Epinephrine/Terbutaline in Acute Asthma Exacerbation

You’re sitting in the critical area when EMS bursts through the trauma bay doors with a 34 year-old male with PMH of asthma in respiratory distress. EMS alerts you that they’ve placed a line, started 1g of magnesium sulfate, given 10 mg of dexamethasone, and the patient is on his second nebulizer treatment of albuterol and ipratropium with no improvement. The nurses hook him up to the monitor and you see his HR is sitting at 130, BP is 145/95, with a RR of 40 and SpO2 94%. You call for BiPAP and your junior frantically tries to draw blood from the patient who is now in a tripod position, diaphoretic, and not responding to your questions. On exam, the patient has supraclavicular and subcostal retractions with poor air entry but is only a little….

The famous “Wheezy F Baby,” which is slang for an asthmatic female neonate

What do you do? A shot of epinephrine or terbutaline? 

Let’s examine the evidence behind parenteral epinephrine and terbutaline for acute asthma exacerbation. The National Heart, Lung, and Blood Institute released guidelines for asthma in 2007. The 417-page document has scant recommendations regarding these medications. They recommend that EMS providers give epinephrine or terbutaline subcutaneously for severe exacerbations if they cannot administer short-acting beta agonists (SABA). They advise against using inhaled epinephrine due to potential for excessive cardiac stimulation, suggesting that systemic therapy does not provide any advantage over inhaled delivery (1). The 2017 Global Initiative for Asthma has no mention of epinephrine but gives a level C evidence rating for terbutaline as an IV bolus followed by infusion for children 5 years and younger if they cannot take an inhaled SABA (2). The 2016 British guideline on the management of asthma recommends intravenous beta₂-agonist use only for those patients who cannot reliably use inhaled therapy but suggests checking serum lactate to monitor for toxicity (3).

You mean to tell me the epinephrine and terbutaline I’ve been taught by my attendings to give these patients isn’t recommended by any professional societies?

When evaluating a potential treatment, we need to ask ourselves if the intervention is safe, effective, and better than existing therapies.

Safety

Concerns about the safety of parenteral epinephrine usually relate to cardiac ischemia, dysrhythmias, and local extravasation injury. Smith et al in 2003 performed a retrospective review of 27 adults in the ED given IV epinephrine in life-threatening asthma and found no significant adverse effects. Nine patients had new tachycardia, and four patients had elevations in their blood pressure, none of which were clinically significant (4). Putland et al performed a similar review in 2006 and found that IV epinephrine was well tolerated in most patients; 10.5% had sinus tachycardia, 13.6% had high blood pressure, 2.3% had hypotension that did not require intervention, 5% had local tissue ischemia (four of these cases occurred in the same patient), and 0.9% had chest pain without ECG or biomarker changes (5). It is important to note that the Smith et al and Putland et al trials excluded patients over the age of 58 and 55, respectively (4,5). Cydulka in 1988 looked at asthmatic patients aged 15 to 96, excluding patients with a history of angina or recent MI, and found no significant ventricular dysrhythmias (6). Based on these studies and extrapolation from another that demonstrated safety of appropriate doses of intramuscular injection of epinephrine (even in older patients) with anaphylaxis (6), we can conclude that parenteral administration of epinephrine for asthma is safe.

Efficacy

There are studies, but no well-developed RCTs, demonstrating the effectiveness of epinephrine or terbutaline for acute asthma. Epinephrine had been used routinely for asthma exacerbations for decades prior to more rigorous study (7,8). The evidence on acute asthma exacerbations is limited by small sample sizes, lack of randomization/blinding/clinically oriented outcomes, sparse use of current standard of care albuterol/ipratropium and steroids, poor stratification by asthma severity, unequal treatment between groups, and exclusion of patients with potential for cardiac disease.

Most studies on this topic were published in the 1970’s and 1980’s and are largely unavailable in digital format. All the studies I found that investigated parenteral or nebulized epinephrine or terbutaline demonstrated improvement in pulmonary function testing in patients with acute asthma. Cydulka’s study on the safety of epinephrine also demonstrated increases in PEFR and a trend toward decreasing HR and RR with each dose of epinephrine (8). In 1983, Pancorbo et al performed a prospective study of 30 patients, 17 to 35 years old, comparing 0.3 mg of subcutaneous epinephrine every 15 minutes x 2 doses to five minutes of weight based nebulized terbutaline. They found that at 60 minutes, patients in each group showed improvements in PEFR from baseline, but there was no difference in mean PEFR improvements between the two groups (9). The significant effects of subcutaneous epinephrine and nebulized terbutaline on pulmonary function testing were confirmed in 33 patients, ages 16 to 64, by Tinkelman et al later that year (10) and in a small pediatric study (n=19) by Uden et al in 1985 (11). Numerous other trials with  different permutations of epinephrine or terbutaline administration were performed in the early part of the 1980s and had similar findings. There is no clear evidence as far as whether epinephrine or terbutaline is better in these studies, but some studies favored epinephrine in terms of PEFRs. Some studies also noted an increase in “adverse events” like tachycardia with epinephrine. I could find no studies evaluating the effectiveness of infusions of epinephrine or terbutaline in acute asthma exacerbations.

