In septic shock, which vasopressor is first‑line, what initial dose should be used, and how should it be titrated to achieve a mean arterial pressure ≥65 mm Hg after adequate fluid resuscitation?

Vasopressor Management in Septic Shock

Norepinephrine is the mandatory first-line vasopressor for septic shock, initiated at 0.05–0.1 µg/kg/min (approximately 5–10 µg/min for a 70-kg adult) via central venous access, targeting a mean arterial pressure (MAP) ≥65 mmHg after administering at least 30 mL/kg of crystalloid within the first 3 hours. 1, 2

Initial Fluid Resuscitation Before Vasopressors

• Administer a minimum of 30 mL/kg of intravenous crystalloid (normal saline or balanced solution) within the first 3 hours of septic shock recognition—this equals approximately 2 liters for a 70-kg patient given as rapid 500–1000 mL boluses over 5–10 minutes. 1, 2, 3

• Continue fluid challenges while hemodynamic improvement is observed, guided by dynamic indices (pulse-pressure variation, stroke-volume variation) or static variables (arterial pressure, heart rate, urine output). 1, 2

• Do not delay norepinephrine while pursuing aggressive fluid resuscitation if severe hypotension threatens life (e.g., critically low diastolic pressure); early vasopressor use is appropriate as an emergency measure. 2

Norepinephrine: First-Line Agent

Why Norepinephrine Over Other Agents

• Norepinephrine reduces 28-day mortality by 11% absolute risk reduction compared to dopamine (number needed to treat = 9 patients), with a 53% reduction in supraventricular arrhythmias (RR 0.47; 95% CI 0.38–0.58) and 65% reduction in ventricular arrhythmias (RR 0.35; 95% CI 0.19–0.66). 2

• It increases MAP primarily through α-adrenergic vasoconstriction with minimal heart rate increase and modest β₁-cardiac stimulation, maintaining cardiac output while raising systemic vascular resistance. 2

Dosing and Administration

• Starting dose: 0.05–0.1 µg/kg/min (5–10 µg/min for a 70-kg adult), titrated to maintain MAP ≥65 mmHg. 1, 2, 3, 4

• Administer through central venous access whenever possible to minimize tissue necrosis risk from extravasation; peripheral administration is acceptable initially to avoid delays. 2

• Place an arterial catheter for continuous blood pressure monitoring as soon as practical after initiating vasopressors. 1, 2, 3

MAP Targets

• Standard target: MAP ≥65 mmHg for most adults—below this threshold, organ autoregulation fails and perfusion becomes pressure-dependent. 1, 2, 3

• Chronic hypertension exception: Target MAP of 70–85 mmHg in patients with pre-existing hypertension because their autoregulatory curve is shifted rightward; this higher target reduces the need for renal replacement therapy. 2, 3

Escalation Strategy for Refractory Hypotension

Adding Vasopressin (Second-Line)

• Add vasopressin at 0.03 units/min (fixed dose, not titrated) when norepinephrine reaches 0.1–0.25 µg/kg/min (approximately 7–17.5 µg/min for a 70-kg adult) and MAP remains <65 mmHg. 1, 2, 4

• Vasopressin can either raise MAP to target or reduce norepinephrine requirements through catecholamine-independent vasoconstriction via V1a receptors. 2

• Never use vasopressin as monotherapy—it must be added to norepinephrine, not used alone. 1, 2, 4

• Do not exceed 0.03–0.04 units/min except as salvage therapy; higher doses cause cardiac, digital, and splanchnic ischemia without additional hemodynamic benefit. 1, 2, 4

• Early addition matters: Adding vasopressin within 3 hours of norepinephrine initiation (versus ≥3 hours) reduces time to shock resolution from 60.7 to 37.6 hours (adjusted HR 2.07; 95% CI 1.48–2.89; P <0.001) and decreases ICU length of stay. 5

Adding Epinephrine (Third-Line)

• Add epinephrine (starting at 0.05 µg/kg/min, titrating up to 0.3 µg/kg/min) when MAP targets cannot be achieved with norepinephrine plus vasopressin. 1, 2, 3

• Epinephrine causes transient lactic acidosis through β₂-adrenergic stimulation of skeletal muscle, which interferes with lactate clearance as a resuscitation endpoint. 2

• It increases myocardial oxygen consumption more than norepinephrine and carries higher risk of serious cardiac arrhythmias, particularly when combined with other sympathomimetic agents. 2

Adding Dobutamine (For Persistent Hypoperfusion)

• Add dobutamine 2.5–20 µg/kg/min when MAP is adequate (≥65 mmHg) but signs of tissue hypoperfusion persist (elevated lactate, reduced urine output, altered mental status, cold extremities), especially with evidence of myocardial dysfunction. 1, 2, 3, 4

