What is the order of adding vasopressor agents in a patient with septic shock?

Vasopressor Sequencing in Septic Shock

Start with norepinephrine as your first-line vasopressor, add vasopressin at 0.03 units/minute when norepinephrine requirements exceed 0.25-0.50 mcg/kg/min, and consider epinephrine as a third agent if hypotension remains refractory. 1, 2

First-Line Vasopressor: Norepinephrine

Norepinephrine is the mandatory initial vasopressor for septic shock. 1, 2 This recommendation is based on strong evidence (Grade 1B) demonstrating superior efficacy and safety compared to dopamine, including lower mortality and fewer cardiac arrhythmias. 1, 3

Administration Protocol

• Initiate norepinephrine immediately when hypotension persists after initial fluid resuscitation (minimum 30 mL/kg crystalloids). 2, 4
• Target a mean arterial pressure (MAP) of 65 mmHg. 1, 2
• Requires central venous access for safe administration. 2, 4
• Place an arterial catheter for continuous blood pressure monitoring as soon as practical. 2, 4

Second-Line Vasopressor: Vasopressin

Add vasopressin at 0.03 units/minute when norepinephrine requirements remain elevated, specifically when the norepinephrine base dose exceeds 0.25-0.50 mcg/kg/min. 1, 2, 5

Key Implementation Points

• The FDA-approved starting dose for septic shock is 0.01 units/minute, titrated up by 0.005 units/minute at 10-15 minute intervals. 5
• However, the most common clinical practice is to add vasopressin at a fixed dose of 0.03 units/minute. 1, 2
• Never use vasopressin as monotherapy—it must always be added to norepinephrine, not used as the sole initial vasopressor. 1, 2, 5
• Do not exceed 0.03-0.04 units/minute except as salvage therapy when other vasopressors have failed. 1, 2, 5

Rationale for Early Addition

Vasopressin provides a norepinephrine-sparing effect and may reduce complications from high-dose catecholamines, though definitive mortality benefit remains unproven. 2, 6 Current guidelines suggest adding vasopressin rather than escalating norepinephrine doses beyond 0.25-0.50 mcg/kg/min. 1, 2

Third-Line Vasopressor: Epinephrine

If target MAP cannot be achieved with norepinephrine plus vasopressin, add epinephrine as your third agent. 1, 2 Epinephrine can be added to norepinephrine with the intent of raising MAP to target or potentially substituted for norepinephrine when an additional agent is needed. 1, 2

Dosing

• FDA-approved dosing range: 0.05-2 mcg/kg/min IV infusion. 2
• Titrate to achieve target MAP while monitoring for metabolic and cardiac adverse effects. 7

Agents to Avoid or Use Only in Specific Circumstances

Dopamine: Avoid as First-Line

Do not use dopamine as your initial vasopressor—it is associated with higher mortality and more arrhythmias compared to norepinephrine. 1, 2, 3 Use dopamine only in highly selected patients with low risk of tachyarrhythmias and absolute or relative bradycardia. 1, 2

Never use low-dose dopamine for renal protection—this is strongly discouraged and has no benefit. 2, 8

Phenylephrine: Reserve for Rare Situations

Avoid phenylephrine except in three specific circumstances: 2, 9

• When norepinephrine causes serious arrhythmias
• When cardiac output is documented to be high with persistently low blood pressure
• As salvage therapy when all other agents have failed

Phenylephrine may raise blood pressure numbers on the monitor while actually worsening tissue perfusion through excessive vasoconstriction without cardiac output support. 2

Additional Considerations for Persistent Hypoperfusion

Dobutamine for Myocardial Dysfunction

Add dobutamine (up to 20 mcg/kg/min) if persistent hypoperfusion exists despite adequate fluid loading and vasopressor therapy, particularly when myocardial dysfunction is evident. 2, 4 This addresses the inotropic component rather than further escalating vasopressors. 2

Critical Pitfalls to Avoid

• Do not delay norepinephrine initiation waiting to complete all fluid resuscitation if life-threatening hypotension is present. 2, 8
• Do not titrate to supranormal blood pressure targets—excessive vasoconstriction can compromise microcirculatory flow and tissue perfusion despite adequate MAP numbers. 2
• Monitor perfusion markers (lactate, urine output, mental status) rather than relying solely on blood pressure. 2, 8
• Ensure adequate fluid resuscitation precedes or accompanies vasopressor therapy. 1, 2