Okay, great! Is it better than existing therapy?

In 2012, a Cochrane review by Travers et al evaluated the addition of intravenous beta₂-agonists to inhaled beta₂-agonists for acute asthma and only found three articles. The three studies (n=104) looked at adults, pediatric ED and ICU patients. One study showed no significant difference in adding intravenous terbutaline to nebulized albuterol in terms of Clinical Asthma Severity Scores, while another showed significant benefit of intravenous salbutamol in addition to nebulized salbutamol on different pulmonary index scores. In the study of adult patients, there was no significant difference adding intravenous bedoradrine to standard nebulized albuterol, ipratropium, and steroids for hospital admission. There were significant decreases in recovery times in the pediatric ED with intravenous beta₂-agonists, but no significant difference in length of stay for PICU admissions. The authors conclude that there is limited evidence for addition of intravenous beta₂-agonists, and firm recommendations cannot be made (12).

Expanding the search beyond the strict criteria utilized by the Cochrane group did little to answer the question. A prospective, randomized control trial in the prehospital setting compared three groups that received subcutaneous epinephrine, nebulized metaproterenol, or both in adults with acute asthma exacerbation that found no difference in the primary outcome of peak expiratory flow rate (PEFR) change (13). In 1984, Turpeinen et al randomized 46 pediatric clinic patients with acute asthma to intramuscular epinephrine or nebulized salbutamol and found that nebulized salbutamol was superior in producing sustained increases in PEFR. Furthermore, a higher proportion of patients who received epinephrine were admitted to the hospital (14). Another study compared the addition of terbutaline, aminophylline, or magnesium sulfate to inhaled beta₂-agonists in children with acute asthma and found that magnesium sulfate was significantly better than terbutaline and aminophylline in terms of resolution of symptoms, time to resolution, and side effects (15).

So is there any real support for parenteral epinephrine/terbutaline over nebulized meds?

One of the few exceptions is a small crossover study by Appel et al that compared epinephrine to metaproterenol in adults with severe acute asthma (PEFR < 150 L/min). They found significantly more patients responded to epinephrine (89%) compared to metaproterenol (61%). After crossover, Appel et al noted only 1/6 patients who failed to respond to epinephrine responded to metaproterenol, whereas 13/18 metaproterenol non-responders had subsequent response to epinephrine (17). The major limitation of all crossover studies is that there may be carryover effects from the initial treatment that confound the findings after crossover of groups. This makes it difficult to tease out whether the effects are truly due to the epinephrine or a delayed effect of metaproteronol.

Parenteral epinephrine was routinely used for asthma exacerbations until subsequent, more rigorous studies demonstrated inhaled beta₂-agonists had similar efficacy without the pain of an injection and fewer side effects. This is likely why professional societies do not recommend the routine use of epinephrine or terbutaline. Based upon these trials, parenteral epinephrine and terbutaline may be effective for the population of asthma exacerbations, but perhaps no more so than our current standard practice.

Okay, but I swear I’ve seen epinephrine work when nothing else did!

Asthma research and treatment has made tremendous progress overall since its infancy. However, as you can now see, there are still knowledge gaps regarding epinephrine and terbutaline.

Remember, it’s okay for your six-year-old to smoke, but keep your five-year-old away!

There may still be a role for epinephrine in the acute asthmatic as a rescue medication for severe attacks. It physiologically makes sense. Ask around and you will find anecdotal support that corroborate the findings in Appel’s crossover study. In my very short career, I have encountered severe asthmatics where wheezing cannot be appreciated on exam due to a lack of air movement. After receiving subcutaneous epinephrine, wheezing is often discovered as their air entry improves. For these very “tight” patients with decreased air entry, parenteral epinephrine may be effective since nebulized treatments may not reach the areas of bronchospasm. This may be due to respiratory insufficiency from muscle fatigue, increased bronchial edema, inflammation, and mucus plugging associated with severe attacks. This is supported by a small prospective randomized study by Pliss et al (n=25) that compared nebulized and subcutaneous administration of epinephrine in acute asthma and found that parenteral epinephrine significantly improved PEFR compared to aerosolized but only in those patients with severe asthma (PEFR < 120) (19). Moribund, severe asthmatics are more likely to benefit from parenteral epinephrine or terbutaline, but likely cannot perform accurate spirometry, excluding them from most trials that measure pulmonary function as the outcome. Research is clearly lacking on this subset of severe acute asthma patients. Conducting further research on this topic may be difficult since there are ethical concerns in randomizing patients to receive either placebo or widely-accepted life/intubation-saving treatment.

