(March 2023)

Norepinephrine (NE) is used for hemodynamic support frequently as a first-line vasopressor with the exception of anaphylaxis (epinephrine) and post cardiac arrest care (epinephrine). Consider using noradrenaline in combination with inodilator drugs in cardiogenic shock. 

Adult dose for shock:
0.01-0.3 ug/kg/min IV.

• Calculate with total body weight.

• Usually started at 0.05 ug/kg/min IV. 

NE is an endogenous sympathomimetic catecholamine (acts as a hormone and neurotransmitter). It has alpha-1 and beta-1 adrenergic activity, causing arterial vasoconstriction (alpha-1), increased  heart rate (beta-1) and contractility (beta1), thereby increasing systemic blood pressure and coronary blood flow. Clinically alpha effects are greater than beta effects. In short, it has  inoconstrictor effects, and it also mobilizes unstressed venous blood volume.

The following clinical scenarios include NE for hemodynamic support:

• Shock: predominantly distributive shock (eg. septic and neurogenic shock). 

  • Septic shock:
    Universally accepted as first line vasopressor (1,3,5), its early administration is associated with improved survival (3), and is less arrhythmogenic than dopamine (4). 

  • Cardiogenic shock:
    According to the European Society of Cardiology Guidelines NE is the vasopressor of choice for the treatment of cardiogenic shock (8). It is commonly used in combination of inodilators (eg. dobutamine + NE, milrinone + NE). The combination is primarily used to mitigate the Beta-2 vasodilatory effect of those medications. NE is associated with improved survival at 28 days compared with dopamine in cardiogenic shock(4). 

  • Anaphylactic shock:
    NE or vasopressin are frequently used in combination with epinephrine infusion in refractory hypotension secondary to anaphylaxis (1). 

• Post-cardiac arrest care:
  Usually used as a second line vasopressor with epinephrine infusion. 

• Profound sedation:
  Usually used to increase vascular resistance attenuated by sympatholytic and parasympathomimetic effects of sedative and opioids agents.

• FDA-Labeled

• Severe hypotension unresponsive to volume replacement*
  *FDA approved in 1982 (6)

• Off-label
  Consider that the only FDA approved labeled indication is not specific, it could include all the following conditions, but is not stated officially by the manufacturer or other health authority (7). 

• Septic shock and other vasodilatory shock states

• Cardiogenic shock

• Post-cardiac arrest care

Adult dose for shock

0.01-3 ug/kg/min IV.

• Starting dose in shock 0.05-0.1ug/kg/min IV.

• In refractory shock, high doses of 1-3ug/kg/min are generally combined with other vasoactive or inotropic drugs. 

Preparation:

• Peripheral access: 4mg in 500ml NaCl 0.9% or D5%.

• Central access: 8mg in 250ml NaCl 0.9% or D5%.

Pediatric dose for shock

0.05-2ug/kg/min IV

• In refractory shock higher doses may be needed. 

• Usually similar dosing than adults. 

No adjustments needed. 

• Levophed™ (US, Canada, Australia, UK, Chile) 4mg/4ml, IV use.

• Adine™ (Chile) 4mg/4ml, IV use.

• Pridam™ (Latin-America) 4mg/4ml, IV use.

• Arterenol™, Tartrato™, Norages™, Noradrenaline™ (Europe), etc..

• Contraindications

Not contraindications determined.

• Adverse Effects

• Cardiovascular: reflex bradyarrhythmia. Hypertension and subsequent hypertensive emergencies may occur if supraoptimal dosing is used. 

• Extravasation complications: peripheral gangrene can occur, but is rare in <1%. In case of extravasation local infiltration with phentolamine is indicated. 

Central venous access is preferred for infusion, but peripheral use is reasonably safe when taken  appropriate precautions (1, 2). Consider large veins particularly antecubital vein, and using peripheral catheters of at least 20G in caliber.

Emergency Treatment of Extravasation (7)

• To prevent sloughing and necrosis in areas in which extravasation has occurred, infiltrate the ischemic area as soon as possible, using a syringe with a fine hypodermic needle with 5 to 10 mg of phentolamine in 10 to 15 mL of 0.9% Sodium Chloride Injection in adults.

