Epi Use In Severe Asthma - Zero OR Hero

You and your partner are taking care of a 55 year old male patient having a severe asthma attack, and they are not improving. "We threw everything at him! What else can we do?"....you take a glance at your protocol...."Ah thats right, IM epinephrine, but......I have to call for orders." You call medical control for orders and they are denied due to the patient having a history of coronary artery disease (CAD).

This can be a frustrating situation to be in. Why is there so much concern to give these patients epinephrine? Is it unsafe? Is it effective? 

Here is an example of the protocol referenced (red box meaning call medical control):

The concern with administering epinephrine to patient's older than 40 or having CAD is theoretical. The theory is that epinephrine has inotropic and chronotropic cardiac effects which could cause cardiac ischemia due to increased oxygen demand; this could lead to unfavorable outcomes (arrhythmia, MI, etc.) in older patients, especially those with CAD. There are case studies of patients developing myocardial ischemia and/or arrhythmia after administration; however, these incidences are rare and those studies potentially contain observer bias. A severe asthma patient often has tachycardia which can be contributed to their degree of respiratory distress and impending failure. An argument can be made that the severity of the asthma attack itself could be a contributing cause of these adverse events. 

Okay enough theory. What does the evidence show? And is it quality research? Time to get nerdy!

Safety & Efficacy Based on Age

A prospective study by Cydulka et al. (1988) looked at the effect of patient age when SQ epinephrine is administered to 95 asthma patients aged 15-96, for a total of 108 exacerbations. The two cohorts included "patients less than 40 and more than 40 years old" in which "three subcutaneous doses of 0.3 mL 1:1,000 epinephrine were given 20 minutes apart" (Cydulka et al., 1988). Exclusion criteria included "recent myocardial infarction or...angina" (Cydulka et al. 1988).

Overall, Cydulka et al, (1988) deem the efficacy of SQ epinephrine in an acute asthma exacerbation is not impacted by age. In fact, when comparing the two cohorts, "there was no significant difference in the occurrence of ventricular arrhythmias" and "the mean systolic and diastolic blood pressures, mean heart rate, and mean respiratory rate decreased with treatment in the older population" (Cydulka et al., 1988). 

Safety & Efficacy of IV Epinephrine

A retrospective study completed in 2006 by Putland et al. looked at adverse affects of IV epinephrine in 220 severe asthma patients. Patient's were included if they were "between the ages of 18 and 55 years", positive asthma diagnosis, and "receive[d] IV epinephrine as part of their treatment" (Putland et al. 2006). Of note, exclusion criteria failed to look for comorbidities such as CAD (Putland et al. 2006).

An "average epinephrine infusion rate was 1.5 mcg/min (range 0.5 - 13.3 mcg/min)" over "10 minutes to 11.4 days with a median of 19.5 hours" (Putland et al.).  "Eighty-eight adverse events occurred in 67 episodes of use" in which "uncomplicated sinus tachycardia and hypertension accounted for the majority of the episodes (23/88 and 30/88, respectively)" (Putland et al.). Serious adverse events occurred in 3.6% of patients (Putland et al. 2006). 

The authors concluded that IV epinephrine is associated with a low rate of serious complications and a moderate rate of minor complications (Putland et al. 2006).

Pediatric Severe Asthma

Research in this patient population is difficult to come by. The studies vary in route of epinephrine administration. Some studies were comparing epinephrine versus salbutamol, other studies compared epinephrine + inhaled bronchodilator versus bronchodilator alone. A few studies also looked at nebulized epinephrine versus nebulized B2 agonists. Most of these studies were utilizing observational methodology. Conclusions varied from epinephrine showing improved outcomes, no difference, or epinephrine potentially being harmful (due to side affects of nausea/vomiting/headache/chest discomfort). No lethal arrhythmias or myocardial injury was reported in these studies. 

Baggot et al. (2021) conducted a meta-analysis which included the following findings: 

"Kornberg et al. reported an unblinded parallel group RCT of 43 children aged 3 to 12yrs attending a paediatric emergency department for acute asthma. Patients received either 2.5mg salbutamol nebuliser repeated as required every 20 to 30 minutes or a single subcutaneous injection of Sus-Phrine...0.005ml/kg followed by 2.5mg salbutamol nebuliser repeated as required every 20 to 30 minutes... Treatment failure, in the form of hospitalisation, was present in 1/20 patients in the adrenaline group compared with 3/23 patients who received only selective β2-agonist. Both groups showed significant improvement in clinical score, peak flow and respiratory rate; with no difference between the groups."

Final Thoughts

I think it is important to start off by stating that this blog is focused on severe asthma care, specifically in the pre-hospital environment. There are multiple definitions of severe asthma that you can find. Here is my definition for severe asthma: 

• Clinical presentation: increased work of breathing (intercostal retractions/accessory muscle use/belly breathing/nasal flaring), prolonged expiration, tripoding or can't sit still, fatigued look 
• History: they have been put on CPAP or intubated in the past for their asthma, compared to other asthma attacks in the past they rank their SOB a 10/10
• Vitals: RR >=22, tachycardia, usually hypertensive or normal BP, elevated ETCO2, absent or severely diminished lung sounds/wheezing throughout, SpO2 is usually normal

*IF THE PATIENT HAS HYPOXIA (REFRACTORY TO INITIAL TREATMENT) THEY ARE EXPERIENCING A SEVERE ATTACK. 

PRAM score for pediatrics:

The evidence currently available is 15-30+ years old . Most methods utilized an observational approach with very few randomized control trials (RCT). The studies have the potential for several types of bias and small sample sizes. In order to improve severe asthma care in the pre-hospital setting, a double-blind RCT is needed. The control groups should match current protocols utilized in the pre-hospital environment. 

The goal of future studies should aim to see if IM/IV epinephrine has any efficacy in severe asthma. Answering this question will have heavy weight on the future care of severe asthma patients in the pre-hospital setting, a protocol that has not changed in decades.

My take away based on current evidence:

1. Epinephrine, both IM and IV routes, is safe and has withstood to test of time (used in asthma for over 100 years).
2. Epinephrine is safe for all ages.
3. Epinephrine is safe for patients with history of CAD, especially when administered IM.
4. Epinephrine's efficacy is unknown.
5. Protocols should not require medical control contact prior to administration of epinephrine. 

What is your take......Is Epi in asthma a hero or zero?

References

Baggott, Christina, and Hardy, Joe. 2021. "Adrenaline (epinephrine) compared to selective beta-2-agonist in adults or children with acute asthma: a systematic review and meta-analysis." Medrvix, doi: 10.1101/2021.02.17.21251734.

Cydulka, R et al. “The use of epinephrine in the treatment of older adult asthmatics.” Annals of emergency medicine vol. 17,4 (1988): 322-6. doi:10.1016/s0196-0644(88)80772-8

Kornberg, A., Zuckerman, S., JR, W., Mezzadri, F., & Aquino, N. (1991). Effect of injected long-acting epinephrine in addition to
aerosolized albuterol in the treatment of acute asthma in children. Pediatric Emergency Care, 7(1PG-1–3), 1–3.

Putland, Mark, Debra Kerr, Anne-Maree Kelly. 2006. "Adverse Events Associated With the Use of Intravenous Epinephrine in Emergency Department Patients Presenting With Severe Asthma." Annals of emergency medicine, PMID: 16713785.