Corticosteroids in Sepsis: Friend, Foe, or Fence-Sitter?

A Contemporary Review of Evidence-Based Practice in Critical Care

Dr Neeraj Manikath ,claude.ai

Abstract

Background: The role of corticosteroids in sepsis management remains one of the most contentious topics in critical care medicine. Despite decades of research, clinicians continue to grapple with questions of when, which, and how to use these potent anti-inflammatory agents.

Objective: To provide a comprehensive review of current evidence regarding corticosteroid use in sepsis, with particular emphasis on landmark trials including CORTICUS, ADRENAL, and recent studies, while offering practical clinical guidance for the modern intensivist.

Methods: Narrative review of key randomized controlled trials, meta-analyses, and recent observational studies published between 2002-2024.

Results: Current evidence suggests a nuanced approach to corticosteroid therapy in sepsis, with potential benefits in specific subgroups, particularly those with refractory shock and evidence of relative adrenal insufficiency.

Conclusions: Corticosteroids in sepsis are neither uniformly beneficial nor harmful—they are context-dependent therapeutic tools requiring judicious application based on individual patient characteristics and clinical presentation.

Keywords: Sepsis, septic shock, corticosteroids, hydrocortisone, dexamethasone, vasopressor, CORTICUS, ADRENAL

Introduction

The management of sepsis has evolved dramatically over the past two decades, yet few interventions have generated as much debate as corticosteroid therapy. From the early enthusiasm of the 1970s through the sobering realities of the 1980s and 1990s, to the current era of selective application, our understanding of corticosteroids in sepsis reflects the broader maturation of critical care medicine itself.

The fundamental question persists: Are corticosteroids in sepsis a friend that can save lives, a foe that causes harm, or a fence-sitter whose effects depend entirely on context? This review synthesizes current evidence to provide practical guidance for the modern intensivist.

Historical Context: The Pendulum Swings

The Early Years (1970s-1990s)

The initial excitement surrounding high-dose corticosteroids in sepsis was based on compelling pathophysiological rationale. The "cytokine storm" hypothesis suggested that massive anti-inflammatory intervention could interrupt the cascade leading to multi-organ failure. However, large randomized trials consistently failed to demonstrate mortality benefit, and some suggested harm.

The Paradigm Shift (2000s)

The seminal work by Annane et al. in 2002 marked a paradigm shift. Rather than using high-dose, short-duration "pulse" therapy, they introduced the concept of physiologic replacement doses (hydrocortisone 200-300 mg/day) for patients with relative adrenal insufficiency. This approach showed promise, setting the stage for subsequent landmark trials.

Pathophysiology: Understanding the Rationale

The Hypothalamic-Pituitary-Adrenal Axis in Sepsis

Clinical Pearl: The HPA axis in sepsis is not simply "insufficient"—it's dysregulated. Understanding this distinction is crucial for therapeutic decision-making.

During sepsis, the HPA axis undergoes complex changes:

Acute Phase (0-24 hours): Appropriate cortisol elevation in response to stress
Prolonged Phase (>24 hours): Potential exhaustion of adrenal reserve
Recovery Phase: Gradual normalization or persistent dysfunction

Relative Adrenal Insufficiency (RAI)

RAI represents inadequate cortisol production relative to the severity of illness, rather than absolute deficiency. Traditional definitions relied on:

Baseline cortisol <10 μg/dL (276 nmol/L)
Inadequate response to cosyntropin stimulation test (<9 μg/dL increase)

Teaching Point: Modern practice increasingly focuses on clinical indicators rather than rigid biochemical thresholds.

Landmark Trials: Lessons Learned

CORTICUS Trial (2008)

Study Design: Multicenter RCT, 499 patients with septic shock Intervention: Hydrocortisone 50 mg q6h for 5 days vs. placebo Primary Outcome: 28-day mortality

Key Findings:

No significant mortality benefit (34.3% vs. 31.5%, p=0.51)
Faster shock reversal in steroid group (HR 1.91, 95% CI 1.29-2.84)
Increased risk of hyperglycemia and acquired infections

Clinical Pearl: CORTICUS taught us that faster hemodynamic improvement doesn't always translate to survival benefit—a lesson applicable beyond steroid therapy.

