Are norepinephrine (NORAD), vasopressin, and adrenaline (epinephrine) triple vasopressors?

Understanding "Triple Vasopressors" in Septic Shock

Yes, norepinephrine (NORAD), vasopressin, and epinephrine (adrenaline) are commonly referred to as "triple vasopressors" when used simultaneously in refractory septic shock, representing an escalation strategy when single or dual vasopressor therapy fails to achieve adequate mean arterial pressure.

Recommended Escalation Strategy

First-Line Therapy

• Norepinephrine is the first-choice vasopressor for septic shock and should be initiated as the primary agent 1.
• Target a mean arterial pressure (MAP) of 65 mmHg 1.
• Norepinephrine demonstrates superior outcomes compared to dopamine, with lower mortality (RR 0.91) and fewer arrhythmias 1, 2.

Second-Line Addition (Dual Therapy)

When norepinephrine alone fails to achieve target MAP, you have two evidence-based options:

• Vasopressin (0.03 units/min) added to norepinephrine is recommended to either raise MAP or decrease norepinephrine dosage 1.

  • The VASST trial showed potential benefit in patients requiring <15 μg/min norepinephrine at randomization 1.
  • Vasopressin should NOT be used as a single initial agent 1.
  • Doses higher than 0.03-0.04 units/min should be reserved for salvage therapy due to risk of digital and splanchnic ischemia 1.

• Epinephrine added to norepinephrine is an alternative second-line option when additional vasopressor support is needed 1.

  • Four randomized trials (n=540) showed no mortality difference between norepinephrine and epinephrine (RR 0.96) 1.
  • Epinephrine may increase aerobic lactate production via β2-adrenergic stimulation, potentially confounding lactate clearance as a resuscitation endpoint 1.

Third-Line Addition (Triple Therapy)

When dual vasopressor therapy (norepinephrine + vasopressin OR norepinephrine + epinephrine) remains inadequate, adding the third agent creates "triple vasopressor" therapy:

• If using norepinephrine + vasopressin, add epinephrine as the third agent 1.
• If using norepinephrine + epinephrine, add vasopressin (up to 0.03 units/min) as the third agent 1.

Critical Caveats and Pitfalls

Avoid These Common Errors:

• Do NOT use dopamine as first-line therapy - it increases arrhythmias without mortality benefit and should only be considered in highly selected patients with bradycardia and low arrhythmia risk 1, 2.
• Do NOT use phenylephrine routinely - reserve for specific circumstances: norepinephrine-associated arrhythmias, documented high cardiac output with persistent hypotension, or salvage therapy 1.
• Do NOT exceed vasopressin 0.03-0.04 units/min except as salvage therapy, as higher doses cause ischemic complications 1.

Monitoring Requirements:

• Place an arterial catheter as soon as practical when vasopressors are required 1.
• Monitor cardiac output when using pure vasopressors (vasopressin, phenylephrine) to ensure adequate flow is maintained 1.
• Consider adding inotropic support (dobutamine up to 20 μg/kg/min) if evidence of persistent hypoperfusion exists despite adequate MAP, as this may indicate inadequate cardiac output rather than purely vasodilatory shock 1.

Emerging Alternatives

While not part of standard "triple therapy," angiotensin II represents a newer option for refractory shock, particularly in patients with acute kidney injury requiring renal replacement therapy 3, 4. However, it is not currently recommended in standard guidelines due to limited evidence and safety concerns 3.

The term "triple vasopressors" specifically refers to the simultaneous use of three vasopressor agents in refractory shock, most commonly the combination of norepinephrine, vasopressin, and epinephrine, representing maximal medical vasopressor support before considering mechanical circulatory support or other salvage therapies.