Norepinephrine (Levophed®) | Medication Reference

Bedside Snapshot

Core dose: 0.1–0.5 mcg/kg/min IV infusion; titrate to MAP goal (typically ≥65 mmHg); max ~30 mcg/min in severe shock
Onset/duration: Onset immediate (seconds); half-life 2–3 min; effects dissipate within minutes of stopping
Key danger: Extravasation causes severe tissue necrosis—use central line; excessive vasoconstriction can worsen organ perfusion; arrhythmias at high doses
Special: First-line vasopressor for septic shock per Surviving Sepsis; potent α1-agonist with mild β1 activity; maintains cardiac output better than pure vasoconstrictors

Brand & Generic Names

Generic Name: Norepinephrine bitartrate
Brand Names: Levophed®

Medication Class

Endogenous catecholamine; potent α1-adrenergic agonist with β1 activity (minimal β2)

Pharmacology

Mechanism of Action:

Stimulates α1-adrenergic receptors on vascular smooth muscle causing potent vasoconstriction and increased SVR
β1 stimulation increases inotropy (with minimal chronotropic effect)
Net effect is increased MAP with generally minimal effect on heart rate due to baroreflex

Pharmacokinetics:

Onset: 1–2 min
Duration: Very short; only while infusion runs
Metabolism: Rapid neuronal and hepatic metabolism
Elimination: Primarily renal excretion of metabolites

Indications

Restoration of blood pressure in acute hypotensive states (septic shock, anesthesia-related hypotension, neurogenic shock)
Post–cardiac arrest hypotension
Adjunct in cardiac arrest and profound hypotension
First-line vasopressor for adults with septic shock after adequate volume resuscitation

Conditions Treated

Septic shock
Distributive shock (anaphylactic, neurogenic)
Post-cardiac arrest hypotension
Anesthesia-related hypotension
Refractory hypotensive states

Dosing & Administration

Available Forms:

Vial: 1 mg/mL norepinephrine base (as bitartrate) for dilution
Typical infusion concentration (institution-specific): 4 mg in 1000 mL D5W (4 mcg/mL)

Preparation:

Avoid mixing with sodium bicarbonate
Administer via dedicated line
Central venous access preferred as soon as feasible

Adult Dosing (Septic/Distributive Shock):

Start: 0.01–0.1 mcg/kg/min IV; titrate to achieve target MAP (initial adult target 65 mmHg)
Common fixed-start alternative: 4 mcg/min, titrate to effect
Reported maximum: Around 3 mcg/kg/min

Pediatric Dosing:

Start: 0.05–0.2 mcg/kg/min IV
Titrate: Increase by 0.02–0.05 mcg/kg/min to hemodynamic goals
Higher doses: Up to ~1–2 mcg/kg/min may be used in refractory shock
Current pediatric sepsis guidance permits either epinephrine or norepinephrine as initial vasoactive agent; selection should be tailored to origin of shock and myocardial function

Contraindications

Contraindications:

Uncorrected hypovolemia (except as a temporizing measure)
Mesenteric or peripheral vascular thrombosis (risk of worsening ischemia)
Concomitant use with certain volatile anesthetics (e.g., cyclopropane, halothane) due to arrhythmia risk

⚠️ Extravasation Risk: Extravasation can cause severe tissue necrosis. Use central venous access when possible. If extravasation occurs, promptly infiltrate affected area with phentolamine 5 mg in 10 mL NS (may repeat once in 30 min).

Adverse Effects

Ischemic Complications:

Digital/skin ischemia
Mesenteric ischemia
Limb ischemia
Extravasation-induced tissue necrosis

Cardiac:

Arrhythmias
Reflex bradycardia
Hypertension
Stress cardiomyopathy with overdose

Metabolic:

Mild hyperglycemia

Drug Interactions

MAO inhibitors/linezolid, tricyclics/SNRIs: Risk of hypertensive crisis or potentiation—avoid or monitor closely
Ergot alkaloids: Additive vasospasm—contraindicated
Inhaled anesthetics (e.g., isoflurane): Arrhythmia risk—avoid
Insulin/antidiabetics: Opposing glycemic effects; monitor glucose

Monitoring

Hemodynamic Monitoring:

Continuous BP monitoring
Invasive arterial pressure monitoring recommended when feasible
Initial MAP target 65 mmHg in adults

End-Organ Perfusion:

Mental status
Capillary refill and skin perfusion
Urine output ≥0.5 mL/kg/h
Lactate trends

Infusion Safety:

Central venous access when possible
Frequent site checks if peripheral initiation
Extravasation management ready (phentolamine)

Clinical Pearls

Early Initiation: Start early after adequate fluid resuscitation. Do not delay for central access—initiate peripherally if needed, then convert to central line when feasible.

⚠️ Extravasation Management: If extravasation occurs, promptly infiltrate with phentolamine 5 mg in 10 mL NS (may repeat once in 30 min). Have this antidote readily available when running norepinephrine peripherally.

Lactate Interpretation: Rising lactate on epinephrine may reflect increased aerobic production—interpret with caution. This is less an issue with norepinephrine, making it preferred in septic shock.

Vasopressin Synergy: Consider adding vasopressin when norepinephrine is ~0.25–0.5 mcg/kg/min to spare dose and improve MAP. Vasopressin is typically fixed at 0.03 U/min and not titrated.

ℹ️ Vasopressor Comparison:

Norepinephrine: α1 > β1; best mortality/arrhythmia profile vs dopamine; first-line in adult septic shock
Vasopressin: V1 receptor agonist at fixed dose (0.03 U/min) as catecholamine-sparing add-on when norepinephrine dose escalates; not titrated
Epinephrine: More β1/β2 at low doses; can raise lactate and arrhythmia risk; add-on or alternative
Phenylephrine: Pure α1; consider when tachyarrhythmias preclude β activity, but may reduce stroke volume

Surviving Sepsis Guidelines: Norepinephrine is the first-line vasopressor for septic shock in adults per the 2021 Surviving Sepsis Campaign guidelines. It has superior outcomes compared to dopamine in terms of mortality and arrhythmia risk.

References

1. Evans, L., Rhodes, A., Alhazzani, W., Antonelli, M., Coopersmith, C. M., French, C., ... & Levy, M. (2021). Surviving Sepsis Campaign: International guidelines for management of sepsis and septic shock 2021. Intensive Care Medicine, 47, 1181–1247. https://doi.org/10.1007/s00134-021-06506-y
2. Medscape. (2024). Levarterenol, Levophed (norepinephrine) – dosing, indications, interactions. https://reference.medscape.com/drug/levarterenol-levophed-norepinephrine-342443
3. Pfizer. (2018). LEVOPHED (norepinephrine bitartrate injection) Prescribing Information. https://webfiles.pfizer.com/file/2aa809f8-b0a8-4654-b494-5879aa27cf26
4. Papadopoulos, J. (2007). Pocket Guide to Critical Care Pharmacotherapy. Humana Press.
5. Weiss, S. L., Peters, M. J., Alhazzani, W., Agus, M. S. D., Flori, H. R., Inwald, D. P., ... & Kissoon, N. (2020). Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-Associated Organ Dysfunction in Children. Pediatric Critical Care Medicine, 21(2), e52–e106. https://doi.org/10.1097/PCC.0000000000002198
6. American Academy of Pediatrics. (2023). Pediatric Sepsis: Diagnosis, Management, and Sub-classification. Pediatrics, 153(1), e2023062967.