ADRENAL Trial (2018)

Study Design: Multicenter RCT, 3,658 patients with septic shock Intervention: Hydrocortisone 200 mg/day continuous infusion for 7 days vs. placebo Primary Outcome: 90-day mortality

Key Findings:

No significant mortality benefit (27.9% vs. 28.8%, p=0.50)
Faster shock resolution (median 3 vs. 4 days, p<0.001)
Earlier ICU and hospital discharge
Higher rates of hyperglycemia requiring insulin

Teaching Hack: ADRENAL's negative primary outcome masks important secondary benefits—consider the whole patient, not just mortality statistics.

APROCCHSS Trial (2018)

Study Design: Multicenter RCT, 1,241 patients with septic shock Intervention: Hydrocortisone 200 mg/day + fludrocortisone 50 μg/day for 7 days vs. placebo Primary Outcome: 90-day mortality

Key Findings:

Significant mortality reduction (43.0% vs. 49.1%, p=0.03)
Benefit most pronounced in patients with higher illness severity
Combination therapy (hydrocortisone + fludrocortisone) crucial

Oyster Alert: APROCCHSS stands alone in showing mortality benefit—but was it the fludrocortisone that made the difference?

Recent Developments and Emerging Evidence

Dexamethasone in Sepsis

Recent interest in dexamethasone has been fueled by:

Longer half-life (36-72 hours vs. 8-12 hours for hydrocortisone)
Higher anti-inflammatory potency
Minimal mineralocorticoid activity

COVID-19 Lessons: The RECOVERY trial's success with dexamethasone in severe COVID-19 has rekindled interest in its application to bacterial sepsis.

Personalized Medicine Approaches

Emerging biomarkers for steroid responsiveness:

Baseline cortisol levels
Inflammatory markers (IL-6, procalcitonin)
Genetic polymorphisms affecting steroid metabolism
Tissue cortisol sensitivity markers

Current Guidelines and Recommendations

Surviving Sepsis Campaign Guidelines (2021)

Weak Recommendation: IV hydrocortisone 200 mg/day for adults with septic shock if adequate fluid resuscitation and vasopressor therapy do not restore hemodynamic stability.

Society of Critical Care Medicine (SCCM) Position

Consider corticosteroids in refractory septic shock
Hydrocortisone 200 mg/day (continuous infusion or divided doses)
Duration: 5-7 days with gradual taper

Clinical Pearl: Guidelines provide frameworks, not rigid rules. Individual patient factors should always guide decision-making.

Clinical Pearls and Practical Insights

When to Consider Corticosteroids

The "SHOCK" Mnemonic:

Severe hypotension despite adequate fluid resuscitation
High vasopressor requirements (norepinephrine >0.25 μg/kg/min)
Ongoing organ dysfunction
Clinical suspicion of adrenal insufficiency
Key timepoint: After 6-12 hours of optimal sepsis management

Dosing Strategies

Hydrocortisone Dosing Options:

Continuous Infusion: 200 mg/24 hours (preferred)
- More physiologic
- Better glycemic control
- Fewer peaks and troughs
Divided Doses: 50 mg q6h
- Easier to implement
- Traditional approach
- Acceptable alternative

Teaching Hack: Start with 200 mg/day—resist the urge to use higher doses based on illness severity.

Duration and Tapering

Standard Approach:

Initial course: 5-7 days
Begin taper when vasopressors are weaned
Taper over 2-3 days if treatment >3 days
Abrupt discontinuation acceptable if treatment ≤3 days

Clinical Pearl: Abrupt discontinuation after prolonged therapy can precipitate adrenal crisis—always taper gradually.

