trials (ADRENAL, APROCCHSS) and emerging controversies around dexamethasone versus hydrocortisone.

Methods: Comprehensive review of randomized controlled trials, meta-analyses, and observational studies published through 2024, with emphasis on mechanistic insights and practical clinical applications.

Results: Low-dose corticosteroids (hydrocortisone 200mg/day or equivalent) demonstrate modest mortality benefits in vasopressor-dependent septic shock. The APROCCHSS trial suggests hydrocortisone plus fludrocortisone may be superior to hydrocortisone alone, while ADRENAL showed no mortality benefit but faster vasopressor weaning with hydrocortisone. Dexamethasone's role remains controversial given its lack of mineralocorticoid activity.

Conclusions: Current evidence supports judicious use of hydrocortisone in vasopressor-dependent septic shock, preferably with fludrocortisone. Patient selection, timing, and duration require individualized approaches based on shock severity and clinical context.

Keywords: septic shock, corticosteroids, hydrocortisone, dexamethasone, vasopressor, critical care


Introduction

Septic shock affects approximately 6% of intensive care unit (ICU) admissions and carries mortality rates exceeding 40% despite advances in supportive care.¹ The pathophysiology involves a complex interplay of inflammatory cascades, endothelial dysfunction, and relative adrenal insufficiency, making corticosteroids an attractive therapeutic target. However, the journey from bench to bedside has been fraught with conflicting evidence and clinical uncertainty.

The modern era of corticosteroid research in sepsis began with Annane's seminal work in 2002,² but subsequent trials have yielded mixed results. The publication of the ADRENAL³ and APROCCHSS⁴ trials in 2018 marked a watershed moment, providing the largest datasets to date while paradoxically intensifying debates about optimal steroid therapy.

This review examines the current state of knowledge regarding corticosteroid use in septic shock, addressing key clinical questions that face intensivists daily: Which steroid? Which patient? When? For how long?


Pathophysiology: The Rationale for Steroids

Hypothalamic-Pituitary-Adrenal Axis Dysfunction

Critical illness disrupts the hypothalamic-pituitary-adrenal (HPA) axis at multiple levels:

  • Central dysfunction: Reduced CRH and ACTH secretion
  • Peripheral resistance: Tissue glucocorticoid resistance despite normal cortisol levels
  • Relative insufficiency: Inadequate cortisol response relative to illness severity⁵

Beyond Inflammation: Vascular and Metabolic Effects

Modern understanding extends beyond anti-inflammatory properties:

  • Vascular responsiveness: Restoration of α-adrenergic receptor sensitivity
  • Endothelial stabilization: Reduced capillary leak and improved barrier function
  • Metabolic support: Enhanced gluconeogenesis and lipid metabolism⁶

The Mineralocorticoid Question

Septic shock often involves mineralocorticoid deficiency, manifest as:

  • Hyponatremia
  • Hyperkalemia
  • Volume depletion resistant to fluid resuscitation
  • Enhanced vasopressor sensitivity⁷

Evidence Review: Major Trials and Meta-Analyses

Historical Context: Early Studies

The journey began with high-dose methylprednisolone studies in the 1980s, which showed increased mortality and infection rates.⁸ This led to a paradigm shift toward low-dose "physiological" replacement therapy.

The Annane Era (2002-2015)

Annane et al.'s 2002 RCT² demonstrated significant mortality reduction with hydrocortisone 50mg QID plus fludrocortisone 50μg daily in patients with relative adrenal insufficiency. Key findings:

  • 28-day mortality: 63% vs 53% (p=0.02)
  • Benefit limited to non-responders to ACTH stimulation test
  • Faster vasopressor weaning

Subsequent trials yielded conflicting results, leading to the CORTICUS trial,⁹ which failed to show mortality benefit but confirmed faster shock resolution.

