Continuing Education Activity

Untreated hypotension can be a significant cause of morbidity and mortality. Norepinephrine is a first-line agent for hypotension that does not respond to fluid therapy and can be a powerful adjunct in managing a critically ill patient. Members of the interprofessional team must be knowledgeable about pharmacokinetics and pharmacodynamics and the indications and contraindications of norepinephrine use so that it can be utilized effectively to manage hypotension that does not respond to volume resuscitation alone. This activity reviews the indications, dosing, adverse drug reactions, and mechanism of action for norepinephrine as a valuable agent in managing hypotension. It highlights the role of the interprofessional team in caring for patients who may benefit from norepinephrine.

Objectives:

• Describe the treatment considerations for patients with hypotension.
• Review the management for patients with septic shock.
• Explain the common complications of norepinephrine administration.
• Outline the importance of improving care coordination amongst the interprofessional team to improve outcomes for patients receiving norepinephrine.

Indications

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 and is a potential adjunct in the treatment of cardiac arrest with profound hypotension.[1] Also, norepinephrine generally has more predictive pharmacologic properties than other alpha agonists. In combination with some of its beta-agonism (which improves cardiac function relative to pure alpha agonists), this predictive quality 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.[2][3]

Mechanism of Action

Norepinephrine is a sympathomimetic amine derived from tyrosine. It is structurally identical to epinephrine but differs because 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 increase 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.[4][5]

Pharmacokinetics 

According to product labeling, after initiation of intravenous infusion, the steady-state plasma concentration is attained in 5 min. The half-life of norepinephrine is approximately 2.4 min. The apparent volume of distribution is 8.8 L. Plasma protein binding of norepinephrine is approximately 25%. Norepinephrine crosses the placenta, but it doesn't cross the blood-brain barrier(BBB). Norepinephrine is metabolized by the enzymes catechol-O-methyltransferase (COMT) and MAO in the liver and other tissues. The major metabolites are normetanephrine and vanillylmandelic acid, VMA); both are metabolically inactive. Only small quantities of norepinephrine are excreted unchanged. Noradrenaline metabolites are excreted in the urine primarily as sulfate conjugates and, to a lesser extent, as glucuronide conjugates.

Administration

It is available as an intravenous solution of 1 mg/mL, 4 mg/250 mL in dextrose 5%, and 8 mg/250 mL in dextrose 5%. Because of its relatively short half-life of 2.5 minutes, the administration of norepinephrine is typically by continuous infusion. The FDA recommends diluting the concentrated norepinephrine in dextrose-containing solutions before infusion, protecting against potential oxidation and subsequent loss of drug potency. The FDA explicitly recommends against using saline as the sole diluent.[6] 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.[7] 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. If possible, lower extremity veins should be avoided 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 (drawback) any of the injected medication. If continuing the infusion is necessary, it should be restarted at a different site, ideally in a different extremity. The local area should then be infiltrated with phentolamine.[8][9]

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 worsen ischemia and an overall decline in clinical status.

Use In Specific Population

Patients with Hepatic Impairment: There are no dose modifications provided in the manufacturer's labeling for patients with hepatic impairment.

Patients with Renal Impairment: There are no dosage modifications provided per the manufacturer's labeling for patients with renal impairment.

Pregnancy Considerations: A literature review, including a few case reports and small trials involving norepinephrine in pregnant women, has not identified an increased risk of miscarriage or adverse maternal or fetal outcomes. In addition, delaying treatment in pregnant women with hypotension associated with septic shock may increase the risk of maternal and fetal morbidity and mortality. Therefore, clinicians should not withhold life-saving treatment for the pregnant woman due to potential risks regarding the consequences of norepinephrine on the fetus.

Breastfeeding Considerations: Norepinephrine inhibits the synthesis of beta-casein via stimulation of adrenergic beta-2 receptors. Animal data indicate that norepinephrine can decrease serum prolactin, reduce milk production, and inhibit the release of oxytocin, which inhibits milk ejection. Because of its poor oral bioavailability and short half-life, any norepinephrine in milk is unlikely to affect the infant. High intravenous doses of norepinephrine might reduce milk production and decrease the concentration of beta-casein in milk.[10]

Adverse Effects

The most common adverse effects of norepinephrine relate directly to the activation of alpha1 receptors. In addition, excessive vasoconstriction can result in decreased end-organ perfusion, primarily caused by norepinephrine infusions without appropriately treating hypovolemia; this can be detrimental as most patients who require infusions of norepinephrine already have poor oxygen delivery or utilization.[11]

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.

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.[12]

Contraindications

There are no absolute contraindications to the administration of norepinephrine.

Norepinephrine use may be contraindicated to treat hypotension, likely secondary to cardiogenic mechanisms. Additionally, norepinephrine is probably not the best agent for hypotension, primarily related to hypovolemia. However, the FDA states that its use could be considered in low volume states, but only as an emergency measure for maintaining coronary or cerebral perfusion pressure while waiting for appropriate volume resuscitation.[12]

Generally, 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 initiated by norepinephrine - this is also the case with specific anesthetic agents, such as halothane and cyclopropane.[13]

The preparation of norepinephrine, typically utilized in critical care settings, contains sodium metabisulfite, which may cause allergic reactions in susceptible individuals. According to manufacturer labeling, 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. Combining any of these drugs can lead to severe and prolonged hypertension.

Monitoring

Blood pressure requires close monitoring whenever vasopressors such as norepinephrine are used; this is possible via invasive or non-invasive measurement techniques. If following non-invasive measurements, it is recommended to obtain values every 2 to 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 instead of blood pressure changes. Therefore, a method of measuring cardiac output (e.g., echocardiography, pulmonary artery catheter) would be required. 

Similarly, an indwelling arterial catheter (A-line) should be used to monitor the patient's hemodynamic status in MICU/SICU settings.[14]

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 consider that hypertension is a result of alpha1 stimulation, and agents that antagonize the beta-adrenergic receptor may not be appropriate. Extravasation into surrounding tissue can cause local ischemia and necrosis. In such cases, treatment is with a 10 to 15 mL saline solution containing 5 to 10 mg of phentolamine. Phentolamine is an alpha1 antagonist, and this method has shown the capability to significantly reduce adverse events of extravasation if given within 12 hours.[8][9]

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 1] However, it should still be used cautiously (or avoided altogether) if a patient has a poor cardiac function (acute or chronic) or pulmonary hypertension. [Level 4]

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 be highly alert and comply when utilizing this powerful medication. Clinicians (including MDs, DOs, PAs, and NPs) will be prescribing this agent, but the pharmacy should verify dosing and check for drug interactions, reporting any concerns to the team. Nursing will be performing administration and be on the lookout for both systemic adverse effects of issues with the administration itself, such as extravasation, and immediately alert the clinician on duty if they see anything noteworthy. The best and safest outcome will occur when the critical care and emergency nurses work in concert with the clinicians in monitoring patients on this medication for untoward events. The interprofessional team approach and collaborative work are best to guide optimal therapeutic results when administering norepinephrine. [Level 5]