• Sympathetic blockade with phentolamine causes immediate and conspicuous local hyperemic changes if the area is infiltrated within 12 hours.
  
  

• Warnings and Pathophysiological concerns 

• Hypovolemia: address volemia before initiating therapy; hypovolemic patients may experience severe peripheral and visceral vasoconstriction, decreased renal, splanchnic and extremity perfusion. 

• Hypoxia/hypercarbia: individuals with severe hypoxia or hypercarbia are in increased risk of ventricular tachycardia or fibrillation when norepinephrine is used. 

• Abrupt discontinuation: gradually reduce infusion rate before discontinuation, otherwise severe hypotension may occur. During the reduction of infusion rate assess the intravascular volume.
  
  

• Major drug interactions
  The following content includes the most relevant interactions in the emergency department, check for other specific interactions if needed.

• May enhance the sympathomimetic effect: 

• Sympathomimetics (vasopressin, adrenaline, ergotamines, amphetamine-like drugs, etc)

• Monoamine Oxidase Inhibitors

• Serotonin/Norepinephrine Reuptake Inhibitors

• Tricyclic Antidepressants

• Cannabinoid-containing products

• May enhance the arrhythmogenic effect of norepinephrine

• Inhalational anesthetics (isoflurane, sevoflurane, desflurane, etc)

• May diminish the vasoconstricting effect

• Alpha-1 blockers

• Clozapine

• Spironolactone

• Pregnancy Risk Category: not classified as norepinephrine is an endogenous hormone and neurotransmitter. It crosses the placenta and can affect the fetus. For shock management there is not a preference of vasopressor drugs based on pregnancy and fetal risk. 
  
  

• Lactation: infant risk cannot be ruled out, weight risk/benefit in keeping breastfeeding during critical care when other drugs are being administered.

• Onset of action: very rapid acting, usually less than a minute from infusion start. 

• Time to peak, serum: steady state in 5 minutes.

• Duration: 1-2 minutes. 

• Half-life elimination: mean 2.4 minutes.

• Protein binding: 25% mainly albumin.

• Metabolism: via catechol-o-methyltransferase and monoamine oxidase.

• Excretion: urine as inactive metabolites, small amounts as unchanged drug).

1. Ellender TJ, Skinner JC. The use of vasopressors and inotropes in the emergency medical treatment of shock. Emerg Med Clin North Am. 2008;26(3):759-ix. doi:10.1016/j.emc.2008.04.001.
   Pubmed

2. SOAP II - De Backer D, Biston P, Devriendt J, et al. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med. 2010;362(9):779-789. doi:10.1056/NEJMoa0907118.
   Pubmed

3. Bai X, Yu W, Ji W, et al. Early versus delayed administration of norepinephrine in patients with septic shock. Crit Care. 2014;18(5):532. Published 2014 Oct 3. doi:10.1186/s13054-014-0532-y-.
   Pubmed

4. Stratton L, Berlin DA, Arbo JE. Vasopressors and Inotropes in Sepsis. Emerg Med Clin North Am. 2017;35(1):75-91. doi:10.1016/j.emc.2016.09.005.
   Pubmed

5. Tian DH, Smyth C, Keijzers G, et al. Safety of peripheral administration of vasopressor medications: A systematic review. Emerg Med Australas. 2020;32(2):220-227. doi:10.1111/1742-6723.13406.
   Pubmed

6. NIH-NLM (National Institutes of Health National Library of Medicine). DailyMed. Label: Levophed - norepinephrine bitartrate injection, solution, concentrate. Updated November 2020. Accessed in June 2021.
   DailyMed

7. US-FDA (US Food and Drug Administration), Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations, Product Details for NDA 007513, Levophed; Norepinephrine Bitartrate. Accessed in June 2021.
   US-FDA

8. McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure [published correction appears in Eur Heart J. 2021 Oct 14;:]. Eur Heart J. 2021;42(36):3599-3726. doi:10.1093/eurheartj/ehab368
   ESC (Open Access)