Game Changers: ADRENAL and APROCCHSS (2018)

ADRENAL Trial³

  • Design: 3,800 patients, hydrocortisone 200mg/day vs placebo
  • Primary outcome: 90-day mortality (27.9% vs 28.8%, p=0.50)
  • Secondary outcomes: Faster vasopressor weaning, shorter ICU stay
  • Criticism: No mineralocorticoid supplementation

APROCCHSS Trial⁴

  • Design: 1,241 patients, hydrocortisone 200mg/day + fludrocortisone 50μg/day vs placebo
  • Primary outcome: 90-day mortality (43% vs 49.1%, p=0.03)
  • Key difference: Inclusion of fludrocortisone
  • Secondary outcomes: Faster shock resolution, fewer renal replacement therapy days

Meta-Analyses: Making Sense of the Evidence

Recent meta-analyses consistently show:

  • Modest mortality reduction (RR 0.93, 95% CI 0.87-0.99)¹⁰
  • Faster vasopressor weaning
  • Shorter ICU length of stay
  • No increased infection risk with low-dose therapy

The Dexamethasone Controversy

Theoretical Advantages

  • Potency: 25-40x more potent than hydrocortisone
  • Duration: Longer half-life (36-72 hours)
  • Penetration: Better CNS penetration

Critical Limitations

  • No mineralocorticoid activity: Fails to address aldosterone deficiency
  • Excessive potency: May oversuppress immune function
  • Limited sepsis data: Fewer RCTs compared to hydrocortisone

COVID-19 Lessons: RECOVERY Trial Insights

The RECOVERY trial¹¹ demonstrated mortality benefit with dexamethasone 6mg daily in severe COVID-19, but key differences from bacterial sepsis include:

  • Hyperinflammatory phenotype
  • Preserved mineralocorticoid function
  • Different pathophysiology

Pearl: Dexamethasone's success in COVID-19 should not be extrapolated to bacterial septic shock without considering mineralocorticoid requirements.


Clinical Decision Making: Practical Approach

Patient Selection: Who Benefits?

Current evidence suggests benefit in:

  • Vasopressor-dependent shock (norepinephrine ≥0.1-0.25 μg/kg/min)
  • Early presentation (within 24-48 hours of shock onset)
  • Severe illness (higher SOFA scores)

Oyster: ACTH stimulation testing is no longer recommended for routine clinical decision-making given normal test results don't exclude benefit.¹²

Agent Selection: The Hydrocortisone Advantage

Preferred: Hydrocortisone 200mg/day (50mg QID or continuous infusion)

  • Balanced glucocorticoid and mineralocorticoid activity
  • Most studied agent in septic shock
  • Physiological replacement dosing

Consider adding: Fludrocortisone 50μg daily

  • Particularly in patients with hyponatremia, hyperkalemia
  • Supported by APROCCHSS trial data
  • May enhance vasopressor responsiveness

Timing: When to Start?

Optimal window: Within 24 hours of vasopressor initiation

  • Earlier initiation may prevent irreversible shock
  • Delayed therapy (>72 hours) shows diminished benefit¹³

Hack: Start steroids when second vasopressor is considered or when norepinephrine exceeds 0.25 μg/kg/min despite adequate fluid resuscitation.

Duration and Weaning

Standard duration: 5-7 days

  • Longer courses don't improve outcomes
  • May increase infection risk

Weaning strategy:

  • Taper over 2-3 days if used >3 days
  • Abrupt cessation if used ≤3 days
  • Monitor for rebound shock during weaning

Special Populations and Considerations

Immunocompromised Patients

Limited data, but considerations include:

  • Higher infection risk
  • Altered inflammatory response
  • Individual risk-benefit analysis required

Pediatric Septic Shock

Current pediatric guidelines don't routinely recommend steroids:

  • Different pathophysiology than adult sepsis
  • Limited high-quality pediatric data
  • Reserved for refractory shock¹⁴

Post-Cardiac Surgery

Distinct entity with different risk-benefit profile:

