What is the recommended dosing, titration, and dilution protocol for norepinephrine (vasopressor) in managing severe hypotension or septic shock?

Norepinephrine Dosing, Titration, and Dilution Protocol

Norepinephrine is the mandatory first-line vasopressor for septic shock and severe hypotension, administered via central venous access with continuous arterial monitoring, targeting a mean arterial pressure (MAP) of 65 mmHg. 1, 2

Initial Administration Requirements

Before starting norepinephrine:

• Administer at least 30 mL/kg IV crystalloid within the first 3 hours, though do not delay norepinephrine if life-threatening hypotension exists 2, 3
• Establish central venous access for safe administration 2, 4
• Place an arterial catheter as soon as practical for continuous blood pressure monitoring 1, 2

Timing considerations:

• Start norepinephrine early when hypotension persists after initial fluid resuscitation 5, 6
• Use low diastolic arterial pressure as a trigger to initiate norepinephrine urgently, as this indicates depressed vascular tone 6
• Do not wait to complete all fluid resuscitation if severe hypotension threatens organ perfusion 5, 6

Standard Dilution and Starting Dose

While the guidelines do not specify exact dilution protocols, standard practice involves:

• Common dilution: 4-8 mg norepinephrine in 250 mL D5W or normal saline (16-32 mcg/mL concentration)
• Starting dose: 0.05-0.1 mcg/kg/min IV infusion 2
• Dose range: Typically 0.05-2 mcg/kg/min, though higher doses may be required 2

Titration Protocol

Primary target:

• Titrate to achieve MAP ≥65 mmHg in most patients 1, 2, 3
• Consider higher MAP targets (80-85 mmHg) only in patients with chronic hypertension 3

Titration strategy:

• Increase dose incrementally every 2-5 minutes until MAP target is achieved
• Monitor not just blood pressure, but also markers of tissue perfusion: lactate clearance, urine output, mental status, and skin perfusion 3
• Avoid titrating to supranormal blood pressure targets, as excessive vasoconstriction can compromise microcirculatory flow 2

Management of Refractory Hypotension

When norepinephrine alone fails to achieve MAP target:

First escalation option - Add vasopressin:

• Add vasopressin at 0.03 units/minute (do not exceed 0.03-0.04 units/minute except as salvage therapy) 1, 2, 4
• Vasopressin can either raise MAP to target OR allow you to decrease norepinephrine dosage 1, 2
• Never use vasopressin as monotherapy—it must be added to norepinephrine 1, 2, 4

Second escalation option - Add epinephrine:

• Add epinephrine (0.05-2 mcg/kg/min) as an alternative second agent when additional vasopressor support is needed 1, 2
• This is preferred over escalating vasopressin beyond 0.03-0.04 units/minute 2

For persistent hypoperfusion despite adequate vasopressors:

• Add dobutamine (up to 20 mcg/kg/min) if evidence of myocardial dysfunction or persistent hypoperfusion exists despite adequate fluid loading and vasopressor therapy 1, 2, 4
• Titrate dobutamine to endpoints reflecting perfusion, and reduce or discontinue if worsening hypotension or arrhythmias occur 1

Critical Agents to Avoid

Dopamine:

• Use dopamine ONLY in highly selected patients with low risk of tachyarrhythmias or absolute/relative bradycardia 1, 4
• Dopamine is associated with higher mortality and more arrhythmias compared to norepinephrine 1, 3, 4
• Never use low-dose dopamine for renal protection—this is strongly discouraged with no benefit 1, 4

Phenylephrine:

• Do not use phenylephrine except when: (a) norepinephrine causes serious arrhythmias, (b) cardiac output is documented to be high with persistently low blood pressure, or (c) as salvage therapy when all other agents have failed 1, 2, 4
• Phenylephrine may raise blood pressure numbers while actually worsening tissue perfusion through excessive vasoconstriction 2

Weaning Strategy

When to begin weaning:

• Once hemodynamic stability is achieved and tissue perfusion markers improve (lactate clearance, adequate urine output, improved mental status) 3

Weaning approach:

• Gradual dose reduction is preferred over abrupt discontinuation 2
• If vasopressin was added, wean norepinephrine first while maintaining vasopressin at 0.03 units/minute, then discontinue vasopressin once norepinephrine is at low doses 2

Common Pitfalls to Avoid

• Do not delay norepinephrine waiting for complete fluid resuscitation if life-threatening hypotension exists 2, 4
• Do not use vasopressin as monotherapy—it must always be added to norepinephrine 1, 2, 4
• Do not rely solely on blood pressure numbers—monitor tissue perfusion markers (lactate, urine output, mental status) 2, 3
• Do not use dopamine as first-line therapy—evidence clearly favors norepinephrine 1, 3, 4
• Monitor for excessive vasoconstriction: digital ischemia, decreased urine output, rising lactate, or worsening organ dysfunction despite adequate MAP 2