Introduction with a case

An elderly woman is admitted with atrial fibrillation and fast ventricular rate. She is asymptomatic, with a heart rate of 160 b/m. She is treated with a 20 mg diltiazem bolus followed by an infusion at 15 mg/hour for several hours. Her heart rate slows to 110 b/m.

She is then treated with 5 mg IV metoprolol. A few minutes later, her heart rate drops to a sinus rhythm at 42 b/m and her blood pressure falls to 70 mm systolic. She becomes obtunded.

She is treated with 0.5 mg IV atropine per ALCS algorithms for symptomatic bradycardia. Simultaneous attempts are made to perform transcutaneous pacing. Pads are placed in an anterior-anterior configuration and fail to capture.

Her heart rate continues to drop, as she becomes unresponsive and pulseless. Chest compressions are initiated, and she is given 1 mg of epinephrine. She immediately has return of spontaneous circulation, with a blood pressure of 250/140 and heart rate of 170 b/m. Eventually she recovers fully (1).

We need more precise terminology than “symptomatic bradycardia”

The AHA has a single algorithm for symptomatic bradycardia. However, symptomatic bradycardia is a very broad entity. For example, both of the following patients have symptomatic bradycardia:

A 55-year-old man presents to the emergency department with gradually worsening dyspnea for the past month. He is found to have a third-degree heart block with a ventricular escape rhythm at 45 beats per minute. He looks fine.

The woman in the case above.

It may be useful to split symptomatic bradycardia into two conditions:

Stable symptomatic bradycardia: These patients have reached an equilibrium with stable vital signs and symptoms. They have achieved a compensated state (for example, maintaining their blood pressure due to increased stroke volume and vasoconstriction). They require monitoring and urgent therapy, but they are not actively dying.

Bradycardic periarrest: These patients have deteriorating vital signs and worsening symptoms. They are in a decompensated state, with progressive instability as they slip into a death spiral (figure below). These patients require emergent therapy to avert progression to full arrest (2).

In some ways, the therapeutic approach to a patient with stable symptomatic bradycardia is opposite to the approach to a patient with bradycardic periarrest:

Stable symptomatic bradycardia: These patients are stable. Therefore, it makes sense to start with the least aggressive treatments. If these fail, then therapy can be gradually escalated to more aggressive treatments.

Bradycardic periarrest: These patients are actively dying. Therefore, it makes sense to start with aggressive treatments that are most likely to achieve stability immediately. After the patient is stabilized, the intensity of therapy can be gradually de-escalated.

Approaches of different guidelines to symptomatic bradycardia.

Let's consider the strategies recommended by three guidelines for management of bradycardia.

Above is the AHA guideline for adult bradycardia. This is a good approach to a patient with stable symptomatic bradycardia. The algorithm starts with atropine (the safest therapy), and escalates to more aggressive therapies. Even the most aggressive therapy recommended (epinephrine infusion 2-10 mcg/min) is fairly tame.

Above is the AHA guideline for pediatric bradycardia algorithm. Unlike the adult algorithm, this seems designed for bradycardic peri-arrest. The first drug on the algorithm is an epinephrine bolus of 10 mcg/kg. This is far more aggressive than the adult algorithm. For example, Harry Potter would receive about 100 times more epinephrine than Vin Diesel would:

Finally, a bradycardia algorithm designed for anesthesia is shown below (Moitra 2012). This algorithm strikes a middle-ground between the two guidelines above: its options include atropine or bolusing with 10-100 micrograms of epinephrine.

Rationale for using epinephrine in bradycardic periarrest

There aren't any prospective RCTs comparing atropine vs. epinephrine for bradycardia. In the absence of such evidence, the following is an argument for choosing epinephrine.

#1. Epinephrine is effective in a broader range of patients

Atropine works by poisoning the vagus nerve, thereby removing parasympathetic inputs to the heart. This works beautifully for vagally-mediated bradycardia (e.g. vagal reflexes, cholinergic drugs). However, it fails for bradycardias caused by other mechanisms (e.g. heart block beyond the AV node). Overall, atropine is completely effective in only 28% of patients with symptomatic bradycardia (Brady 1999).