TL;DR – The evidence is limited, but epinephrine and terbutaline are fairly safe, effective, and may be especially useful in sick asthmatics refractory to standard therapies.

Peer Reviewers: Wendy Chan, MD and Raul Hernandez, MD

Faculty Advisor: Ian deSouza, MD

References

1. National Heart, Lung, and Blood Institute. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma, 2007. Available from: https://www.nhlbi.nih.gov/files/docs/guidelines/asthgdln.pdf

2. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2017. Available from: www.ginasthma.org
3. British Thoracic Society/Scottish Intercollegiate Guidelines Network. Guideline for the management of asthma, 2016. Available from: https://www.brit-thoracic.org.uk/standards-of-care/guidelines/btssign-british-guideline-on-the-management-of-asthma/
4. Smith D, Riel J, Tilles I, Kino R, Lis J, Hoffman JR. Annals of Emergency Medicine. May 2003;41(5):706-11.
5. Putland M, Kerr D, Kelly AM. Adverse events associated with the use of intravenous epinephrine in Emergency Department patients presenting with severe asthma. Ann Emerg Med. June 2006;47(6):559-563.
6. Kawano T, Scheuermeyer FX, Stenstrom R, Rowe BH, Grafstein E, Brunau B. Epinephrine use in older patients with anaphylaxis: Clinical outcomes and cardiovascular complications. Resuscitation. March 2017;112:53-58
7. Arthur, G. Epinephrine: a short history. The Lancet. May 2015;3(5):350-51.
8. Cydulka R, et al.The Use of Epinephrine in the Treatment of Older Adult Asthmatics. Ann Emerg Med. 1988;17(4):322
9. Arthur, G. Epinephrine: A short history. The Lancet. May 2015;3(5):350-51.
10. Pancorbo S, Fifield G, Davies S, Fraser G, Helmink R, Heissler J. Subcutaneous epinephrine versus nebulized terbutaline in the emergency treatment of asthma. Clin Pharm. Jan-Feb 1983;2(1):45-8.
11. Tinkelman DG, Vanderpool GE, Carroll MS, Lotner GZ, Spangler DL. Comparison of nebulized terbutaline and subcutaneous epinephrine in the treatment of acute asthma. Ann Allergy. June 1983;59(6):398-401.
12. Uden DL, Goetz DR, Kohen DP, Fifield GC. Comparison of nebulized terbutaline and subcutaneous epinephrine in the treatment of acute asthma. Ann Emerg Med. Mar 1985; 14(3)229-32.
13. Travers AH, Milan SJ, Jones AP, Camargo CA Jr, Rowe BH. Addition of intravenous beta(2)-agonists to inhaled beta(2)-agonists for acute asthma. Cochrane Database Syst Rev. Dec 12, 2012;12:CD010179.
14. Quandrel M, Lavery RF, Jaker M, Atkin S, Tortella BJ, Cody RP. Prospective, randomized trial of epinephrine, metaproterenol, and both in the prehospital treatment of asthma in the adult patient. Ann Emerg Med. Oct 1995;26(4):469-73.
15. Turpeinen M, Kuokkanen J, Backman A. Adrenaline and nebulized salbutamol in acute asthma. Ach Dis Child. July 1984;59(7):666-8.
16. Singhi S, Grover S, Bansal A, Chopra K. Randomised comparison of intravenous magnesium sulphate, terbutaline, and aminophylline for children with acute severe asthma. Acta Paediatr. Dec 2014;103(12):1301-6.
17. http://vevmo.com/sites/default/files/debbie-downer.gif
18. Appel D, Karpel JP, Sherman M. Epinephrine improves expiratory flow rates in patients with asthma who do not respond to inhaled metaproterenol sulfate. J Allergy Clin Immunol. July 1989; 84(1):90-8.
19. Pliss LB, Gallagher EJ. Aerosol vs. injected epinephrine in acute asthma. Ann Emerg Med. July 1981;10(7):353-5.

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edenkim

Eden Kim, DO, MPH PGY-3 Emergency Medicine Resident

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