• Dobutamine augments cardiac output rather than vascular tone and should be used when the problem is "cold shock" (low cardiac output) despite adequate MAP. 2, 3

Hydrocortisone (For Refractory Shock)

• Consider hydrocortisone 200 mg/day IV (e.g., 50 mg every 6 hours or continuous infusion) if hypotension remains refractory after ≥4 hours of high-dose vasopressor therapy (norepinephrine + vasopressin). 2, 3

Monitoring Beyond MAP: Tissue Perfusion Markers

MAP alone does not guarantee adequate tissue perfusion—you must concurrently assess: 2, 3

• Serum lactate: Obtain baseline immediately at septic shock recognition and repeat within 6 hours if elevated (≥2 mmol/L); use lactate normalization as a resuscitation endpoint. 1, 2, 3

• Urine output: Maintain ≥0.5 mL/kg/h as a bedside indicator of renal perfusion. 1, 2, 3

• Mental status: Regular neurologic checks to assess cerebral perfusion. 2, 3

• Skin perfusion / capillary refill: Target capillary refill <2 seconds with warm extremities and palpable peripheral pulses. 2, 3

• Central venous oxygen saturation (ScvO₂): Target ≥70% (or mixed venous O₂ saturation ≥65%) to confirm adequate tissue oxygen delivery. 2, 3

Agents to Avoid

Dopamine

• Dopamine should NOT be used as first-line therapy—it is associated with an 11% absolute increase in mortality and significantly more arrhythmias compared to norepinephrine. 1, 2, 4

• Reserve dopamine only for highly selected patients with low risk of tachyarrhythmias and absolute or relative bradycardia. 1, 2, 4

• Low-dose dopamine for renal protection is strongly contraindicated (Grade 1A recommendation). 1, 2, 4

Phenylephrine

• Phenylephrine is NOT recommended except in three specific circumstances: (1) norepinephrine causes serious arrhythmias, (2) cardiac output is documented to be high with persistent hypotension, or (3) salvage therapy when all other agents have failed. 1, 2, 4

• As a pure α-agonist, phenylephrine can raise blood pressure on the monitor while actually worsening tissue perfusion through excessive vasoconstriction and reflex bradycardia. 2

Common Pitfalls and How to Avoid Them

• Delaying norepinephrine while completing fluid resuscitation: In severe hypotension, start norepinephrine emergently even before fluids are complete—do not wait for life-threatening hypotension to worsen. 2

• Using vasopressin as monotherapy: Vasopressin must always be added to norepinephrine, never used alone as the initial vasopressor. 1, 2, 4

• Relying solely on MAP: Normal MAP can coexist with severe tissue hypoperfusion ("cold shock")—always assess lactate, urine output, mental status, and skin perfusion. 2, 3

• Escalating vasopressin beyond 0.03–0.04 units/min: Higher doses cause end-organ ischemia without benefit; if MAP remains inadequate, add epinephrine instead. 1, 2, 4

• Using dopamine for renal protection: This practice has no benefit and is strongly discouraged. 1, 2, 4

• Ignoring chronic hypertension: Patients with pre-existing hypertension require higher MAP targets (70–85 mmHg) to prevent organ hypoperfusion. 2, 3

• Excessive fluid administration when vasopressors are needed: Prolonged aggressive fluid resuscitation in vasopressor-dependent shock risks fluid overload, abdominal compartment syndrome, and delays definitive therapy. 3

Practical Titration Algorithm

1. After 30 mL/kg crystalloid bolus: If MAP <65 mmHg, start norepinephrine at 0.05–0.1 µg/kg/min. 1, 2, 3

2. Titrate norepinephrine in increments based on hemodynamic response to maintain MAP ≥65 mmHg (or 70–85 mmHg in chronic hypertension). 1, 2, 3

3. At norepinephrine 0.1–0.25 µg/kg/min: If MAP still <65 mmHg, add vasopressin 0.03 units/min (fixed dose). 1, 2, 4

4. If MAP remains inadequate: Add epinephrine 0.05 µg/kg/min, titrating up to 0.3 µg/kg/min. 1, 2, 3

5. If MAP adequate but hypoperfusion persists: Add dobutamine 2.5–20 µg/kg/min to improve cardiac output. 1, 2, 3

6. After ≥4 hours of high-dose vasopressors: If still refractory, add hydrocortisone 200 mg/day IV. 2, 3

7. Monitor tissue perfusion every 2–6 hours: Lactate trend, urine output, mental status, capillary refill, ScvO₂. 2, 3