Tuesday, August 30, 2016

Is It Time to Ditch Isoproterenol for Bradycardia?

The acquisition cost of isoproterenol (Isuprel®) has dramatically increased from approximately $60 per vial in 2012 to over $2,150 per vial today, a nearly 4000% increase. 

In order to minimize costs associated with therapy, the following represents alternative agents that may be utilized in the management of bradyarrhythmia:

Recommendations for the management of bradyarrhythmia based on the Advanced Cardiovasular Life Support guidelines are as follows (1):
  • Patients who are asymptomatic from their bradycardia typically do not need aggressive therapy and can be monitored while the underlying cause is being investigated
  • Underlying causes of bradycardia should be investigated in all patients.  
    • If drug overdose is suspected, appropriate antidote therapy (if available) should be administered 
  • For asymptomatic patients (e.g. "unstable" as evidenced by hypotension, acute altered mental status, signs of shock, ischemic chest discomfort, or acute heart failure), it is recommended to administer atropine at a dose of 0.5 mg every 3 to 5 minutes to a maximum dose of 3 mg
    • In the scenario where atropine fails or is not indicated, the following options may be considered:
      1. Transcutaneous pacing
      2. Epinephrine continuous infusion
      3. Dopamine continuous infusion
    • For patients without intravenous (IV) access, transcutaneous pacing is likely the best option to quickly stabilize the patient
    • For patients with IV access, a continuous infusion of either epinephrine or dopamine may be used to maintain heart rate as a means to ensure symptomatic improvement
Although isoproterenol is not the ACLS algorithm for the management of bradyarrhythmia, some providers may utilize this agent based on its B1 activity.

Comparison of Mechanisms of Action
  • Isoproterenol is a non-selective beta agonist that stimulates B1 receptors, resulting in increased chronotropy and inotropy as well as B2 receptors, leading to vasodilation of bronchial, gastrointestinal, and uterine smooth muscles, with some degree of peripheral vasodilation (2)
 Alternative agents to isoproterenol for the treatment of bradyarrhythmia include the following (2):
  • Epinephrine: 
    • Potent B1 activity similar to isoproterenol but with more alpha1 effects, leading to vasoconstriction (which offsets any B2 activity)
    • High-dose epinephrine (> 0.1 mcg/kg/minute) provides additional increases in alpha1 mediated vasoconstriction but only a slight increase in B1 effects
  • Dopamine
    • Potent B1 activity similar to isoproterenol and epinephrine with moderate dosing rates (about 4-10 mcg/kg/min)
    • More vasoconstrictive effects are seen as the dose is increased above 10 mcg/kg/min with little change in B1 effects  
  • Dobutamine:
    • Closest agent to isoproterenol based on mechanism of action as both only affects B1 and B2 receptors
    • However, at this point, dobutamine it is not routinely recommended for treatment of isolated bradycardia 
  • Norepinephrine:
    • Minimal B1 effects compared to other agents;, therefore, not recommended for the treatment of isolated bradycardia 
Recommendations
  • Underlying causes of bradycardia should be investigated in all patients 
    • If drug overdose is suspected, appropriate antidote therapy (if available) should be administered 
  • For unstable patients without IV access, transcutaneous pacing is recommended as initial therapy in unstable bradycardic patients 
  • For bradycardic patients with IV access who have failed atropine, continuous infusions of epinephrine or dopamine infusions (and not isoproterenol) are reasonable first-line options while the cause of bradycardia is being investigated 
    • Target doses for epinephrine infusions are between 1 and 10 mcg/min, although higher doses may be required depending on patient hemodynamics 
      • In hypotensive patients, epinephrine may be preferred over dopamine as epinephrine possesses more vasoconstrictive properties 
    • Target doses for dopamine are 4 to 10 mcg/kg/min 
      • Starting at doses lower than 4 mcg/kg/min has little effect on heart rate 
      • Doses higher than 10 mcg/kg/min provide minimal increases in heart rate but may be considered if the patient is hypotensive 
  • The Surviving Sepsis 2012 Guidelines (3) recommend dopamine as an alternative vasopressor to norepinephrine only in patients with a low risk of tachyarrhythmias and/or relative or absolute bradycardia 
    • For septic bradycardic patients (or patients in whom sepsis is a concern), dopamine can be considered, but still may not be the best option as we have more potent vasopressors options available (like epinephrine) 
  • There are new data emerging that peripherally administered vasopressor agents are safe if used for short periods in a peripheral IV (4-5) at least proximal to the antecubital fossa 
    • Epinephrine or dopamine infusion can be utilized initially to stabilize unstable bradycardic patients until more definitive access can be established 
    • Similar to @PulmCrit’s recommendation for the  treatment of BRASH Syndrome (6), isoproterenol may still have a niche use for normotensive patients requiring inotropic support without central access or a good proximal peripheral line. 
    • Isoproterenol does not cause vasoconstriction and is therefore theoretically safer for peripheral administration than epinephrine or dopamine when considering risks of extravasation

Conclusions
Continuous infusion therapy may be required for symptomatic bradycardic patients as a bridge until more definitive therapy can be established. Due to the drastic price increase, isoproterenol should not routinely be utilized for this indication as there are other equally efficacious and more cost-effective options available such as epinephrine or dopamine.  

Scott Dietrich, PharmD (@PCC_PharmD)
ED Clinical Pharmacist
St Joseph’s Hospital
Tampa, Florida 

Peer reviewed by Craig Cocchio, PharmD, BCPS (@iEMPharmD) and Nadia Awad, PharmD, BCPS (@Nadia_EMPharmD


References:
  1. Link et al. Part 7:adult advanced cardiovascular life support: American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2015; 132(suppl 2):S444-S464.
  2. Jentzer JC, Coons JC, Link CB, Schmidhofer M. Pharmacotherapy update on the use of vasopressors and inotropes in the intensive care unit. Journal of Cardiovascular Pharmacology and Therapeutics. 2015; 20(3):249-260.
  3. Dellinger et al. Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock. Critical Care Medicine. 2013; 41(2):580-637.
  4. Cardenas-Garcia J, Schaub KF, Belchikov YG, Narasimhan M, Koenig S, Mayo PH. Safety of peripheral intravenous administration of vasoactive medication. Journal of Hospital Medicine. 2015; 0(0):1-5.
  5. Loubani OM, Green RS. A systematic review of extravasation and local tissue injury from administration of vasopressors through peripheral intravenous catheters and central venous catheters. Journal of Critical Care. 2015; 30(3):653.e9-17. 
  6. Farkas J. BRASH Syndrome: Bradycardia, Renal Failure, AV Blocker, Shock, Hyperkalemia. EMCrit. February 2016. Available at: http://emcrit.org/pulmcrit/brash-syndrome-bradycardia-renal-failure-av-blocker-shock-hyperkalemia/