What is Levophed (norepinephrine)?

What is Levophed (Norepinephrine)?

Levophed is the brand name for norepinephrine, a potent sympathomimetic vasopressor that functions primarily as a peripheral vasoconstrictor through alpha-adrenergic action and secondarily as an inotropic stimulator of the heart through beta-adrenergic action. 1

Chemical Composition and Formulation

• Norepinephrine (also called l-arterenol or l-norepinephrine) is a sympathomimetic amine that differs from epinephrine by the absence of a methyl group on the nitrogen atom 1
• Supplied as norepinephrine bitartrate in sterile aqueous solution for intravenous infusion after dilution 1
• Each mL contains the equivalent of 1 mg base of norepinephrine, with sodium chloride for isotonicity and sodium metabisulfite as an antioxidant 1
• The solution has a pH of 3 to 4.5, with nitrogen gas displacing air in the vials 1

Mechanism of Action

• Increases mean arterial pressure (MAP) primarily through vasoconstriction (alpha-adrenergic receptors) with minimal changes in heart rate and stroke volume 2
• Acts as an inotropic stimulator of the heart and dilator of coronary arteries through beta-adrenergic action 1
• More potent than dopamine and more effective at reversing hypotension in septic shock 2

Clinical Indications and First-Line Status

Septic Shock (Primary Indication)

• Norepinephrine is strongly recommended as the first-choice vasopressor for septic shock over all alternatives including dopamine, epinephrine, and phenylephrine 3, 2, 4
• This recommendation is based on moderate-quality evidence showing superior outcomes with norepinephrine compared to dopamine 4
• Should be initiated when adequate fluid resuscitation fails to restore hemodynamic stability and maintain adequate MAP 3

Other Shock States

• Indicated for severe hypotension (systolic BP ≤70 mmHg) with low peripheral vascular resistance 4
• Used in cardiogenic shock when inotropic agents and fluid challenge fail to restore adequate arterial and organ perfusion, though should be used cautiously and transiently due to increased afterload risk 4
• Preferred vasopressor in situations with low blood pressure related to reduced systemic vascular resistance 4

Administration and Dosing

Route and Preparation

• Must be administered through a central venous line whenever possible to prevent tissue necrosis from extravasation 4
• Requires dilution before intravenous infusion 1

Dosing Parameters

• Typical dosage range: 0.2-1.0 μg/kg/min 4
• Titrate to achieve a target MAP of 65-100 mmHg, sufficient to maintain vital organ perfusion 4
• The titration of norepinephrine to a MAP as low as 65 mmHg has been shown to preserve tissue perfusion 3

Monitoring Requirements

• Continuous hemodynamic monitoring is essential during administration 4
• Place an arterial catheter as soon as practical in all patients requiring vasopressors 4
• Monitor for signs of extravasation; if it occurs, infiltrate 5-10 mg of phentolamine diluted in 10-15 mL of saline into the site to prevent tissue necrosis 4
• Assess peripheral perfusion regularly (skin temperature, capillary refill) 4

Advantages Over Alternative Vasopressors

Compared to Dopamine

• Norepinephrine is associated with significantly fewer arrhythmias compared to dopamine (RR 0.35; 95% CI 0.19-0.66 for ventricular arrhythmias) 2
• Dopamine should only be used in highly selected patients with low risk of tachyarrhythmias and absolute or relative bradycardia 3, 4
• Dopamine is associated with higher mortality rates in some patient populations 3

Compared to Epinephrine

• Epinephrine increases aerobic lactate production via stimulation of skeletal muscles' β2-adrenergic receptors, potentially interfering with the use of lactate clearance to guide resuscitation 2, 5
• Epinephrine should be considered the first alternative to norepinephrine when norepinephrine is unavailable or ineffective 2
• Despite concerns about splanchnic circulation effects, randomized trials comparing norepinephrine to epinephrine found no significant differences in mortality (RR 0.96; 95% CI 0.77-1.21) 2

Compared to Phenylephrine

• Phenylephrine is not recommended except in specific circumstances: (a) norepinephrine is associated with serious arrhythmias, (b) cardiac output is known to be high and blood pressure persistently low, or (c) as salvage therapy when other agents have failed 3

Second-Line Vasopressor Options

Vasopressin

• Vasopressin (up to 0.03 U/min) can be added to norepinephrine with the intent of raising MAP to target or decreasing norepinephrine dosage 3
• Adding vasopressin is recommended in case of shock refractory to norepinephrine 6
• Low-dose vasopressin is not recommended as the single initial vasopressor for sepsis-induced hypotension 3

When to Add Second-Line Agents

• If blood pressure remains inadequate despite increasing doses of norepinephrine, consider adding a second vasopressor agent 4
• Higher doses of norepinephrine (>10 mcg/minute) are associated with increased mortality and should be avoided if possible 4

Precautions and Contraindications

Relative Contraindications

• Relatively contraindicated in hypovolemic patients; always correct volume depletion before or concurrently with norepinephrine administration 4
• Use cautiously in patients with ischemic heart disease as it may increase myocardial oxygen requirements 4

Adverse Effects

• Increased myocardial oxygen consumption 4
• Tissue necrosis if extravasation occurs 4
• Arrhythmias at higher doses 4
• Excessive vasoconstriction leading to end-organ hypoperfusion 4
• May increase cardiac afterload, potentially reducing cardiac output in patients with heart failure 4
• May reduce splanchnic blood flow 4

Special Considerations

Renal Effects

• While norepinephrine typically causes renal and mesenteric vasoconstriction, it may actually improve renal blood flow and urine output in septic shock 4

Timing of Initiation

• Early administration of norepinephrine is beneficial for septic shock patients to restore organ perfusion, as profound and durable hypotension is an independent factor of increased mortality 6
• Early administration increases cardiac output, improves microcirculation, and avoids fluid overload 6

Weaning Protocol

• Decrease the norepinephrine dose by 25% of the current dose every 30 minutes as tolerated 4

Common Pitfalls to Avoid

• Do not delay norepinephrine initiation while pursuing excessive fluid resuscitation, as early vasopressor use prevents prolonged hypotension and its associated complications 6
• Do not use dopamine as first-line therapy due to increased arrhythmia risk without mortality benefit 3, 2
• Do not administer through peripheral IV lines when central access is available, due to extravasation risk 4
• Do not interpret elevated lactate as tissue hypoperfusion if patient is also receiving epinephrine, as epinephrine directly increases lactate production through beta-2 receptor stimulation 5