  • Higher baseline steroid exposure
  • Different inflammatory triggers
  • Separate evidence base required

Monitoring and Safety

Efficacy Monitoring

  • Hemodynamics: Vasopressor requirements, blood pressure
  • Metabolic: Electrolytes, glucose control
  • Inflammatory: Not routinely measured (CRP, PCT)

Safety Surveillance

  • Hyperglycemia: Most common side effect, requires insulin protocol
  • Infections: Monitor for secondary infections, but risk not significantly increased with low-dose therapy
  • GI bleeding: Stress ulcer prophylaxis considerations
  • Neuropsychiatric: Delirium, agitation (more common with higher doses)

Pearl: Tight glucose control (140-180 mg/dL) is crucial but avoid hypoglycemia, which may negate steroid benefits.


Controversies and Unknowns

The Mineralocorticoid Debate

Question: Is fludrocortisone necessary with hydrocortisone?

Current thinking:

  • APROCCHSS suggests yes, but ADRENAL used hydrocortisone alone
  • Hydrocortisone 200mg/day provides some mineralocorticoid activity
  • Patient-specific factors (electrolytes, fluid balance) should guide decisions

Biomarker-Guided Therapy

Emerging area: Using inflammatory biomarkers to guide steroid therapy

  • IL-6, presepsin, PCT levels
  • Genomic markers of steroid responsiveness
  • Currently investigational, not ready for clinical use¹⁵

Personalized Medicine

Future direction: Tailoring therapy based on:

  • Genetic polymorphisms affecting steroid metabolism
  • Immune phenotyping (hyperinflammatory vs immunosuppressed)
  • Pharmacokinetic/pharmacodynamic modeling

Guidelines and Recommendations

Current Guideline Summary

Surviving Sepsis Campaign 2021¹⁶:

  • Weak recommendation for hydrocortisone in vasopressor-dependent septic shock
  • Suggests against routine use in sepsis without shock
  • Recommends 200mg/day hydrocortisone equivalent

Society of Critical Care Medicine:

  • Similar recommendations
  • Emphasizes individualized approach
  • Acknowledges ongoing uncertainties

Practical Algorithm

Septic Shock Patient
↓
Vasopressor-dependent (NE ≥0.1 μg/kg/min)?
↓ YES
Within 24-48 hours of shock onset?
↓ YES
Start: Hydrocortisone 50mg IV q6h
Consider: Fludrocortisone 50μg daily PO/NG
Duration: 5-7 days with taper if >3 days
Monitor: Hemodynamics, glucose, electrolytes

Practical Pearls and Oysters

Pearls 💎

  1. Start early: Greatest benefit within 24 hours of vasopressor initiation
  2. Physiological dosing: 200mg/day hydrocortisone equivalent is optimal
  3. Add fludrocortisone: Particularly valuable in hyponatremic patients
  4. Monitor glucose: Hyperglycemia is common but manageable
  5. Short duration: 5-7 days maximum, taper if used >3 days

Oysters 🦪

  1. ACTH testing: Not routinely recommended for decision-making
  2. High-dose steroids: No benefit and potential harm
  3. Sepsis without shock: Steroids not recommended
  4. Late therapy: Minimal benefit if started >72 hours after shock onset
  5. Dexamethasone dogma: Limited evidence in bacterial septic shock

Clinical Hacks 🔧

  1. The "Second Vasopressor Rule": Start steroids when considering adding vasopressin or epinephrine
  2. Electrolyte clues: Hyponatremia + hyperkalemia = strong indication for steroids ± fludrocortisone
  3. Weaning test: If patient deteriorates during steroid taper, consider longer course or slower wean
  4. Glucose protocol: Have insulin infusion protocol ready before starting steroids
  5. Documentation: Clearly document indication, planned duration, and weaning strategy

