Tale of the Comeback Kid: Procainamide in the ED

It seems as though the traditional "go-to" management of atrial fibrillation in the setting of rapid ventricular response in the emergency department involves rate control and anticoagulation.

Can we break this tradition and consider alternative therapeutic management in certain subpopulations of patients with dysrhythmias?

Recently, there has been some discussion regarding the use of rhythm control for new-onset atrial fibrillation, particularly procainamide, which used to be used back in the day and has started to make a comeback.

You may ask why. Here's the story of the revived interest in the emergent use of procainamide in recent-onset atrial fibrillation as well as other dysrhythmias:

The Procainamide Comeback: Blasts from the Past and Hints for the Future
Indication	Recommendation	Proof
Conversion of recent-onset atrial fibrillation	Class Ia recommendation for our northern neighbors in Canada	·         One study demonstrated conversion rate of new-onset atrial fibrillation with the use of IV procainamide in nearly 52% of all patients. ·         Another study demonstrated 59.9% conversion rate in patients treated with IV procainamide using the Ottawa Protocol.
Wide-complex atrial fibrillation associated with Wolff-Parkinson-White (WPW) syndrome	Class I recommendation for management of atrial fibrillation in the setting of WPW as of 2011 ACCF/AHA/HRS guidelines	·         A review of various studies show amiodarone to not be the preferred treatment option for atrial fibrillation associated with WPW due to inducible proarrhythmias ·         Incidence was less with procainamide.
Stable monomorphic ventricular tachycardia	Class IIa recommendation (preferred over amiodarone [Class IIb]) based on 2010 AHA guidelines	·         One study demonstrated superiority of IV procainamide over IV lidocaine in terminating episodes of stable monomorphic ventricular tachycardia (79% versus 19%).

Interestingly enough, the Canadians seem to have a lot more to offer in terms of evidence surrounding the use of procainamide in the emergency department; perhaps we can adopt this practice more routinely when the situation arises.

To complete the preparation for the comeback of procainamide, let us now retrieve that vial sitting all the way in the back corner of the top shelf in your pharmacy and review the dosing just for kicks:

The loading dose of procainamide can be administered in a number of ways:

• 20 to 50 mg/min IV OR 100 mg IV at a rate not exceeding 50 mg/min repeated every five minutes as needed to a total dose of 1 g
• When a total of 500 mg has been given, one should wait ten minutes before continuing with administration to prevent profound hypotension.
• Infusion of 17 mg/kg IV over one hour
• In patients with renal dysfunction or congestive heart failure, loading dose should not exceed 12 mg/kg.

The maintenance dose of procainamide typically ranges between 1 and 4 mg/min administered via continuous IV infusion.

Procainamide is looking to redeem itself for use in the ED...are you up to the challenge?

STEMI Meds TOT

Here is my attempt at a trick of the trade. This one is focused at the intubated STEMI patient in whom the EMS crew couldn’t get the 324mg of aspirin on board, and the cardiologist wants to load with clopidogrel 600mg as well as atorvastatin 80mg. Provided we can drop an OG tube before the patient gets sent to the cath-lab, this is how we get the meds into the patient:

Grab a Toomey Tip 60mL syringe, the meds, some water and something to crush the tablets (In our ED, commercial pill crushers disappear within a day, so we often use a blunt object located nearest t0 the pharmacy).

First, crush the tablets while still in the blister pack so fragments don’t go flying everywhere (easy to do with chewable aspirin, not so much with clopidogrel and atorvastatin).

Draw up about 25 mL of water into the syringe from the cup. While plugging the end of the Toomey tip with your thumb, remove the plunger of the syringe.

Dump the contents of the crushed tablet blister packs into the syringe through the opening created by the missing plunger.

Return the plunger into the syringe, and shake (Don’t take your thumb of the Toomey tip unless you want aspirin/Plavix/Lipitor shake all over the place).

Draw up some extra water (to a total of about 45-50mL).

If there are still some tablet fragments after administering, draw up an extra 25-30mL of water to flush.

Done and done.

Low vs Standard Dose Diltiazem

A few days ago I read a few tweets about evidence versus eminence-based medicine and the ensuing discussions.  I started to think of a number of examples of eminence based medicine I practice; but not out of old habits, or limited knowledge – but because there’s simply a lack of evidence.

Diltiazem dosing for AFIB rate control was one of them.  So sayeth the drug reference; the initial weight based diltiazem dose for rate control is 0.25mg/kg. If that didn’t control a patients rate, you could repeat a dose of 0.35mg/kg. Those large doses could drop a patient’s blood pressure, and a particular concern for patients with borderline blood pressure in the neighborhood of 90-100 systolic. Clinically, the dose could be empirically lowered in this case to say 0.15mg/kg to try to minimize the drop in SBP. But what’s the evidence?

Old data existed comparing standard dose diltiazem to various other rate control treatments: digoxin, amiodarone, metoprolol, etc. But until recently, evidence to suggest the effects of using a normal vs low dose diltiazem did not exist.

Now, I’m certain this article has been reviewed elsewhere, so I’ll try to summarize the meat of it briefly. The tagline of the study was low-dose diltiazem (0.14mg/kg ± 0.04) was as good as standard dose diltiazem (0.24mg/kg ± 0.02) and high dose (0.34 mg/kg ± 0.02) at achieving a positive therapeutic response (30 min post administration - reduction of the ventricular response rate to < 100 OR > 20% reduction from baseline).  Not surprisingly, there was a lower incidence of hypotension (but no clinically significant events as a result of the hypotension) in the low dose arm compared to standard and high dose.[1]

Although it wasn’t the most robust study, and no slam-dunk, it did finally provide some evidence to support using a lower dose in situations. More importantly, the ethos of this study was what I enjoyed the most – challenging what we think we know and putting our clinical habits to the test. Hopefully, this will inspire others to challenge their eminence-based practices. I know it has for me.

[1] J. Lee et al. Low-dose diltiazem in atrial fibrillation with rapid ventricular response. American Journal of Emergency Medicine (2011) 29, 849–854

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.

Pharmacy Consult: Nitroglycerin Paste to IV Conversion

While I’m not a huge fan of nitroglycerin paste, I understand it’s clinical usefulness. The ability of slapping on an inch of paste to relieve chest discomfort is certainly non-invasive and can achieve effective results.  With this simplicity, a degree of randomness exists with regard to the ability to titrate the dose.  If the desired clinical effect is not achieved, how much more can we apply safely? Conversely, if hypotension results, how long will the effects last after the paste is wiped off?

Though more invasive, IV nitroglycerin provides greater control and titratablility and one study suggests a dose conversion between the dosage forms. (Am J Crit Care. 1998 Mar;7(2):123-30)

The conversion from IV to PASTE is relatively straightforward. Apply the appropriate amount of PASTE, and then stop the infusion of nitroglycerin 30 minutes later. (see table below for conversions)

Converting from PASTE to IV is a little more difficult (and has not been studied).  After removal of the nitropaste, the duration of effect of nitroglycerin is anywhere from 2 hours to 12 hours. So titration to IV will be more difficult and require close attention. It would therefore make more sense to target the lower end of the conversion range. For example, if 1 inch was applied and the conversion range is 10-39 mcg/min, the IV rate should be started at 10 mcg/min about 1 hour after the paste is removed and subsequently titrated.

Of course if the decision to convert to IV was because the paste is not achieving the desired effect, the infusion could be started earlier, but still targeting the lower dose range.

PASTE	IV
0.5"	5 mcg/min
1.0"	10 – 39 mcg/min
1.5"	40 – 59 mcg/min
2.0"	60 – 100 mcg/min