Oysters and Pitfalls

Common Mistakes (Oysters)

Using Corticosteroids Too Early
- Allow adequate time for standard sepsis management
- Minimum 6-12 hours of optimal care before considering steroids
Chasing Cosyntropin Tests
- Don't delay therapy waiting for stimulation test results
- Clinical indicators more important than biochemical tests
Fear of Hyperglycemia
- Steroid-induced hyperglycemia is manageable
- Benefits may outweigh risks in appropriate patients
One-Size-Fits-All Approach
- Tailor therapy to individual patient characteristics
- Consider comorbidities and contraindications

Contraindications and Cautions

Absolute Contraindications:

Active uncontrolled infection (relative)
Severe immunocompromise (relative)

Relative Contraindications:

Recent surgery or trauma
Active GI bleeding
Uncontrolled diabetes
Psychiatric disorders

Teaching Point: In critical care, few contraindications are absolute—weigh risks versus benefits for each patient.

Special Populations

Pediatric Sepsis

Limited evidence in children. Consider in:

Catecholamine-resistant shock
Suspected adrenal insufficiency
Dose: 1-2 mg/kg/day hydrocortisone

Pregnancy

Pregnancy creates unique considerations:

Physiologic changes affect cortisol metabolism
Fetal considerations with chronic use
Prednisolone preferred over dexamethasone (less placental transfer)

Immunocompromised Patients

Higher risk of secondary infections but potentially greater benefit from anti-inflammatory effects. Requires careful risk-benefit analysis.

Monitoring and Adverse Effects

Essential Monitoring Parameters

Daily Assessments:

Hemodynamic stability
Vasopressor requirements
Glucose control
Electrolyte balance
Signs of secondary infection

Weekly Assessments:

Wound healing
Psychiatric symptoms
Bone metabolism markers (if prolonged use)

Managing Adverse Effects

Hyperglycemia:

Expect glucose elevation
Adjust insulin protocols proactively
Target glucose 140-180 mg/dL (7.8-10.0 mmol/L)

Superinfection:

Maintain high index of suspicion
Consider prophylactic measures in high-risk patients
Fungal infections particularly concerning

Teaching Hack: Hyperglycemia from steroids is predictable—prepare your insulin protocols before starting therapy.

Future Directions

Personalized Medicine

Genomic markers for steroid responsiveness
Biomarker-guided therapy
Artificial intelligence-assisted decision-making

Novel Corticosteroids

Tissue-selective glucocorticoid receptor modulators
Nanoparticle delivery systems
Combination therapies

Precision Timing

Optimal timing relative to sepsis onset
Biomarker-triggered initiation
Personalized duration based on recovery markers

Practical Algorithm for Clinical Decision-Making

Step 1: Assess Appropriateness

Septic shock with adequate fluid resuscitation?
Vasopressor requirement >6 hours?
No absolute contraindications?

Step 2: Initiate Therapy

Hydrocortisone 200 mg/day (continuous infusion preferred)
Consider fludrocortisone 50 μg/day in refractory cases
Document indication and expected duration

Step 3: Monitor Response

Daily assessment of hemodynamic status
Glucose management
Infection surveillance

Step 4: Plan Discontinuation

Begin taper when vasopressors weaned
Gradual reduction over 2-3 days
Consider stress-dose coverage for procedures

Conclusion: The Verdict

Corticosteroids in sepsis are neither universally beneficial nor harmful—they are sophisticated tools requiring thoughtful application. The evidence suggests they function as "fence-sitters," with their utility dependent on patient selection, timing, dosing, and clinical context.

The modern intensivist should view corticosteroids as part of a personalized approach to sepsis management, using them selectively in patients with refractory shock while remaining vigilant for adverse effects. As our understanding of sepsis pathophysiology continues to evolve, so too will our ability to identify patients most likely to benefit from these powerful anti-inflammatory agents.

Final Teaching Point: In critical care medicine, the art lies not in following algorithms blindly, but in knowing when and how to deviate from them based on individual patient needs.

References

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Conflict of Interest: The authors declare no conflicts of interest.
Funding: No external funding was received for this review.

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Thursday, July 17, 2025