Norepinephrine's predominant use is as a peripheral vasoconstrictor. Specifically, the FDA has approved its use for blood pressure control in specific acute hypotensive states, as well as being a potential adjunct in the treatment of cardiac arrest with profound hypotension. Also, norepinephrine generally has more predictive pharmacologic properties than other alpha agonists. This predictive quality, in combination with some of its beta-agonism (which improves cardiac function relative to pure alpha agonists), makes norepinephrine a widely used vasoactive agent. It is commonly utilized in intensive care units to treat hypotension secondary to distributive shock. Specifically, it is the first-line agent for treating hypotension in the setting of sepsis that does not respond to fluid resuscitation.[1]

Norepinephrine is a sympathomimetic amine derived from tyrosine.  It is structurally identical to epinephrine but differs in that it lacks a methyl group on its nitrogen atom.  This difference makes it primarily agonistic at alpha1 and beta1 receptors, with little-to-no beta2 or alpha2 activity.  At low doses (less than 2 mcg/min), the beta1 effects may be more pronounced and potentially increases cardiac output.  However, in doses higher than 3 mcg/min, the alpha1 effects may predominate.  The increased activation of the alpha1 receptors will result in vasoconstriction and dose-dependent increases in systemic vascular resistance.  The ratio of venous to arterial activity is relatively equal.[2][3]

Because of its relatively short half-life of 2.5 minutes, typically, the administration of norepinephrine is by continuous infusion. The FDA recommends diluting of the concentrated norepinephrine in dextrose-containing solutions before infusion, providing protection against potential oxidation and subsequent loss of drug potency. The FDA recommends explicitly against using saline as the sole diluent.[4]  A common technique is to start the infusion at 8 mcg to 12 mcg per minute and titrate to the desired pressure.  The average maintenance dose is around 2 to 4 mcg per minute.[5] If possible, infusions of norepinephrine should use tubing separate from blood products.

It is highly recommended to infuse norepinephrine through large-bore peripheral intravenous catheters or central venous catheters.  Ideally, the peripheral infusion should be in the upper extremity, preferably through an antecubital vein, as this provides the least risk of ischemia secondary to extravasation. Lower extremity veins should be avoided if at all possible as occlusive vascular diseases are more likely to occur in the lower extremities. Extravasation into local tissue can cause significant ischemia and subsequent necrosis. Should extravasation be suspected, the infusion should stop immediately. An attempt should be made to remove (draw back) any of the injected medication. If continuing the infusion is necessary, it should be restarted in a different site, ideally in a different extremity. The local area should then be infiltrated with phentolamine (see below).[6][7]

It is worth noting that hypotension secondary to hypovolemia should have treatment with fluid resuscitation as a priority. Using vasopressors such as norepinephrine in a patient who has not had appropriate resuscitation may result in worsening ischemia and an overall decline in clinical status. 

The most common adverse effects of norepinephrine relate directly to the activation of alpha1 receptors.  That is, excessive vasoconstriction can result in decreased end-organ perfusion, which is primarily caused by infusions of norepinephrine without appropriately treating hypovolemia; this can be detrimental as most patients who require infusions of norepinephrine already have poor oxygen delivery or utilization. 

Vasoconstriction secondary to alpha1 stimulation can result in reflex bradycardia via the baroreceptor reflex, which is generally not compensated for by the beta1 activity. The overall result is that cardiac output may decrease, or at most stay the same, despite beta1 agonism.  At the same time, the increase in systemic vascular resistance increases the work of the heart by increasing afterload, thereby increasing myocardial oxygen demand. Because of these phenomena, the benefits of norepinephrine for cardiogenic shock are still unclear but merit consideration under certain conditions.[8] 

Pulmonary vascular resistance may increase secondary to norepinephrine administration, which could have negative sequelae in patients with pulmonary hypertension. Decreased hepatic blood flow (secondary to alpha-mediated vasoconstriction) can lead to a transient increase in drugs that undergo hepatic metabolism.

There are no absolute contraindications to the administration of norepinephrine.

As mentioned above, norepinephrine use may be contraindicated to treat hypotension that is likely secondary to cardiogenic mechanisms.  Additionally, for hypotension primarily related to hypovolemia, norepinephrine is probably not the best agent. The FDA does state that its use could be a consideration in low volume states, but only as an emergency measure for maintaining coronary or cerebral perfusion pressure while waiting for appropriate volume resuscitation.

Generally, the use of norepinephrine should be avoided in patients with mesenteric or peripheral vascular thrombosis as the subsequent vasoconstriction will increase the area of ischemia and infarction. 

Profound hypoxia or hypercarbia can sensitize the myocardium to unstable arrhythmias, which could be exacerbated or even be initiated by the use of norepinephrine - this is also the case with specific anesthetic agents, such as halothane and cyclopropane. 

Levophed, the preparation of norepinephrine, typically utilized in a clinical setting, contains sodium metabisulfite, which may cause allergic reactions in susceptible individuals. This effect may be more common in asthmatics. 

Care is necessary when using norepinephrine concomitantly with monoamine oxidase inhibitors or amitriptyline and imipramine-type antidepressants.  The combination of any of these drugs can lead to severe, prolonged hypertension.