Continuing Education Activity

Untreated hypotension is a significant contributor to morbidity and mortality, requiring prompt and effective management. Norepinephrine is a first-line pharmacological agent for hypotension unresponsive to fluid therapy. Understanding norepinephrine's pharmacokinetics, pharmacodynamics, and clinical application is essential for optimizing outcomes in critically ill patients. To ensure safe administration, healthcare professionals must also understand norepinephrine's indications, contraindications, dosing strategies, and adverse drug reaction profile.

This activity reviews the mechanism of action of norepinephrine, emphasizing its role in augmenting vascular tone and cardiac output. Strategies for minimizing adverse reactions while maximizing efficacy are highlighted to ensure tailored patient care. The critical role of the interprofessional team in administering norepinephrine is discussed, focusing on collaboration to improve patient outcomes in cases of refractory hypotension. Evidence-based guidance is provided to support the safe and effective use of norepinephrine in clinical practice.

Objectives:

• Identify the indications for initiating norepinephrine therapy.

• Evaluate the mechanism of action of norepinephrine.

• Assess the adverse drug reactions associated with norepinephrine.

• Implement effective collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients who might benefit from norepinephrine pharmacotherapy.

Indications

Norepinephrine is the primary neurotransmitter released from postganglionic sympathetic nerve terminals and a hormone secreted by the adrenal medulla. Norepinephrine also acts as a neurotransmitter within the central nervous system.

FDA-Approved Indications

The FDA has approved the administration of norepinephrine for patients who are acutely hypotensive, and it is a potential adjunct for treating cardiac arrest with profound hypotension.[1] Norepinephrine also generally has more predictive value than other α-agonists. Combined with its β-agonist effects (which improve cardiac function relative to pure α-agonists), this predictive quality makes norepinephrine a widely used vasoactive agent. Norepinephrine is commonly administered in intensive care units to treat hypotension secondary to distributive shock. According to Surviving Sepsis Campaign guidelines, it is the first-line agent for treating hypotension in the setting of sepsis that does not respond to fluid resuscitation.[2][3][4] The findings of the network meta-analysis indicate that the combination of norepinephrine and dobutamine is associated with a reduced mortality risk in patients with septic shock compared to other vasoactive agents.[5]

Off-Label Uses

A meta-analysis review was conducted to evaluate the effectiveness of norepinephrine in reversing hepatorenal syndrome (HRS). The review indicated that norepinephrine effectively improved HRS reversal and short-term survival, although the results were not statistically significant compared to terlipressin.[6] According to the 2024 American Gastroenterological Association (AGA) guidelines, vasoactive agents such as terlipressin, norepinephrine, and the combination of octreotide and midodrine are specifically indicated for the management of hepatorenal syndrome-acute kidney injury (HRS-AKI) in patients with cirrhosis. These agents are not recommended for other forms of acute kidney injury (AKI) in patients with cirrhosis. Terlipressin is the preferred vasoactive agent for managing HRS-AKI; norepinephrine is often utilized where terlipressin is unavailable.[7] According to one meta-analysis, prophylactic administration of norepinephrine is effective in managing hypotension following spinal anesthesia in patients undergoing cesarean delivery. However, it does not offer enhanced safety and may carry the risk of inducing reactive hypertension.[8] According to the American College of Surgeons, the initial management of spinal cord injury should focus on maintaining adequate blood pressure through fluid resuscitation and using vasopressors with α- and β-adrenergic effects, such as norepinephrine.

Mechanism of Action

Norepinephrine is a sympathomimetic amine derived from tyrosine. Norepinephrine is nearly identical to epinephrine but lacks a methyl group on its nitrogen atom. This difference makes it primarily agonistic at α1 and β1 receptors, with minimal α2 or β2 activity. At lower infusion rates (<2 μg/min), the β1 effects may be more pronounced and increase cardiac output. However, for rates exceeding 3 μg/min, the α1 effects may predominate. Increased activation of α1 receptors results in vasoconstriction and dose-dependent increases in systemic vascular resistance. The ratio of venous-to-arterial activity is relatively equal.[9][10] Norepinephrine increases cerebral blood flow in patients with impaired autoregulation, such as those with traumatic brain injury or critical illness, while having little effect in healthy individuals or those without brain injury. These findings highlight the importance of norepinephrine in stabilizing hemodynamics and improving tissue perfusion in critically ill patients.[11]

Pharmacokinetics

Absorption: Norepinephrine has a rapid onset of action. According to product labeling, the steady-state plasma concentration is attained in 5 min after initiating intravenous infusion.

Distribution: The apparent volume of distribution is 8.8 L. Plasma protein binding of norepinephrine is approximately 25%. Norepinephrine crosses the placenta but doesn't cross the blood-brain barrier.

Metabolism: Norepinephrine is metabolized by the enzymes catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO) in the liver and other tissues.[11] The primary metabolites of these reactions are normetanephrine and vanillylmandelic acid.

