In an adult intensive care unit (ICU) patient with low cardiac output and hypotension (systolic blood pressure <90‑100 mmHg), how should norepinephrine be initiated, titrated to achieve a mean arterial pressure (MAP) ≥65 mmHg, and when should a second vasopressor be added?

Norepinephrine Initiation and Titration in ICU Hypotension

Initial Norepinephrine Dosing and Administration

Start norepinephrine at 0.05–0.1 µg/kg/min (approximately 5–10 µg/min for a 70 kg adult) via central venous access immediately after administering at least 30 mL/kg crystalloid within the first 3 hours, targeting a mean arterial pressure (MAP) ≥65 mmHg. 1

• Administer through central venous access whenever possible to minimize tissue necrosis risk from extravasation; if central access is unavailable, use a large peripheral vein with close monitoring, or intraosseous access when other routes are not feasible 1
• Place an arterial catheter for continuous blood pressure monitoring as soon as practical after vasopressor initiation 1, 2
• Do not delay norepinephrine while pursuing aggressive fluid resuscitation in severe hypotension with critically low diastolic pressure—early vasopressor use is appropriate as an emergency measure 1

Titration Strategy

• Increase norepinephrine in increments of 0.02–0.05 µg/kg/min every 5–10 minutes until MAP ≥65 mmHg is achieved 1
• For patients with chronic hypertension, target MAP 70–85 mmHg to reduce the need for renal replacement therapy 1, 2
• For elderly patients >75 years, consider a lower MAP target of 60–65 mmHg, which may reduce mortality compared to higher targets 3, 2

When to Add a Second Vasopressor (Vasopressin)

Add vasopressin at a fixed dose of 0.03 units/min when norepinephrine reaches 0.1–0.25 µg/kg/min and MAP remains <65 mmHg despite adequate fluid resuscitation. 1, 3

• Vasopressin acts on V1a receptors (catecholamine-independent vasoconstriction), remaining effective when adrenergic receptors are down-regulated in septic shock 1
• Never use vasopressin as monotherapy—it must always be added to norepinephrine, not used alone 1, 3
• 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, 3

Rationale for Early Vasopressin Addition

• Early norepinephrine administration increases cardiac output and improves microcirculation while avoiding fluid overload 4, 5
• Adding vasopressin at moderate norepinephrine doses (rather than escalating norepinephrine further) corrects the relative vasopressin deficiency present in septic shock and provides complementary vasoconstriction 1, 4
• Vasopressin preferentially constricts the efferent arteriole, producing higher glomerular filtration and better urine output at the same MAP compared to norepinephrine alone 1

Third-Line Vasopressor Options

If MAP cannot be achieved with norepinephrine plus vasopressin:

• Add epinephrine starting at 0.05 µg/kg/min, titrating up to 0.3 µg/kg/min 1, 3
• Consider hydrocortisone 200 mg/day IV for shock refractory to vasopressors after ≥4 hours of high-dose therapy 1, 3

Monitoring Beyond MAP: Tissue Perfusion Markers

MAP alone is insufficient to assess adequate resuscitation—monitor these parameters every 2–4 hours: 1, 2

• Lactate clearance: Obtain baseline and repeat within 6 hours if elevated; aim for normalization 1, 2
• Urine output: Maintain ≥0.5 mL/kg/h as a renal perfusion indicator 1, 2
• Mental status, skin perfusion, and capillary refill: Assess peripheral perfusion clinically 1, 2
• Central venous oxygen saturation: Gauge global oxygen delivery 1

When to Add Dobutamine (Not a Second Vasopressor)

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

• Dobutamine addresses cardiac output rather than vascular tone, making it appropriate for persistent hypoperfusion despite adequate MAP 1
• Do not use dobutamine to raise blood pressure—it can worsen hypotension through vasodilation at low doses 1

Critical Agents to Avoid

Dopamine

• Strongly contraindicated as first-line therapy (Grade 1A recommendation) 1, 3
• Associated with 11% absolute increase in mortality and significantly more supraventricular (RR 0.47) and ventricular arrhythmias (RR 0.35) compared to norepinephrine 1
• Low-dose dopamine for renal protection is strongly discouraged (Grade 1A)—it provides no benefit 1, 3
• Reserve dopamine only for highly selected patients with absolute or relative bradycardia and low arrhythmia risk 1

Phenylephrine

• Not recommended except in three specific situations: (1) norepinephrine-induced serious arrhythmias, (2) documented high cardiac output with persistent hypotension, or (3) salvage therapy after failure of all other agents 1, 3
• Phenylephrine is a pure α-agonist that can lower cardiac output through reflex bradycardia and increased afterload, potentially compromising microcirculatory flow despite raising MAP 1

Common Pitfalls to Avoid

• Do not focus solely on MAP numbers—incorporate tissue perfusion markers (lactate, urine output, mental status) into decision-making 1, 2
• Do not delay norepinephrine while pursuing excessive fluid resuscitation in profound hypotension 1
• Do not exceed vasopressin 0.03–0.04 units/min to avoid end-organ ischemia 1, 3
• Do not assume MAP 65 mmHg is adequate for all patients—chronic hypertension, elevated intra-abdominal pressure, and other specific scenarios may require higher targets 1, 2
• Increasing MAP above 65 mmHg with norepinephrine does not systematically improve microcirculatory perfusion and may be harmful in some patients 6, 7

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. Titrate norepinephrine in 0.02–0.05 µg/kg/min increments every 5–10 minutes to keep MAP ≥65 mmHg (or 70–85 mmHg in chronic hypertension) 1
3. When norepinephrine reaches 0.1–0.25 µg/kg/min and MAP remains <65 mmHg, add vasopressin 0.03 units/min (fixed dose) 1, 3
4. If MAP is still inadequate, add epinephrine beginning at 0.05 µg/kg/min, titrating up to 0.3 µg/kg/min 1
5. If MAP is adequate but hypoperfusion persists, add dobutamine 2.5–20 µg/kg/min to improve cardiac output 1, 3
6. For refractory shock after ≥4 hours, consider hydrocortisone 200 mg/day IV 1, 3