Unlike atropine, epinephrine stimulates the entire myocardium (atria, SA node, AV node, and ventricles). As such, epinephrine may be effective in a broader range of bradycardias compared to atropine:

Atropine-responsive bradycardias due to excessive parasympathetic tone can generally still be overcome by epinephrine.

Atropine-refractory bradycardias might be responsive to epinephrine.

Vavetsi 2008 evaluated outpatients with bradycardia for the effectiveness of atropine or isoproterenol (a beta-agonist with similar mechanism of action compared to epinephrine). 47 patients responded well to isoproterenol but not atropine, whereas none responded well to atropine but not isoproterenol. This supports the concept that beta-adrenergic stimulation is effective in a broader range of bradycardias compared to atropine (Venn diagram above).

Shown above, the fine print of the AHA guideline for adult bradycardia recommends avoiding atropine in certain types of bradycardias where it will predictably fail. However, for the crashing patient in periarrest, nobody has time to diagnose the precise mechanism of arrhythmia. Thus, it may be best to reduce task-complexity and simply go straight to epinephrine (the Zosyn of bradydysrhythmias).

#2. Epinephrine provides a greater amount of hemodynamic support

Patients dying with bradycardia aren't truly dying from bradycardia itself, but rather from cardiogenic shock (low cardiac output). Atropine offers these patients an increased heart rate, nothing more. Epinephrine offers these patients increased heart rate, increased myocardial contractility, some venoconstriction which increases preload, and some arterial vasoconstriction. Thus, even in an atropine-responsive patient, epinephrine provides much more powerful hemodynamic support.

In periarrest, there isn't time to start adding several drugs (first give some atropine to improve heart rate… then add some norepinephrine to improve the blood pressure…). A single agent is needed that will stabilize the patient. The one drug most likely to do that is epinephrine.

#3. Atropine can cause bradycardia

Atropine has complex effects on heart rate:

At low doses, atropine blocks M1 acetylcholine receptors in the parasympathetic ganglion controlling the SA node. This decreases heart rate (Bernheim 2004).

At higher doses, atropine also blocks M2 acetylcholine receptors on the myocardium itself. This blocks parasympathetic effects on the heart, increasing the heart rate.

Atropine doses below 0.5 mg should be avoided, because sub-therapeutic atropine levels can cause bradycardia. At higher doses, the dominant effect of atropine is usually to increase the heart rate.

Doses <0.5 milligram and slow injection have been associated with paradoxical bradycardia. – Tintinalli's Emergency Medicine 8th edition, page 125.

Among normal patients, atropine doses of 0.4-0.6 mg may cause a transient mild slowing of the heart rate as tissue drug levels increase (3). This is generally short-lived and of little consequence. However, drug distribution is often delayed among patients in cardiogenic shock. Thus, it is possible that in bradycardic periarrest patients, this period of exacerbated bradycardia could be prolonged and clinically harmful. Atropine-induced bradycardia may also be more problematic among patients who are morbidly obese or status post cardiac transplantation (Bernaheim 2004, Carron 2015).

In the absence of prospective RCTs, it is impossible to know the clinical relevance of atropine-induced bradycardia for patients in periarrest. If these patients deteriorate following atropine administration, it will be blamed on their underlying disease (not an adverse effect of atropine). It is possible that occasional patients are harmed by atropine, without our recognition.

Dosing of epinephrine for bradycardic periarrest

Start with a bolus

The ideal dose of epinephrine is unknown, potentially depending on how close the patient is to death. Moitra 2012 recommended a bolus of 10-100 mcg epinephrine. A 20-40 mcg IV bolus seems reasonable for most patients (4).

The best way to achieve this is push-dose epinephrine, a solution of 10 mcg/ml epinephrine which may be formulated as shown below (Weingart 2015). 2-4 ml of push-dose epinephrine will provide a 20-40 mcg epinephrine bolus.