Elimination: Only small quantities of norepinephrine are excreted unchanged. Noradrenaline metabolites are primarily excreted in the urine as sulfate conjugates and, to a lesser extent, glucuronide conjugates. The half-life of norepinephrine is approximately 2.4 min.

Administration

Available Dosage Forms and Strengths

Norepinephrine is available as 1 mg/mL, 4 mg/250 mL in dextrose 5%, and 8 mg/250 mL in dextrose 5% intravenous solutions. Because of its relatively short half-life of 2.5 minutes, norepinephrine is typically administered using continuous infusion. The FDA recommends diluting the concentrated norepinephrine in dextrose-containing solutions before infusion to protect against potential oxidation and subsequent loss of drug potency. The FDA explicitly recommends against using saline as the sole diluent.[12] 

If possible, norepinephrine should be infused through intravenous lines not used for blood products. Infusing norepinephrine through large-bore peripheral intravenous catheters or central venous catheters is highly recommended. The infusion should ideally be administered into an antecubital vein, as this poses the lowest risk of ischemia secondary to extravasation compared to other infusion sites.

Lower extremity veins should be avoided, as occlusive vascular diseases are more likely to occur in the lower extremities. However, the results of a recent study assessing a medical ICU protocol for peripheral norepinephrine administration suggest peripheral administration could reduce the need for central venous catheters (CVC) in many patients, given the minimal extravasation-related complications associated with this method. While the findings suggest that peripheral norepinephrine can safely replace CVC use in some cases, additional research is needed to confirm its benefits and establish long-term outcomes.[13]

Adult Dosage

The infusion is typically initiated at a rate of 8 to 12 μg/min, then titrated according to the desired arterial blood pressure. The average maintenance dose is around 2 to 4 μg/min.[14] Extravasation into local tissue can cause significant ischemia and subsequent necrosis. Should extravasation be suspected, the infusion should be stopped immediately, and an attempt should be made to draw back any 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.[15][16] Hypotension secondary to hypovolemia should initially be treated with fluid resuscitation.

Specific Patient Populations

Hepatic impairment: The manufacturer's labeling does not specify dose modifications for patients with hepatic impairment.

Renal impairment: The manufacturer's labeling does not specify dose modifications for patients with renal impairment.

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

Breastfeeding considerations: Norepinephrine inhibits β-casein synthesis by stimulating adrenergic β2 receptors. The results of animal studies indicate that norepinephrine can decrease serum prolactin levels, reduce milk production, and inhibit the release of oxytocin. As a result, milk ejection is subsequently reduced. Because of its poor oral bioavailability and short half-life, any amount of norepinephrine in breast milk is unlikely to affect the nursing infant. High intravenous doses of norepinephrine may reduce milk production and the concentration of β-casein in milk.[17]

Pediatric patients: The Society of Critical Care Medicine guidelines recommend norepinephrine over dopamine for children with septic shock.[18] In pediatric patients with hypotension or shock resistant to fluid resuscitation, norepinephrine is typically administered as a continuous intravenous or intraosseous infusion, starting at an initial dose of 0.05 to 0.1 μg/kg/min. The dosage can be titrated to achieve the desired effect up to a maximum dose of 2 μg/kg/min.[19][20]

Older patients: Dose selection for older adults should be cautious, initiating at the lower end of the recommended range due to potential declines in hepatic, renal, or cardiac function. Administration of norepinephrine into leg veins should be avoided in older patients. This study investigated the effect of continuous intravenous norepinephrine infusion in older adults undergoing hip surgery with spinal anesthesia and propofol sedation. The results suggest that norepinephrine significantly reduced hypotensive episodes, decreased fluid requirements, and improved urine output compared to the control group without affecting postoperative complications.[21]

Adverse Effects

The most common adverse effects of norepinephrine relate directly to the activation of α1 receptors. Additionally, norepinephrine infusions without appropriately treating hypovolemia can result in reduced end-organ perfusion; this can be detrimental as most patients who require infusions of norepinephrine already have poor oxygen delivery or utilization.[22]

Pulmonary vascular resistance may increase secondary to norepinephrine administration, which could have adverse sequelae in patients with pulmonary hypertension. Reduced hepatic blood flow secondary to α-mediated vasoconstriction can lead to a transient increase in serum concentration of drugs metabolized in the liver.

Vasoconstriction secondary to α1 stimulation can result in reflex bradycardia via the baroreceptor reflex, which is generally not compensated for by the β1 activity. The overall result is cardiac output may remain constant or decrease despite norepinephrine's β1 agonist effects. 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.[23]

Drug-Drug Interactions

Monoamine oxidase inhibitors: Co-administration of norepinephrine with monoamine oxidase inhibitors (MAOIs) (or other drugs with MAO-inhibiting properties, such as linezolid) may result in severe and prolonged hypertension. If norepinephrine administration is necessary in patients who have recently used these drugs and whose MAO activity has not fully recovered, close blood pressure monitoring is recommended.

