How should norepinephrine be initiated in a patient with persistent hypotension (mean arterial pressure < 65 mm Hg) despite adequate fluid resuscitation?

How to Start Norepinephrine in Persistent Hypotension

Start norepinephrine at 0.02 µg/kg/min (approximately 0.5 mg/h for a 70-kg adult) immediately after or during administration of at least 30 mL/kg crystalloid fluid resuscitation, targeting a mean arterial pressure ≥ 65 mmHg. 1, 2

Pre-Administration Fluid Resuscitation

• Administer a minimum of 30 mL/kg crystalloid bolus within the first 3 hours before or concurrently with vasopressor initiation—this translates to approximately 2 liters for a 70-kg adult. 1, 2
• Do not delay norepinephrine while pursuing aggressive fluid resuscitation alone if the patient has profound hypotension (systolic BP < 70 mmHg or diastolic BP ≤ 40 mmHg); start norepinephrine emergently while fluid resuscitation continues. 2, 3
• In pregnant patients with sepsis, limit the initial fluid bolus to 1–2 L because of higher risk of pulmonary edema, then start norepinephrine at 0.02 µg/kg/min. 1, 2

Vascular Access and Preparation

• Central venous catheter placement is strongly preferred to minimize extravasation and tissue necrosis risk. 1, 2, 4
• If central access is unavailable, initiate norepinephrine through a large-bore peripheral IV until central access can be obtained—this is considered safe and reduces treatment delays. 1, 2
• Place an arterial catheter for continuous blood pressure monitoring as soon as practical after starting vasopressors. 2, 5

Dilution and Administration (FDA Label)

• Dilute the 4 mg/4 mL vial in 1,000 mL of 5% dextrose solution (yielding 4 µg/mL concentration). 4
• Do not use saline solution alone as the diluent—dextrose-containing fluids protect against potency loss due to oxidation. 4
• Do not mix with sodium bicarbonate or other alkaline solutions, as this inactivates the drug. 2
• Administer through a plastic intravenous catheter advanced centrally into the vein and securely fixed. 4

Initial Dosing

• Begin at 0.02 µg/kg/min (range 0.02–0.05 µg/kg/min), which equals approximately 1.4 µg/min or 0.5 mg/h for a 70-kg adult. 1, 2
• The FDA label suggests starting with 2–3 mL/min of the diluted solution (8–12 µg base/min), then titrating to response. 4
• Check blood pressure and heart rate every 5–15 minutes during the initial titration phase. 2

Hemodynamic Targets

• Target a minimum MAP of 65 mmHg in most patients with septic shock. 1, 2, 5
• In patients with chronic hypertension, consider targeting a MAP of 70–75 mmHg to reduce the incidence of renal replacement therapy. 2
• Do not routinely target MAP > 85 mmHg—a multicenter trial showed no mortality benefit and higher arrhythmia rates (36.6% vs 34.0%). 2
• Monitor tissue perfusion markers beyond MAP alone: lactate clearance (repeat every 2–4 hours), urine output ≥ 0.5 mL/kg/h, mental status, capillary refill ≤ 2 seconds, and skin perfusion. 1, 2

Titration and Maintenance

• The average maintenance dose ranges from 0.5–1 mL/min of diluted solution (2–4 µg base/min). 4
• Titrate to establish and maintain adequate blood pressure sufficient to maintain circulation to vital organs. 4
• In previously hypertensive patients, raise blood pressure no higher than 40 mmHg below the pre-existing systolic pressure. 4

Escalation Strategy for Refractory Hypotension

• When norepinephrine reaches 0.1–0.25 µg/kg/min without achieving MAP ≥ 65 mmHg, add vasopressin at 0.03 units/min (do not exceed 0.03–0.04 units/min). 1, 2, 5
• For refractory shock despite high-dose vasopressors after at least 4 hours, administer hydrocortisone 50 mg IV every 6 hours (or 200 mg/day continuous infusion). 1, 2
• If myocardial dysfunction persists despite adequate MAP, add dobutamine at 2.5–20 µg/kg/min. 2, 5

Extravasation Management

• If norepinephrine extravasates, immediately infiltrate phentolamine 5–10 mg diluted in 10–15 mL normal saline intradermally at the site to prevent tissue necrosis. 2

Special Clinical Scenarios

Pediatric Dosing

• Start norepinephrine in children at 0.1 µg/kg/min, titrating within a range of 0.1–1.0 µg/kg/min, with maximum doses up to 5 µg/kg/min in refractory cases. 2

Hepatorenal Syndrome

• Start norepinephrine at 0.5 mg/h and increase by 0.5 mg/h every 4 hours up to a maximum of 3 mg/h, aiming for a MAP increase ≥ 10 mmHg or urine output > 50 mL/h for at least 4 hours. 2

Anaphylaxis Refractory to Epinephrine

• Initiate norepinephrine at 0.05–0.1 µg/kg/min after 10 minutes of epinephrine boluses and fluid resuscitation. 2

Critical Pitfalls to Avoid

• Do not use dopamine as first-line therapy—it is associated with an 11% absolute increase in mortality and higher arrhythmia rates compared with norepinephrine. 2, 5, 6
• Low-dose dopamine for renal protection provides no benefit and is strongly discouraged (Grade 1A recommendation). 2, 5
• Phenylephrine should not be used as first-line agent—it may raise blood pressure without improving tissue perfusion and should be avoided except in specific circumstances (norepinephrine-induced arrhythmias, high cardiac output with persistent hypotension, or salvage therapy). 2, 5
• Do not delay norepinephrine in severe hypotension (SBP < 70 mmHg or DBP ≤ 40 mmHg) while waiting for complete volume repletion. 2, 3
• Avoid abrupt withdrawal—reduce the infusion gradually once adequate blood pressure and tissue perfusion are maintained. 4
• Do not use epinephrine as first-line therapy—it causes more metabolic adverse effects and transient lactic acidosis that interferes with lactate clearance as a resuscitation endpoint. 6