What are the reasons to administer nebulized epinephrine?
Background
Epinephrine is an endogenous catecholamine that acts directly on both α- and β-adrenergic receptors.1 Epinephrine is recommended for use in patients having systemic reactions such as airway swelling, breathing difficulty, or hypotension. Its pharmacologic effects are mediated by α- and β-adrenergic properties which can increase the force/ rate of cardiac contraction, bronchodilation, increase blood pressure, and help suppress release of anaphylactic mediators. There are 2 different forms of epinephrine that are mainly used: racemic and L-epinephrine.2 Racemic epinephrine is made of an equal ratio of L-epinephrine and D-epinephrine. Different routes of administration are also available for epinephrine use including intravenous formulations that are used off-label via nebulization and oral inhalation formulations using a nebulizer.1
Tertiary drug databases state that epinephrine can be nebulized for various approved and off-label indications such as asthma, bronchospasm, croup, and suspected laryngeal/pharyngeal edema or stridor.3,4 Indications for use in adults include mild intermittent symptoms of asthma and laryngeal/pharyngeal edema or stridor. Indications for use in pediatric and adolescent patients include relief of mild asthma symptoms (ie, bronchospasm), laryngeal/pharyngeal edema or stridor, and croup. It is important to note that nebulized epinephrine is not recommended for the routine management and treatment of asthma, and other indications for use are off-label.3 Table 1 shows the recommended nebulized epinephrine dosing for the above mentioned indications.
| Table 1. Recommended dosing for nebulized epinephrine solution3,4 | ||
|---|---|---|
| Indication | Dose | Frequency |
| Adult patients |
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| Asthma, mild intermittent symptoms | Via hand-bulb nebulizer: 1 to 3 inhalations of 2.25% oral inhalation solution (1 vial) | May repeat dose after ≥3 hours PRN Maximum dose: 12 inhalations per 24 hours |
| Suspected laryngeal/pharyngeal edema or stridor | Using parenteral 1 mg/mL solution: 1 mg epinephrine solution diluted with 4 mL NS administered via nebulizer as a supplement to IM epinephrine | May repeat dose PRN |
| Pediatric patients |
||
| Bronchospasm, relief of mild asthma symptoms | Children ≥4 years: via handheld bulb nebulizer: Add 0.5 mL (1 vial) of 2.25% solution to nebulizer for 1 to 3 inhalations | May repeat dose after ≥3 hours PRN Maximum dose: 12 inhalations per 24 hours |
| Suspected laryngeal/pharyngeal edema or stridor | Using parenteral 1 mg/mL solution: 1 mg epinephrine solution diluted with 4 mL NS administered via nebulizer as a supplement to IM epinephrine | May repeat dose PRN |
| Croup | Racemic epinephrine (using 2.25% oral inhalation solution): Nebulization: 0.05 to 0.1 mL/kg (maximum dose: 0.5 mL) diluted in 2 to 3 mL NS L-epinephrine (using parenteral 1 mg/mL solution): Nebulization: 0.5 mL/kg of 1:1,000 solution diluted in NS | Using 2.25% oral inhalation solution: May repeat dose every 20 minutes. Maximum dose: 0.5 mL/kg Using parenteral 1 mg/mL: May repeat dose every 20 minutes. Maximum dose: 5 mL |
| Abbreviations: IM, intramuscular; NS, normal saline; PRN, as needed |
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Guideline recommendations
In 2022, the Global Initiative for Asthma (GINA) released updated guidelines for asthma management and prevention.5 Epinephrine is mentioned several times in the guideline for use in the management of anaphylaxis, however only the intramuscular administration route is specifically mentioned. The guideline states that intramuscular epinephrine is indicated in addition to standard therapy for acute asthma that is associated with angioedema and anaphylaxis, but it is not routinely indicated for other asthma exacerbations.
