In a patient with septic shock whose blood pressure remains low despite adequate fluid resuscitation and norepinephrine (or other vasopressor) support, what adjunctive therapies should be administered?

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Last updated: October 26, 2026 • View editorial policy

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Adjunctive Therapies in Refractory Septic Shock

When blood pressure remains low despite adequate fluid resuscitation and norepinephrine, add vasopressin (0.03 units/min) or epinephrine as the first adjunctive vasopressor, followed by consideration of IV hydrocortisone 200 mg/day if hemodynamic instability persists. 1

Primary Adjunctive Vasopressor Strategy

The Surviving Sepsis Campaign guidelines provide clear direction for escalating vasopressor therapy:

First-Line Adjunctive Agents

Add vasopressin (up to 0.03 units/min) OR epinephrine to norepinephrine when MAP targets cannot be achieved with norepinephrine alone 1. Both options are acceptable:

  • Vasopressin can be added with the intent of either raising MAP or decreasing norepinephrine dosage (weak recommendation, moderate quality evidence)
  • Epinephrine can be added to or potentially substituted for norepinephrine (weak recommendation, low quality evidence)

Critical caveat: Vasopressin should NOT be used as the single initial vasopressor, and doses higher than 0.03-0.04 units/minute should be reserved only for salvage therapy when other agents have failed 1.

Agents to Avoid

Do NOT use dopamine for renal protection - this is strongly contraindicated (strong recommendation, high quality evidence) 1. Dopamine should only be considered as an alternative to norepinephrine in highly selected patients with low risk of tachyarrhythmias and absolute or relative bradycardia.

Phenylephrine is NOT recommended except in three specific circumstances: (a) norepinephrine causes serious arrhythmias, (b) cardiac output is known to be high with persistently low blood pressure, or (c) as salvage therapy when combined inotrope/vasopressor drugs and low-dose vasopressin have failed 1.

Corticosteroid Therapy

Consider IV hydrocortisone 200 mg/day when adequate fluid resuscitation and vasopressor therapy fail to restore hemodynamic stability (weak recommendation, low quality evidence) 1.

Key implementation points:

  • Do NOT use hydrocortisone if hemodynamic stability can be achieved with fluids and vasopressors alone
  • Do NOT use ACTH stimulation testing to identify patients who should receive hydrocortisone
  • Taper hydrocortisone when vasopressors are no longer required
  • Use continuous flow administration (not bolus dosing)
  • Do NOT administer corticosteroids for sepsis without shock

Inotropic Support for Persistent Hypoperfusion

Add dobutamine (up to 20 μg/kg/min) when evidence of persistent hypoperfusion exists despite adequate fluid loading and vasopressor use (weak recommendation, low quality evidence) 1.

Implementation guidance:

  • Titrate dosing to endpoints reflecting tissue perfusion (e.g., lactate clearance, capillary refill time, skin mottling)
  • Reduce or discontinue if worsening hypotension or arrhythmias develop
  • The 2025 ESICM guidelines emphasize that peripheral perfusion markers (capillary refill time, skin mottling) should guide resuscitation, as normalizing these markers may be more beneficial than targeting lactate alone 2

Monitoring Considerations

Place an arterial catheter as soon as practical in all patients requiring vasopressors (weak recommendation, very low quality evidence) 1.

Monitor peripheral perfusion markers including capillary refill time and skin mottling, as persistence of abnormal peripheral perfusion is associated with increased morbidity and mortality 2. Recent evidence suggests resuscitation guided by peripheral perfusion may be superior to lactate-guided resuscitation alone.

Algorithmic Approach

  1. Ensure adequate fluid resuscitation first - vasopressors are not a substitute for volume
  2. Optimize norepinephrine to achieve MAP ≥65 mmHg
  3. If MAP target not achieved: Add vasopressin 0.03 units/min OR epinephrine
  4. If hemodynamic instability persists: Add IV hydrocortisone 200 mg/day
  5. If signs of persistent hypoperfusion despite adequate MAP: Add dobutamine up to 20 μg/kg/min
  6. Reserve for salvage only: Higher-dose vasopressin (>0.03 units/min), phenylephrine, or angiotensin II

Common Pitfalls

  • Delaying adjunctive vasopressors: Don't wait for excessively high norepinephrine doses before adding second agents. Emerging evidence suggests earlier addition of vasopressin at moderate norepinephrine requirements may be beneficial 3, 4
  • Using dopamine for renal protection: This is ineffective and strongly discouraged
  • Ignoring tissue perfusion markers: Achieving MAP targets without improving peripheral perfusion is associated with worse outcomes 2
  • Forgetting to taper steroids: Hydrocortisone should be weaned when vasopressors are discontinued

References

4
Research

[Vasoactive agents in septic shock-individualized strategies].

Medizinische Klinik, Intensivmedizin und Notfallmedizin, 2025

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