Without evidence of benefit, an intervention should not be presumed to be beneficial or safe.

- Rogue Medic

Drug Shortage Update – Norepinephrine

The FDA (Food and Drug Administration) has advised of another drug shortage. Norepinephrine Bitartrate Injection (Levophed brand, but also the generic version). This adds to the potential entertainment value in ACLS (Advanced Cardiac Life Support) classes.

This may also contribute to problems when treating real patients, so it is a good idea to prepare for the use of alternatives to the drugs that are not available, or those that are not available in the strength/packaging we are familiar with.

Ironically, as far as using norepinephrine for cardiac arrest, the 2010 ACLS guidelines state –

Other Vasopressors
There are no alternative vasopressors (norepinephrine, phenylephrine) with proven survival benefit compared with epinephrine.268,281,282
[1]

Why ironically?

Vasopressors
To date no placebo-controlled trials have shown that administration of any vasopressor agent at any stage during management of VF, pulseless VT, PEA, or asystole increases the rate of neurologically intact survival to hospital discharge. There is evidence, however, that the use of vasopressor agents is associated with an increased rate of ROSC.
[2]

Epinephrine has not been shown to produce any survival benefit, but norepinephrine has not been shown to produce more of a survival benefit than epinephrine.

We could just as easily state –

There are no alternative vasopressors (epinephrine, norepinephrine, phenylephrine) with proven survival benefit compared with Placebo.

For post-cardiac arrest care, the 2010 ACLS guidelines state –

There is no proven benefit or harm associated with administration of routine IV fluids or vasoactive drugs (pressor and inotropic agents) to patients experiencing myocardial dysfunction after ROSC. Although some studies found improved outcome associated with these therapies, the outcome could not be solely ascribed to these specific interventions because they were only one component of standardized treatment protocols (eg, PCI and therapeutic hypothermia).6,11,12,166 Invasive monitoring may be necessary to measure hemodynamic parameters accurately and to determine the most appropriate combination of medications to optimize perfusion.

Fluid administration as well as vasoactive (eg, norepinephrine), inotropic (eg, dobutamine), and inodilator (eg, milrinone) agents should be titrated as needed to optimize blood pressure, cardiac output, and systemic perfusion (Class I, LOE B). Although human studies have not established ideal targets for blood pressure or blood oxygenation,11,12 a mean arterial pressure ≥65 mm Hg and an ScvO2 ≥70% are generally considered reasonable goals.[3]

As with treatment during cardiac arrest, we could state this as –

There are no treatments (fluids, epinephrine, norepinephrine, phenylephrine) with proven survival benefit compared with Benign Neglect.

For norepinephrine in special resuscitation situations, the 2010 ACLS has –

Recently vasopressin has been used successfully in patients with anaphylaxis (with or without cardiac arrest) who did not respond to standard therapy.77–79 Other small case series described successful results with administration of alternative -agonists such as norepinephrine,80 methoxamine,81,82 and metaraminol.83–85 Alternative vasoactive drugs (vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in cardiac arrest secondary to anaphylaxis that does not respond to epinephrine (Class IIb, LOE C). No randomized controlled trials have evaluated epinephrine versus the use of alternative vasoactive drugs for cardiac arrest due to anaphylaxis.[4]

And –

A number of vasopressors and inotropes have been associated with improvement in the treatment of tricyclic-induced hypotension, ie, epinephrine,239,344,345 norepinephrine,345–348 dopamine,348–350 and dobutamine.349[5]

Back to the drug shortage information.

Bedford attributes the lack of availability to manufacturing delays –

Bedford has Norepinephrine Bitartrate Injection 1 mg/mL 4 mL vials on back order and the company cannot estimate a release date.[6]

Hospira claims that the problem is increased demand –

Levophed (Norepinephrine Bitartrate Injection) 1 mg/mL 4 mL ampules (NDC 0409-1443-04) and 4 mL vials (NDC 0409-3375-04) are on back order, and the company expects continuous deliveries going forward, with recovery estimated to occur in 3Q 2011.[6]

Teva states that they only temporarily discontinued norepinephrine, but that was in June of 2010 –

Teva anticipates having product available again 4th quarter 2011.[6]

There is probably not an increased overall demand for norepinephrine. More likely is that it is a chain of events. Teva stopped manufacture, Bedford has manufacturing delays, and Hospira is trying to make up for the lack of supply from the other drug companies. This seems to be a trend among the drug shortages.


Footnotes:

[1] Other Vasopressors
2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care
Part 8: Adult Advanced Cardiovascular Life Support
Part 8.2: Management of Cardiac Arrest
Medications for Arrest Rhythms
Vasopressors
Free Full Text Article with links to Free Full Text PDF download

[2] Vasopressors
2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care
Part 8: Adult Advanced Cardiovascular Life Support
Part 8.2: Management of Cardiac Arrest
Medications for Arrest Rhythms
Free Full Text Article with links to Free Full Text PDF download

[3] Use of Vasoactive Drugs After Cardiac Arrest
2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care
Part 9: Post–Cardiac Arrest Care
Vasoactive Drugs for Use in Post–Cardiac Arrest Patients
Free Full Text Article with links to Free Full Text PDF download

[4] Vasopressors
2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care
Part 12: Cardiac Arrest in Special Situations
Part 12.2: Cardiac Arrest Associated With Anaphylaxis
ACLS Modifications
Free Full Text Article with links to Free Full Text PDF download

[5] Cyclic Antidepressants
2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care
Part 12: Cardiac Arrest in Special Situations
Part 12.7: Cardiac Arrest Associated With Toxic Ingestions
Free Full Text Article with links to Free Full Text PDF download

[6] Norepinephrine Bitartrate Injection
FDA
updated 3/10/2011
Drug Shortage Update
Drug Shortages – norepinephrine

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Comments

  1. Reminds me of the old axiom, “Leave ’em dead with Levophed”

  2. What is the difference between Norepinephrine and Epinephrine?