Norepinephrine bitartrate is an endogenous catecholamine vasopressor that predominantly acts by a direct effect on α-adrenergic receptors and to a lesser extent on β-adrenergic receptors.101, 173
Norepinephrine bitartrate is used to raise blood pressure in the management of adults with severe, acute hypotension.101, 153, 154, 155, 156, 157, 163, 174, 175, 407 Studies evaluating safety and efficacy of norepinephrine for this use have generally found that compared with other vasopressors, norepinephrine was associated with similar hemodynamic and mortality outcomes and lower risk for arrhythmia.176, 177, 178, 179 Guidelines for the treatment of sepsis and septic shock generally recommend norepinephrine as a first-line vasopressor for hemodynamic management.153, 407 The American Heart Association (AHA) states that in the management of cardiogenic shock, norepinephrine may be the vasopressor of choice in many patients, although the optimal first-line vasopressor in this setting remains unclear.180
Although not FDA-labeled for use in pediatric patients, norepinephrine also has been used for blood pressure management in pediatric patients with fluid-refractory septic shock†.407
Norepinephrine in the management of sepsis and septic shock has been evaluated in various studies.176, 177 One meta-analysis of 11 randomized controlled trials, which included a total of approximately 4800 patients, evaluated the efficacy and safety of norepinephrine compared with other vasopressors, including dopamine, epinephrine, phenylephrine, and vasopressin.176 Analysis of the primary outcomes revealed no substantial differences between norepinephrine and other vasopressors in the number of patients achieving target mean arterial pressure [MAP] (based on data from 2 trials rated as low-quality) or in all-cause 28-day mortality (based on data from 7 high-quality trials).176 However, norepinephrine was associated with substantially lower risk for arrhythmia compared with other vasopressors (based on data from 6 trials rated as moderate-quality).176 Another meta-analysis of 11 trials comparing norepinephrine with dopamine found that norepinephrine was associated with a substantially reduced risk of all-cause mortality as well as reduced risk of major adverse events and cardiac arrhythmias.177 No other substantial differences in mortality were identify in other comparisons of norepinephrine with epinephrine, phenylephrine, and vasopressin.177
Safety and efficacy of norepinephrine in the treatment of cardiogenic shock have also been evaluated in various studies.178, 179 One meta-analysis of 9 trials comparing norepinephrine with dopamine found that norepinephrine was associated with substantially lower risks of 28-day mortality, arrhythmic events, and GI effects.178 Another meta-analysis, which identified only one trial that compared norepinephrine with epinephrine in the treatment of cardiogenic shock, found no substantial difference in the risk of all-cause 28-day mortality.179
Vasopressors such as norepinephrine are used in the management of shock to restore blood pressure and tissue perfusion after initial fluid resuscitation is attempted.153, 154, 155, 156, 157, 158, 159, 163 Norepinephrine is a potent vasoconstrictor that increases MAP with minimal change in heart rate and cardiac output, and has been shown to preserve tissue perfusion when titrated to effect (i.e., MAP of at least 65 mm Hg).153, 156, 158 The Surviving Sepsis Campaign provides recommendations on the management of sepsis and septic shock, which includes guidance on resuscitation and hemodynamic management in this setting.153 Initial management involves administration of IV crystalloid fluid within the first 3 hours of resuscitation in patients with sepsis-induced hypoperfusion or septic shock.153 The guideline recommends norepinephrine as the first-line vasopressor of choice in adults with septic shock over other vasopressors; in settings where norepinephrine is not available, epinephrine or dopamine may be used as alternatives.153 For adults with inadequate MAP response to norepinephrine, the guideline suggests adding vasopressin instead of escalating the dose of norepinephrine.153 For adults with continued inadequate MAP response despite norepinephrine and vasopressin, the guideline suggests adding epinephrine.153 For adults with cardiac dysfunction and persistent hypoperfusion despite adequate volume status and arterial blood pressure, addition of dobutamine to norepinephrine or use of epinephrine alone is recommended.153 Vasopressor therapy in adults should initially target a MAP of 65 mm Hg.153
