In a septic patient with hypotension refractory to adequate fluid resuscitation, what is the first‑line vasopressor, its initial dosing and titration to maintain MAP ≥65 mmHg, and which additional agents should be added if the MAP goal is not achieved?

Vasopressor Management in Septic Shock

Norepinephrine is the mandatory first-line vasopressor for septic shock, initiated immediately when hypotension persists after adequate fluid resuscitation, targeting a mean arterial pressure (MAP) of 65 mmHg. 1

Initial Resuscitation and Vasopressor Initiation

Fluid resuscitation must precede or accompany vasopressor therapy:

• Administer a minimum of 30 mL/kg of crystalloids within the first 3 hours for sepsis-induced hypotension 1
• Continue fluid challenges as long as hemodynamic improvement occurs based on dynamic variables (pulse pressure variation, stroke volume variation) or static variables (arterial pressure, heart rate) 1
• Do not delay norepinephrine if life-threatening hypotension (systolic BP <80 mmHg) is present—early vasopressor use is appropriate as an emergency measure 2, 3

Establish monitoring before or immediately after starting vasopressors:

• Place an arterial catheter for continuous blood pressure monitoring as soon as practical 1, 2
• Secure central venous access for safe norepinephrine administration to minimize extravasation risk 2, 4

Norepinephrine: First-Line Agent

Why norepinephrine is superior to alternatives:

• Reduces 28-day mortality by 11% absolute risk reduction compared to dopamine (number needed to treat = 9) 2
• Carries 53% lower risk of supraventricular arrhythmias and 65% lower risk of ventricular arrhythmias versus dopamine 2, 5
• Increases MAP through alpha-adrenergic vasoconstriction with minimal heart rate increase and modest beta-1 cardiac stimulation, maintaining cardiac output while raising systemic vascular resistance 2, 6

Norepinephrine dosing and titration:

• Start at 0.1-0.5 mcg/kg/min and titrate to achieve MAP ≥65 mmHg 2
• Titrate in increments based on hemodynamic response—doses must be individualized but typically increase by 0.01-0.02 mcg/kg/min every 5-15 minutes 2
• Target MAP of 65 mmHg for most patients; consider 70-75 mmHg in patients with chronic hypertension to reduce renal replacement therapy requirements 2

Adding Second-Line Agents When MAP Goal Not Achieved

When norepinephrine alone fails to maintain MAP ≥65 mmHg despite adequate fluid resuscitation, add vasopressin as the preferred second-line agent:

• Add vasopressin at 0.03 units/minute (do not use as monotherapy) 1, 2, 7
• Vasopressin provides catecholamine-independent vasoconstriction through V1a receptors, sparing norepinephrine requirements 2, 7
• Never exceed 0.03-0.04 units/minute except as salvage therapy—higher doses cause cardiac, digital, and splanchnic ischemia 1, 2, 7
• Once vasopressin is added, you can either raise MAP to target or decrease norepinephrine dosage while maintaining hemodynamic stability 2, 7

Alternative second-line option—epinephrine:

• Add epinephrine when vasopressin is unavailable or as an alternative to vasopressin 1
• Start at 0.05 mcg/kg/min and titrate in increments of 0.03 mcg/kg/min up to maximum 0.3 mcg/kg/min 2
• Caution: Epinephrine increases risk of tachyarrhythmias, causes transient lactic acidosis through β2-adrenergic stimulation, and increases myocardial oxygen consumption more than norepinephrine 2

Third-Line and Rescue Strategies

If MAP goal remains unmet despite norepinephrine plus vasopressin (or epinephrine):

• Add epinephrine as a third agent if vasopressin was used second-line 2, 7
• Consider dobutamine (2.5-20 mcg/kg/min) if persistent hypoperfusion exists despite adequate MAP, particularly when myocardial dysfunction is evident (elevated cardiac filling pressures, low cardiac output) 1, 2, 4
• Add hydrocortisone 200 mg/day IV for refractory shock unresponsive to catecholamines and vasopressin 1, 2, 4

Norepinephrine doses above 1 mcg/kg/min are associated with mortality rates exceeding 80%—implement adjunctive strategies before reaching this threshold 8

Agents to Avoid

Dopamine is contraindicated as first-line therapy:

• Use only in highly selected patients with low risk of tachyarrhythmias and absolute or relative bradycardia 1
• Associated with higher mortality and significantly more arrhythmias compared to norepinephrine 2, 5, 6

Low-dose dopamine for renal protection is strongly contraindicated (Grade 1A) 1, 2, 7

Phenylephrine is not recommended except in three specific circumstances:

• Norepinephrine causes serious arrhythmias 1, 2
• Cardiac output is documented to be high with persistently low blood pressure 1, 2
• Salvage therapy when combined inotrope/vasopressor drugs and low-dose vasopressin have failed 1, 2

Monitoring Beyond MAP

Assess tissue perfusion using multiple parameters:

• Urine output ≥0.5 mL/kg/h 2, 7
• Lactate clearance every 2-4 hours 2
• Mental status and capillary refill 2, 7
• Skin temperature and peripheral perfusion 2, 7

Watch for signs of excessive vasoconstriction:

• Digital ischemia, cold extremities 2, 7
• Decreased urine output despite adequate MAP 2, 7
• Rising lactate despite hemodynamic targets being met 2, 7

Common Pitfalls to Avoid

• Do not delay norepinephrine while pursuing aggressive fluid resuscitation in severe hypotension—profound and durable hypotension is an independent mortality risk factor 2, 3
• Do not escalate vasopressin beyond 0.03-0.04 units/minute—this causes end-organ ischemia without additional hemodynamic benefit 1, 2, 7
• Do not use dopamine for renal protection—this practice is strongly discouraged with no demonstrated benefit 1, 2, 7
• Do not focus solely on MAP numbers—tissue perfusion markers are equally critical for guiding therapy 2, 7
• Do not use phenylephrine as first-line therapy—it may raise blood pressure while actually worsening tissue perfusion through excessive vasoconstriction 2