Norepinephrine

Article Author:
Matthew Smith
Article Editor:
Christopher Maani
Updated:
5/16/2019 2:19:53 PM
PubMed Link:
Norepinephrine

Indications

Norepinephrine's predominant use is as a peripheral vasoconstrictor.  Specifically, the FDA has approved its use for blood pressure control in certain acute hypotensive states, as well as a potential adjunct in the treatment of cardiac arrest with profound hypotension.  In addition, norepinephrine is generally considered to have more predictive pharmacologic properties than other alpha agonists.  This predictive quality in combination with some of its ß agonism (which improves cardiac function relative to pure alpha agonists), makes norepinephrine a widely used vasoactive agent.   It is commonly used 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]

Mechanism of Action

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 ß1 receptors, with little-to-no ß2 or alpha2 activity.  At low doses (less than 2 mcg/min) the ß1 effects may be more pronounced and potentially increases cardiac output.  However, in doses greater 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]

Administration

Because of its relatively short half-life of 2.5 minutes, norepinephrine is typically administered by continuous infusion.  The FDA recommends diluting of the concentrated norepinephrine in dextrose-containing solutions prior to infusion, providing protection against potential oxidation and subsequent loss of drug potency.  The FDA specifically recommends against using saline as the sole diluent.[4]  A common technique is to start the infusion at 8 mcg – 12 mcg per minute and titrate to the desired pressure.  The average maintenance dose is around 2 – 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, 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 be stopped immediately.  An attempt should be made to remove (draw back) any of the injected medication.  If continuation of 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. 

Adverse Effects

The most common adverse effects of norepinephrine relate directly to its 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 ß1 activity.  The overall result is that cardiac output may decrease, or at most stay the same, despite ß1 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.

Contraindications

There are no absolute contraindications to administration of norepinephrine.

As mentioned above, it may be contraindicated to use norepinephrine to treat hypotension that is likely secondary to cardiogenic mechanisms.  Additionally, if the hypotension is 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 use of norepinephrine.  This is also the case with certain 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 people.  This 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.

Monitoring

Blood pressure requires close monitoring whenever vasopressors such as norepinephrine are in use.  This can be accomplished via invasive or non-invasive measurement techniques.  If following non-invasive measurements, then it is recommended to obtain values every 2-3 minutes during initial titration and then at least every 5 minutes following the determination of the appropriate maintenance dose.

When being used in low doses for its inotropic effect, it is preferred to titrate the dosage via cardiac output as opposed to blood pressure changes.  Therefore, a method of measuring cardiac output (e.g., echocardiography, pulmonary artery catheter) would be required.

Toxicity

The toxicity of norepinephrine is generally directly related to its mechanism of action.  Systemic toxicity manifests as uncontrolled hypertension with signs and symptoms of end-organ ischemia.  Treatment should take into consideration that the hypertension is a result of alpha1 stimulation and agents that antagonize the ß adrenergic receptor may not be appropriate.  Extravasation into surrounding tissue can cause local ischemia and necrosis.  In such cases treatment is with a 10 mL – 15 mL saline solution containing 5 mg – 10 mg of phentolamine.  Phentolamine is an alpha1 antagonist, and this method has been shown to significantly reduce adverse events of extravasation if given within 12 hours.[6][7]

Enhancing Healthcare Team Outcomes

Norepinephrine is a vasopressor that is most appropriate for maintaining mean arterial pressure via an increase in systemic vascular resistance after or during appropriate fluid resuscitation.  It has some beta activity, making it more suitable than pure alpha 1 agonists in many situations. (Level I)  However, it should still be used cautiously (or avoided completely) if a patient has poor cardiac function (acute or chronic) or pulmonary hypertension. (Level IV)

Although the use of this drug can be life-saving, improper monitoring can lead to malignant hypertension, arrhythmias, or tissue necrosis.  Therefore, all members of the interprofessional care team should highly alert and avoid compliance when utilizing this powerful medication. The best and safest outcome will occur when the critical care and emergency nurses work the clinicians in monitoring patients on this medication for untoward events. [Level V]


References

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