The American Heart Association (AHA) guideline for pediatric basic and advanced life support provides recommendation for resuscitation in infants and children with septic shock.407 In those with fluid-refractory septic shock, the guideline states that it is reasonable to use either norepinephrine or epinephrine as an initial vasopressor infusion; if these are unavailable, dopamine may be considered.407
AHA published a scientific statement on the contemporary management of cardiogenic shock, offering insight on the medical management of hemodynamic instability.180 Initial management with vasopressors is directed by the cause and presentation of cardiogenic shock.180 Norepinephrine is generally listed as an option for management of cardiogenic shock with presentation that is classic wet and cold, euvolemic cold and dry, vasodilatory warm and wet or mixed cardiogenic and vasodilatory, right ventricular shock, mitral regurgitation, and pericardial tamponade.180 Norepinephrine is associated with lower risk of arrhythmia and may be the vasopressor of choice in many patients, although the optimal first-line vasopressor in cardiogenic shock remains unclear.180
Norepinephrine has been added to solutions of some local anesthetics to decrease the rate of vascular absorption of the anesthetic and prolong the duration of anesthesia†.165, 166, 167 Because norepinephrine is less potent than epinephrine and must be used in higher concentrations potentially causing greater risk of adverse effects, epinephrine is more commonly used for this purpose.165, 166, 167
Dispensing and Administration Precautions
Norepinephrine bitartrate is administered by IV infusion.101 To minimize the risk of necrosis, infusion of the drug should be given into a large vein; avoid infusions into the veins of the leg in elderly patients or in patients with occlusive vascular disease of the legs.101 Care must be taken to avoid extravasation because local necrosis may result; check the infusion site frequently for free flow and monitor for signs of extravasation.101
Visually inspect solutions of norepinephrine for particulate matter and discoloration prior to administration whenever solution and container permit.101 Do not use the drug if it is discolored (e.g., pink, dark yellow) or contains any particulate matter.101
Store norepinephrine bitartrate at 20-25°C (excursions permitted to 15-30°C) in the original carton until the time of administration and protect from light.101 Discard any unused portion.101 Avoid contact of the drug with iron salts, alkalies, or oxidizing agents.101 Administer whole blood or plasma, if indicated during therapy with norepinephrine, separately.101
Norepinephrine bitartrate injection concentrate must be diluted prior to administration;101 alternatively, commercially available solutions of norepinephrine in 5% dextrose or norepinephrine in 0.9% sodium chloride may be used without dilution.102, 103
Prior to administration, the commercially available concentrate for injection must be diluted with a dextrose-containing solution (5% dextrose injection, with or without 0.9% sodium chloride injection); the manufacturer states that dilution with 0.9% sodium chloride injection alone is not recommended because of possible loss of potency due to oxidation.101 The concentration of norepinephrine and the infusion rate depend on the drug and fluid requirements of the individual patient; use higher concentration solutions in patients requiring fluid restriction.101 The infusion solution is usually prepared by adding 4 mg of norepinephrine (4 mL of the commercially available injection) to 1 liter of a 5% dextrose-containing solution; the resultant solution contains 4 mcg/mL.101 The diluted norepinephrine solution may be stored for up to 24 hours at room temperature prior to use.101
Standardized concentrations for norepinephrine have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care.249, 250 Multidisciplinary expert panels were convened to determine recommended standard concentrations.249, 250 Because recommendations from the S4S panels may differ from the manufacturer's prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label.249, 250 For additional information on S4S (including updates that may be available), see [Web].249, 250
Patient Population | Concentration Standardsa | Dosing Units |
|---|---|---|
