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M2E Too! Mellick's Multimedia EduBlog

The M2E Too! Blog by Larry Mellick, MD, presents important clinical pearls using multimedia.

By its name, M2E Too! acknowledges that it is one of many emergency medicine blogs, but we hope this will serve as a creative commons for emergency physicians.

Wednesday, May 1, 2019

Racemic Epinephrine Deserves More Respect

Some medications enjoyed years of glory but later ended up on the trash heap of clinical medicine, often put there by a systematic review or small case series of adverse outcomes or complications that led to black box warnings and a culture of fear and rejection. Still, the heyday lasted for years for some medication outcasts, such as acetaminophen with codeine, promethazine (Phenergan), aminophylline, droperidol, and meperidine (Demerol).

Of course, a few of these medications probably deserved their bad rap, but most of them served us well for many years when we had few other options. Medications like racemic epinephrine are still widely used but carry an undeserved negative reputation or have unrecognized benefits. In fact, the malicious and false accusations against racemic epinephrine (or racemic adrenaline; RA) actually occurred on several clinical fronts.

The Rebound Myth

I was taught during my pediatric residency about the dreaded rebound reaction that happens to croup patients treated with RA. Supposedly, these children would transiently improve only to rebound with significantly worse symptoms. This, unfortunately, was not true, and if anything, the croupy child just returned to his initial baseline degree of severity.

I'm not sure why rebound was applied to RA. Its effects eventually wear off, and the term rebound has negative connotations. The debate on mandatory observation after RA for croup has resulted in millions of hours of wasted time for patients who could have easily gone home. Steroids also take some time to take effect, but dexamethasone starts to work about an hour or two after administration. Some children with croup should be observed after RA is given, but it is their disease severity that mandates that, not the risk of rebound.

We debated observation for croup recently in our pediatric ED. Our department is developing a clinical pathway for managing croup, but physicians disagreed on whether it was necessary to observe a child treated with RA for three hours. Those favoring mandatory observation pointed to a study by Smith, et al., on observation times. (Clin Pediatr [Phila] 2018;57[6]:706.) Patients observed for 2.1-3 hours had a higher rate of treatment failure than those observed 3.1-4 hours.

This retrospective study reported that one-third of their patients were managed in under two hours. Of those, 83 percent were promptly admitted and 17 percent were sent home and did not return. Nearly 17 percent of those observed for three hours required admission for a second treatment of RA. (Clin Pediatr [Phila] 2018;57[6]:706.)

The criteria for ordering RA treatments differ among clinicians. I am liberal with RA because I like to package patients nicely for parents before sending them home. Any degree of stridor is enough for me to use steroids and RA, but it would be silly to take up a bed in the pediatric ED for three hours to watch these mildly ill patients. The bottom line is that you can send a child with mild illness home immediately after racemic epinephrine without observation.

An article by Yang, et al., nicely demonstrated that you can use a croup scoring system to know who needs to be admitted, observed, or can go home. (Pediatr Pulmonol 2017;52[10]:1329.) Overall, croup is a relatively minor illness, though it still presents with a spectrum of severity. You can easily document where your patient falls on the severity spectrum using a scoring system such as the Westley Croup Score. You can also determine the most appropriate disposition after treatment. (Pediatr Pulmonol 2017;52[10]:1329.)

RA and Asthma

RA is not commonly used for asthma but can be effective for acute exacerbations. Decades ago subcutaneous epinephrine was one of the few treatments available for acute asthma presentations. Intravenous aminophylline and steroids were generally added for seriously ill children who did not respond to epinephrine. Nebulized RA (11.25 mg of epinephrine) is well documented as an asthma treatment. Interestingly, most of the papers that compared nebulized epinephrine with drugs like albuterol and terbutaline similarly concluded that RA is no better than these other drugs. (Acad Emerg Med 2000;7[10]:1097; J Crit Care 2004;19[2]:99; http://bit.ly/2HqRTKp; Am J Emerg Med 2006;24[2]:217; http://bit.ly/2EKf13p.)

These noninferiority studies never said RA was less effective or didn't work. RA is acknowledged to have a few more minor side effects, but significant hypertension and tachycardia are not among them.

We use RA on asthma patients who have already had multiple doses of albuterol without a response. The goal when we throw RA into the ring is to hit more and other β2 receptors when the β2 receptors appear to be fatigued and less responsive to albuterol. Anecdotally, we have had some dramatic results when adding nebulized RA for airway smooth muscle bronchospasm.

Are there different β2 receptors that these drugs affect or does RA attach to a few extra β2 receptors and dry up secretions in smaller airways? Rodrigo, et al., said epinephrine will activate 20 times more β2 adrenoceptors than salbutamol when both drugs occupy the same number of receptors, causing it to be referred to as a full agonist. (Am J Emerg Med 2006;24[2]:217; http://bit.ly/2EKf13p.)

I'm not completely comfortable using this medication on older adults at risk for coronary vascular disease, but I've had success with adults and children. Nevertheless, be ready! If you use RA on asthma patients, expect to be questioned by residents and staff about the need for observation.

Racemic Epinephrine and Bronchiolitis

Despite what the AAP bronchiolitis guidelines recommend, epinephrine does work for bronchiolitis in outpatients. No new Cochrane guidelines exist for bronchiolitis, but the 2004 and 2011 Cochrane reviews acknowledged the outpatient benefit of epinephrine for this disease. Nevertheless, the AAP guidelines inexplicably discourage using nebulized epinephrine in outpatients. (Read my blog post about the bronchiolitis guidelines at http://bit.ly/2Tp92v1.)

These guidelines selectively address inpatient management while ignoring the benefit of epinephrine in the outpatient. Importantly, newer studies support epinephrine in outpatient management of bronchiolitis. (Ann Emerg Med 2013;61[3]:289; http://bit.ly/2XLYdBN.) A 2015 paper of systematic reviews for bronchiolitis therapies reported that nebulized epinephrine is effective for bronchiolitis in the outpatient setting. (Paediatr Respir Rev 2015;16[4]:267; http://bit.ly/2VIxTqk.)

Not only has racemic epinephrine not received the respect it deserves, it has been the object of false rumors. It is finally time that racemic epinephrine receive respect and attention.

racemic epinephrine.jpg

Watch a video of a baby admitted for croup after being given RA and steroids.