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Monday, November 19, 2012

Aminophylline and Bradyasystolic Cardiac Arrest


When it comes to drug therapy in cardiac arrest, we just can’t get it right.  Granted, the heterogeneity of the causes of cardiac arrest as well as patient population characteristics make it difficult to find a drug (or combination of drugs) that will improve survival.  But that doesn’t stop us from looking for one.  Take for instance, aminophylline. Yes, aminophylline.

The ethylenediamine salt of theophylline, aminophylline is thought to counteract the effects of adenosine on the heart (and lungs) by antagonizing the A1 receptor.  While various other mechanism of modulating inflammation exist, the PDE inhibiting effects of aminophylline leads to increases in cAMP and cGMP concentrations and has the potential to exert synergistic effects when given with beta-agonists though augmented cAMP concentrations. [1] These mechanisms provide bronchodilation during asthma exacerbations, and are thought to also produce favorable effects in bradyasystolic cardiac arrest.

Initial case reports and small trials suggested promising ROSC outcomes in patients who received aminophylline after other efforts in CPR failed. [2, 3, 4] These initial findings and theoretical benefits in cardiac arrest were put to the test in a large trail (N=971) in Canada [5]. In this study, patients who suffered an out-of-hospital cardiac arrest with asystole or pulseless electrical activity and who were unresponsive to initial treatment with epinephrine and atropine were randomized to blinded aminophylline or placebo. Aminophylline was administered as a 250mg IV bolus, which could be repeated after 90s for a total dose of 500mg (94% of patients received 500mg). Aminophylline did not improve any outcomes including ROSC or survival to hospital discharge.

Aside from other methodological limitations with this study, the use of aminophylline requires more attention.  When one considers aminophylline essentially as theophylline, nightmares of pharmacokinetics should swiftly come back to haunt the mind. The pharmacokinetics of theophylline varies widely between patients and cannot be predicted by age, body weight, sex or virtually any other characteristic. Dosing aminophylline at 500mg (typical dose used for asthma is 6mg/kg) will likely achieve a concentration of about 15 mcg/mL – the upper limit of the therapeutic window (5-15mcg/mL).  Not forgetting the complex kinetics (again), this concentration could be much higher, or much lower. Above the therapeutic window, seizures can occur though central A1 antagonism. Below the therapeutic window, the beneficial effects on the heart and lungs may not occur. The balancing of these effects and the drug interactions causing both decreased clearance and increased clearance make it difficult to dose safely and a less than ideal agent to use as a one-dose-fits-all strategy.

It seems that the search continues for a drug that will join the ranks of good quality early chest compressions and defibrillation.  Let’s move on and remember aminophylline as one of the many the cautionary tales of pharmacokinetics.

1. Barnes PJ. Chapter 36. Pulmonary Pharmacology. In: Brunton LL, Chabner BA, Knollmann BC, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill; 2011. http://www.accessmedicine.com.libproxy2.umdnj.edu/content.aspx?aID=16671685. Accessed November 17, 2012.

2. Mader TJ, Gibson P. Adenosine receptor antagonism inrefractory asystolic cardiac arrest: results of a human pilot study. Resuscitation1997;35:3–7
3. Mader TJ, Smithline HA, Gibson P. Aminophylline in undifferentiated out-of-hospital asystolic cardiac arrest. Resuscitation 1999;41:39–45.
4. Mader TJ, Sminthline HA, Durkin L, et al. A randomized controlled trial of intravenous aminophylline for atropine-resistant out-of-hospital asystolic cardiac arrest. Acad Emerg Med 2003;10:192–7.

5. Abu-Laban RB, McIntyre CM, Christenson JM, et al. Aminophylline in bradyasystolic cardiac arrest: a randomised placebo-controlled trial. Lancet 2006;367:1577–84.

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