Adults | 16 mcg/mL | mcg/kg/min |
32 mcg/mL | ||
64 mcg/mL | ||
Pediatric patients (<50 kg) | 16 mcg/mLb | mcg/kg/min |
32 mcg/mL | ||
64 mcg/mL |
aThe concentrations for epinephrine and norepinephrine are intentionally different to avoid confusion as recommended by the S4S panel and ISMP
Avoid abrupt withdrawal of norepinephrine infusion; discontinue by reducing the flow rate gradually.101
If norepinephrine is used in pediatric patients†, some clinicians have recommended an infusion rate ranging from 0.05-2.5 mcg/kg per minute, titrated to effect.175
For restoration of blood pressure in adults with acute hypotensive states, the usual initial dosage of norepinephrine is 8-12 mcg/minute.101 The typical maintenance IV dosage is 2-4 mcg/minute.101 Other experts have described common dosage ranges of norepinephrine as 0.01-0.5 mcg/kg per minute.173 Adjust the dosage to maintain the desired hemodynamic effect.101
The manufacturer makes no specific dosage recommendations for patients with hepatic impairment.101
The manufacturer makes no specific dosage recommendations for patients with renal impairment.101
The manufacturer makes no specific dosage recommendations for geriatric patients.101 In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.101
In patients who have hypovolemia-related hypotension, norepinephrine can cause severe peripheral and visceral vasoconstriction, decreased renal perfusion and reduced urine output, tissue hypoxia, lactic acidosis, and reduced systemic blood flow, even in patients with “normal” blood pressure.101 Address hypovolemia prior to initiating norepinephrine.101 Avoid norepinephrine in patients with mesenteric or peripheral vascular thrombosis, which may increase ischemic risk and extend the area of infarction.101
Extravasation may occur with administration of norepinephrine.101 To prevent sloughing and necrosis in areas in which extravasation has occurred, infiltrate the extravasated area with 10-15 mL of sodium chloride solution containing 5-10 mg of phentolamine mesylate using a syringe with a fine hypodermic needle.101 Immediate and conspicuous local hyperemic changes occur if the area is infiltrated within 12 hours; therefore, administer phentolamine as soon as possible after extravasation is noted.101
Hypotension After Abrupt Discontinuation
Abrupt cessation of norepinephrine infusion can cause marked hypotension.101 When discontinuing the infusion, gradually reduce the infusion rate while expanding blood volume with intravenous fluids.101
Norepinephrine increases intracellular calcium concentrations, which may cause arrhythmias, particularly in patients with hypoxia or hypercarbia.101 Perform continuous cardiac monitoring of patients with arrhythmias.101
Allergic Reactions Associated with Sulfite
Norepinephrine bitartrate injection concentrate (e.g., Levophed®) contains sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals.101 The overall prevalence of sulfite sensitivity in the general population is unknown; such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals.101
Limited data on the use of norepinephrine in pregnant women at the time of delivery have not identified an increased risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.101 There are risks to the mother and fetus from acute hypotensive states that are medical emergencies in pregnancy (e.g., in septic shock, myocardial infarction, and stroke); these can be fatal if untreated.101 Delaying necessary treatment may increase the risk of maternal and fetal morbidity and mortality.101 Life-sustaining therapy for the pregnant woman should not be withheld due to potential concerns regarding the effects of norepinephrine on the fetus.101
In animal reproduction studies, high doses of IV norepinephrine resulted in lowered maternal placental blood flow; however, the clinical relevance to changes in the human fetus is unknown.101 Studies of norepinephrine administration to pregnant animals demonstrated decreases in fetal oxygenation, urine and lung liquid flow, production of cataracts, fetal microscopic liver abnormalities, and delayed skeletal ossification.101
There are no data on the presence of norepinephrine in either human or animal milk, the effects on the breastfed infant, or the effects on milk production.101 Because of its short half-life and poor oral bioavailability, clinically relevant exposure of norepinephrine in the infant is unlikely.101
Safety and effectiveness in pediatric patients have not been established.101
