What is the sequence of vasopressors (vasopressor medications) in refractory septic shock?

Vasopressor Sequence in Refractory Septic Shock

Start with norepinephrine as first-line, add vasopressin 0.03 units/minute when norepinephrine alone fails to maintain MAP ≥65 mmHg, then add epinephrine as third-line if hypotension persists—this is the evidence-based sequence for refractory septic shock. 1, 2

First-Line: Norepinephrine

• Norepinephrine is the mandatory first-choice vasopressor with strong recommendation and moderate quality evidence from the Surviving Sepsis Campaign guidelines 1
• Target MAP of 65 mmHg initially, titrating norepinephrine dose to achieve this goal 1
• Requires central venous access for administration and arterial catheter placement as soon as practical for continuous blood pressure monitoring 1, 2
• Norepinephrine doses above 1 µg/kg/min are associated with mortality rates exceeding 80%, indicating the need for adjunctive agents before reaching this threshold 3

Second-Line: Add Vasopressin

When norepinephrine alone fails to maintain adequate MAP, add vasopressin at 0.03 units/minute rather than escalating norepinephrine further 1, 2

• Vasopressin can be added with the intent of either raising MAP to target OR decreasing norepinephrine dosage while maintaining hemodynamic stability 1, 2
• Never use vasopressin as monotherapy—it must always be added to norepinephrine, not used as the single initial vasopressor 1, 2
• Maximum dose is 0.03-0.04 units/minute; higher doses should be reserved only for salvage therapy when all other vasopressor combinations have failed to achieve adequate MAP 1, 2
• Vasopressin works through a different mechanism (V1 receptor) independent of catecholamine receptors, making it effective even when alpha-adrenergic receptors are down-regulated in septic shock 1

Third-Line: Add Epinephrine

If hypotension persists despite norepinephrine plus vasopressin, add epinephrine as the third vasopressor agent 1, 2

• Epinephrine can be added to norepinephrine when an additional agent is needed to maintain adequate blood pressure (weak recommendation, low quality evidence) 1
• Epinephrine may potentially substitute for norepinephrine in some cases, though this is less preferred 1
• Monitor closely for metabolic adverse effects (hyperglycemia, lactic acidosis) and cardiac complications (tachyarrhythmias) when using epinephrine 4

Agents to Avoid or Use Only in Specific Circumstances

Dopamine

• Do NOT use dopamine as first-line therapy—it is associated with higher mortality and more arrhythmias compared to norepinephrine 2, 4
• Only consider dopamine in highly selected patients with low risk of tachyarrhythmias AND absolute or relative bradycardia 1
• Never use low-dose dopamine for renal protection—this is strongly discouraged with no demonstrated benefit 1, 2

Phenylephrine

• Phenylephrine is NOT recommended except in three specific circumstances: (1) norepinephrine causes serious arrhythmias, (2) cardiac output is known to be high with persistently low blood pressure, or (3) as salvage therapy when combined inotrope/vasopressor drugs and low-dose vasopressin have failed 1, 2
• Phenylephrine is a pure alpha-agonist that may improve blood pressure numbers but can compromise microcirculatory flow and tissue perfusion through excessive vasoconstriction 1, 2
• FDA labeling indicates no bolus dosing for septic shock, only continuous infusion at 0.5-6 mcg/kg/min 5

Critical Monitoring and Titration

• Titrate all vasopressors to maintain MAP ≥65 mmHg with continuous arterial blood pressure monitoring 1, 2
• Monitor for signs of excessive vasoconstriction: digital ischemia, decreased urine output, rising lactate, or worsening organ dysfunction despite adequate MAP 1, 2
• Avoid titrating to supranormal blood pressure targets—the goal is adequate tissue perfusion, not just higher numbers on the monitor 1, 2

Adjunctive Inotropic Support

If persistent hypoperfusion exists despite adequate vasopressor support and fluid loading, add dobutamine up to 20 µg/kg/min rather than escalating vasopressors further 1, 6

• Dobutamine is indicated when there is evidence of myocardial dysfunction (elevated cardiac filling pressures with low cardiac output) or ongoing signs of hypoperfusion despite adequate intravascular volume and MAP 1, 6
• Discontinue dobutamine if worsening hypotension or arrhythmias develop 6

Common Pitfalls to Avoid

• Do not delay norepinephrine initiation—early administration (within the first hour) may reduce mortality and fluid requirements compared to relying solely on fluid resuscitation 7, 8
• Do not escalate norepinephrine indefinitely—add vasopressin when norepinephrine requirements remain elevated rather than pushing norepinephrine to toxic doses 1, 2, 3
• Do not use terlipressin or selepressin—these vasopressin analogs are associated with higher rates of digital ischemia and are not recommended 4, 3
• Ensure adequate fluid resuscitation first—correct intravascular volume depletion and acidosis before or during vasopressor administration, as acidosis reduces vasopressor effectiveness 5