The VANISH Trial and Steroid Use in Septic Shock
Direct Answer
The VANISH trial investigated vasopressin versus norepinephrine as first-line vasopressor therapy in septic shock, with a secondary factorial design examining hydrocortisone versus placebo, but this trial is not explicitly detailed in the provided evidence—however, current guidelines strongly recommend hydrocortisone (≤400 mg/day for ≥3 days) for patients with septic shock that remains unresponsive to fluid resuscitation and moderate-to-high dose vasopressor therapy. 1
When to Use Hydrocortisone in Septic Shock
Clear Indication Criteria
Hydrocortisone should be initiated when:
- Septic shock persists despite adequate fluid resuscitation 1
- Vasopressor requirement is moderate-to-high dose (norepinephrine ≥0.1 μg/kg/min or equivalent) 1
- Most commonly interpreted as requiring two vasopressors simultaneously (64% of patients in practice patterns) 2
- Hypotension remains refractory after at least 60 minutes of vasopressor therapy 1
Do NOT Use Hydrocortisone When:
- Sepsis without shock is present (no mortality benefit, potential harm) 1
- Hemodynamic stability is achieved with fluid and single low-dose vasopressor 1
Dosing Protocol
Standard Regimen
Hydrocortisone 200 mg/day IV for ≥3 days at full dose 1, 3
Administration options:
Continuous infusion is preferred over bolus dosing to minimize hyperglycemia peaks 1
Duration and Tapering
- Maintain full dose for minimum 3-5 days before considering taper 1, 3
- Begin taper when vasopressors are discontinued, not before 1, 3
- Taper gradually over 6-14 days rather than abrupt cessation 3
- 76% of patients are off vasopressors when first dose change occurs in clinical practice 2
Evidence Quality and Nuances
Mortality Benefit Evidence
The evidence shows conflicting results regarding mortality:
- Meta-analysis of 27 RCTs showed trend toward reduced 28-day mortality (29.3% vs 31.8%, RR 0.87,95% CI 0.76-1.0) but low-quality evidence 1
- CORTICUS trial (2008) showed no mortality benefit overall (34.3% vs 31.5%, p=0.51) 5
- However, hydrocortisone consistently achieves faster shock reversal 1, 5
Recent High-Quality Evidence
Fludrocortisone plus hydrocortisone may be superior to hydrocortisone alone (RR 0.88,95% CrI 0.74-1.03,94.2% probability of superiority, moderate-certainty evidence from 2024 network meta-analysis) 6
Timing Considerations
Early initiation (≤3 hours) versus late (>3 hours) showed:
- Faster vasopressor discontinuation (25 vs 37 hours, p=0.009) 7
- No difference in ICU mortality or length of stay 7
Critical Pitfalls to Avoid
Do NOT Use ACTH Stimulation Testing
The ACTH stimulation test should NOT guide treatment decisions 1, 3
- No difference in outcomes between "responders" and "non-responders" 1, 5
- Treatment decisions should be based on clinical hemodynamic response, not cortisol levels 3
Etomidate Warning
Prior etomidate use for intubation is associated with increased 28-day mortality when combined with hydrocortisone 1, 3
Abrupt Discontinuation Risk
Never stop hydrocortisone abruptly—this causes hemodynamic and immunologic rebound effects 1, 3
Monitoring Requirements
Essential Monitoring
- Hyperglycemia (most common adverse effect—90.9% vs 81.5% in treatment vs placebo) 1
- Hypernatremia (especially with prolonged therapy >48-72 hours) 1, 4
- Secondary infections (21.5% vs 16.9%, though not statistically significant) 1
- Blood pressure response and vasopressor requirements 3
No Increased Risk Of:
Practical Algorithm
Step 1: Patient has septic shock requiring vasopressors
Step 2: Adequate fluid resuscitation completed
Step 3: Vasopressor dose ≥0.1 μg/kg/min norepinephrine OR two vasopressors required
Step 4: Initiate hydrocortisone 50 mg IV q6h or 200 mg/24h continuous infusion 1, 4
Step 5: Continue full dose minimum 3-5 days 1, 3
Step 6: When vasopressors discontinued, begin taper over 6-14 days 3
Step 7: Monitor glucose, sodium, blood pressure throughout 1, 3