Clinical studies of norepinephrine bitartrate did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients.101 Clinical experience to date has not identified any differences in responses between geriatric and younger patients.101 If norepinephrine is used in geriatric patients, dosage should be selected carefully, usually starting at the low end of the dosage range, since renal, hepatic, and cardiovascular dysfunction and concomitant disease or other drug therapy are more common in this age group.101 Do not infuse into the leg veins of geriatric patients.101
The most common adverse reactions associated with norepinephrine are ischemic injury, bradycardia, anxiety, transient headache, respiratory difficulty, and extravasation necrosis at injection site.101
Monoamine Oxidase-Inhibiting Drugs
Coadministration of norepinephrine with inhibitors of monoamine oxidase (MAO) or other drugs with MAO-inhibiting properties (e.g., linezolid) can cause severe and prolonged hypertension.101 If coadministration cannot be avoided in patients who recently have received MAO-inhibiting drugs and in patients who have not yet experienced sufficient recovery of MAO activity following discontinuation of the MAO-inhibiting drug, monitor for hypertension.101
Coadministration of norepinephrine with tricyclic antidepressants (e.g., amitriptyline, nortriptyline, protriptyline, clomipramine, desipramine, imipramine) can cause severe and prolonged hypertension.101 Monitor for hypertension if coadministration cannot be avoided.101
Norepinephrine can decrease insulin sensitivity and raise blood glucose concentrations.101 Monitor glucose and consider dosage adjustment of antidiabetic drugs.101
Concomitant use of norepinephrine with halogenated anesthetics (e.g., cyclopropane, desflurane, enflurane, isoflurane, and sevoflurane) may cause ventricular tachycardia or ventricular fibrillation.101 Monitor cardiac rhythm in patients receiving concomitant halogenated anesthetics.101
Norepinephrine acts predominantly by direct effects on α-adrenergic receptors to cause peripheral vasoconstriction and to a lesser extent acts on β-adrenergic receptors to cause inotropic stimulation of the heart, dilation of coronary arteries, and substantially increased coronary blood flow.101 Norepinephrine generally does not affect cardiac output, although it can be decreased.101 Norepinephrine primarily increases systolic, diastolic, and pulse pressures and has minimal effects on chronotropy.173, 181 The elevations in resistance and blood pressure cause reflex vagal activity, slowing heart rate and increasing stroke volume.101 The elevation in vascular tone or resistance reduces blood flow to major abdominal organs and skeletal muscle.101 The pressor response following IV administration of norepinephrine occurs rapidly and reaches steady state within 5 minutes.101 The pharmacologic actions of norepinephrine are terminated primarily by uptake and metabolism in sympathetic nerve endings.101 The pressor action stops within 1-2 minutes after the infusion is discontinued.101
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection concentrate, for IV infusion | 1 mg (of norepinephrine) per mL* | ||
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection, for IV infusion | 16 mcg/mL norepinephrine (4 mg) in 5% dextrose* | Norepinephrine Bitartrate in Dextrose 5% | |
32 mcg/mL norepinephrine (8 mg) in 5% dextrose* | Norepinephrine Bitartrate in Dextrose 5% | |||
64 mcg/mL norepinephrine (16 mg) in 5% dextrose* | Norepinephrine Bitartrate in Dextrose 5% |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection, for IV infusion | 16 mcg/mL norepinephrine (4 mg) in 0.9% sodium chloride* | Norepinephrine Bitartrate in Sodium Chloride Injection | |
32 mcg/mL norepinephrine (8 mg) in 0.9% sodium chloride* | Norepinephrine Bitartrate in Sodium Chloride Injection | |||
64 mcg/mL norepinephrine (16 mg) in 0.9% sodium chloride* | Norepinephrine Bitartrate in Sodium Chloride Injection |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Only references cited for selected revisions after 1984 are available electronically.
101. Hospira. Levophed® (norepinephrine bitartrate injection) prescribing information. Lake Forest, IL; 2020 Oct.
102. Baxter. Norepineprhine bitartrate in dextrose injection. Deerfield, IL; 2022 June.
103. Par Pharmaceuticals. Norepinephrine in sodium chloride injection solution. Chestnut Ridge, NY. 2022 Oct.
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