Future Directions

Ongoing Research

  • Precision medicine: Genomic markers of steroid responsiveness
  • Biomarker studies: Inflammatory profiles to guide therapy
  • Novel agents: Modified corticosteroids with improved safety profiles
  • Combination therapy: Steroids plus other anti-inflammatory agents

Unanswered Questions

  1. Optimal duration in different patient subgroups
  2. Role of continuous vs intermittent dosing
  3. Interaction with other sepsis therapies (immunoglobulins, cytokine modulators)
  4. Long-term outcomes and quality of life impacts

Conclusions

The evidence for corticosteroids in septic shock has evolved from early enthusiasm through periods of skepticism to current cautious optimism. Key takeaways for clinical practice include:

  1. Clear benefit exists for vasopressor-dependent septic shock patients when started early
  2. Hydrocortisone remains the preferred agent, with growing evidence for adding fludrocortisone
  3. Patient selection matters: Benefits are most apparent in sicker patients with vasopressor dependence
  4. Timing is crucial: Earlier intervention yields better results
  5. Individualization is key: One size does not fit all patients

The field continues to evolve toward personalized approaches based on patient phenotype, biomarkers, and clinical context. While we await further definitive studies, current evidence supports judicious use of low-dose hydrocortisone in appropriately selected patients with septic shock.

Final Pearl: The question is no longer whether to use steroids in septic shock, but rather which patients, when, and with what adjuncts will maximize benefit while minimizing harm.


References

  1. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-810.

  2. Annane D, Sébille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002;288(7):862-871.

  3. Venkatesh B, Finfer S, Cohen J, et al; ADRENAL Trial Investigators. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock. N Engl J Med. 2018;378(9):797-808.

  4. Annane D, Renault A, Brun-Buisson C, et al; CRICS-TRIGGERSEP Network. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock. N Engl J Med. 2018;378(9):809-818.

  5. Marik PE, Pastores SM, Annane D, et al. Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force. Crit Care Med. 2008;36(6):1937-1949.

  6. Cronin L, Cook DJ, Carlet J, et al. Corticosteroid treatment for sepsis: a critical appraisal and meta-analysis of the literature. Crit Care Med. 1995;23(8):1430-1439.

  7. Annane D, Bellissant E, Bollaert PE, et al. Corticosteroids for treating sepsis. Cochrane Database Syst Rev. 2015;(12):CD002243.

  8. Bone RC, Fisher CJ Jr, Clemmer TP, et al. A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med. 1987;317(11):653-658.

  9. Sprung CL, Annane D, Keh D, et al; CORTICUS Study Group. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008;358(2):111-124.

  10. Rochwerg B, Oczkowski SJ, Siemieniuk RAC, et al. Corticosteroids in Sepsis: An Updated Systematic Review and Meta-Analysis. Crit Care Med. 2018;46(9):1411-1420.

  11. RECOVERY Collaborative Group. Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. 2021;384(8):693-704.

  12. Marik PE, Annane D. Hydrocortisone treatment for patients with septic shock: ADRENAL or not? Lancet. 2018;392(10141):7-9.

  13. Keh D, Trips E, Marx G, et al; SepNet–Critical Care Trials Group. Effect of Hydrocortisone on Development of Shock Among Patients With Severe Sepsis: The HYPRESS Randomized Clinical Trial. JAMA. 2016;316(17):1775-1785.

  14. Davis AL, Carcillo JA, Aneja RK, et al. American College of Critical Care Medicine Clinical Practice Parameters for Hemodynamic Support of Pediatric and Neonatal Septic Shock. Crit Care Med. 2017;45(6):1061-1093.

  15. Wong HR, Cvijanovich NZ, Anas N, et al. Developing a clinically feasible personalized medicine approach to pediatric septic shock. Am J Respir Crit Care Med. 2015;191(3):309-315.

  16. Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Crit Care Med. 2021;49(11):e1063-e1143.


Conflict of Interest Statement: The authors declare no conflicts of interest related to this review.

Funding: This review received no specific funding.


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