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 
  • 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

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

  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/

Monday, August 15, 2016

Mirror Mirror on the Wall, Who's the Most Fragile of Them All? Assessing the Fragility Index of ECASS III

There are two kinds of people in the emergency department: those who are advocates of intravenous tPA for the treatment of acute ischemic stroke, and those who aren’t. Among twelve large clinical trials, only two have demonstrated statistically beneficial results of systemic thrombolytics in the setting of acute ischemic stroke: NINDS and ECASS III [1,2,3]. Despite the lack of robust high quality evidence, current American Heart Association/American Stroke Association guidelines recommend the administration of intravenous tissue plasminogen activator (tPA) as the “standard of care” for treatment of acute ischemic stroke [4].

Josh Farkas (@PulmCrit) recently posted a brilliant reanalysis of the NINDS trial using a metric known as Fragility Index [5]. Fragility Index measures the statistical reproducibility of a trial by determining the minimal number of patient outcomes that must be changed in order to shift the p-value above 0.05. The smaller the Fragility Index, the more fragile the study. Although this concept is relatively new, it has already been used to evaluate a large number of trials in the critical care setting [6].

The NINDS trial was found to have an overall Fragility Index of three, meaning that if three additional patients in the control group were to have a favorable outcome the study would have shown no statistically significant difference between tPA and placebo at 90 days. Frightening, right?

Similar to NINDS, ECASS III is fraught with limitations. Both trials were poorly randomized with an imbalanced, sicker (greater NIHSS score) placebo group. Furthermore, the primary end point of disability at 90 days was dichotomized as "favorable" for modified Rankin scale (mRS) scores of 0-1 or "unfavorable" for mRS scores between 2-6. So based on this, a mRS score of 2 (slight disability, still independent) is considered the same outcome as a mRS score of 6 (dead). This is rubbish.
Not surprisingly, the beneficial signal of tPA is lost when patients with mRS scores between 0-2 at 90 days are considered favorable. Given these limitations, the Fragility Index of ECASS III should be evaluated to determine if the results are more reproducible than the NINDS trial.

Calculating the Fragility Index of ECASS III 

ECASS III assessed the efficacy and safety of tPA administered between 3 and 4.5 hours after the onset of stroke symptoms and provided the rationale for the “extended treatment window” in current practice guidelines.  The authors concluded that more patients had a favorable outcome with alteplase vs. placebo (52.4% vs. 45.2%; OR, 1.34; 95%  CI 1.02-1.76, P = 0.04). These results are depicted in the table below.

To determine the Fragility Index of the primary endpoint, contingency tables were created to move one patient at a time in the control group from an unfavorable outcome to a favorable outcome. After each data point manipulation, subsequent p-values were recalculated with Fisher’s exact test until the p-value reached 0.05. Figures were checked for accuracy with the use of an online Fragility Index calculator [7]. The result was almost unbelievable: one. If only one additional patient in the control group were to have a favorable outcome the study would be considered negative. [The Fragility Index of the primary outcome is increased to eight when data from the per-protocol analysis is used. This larger value is expected given that per-protocol analyses are subject to bias and often favor the intervention arm.] 

A favorable “global outcome” with alteplase compared to placebo was also reported as a secondary end point. This was the composite of several individual outcome scales which included mRS, Barthel Index, NIHSS, and Glasgow Outcome Scale (see table above). The positive global outcome signal is primarily driven by statistically significant differences in mRS and NIHSS scores. By simply using Fisher’s exact test to produce an exact p-value rather than an estimate for differences in NIHSS scores, the p-value is then shifted to 0.0501. This would result in a Fragility Index of zero, extremely unlikely to be reproducible.

Number of “favorable outcomes” added to control group
mRS score 0-1
NIHSS score 0-1

Intracranial hemorrhage and symptomatic intracranial hemorrhage (sICH) rates were associated with larger Fragility Indices of fourteen and three, respectively. This provides further validation that the detrimental effects of tPA are much more reproducible compared to those of it's efficacy. 

In the meantime, intravenous tPA will continue to remain the "standard of care" for up to 4.5 hours after stroke onset despite overwhelming evidence of no benefit or harm. The American College of Emergency Physicians have at least downgraded the strength of this recommendation:
"Despite the known risk of sICH and the variability in the degree of benefit in functional outcomes, IV tPA may be offered and may be given to carefully selected patients with acute ischemic stroke within 3 to 4.5 hours after symptom onset at institutions where systems are in place to safely administer the medication." [8]
The glass remains half empty...

Take home points 
  • Fragility Index measures the statistical reproducibility of study outcomes. A low Fragility Index indicates less statistically robust results.
  • ECASS III has a Fragility Index of one, meaning it would only take one additional favorable outcome in the control group to render a nonsignificant difference between tPA and placebo. 
  • Similar to the NINDS trial, ECASS III has an extremely low Fragility Index which suggests that the "beneficial" results of these studies are likely not reproducible.
  1. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995;333(24):1581-7. 
  2. Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke. N Engl J Med 2008;359:1317-29.
  3.  http://www.thennt.com/nnt/thrombolytics-for-stroke/. Accessed electronically August 2, 2016.
  4. Guidelines for the Early Management of Patients With Acute Ischemic Stroke. Stroke 2013;44:870-947
  5. http://emcrit.org/pulmcrit/fragility-index-ninds/. Accessed electronically August 2, 2016.
  6. Ridgeon EE, Young PJ, Bellomo R, et all. The Fragility Index in Multicenter Randomized Controlled Critical Care Trials. Crit Care Med 2016;44(7):1278-84.
  7. http://www.fragilityindex.com. Accessed electronically August 2, 2016.
  8. Clinical Policy: Use of Intravenous Tissue Plasminogen Activator for the Management of Acute Ischemic Stroke in the Emergency Department. Ann Emerg Med 2015;66:322-333.

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