Tricyclic antidepressants: Concomitant administration of norepinephrine and tricyclic antidepressants (eg, amitriptyline, nortriptyline, protriptyline, clomipramine, desipramine, imipramine) can lead to severe and prolonged hypertension. If norepinephrine administration cannot be avoided, continuous monitoring for hypertension is advised.

Oral hypoglycemic drugs: Norepinephrine administration may reduce insulin sensitivity and increase blood glucose levels. Regular monitoring of glucose levels is recommended, and medication dosage adjustments should be considered.

Halogenated anesthetics: The concomitant administration of norepinephrine with halogenated anesthetics (eg, sevoflurane, desflurane, cyclopropane, enflurane, isoflurane) may increase the risk of ventricular tachycardia or ventricular fibrillation. Continuous cardiac monitoring is essential in patients receiving norepinephrine and halogenated anesthetics.

Contraindications

There are no absolute contraindications for norepinephrine administration.

Warning and Precautions

• Norepinephrine administration may be contraindicated for patients with hypotension secondary to cardiogenic mechanisms. Norepinephrine is not an ideal agent for hypotension secondary to hypovolemia, but it may be considered in combination with appropriate volume resuscitation for patients with hypovolemia as an emergency measure to maintain coronary or cerebral perfusion pressure.[23]
• Norepinephrine should be avoided for 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 may be exacerbated or even initiated by norepinephrine; this is also the case with specific anesthetic agents (eg, halothane and cyclopropane).[24]
• The preparation of norepinephrine typically administered in critical care settings contains sodium metabisulfite, which may cause allergic reactions in susceptible individuals.[25][26] According to manufacturer labeling, this effect may be more common in patients with asthma. 
• Caution is advised when administering norepinephrine concomitantly with monoamine oxidase inhibitors, amitriptyline, and imipramine-type antidepressants. Combining any of these drugs can lead to severe and prolonged hypertension.

Monitoring

Clinicians should closely monitor blood pressure whenever vasopressors such as norepinephrine are administered; this can be performed via invasive or noninvasive measurement techniques. If using noninvasive measurements, values should be obtained every 2 to 3 minutes during initial titration and then at least every 5 minutes following the determination of the appropriate maintenance dose.  

When norepinephrine is administered in low doses for its inotropic effects, clinicians are advised to titrate the dose according to cardiac output instead of blood pressure changes. Therefore, a method of measuring cardiac output (ie, echocardiography or pulmonary artery catheter) is required. Similarly, an indwelling arterial catheter (or "A-line") should be used to monitor the patient's hemodynamic status in MICU/SICU settings.[27] Clinicians should evaluate peripheral perfusion and urine output in patients receiving norepinephrine and monitor the infusion site closely for any signs of extravasation or tissue damage.

Toxicity

Signs and Symptoms of Overdose

Norepinephrine's toxicity is generally directly related to its mechanism of action. An overdose can cause several harmful effects, including intense headache, hypertensive urgency/emergency, a significant rise in peripheral vascular resistance, and reduced cardiac output. These reactions occur due to excessive stimulation of adrenergic receptors, leading to vasoconstriction and altered cardiovascular function. If left untreated, systemic toxicity can lead to end-organ ischemia.

Management of Overdose

Clinicians should understand that hypertension results from α1 stimulation, and agents that antagonize the β-adrenergic receptor may not be appropriate. Extravasation into surrounding tissue can cause local ischemia and necrosis. In these cases, treatment involves a 10 to 15 mL saline solution containing 5 to 10 mg of phentolamine. Phentolamine is an α1 antagonist, and this method has shown the capability to significantly reduce adverse events of extravasation if given within 12 hours.[15][16]

Enhancing Healthcare Team Outcomes

Norepinephrine is a vasopressor typically administered to maintain mean arterial pressure via increased systemic vascular resistance after or during appropriate fluid resuscitation. Norepinephrine exhibits some β activity, making it more suitable than pure α1 agonists in certain situations. However, it should still be administered cautiously (or avoided altogether) in patients with poor cardiac function (acute or chronic) or pulmonary hypertension.

Although this drug can be life-saving, improper monitoring can lead to malignant hypertension, arrhythmias, or tissue necrosis. Norepinephrine is classified as a "high-alert" medication by the Institute for Safe Medication Practices due to its increased potential to cause significant harm if administered incorrectly.[28] Therefore, all members of the interprofessional care team should be vigilant and comply when utilizing this powerful medication. Clinicians prescribe norepinephrine, but pharmacy personnel should verify dosing, check for drug interactions, and report any concerns to the team. Nurses administer the drug and should be on the lookout for adverse effects (e.g., extravasation). They should immediately alert the clinician on duty if they observe any adverse effects. The best outcome occurs when the critical care and emergency nurses cooperate with clinicians to monitor patients receiving this medication for untoward events. The interprofessional team approach and collaborative work best guide optimal therapeutic results when administering norepinephrine.