Mixing Epinephrine for Push-Dose Pressors from Scott from EMCrit on Vimeo.

A quick and dirty approach is to push 1/2 ml of 100 mcg/ml epinephrine (cardiac epinephrine). If no push-dose epinephrine is available, this may be faster because it requires no dilution. For a patient whose heart rate is rapidly dropping and is about to arrest, this may be a reasonable maneuver (5). However, there is a risk of inaccurate dosing.

Continue with an infusion

If the patient responds to a bolus of epinephrine, an epinephrine infusion should be started immediately. An epinephrine infusion at 2-10 mcg/min is generally recommended for bradycardia. For bradycardic periarrest, it may be best to start at 10 mcg/min and then wean down once the patient is stabilized (6).

Overcoming epinephrophobia

Epinephrine requires respect. It is prone to dosing errors, which can be dangerous. However, this shouldn't lead us to epinephrophobia: irrational fear of epinephrine, even in situations where it is life-saving (e.g. anaphylaxis).

Resuscitationists must become comfortable with epinephrine in its various forms (intramuscular, push-dose, and IV infusion). When dosed appropriately, this is a safe medication. Please note, however, that intracardiac epinephrine is no longer recommended (7):

Overall schema for resuscitation of the bradycardic periarresting patient

A patient with bradycardic periarrest may be rescued with medical therapy (e.g. epinephrine) or electrical therapy (e.g. transcutaneous pacing). It's unpredictable which therapies will work for which patients. Therefore, a reasonable strategy is to simultaneously attempt both types of treatments (figure below).

The use of calcium for refractory bradycardia has been discussed in a prior post on BRASH syndrome.

It may be useful to make a distinction between patients with stable, symptomatic bradycardia versus patients who are actively dying from bradycardia (bradycardic periarrest). The best approach to these situations is different.

Epinephrine may be superior for patients with bradycardic periarrest for three reasons: (1) It works in a broader range of bradycardias. (2) It provides more powerful hemodynamic support (chronotropy, inotropy, and vasoconstriction). (3) It doesn't cause paradoxical bradycardia.

The best initial medical therapy for bradycardic periarrest may be push-dose epinephrine, followed by an epinephrine infusion. However, this shouldn't delay efforts to perform electrical pacing as well.

Related

Notes

This is an imaginary case, but it is based on a conglomeration of similar cases that I've encountered at a variety of different institutions. Thanks to Dr. Greg Adaka for recently promoting the use of the term periarrest on EM:RAP. This is a great term. The next time I order a pizza, I'm going to ask the restaurant to make it STAT because I'm in hypoglycemic periarrest. Goodman & Gillman's The Pharmacological Basis of Therapeutics, 12th edition, 2011, page 227. This seems to be the most common explanation for atropine-induced bradycardia, although a variety of theories exist in the literature. Some case reports also exist of atropine appearing to cause heart block (e.g. Chin 2005, Maruyama 2003). It is generally quoted that the half-life of epinephrine in the blood is 2-3 minutes. Based on this half-life, a bolus of 20-40 mcg epinephrine should produce similar concentrations compared to the steady-state concentration obtained from a continuous infusion of 10 mcg/min epinephrine. Of course, in reality the correct dose of epinephrine is the one that keeps your patient alive. It's probably better to push a bit too much epinephrine (e.g. 50-70 mcg of epinephrine) and avert a full-on cardiac arrest, rather than allow the patient to arrest (in which case you will be pushing the entire vial). However, I don't think that there is actually any “max” infusion rate epinephrine. If the patient is responding to push-dose epinephrine but not 10 mcg/min infusion, then you could try increasing the infusion higher. However, this procedure isn't so bad. The site is pre-marked. The team discusses various approaches and reaches consensus rapidly. I've seen some codes that aren't nearly this well-organized. However, there is excess rudeness involved which probably doesn't help any. This is also a good depiction of the post-resuscitation exhaustion when John Travolta collapses afterwards.

Image credits: epinephrine phobia. Opening picture is from Sukiyaki Western Django.