The National Asthma Education and Prevention Program (NAEPP) 2020 focused guideline update for the diagnosis and management of asthma does not mention use of nebulized epinephrine.6 The NAEPP 2007 expert panel report recommends against the use of epinephrine for treatment of asthma exacerbations stating that less beta 2-selective agents (eg, epinephrine, isoproterenol, metaproterenol, isoetharine) are not recommended because of their potential to cause excessive cardiac stimulation.7
In 2021, the European Academy of Allergy and Clinical Immunology (EAACI) anaphylaxis task force updated its 2014 guideline.8 The EAACI does mention the use of nebulized epinephrine in the context of suspected laryngeal/pharyngeal edema. Inhaled administration of epinephrine through a nebulizer together with oxygen is recommended; it is noted that the systemic absorption of inhaled epinephrine is negligible, and it should only be used as adjunct to intramuscular administration. The American Academy of Allergy, Asthma, and Immunology (AAAAI) and American College of Allergy, Asthma, and Immunology (ACAAI) also have an anaphylaxis management guideline, however nebulized epinephrine is not mentioned.9 The American Academy of Pediatrics (AAP) released a 2017 clinical report on use of epinephrine for first-aid management of anaphylaxis, but nebulized epinephrine was not mentioned.10
The American Academy of Pediatrics Red Book has a chapter on parainfluenza viral infections where management for laryngotracheobronchitis (eg, croup) is discussed.11 The chapter states that racemic epinephrine aerosol is usually given to critically ill hospitalized patients with croup to decrease airway obstruction along with supportive measurements. Oral steroids are an effective treatment regimen in patients who have less severe croup. The AAP also has a 2014 clinical practice guideline on bronchiolitis that discusses use of nebulized epinephrine. It states that epinephrine should not be administered to infants and children with a diagnosis of bronchiolitis; studies referenced in the guideline report that nebulized epinephrine was no superior to placebo or other active controls in improving outcomes in bronchiolitis.12
Evidence review
Clinical trials to support use of nebulized epinephrine are sparse. Table 2 summarizes relevant recent systematic reviews, meta-analyses, and randomized controlled trials (within the past 10 years) on the use of nebulized epinephrine for various indications.
| Table 2. Studies evaluating the use of nebulized epinephrine2,13-17 | ||||
|---|---|---|---|---|
| Citation/ study design | Population | Interventions | Results | Conclusion |
| Systematic reviews and meta-analyses |
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| Pereira 202213 MA of 16 RCTs | N=1756 children (up to 24 months of age) with acute bronchiolitis | Nebulized HS + epinephrine Nebulized 0.9% NS Nebulized HS Nebulized epinephrine | Combination therapy with nebulized HS and epinephrine showed positive impact of decreasing LOS compared to control groups (MD -0.35 days; 95% CI, -0.62 to -0.08; p = 0.01; I2 = 91%), favorable impact on CSS scores assessed at 48h and 72h after admission, and no difference in oxygen saturation | Nebulized HS + epinephrine combination therapy showed statistically significant outcomes in decreasing LOS and CSS, however there was significant heterogeneity and low-quality evidence |
| Baggot 202217 MA of 38 RCTs (6 RCTs that included nebulized epinephrine) | N=2275 children (up to 17 years) and adults with an acute asthma exacerbation | Epinephrine (by any route, including nebulization) Selective β2 -agonist (by any route) | Overall, the probability of treatment failure (analyzed using the Peto’s OR fixed and random effects estimates) did not favor one treatment over another | The included studies had significant heterogeneity (in design, country, population, intervention and control), however the low-quality evidence suggests that epinephrine and selective β2-agonists have similar effects in acute asthma exacerbation |
| Elliot 202116 MA of 150 RCTs | N=19,090 in children (up to 24 months) with acute bronchiolitis | Nebulized epinephrine Bronchodilators Glucocorticoid steroid (inhaled or systemic) Nebulized HS Antibiotics Heliox therapy High-flow oxygen therapy | Nebulized epinephrine (OR, 0.64; 95% CI, 0.44 to 0.93) and nebulized HS + salbutamol (OR, 0.44; 95% CI, 0.23 to 0.84) significantly reduced hospital admission rate on day 1 compared to other treatments; no treatment significantly reduced hospital admission rate on day 7. Both nebulized HS and combination therapy (HS + epinephrine) reduced LOS | Although nebulized epinephrine showed significantly reduced hospital admission rate on day 1 and the combination of HS + epinephrine significantly reduced LOS, there was low-quality evidence |
| Bjornson 201314 SR of 8 RCTs | N=225 children with croup evaluated in an ED or hospital setting | Nebulized epinephrine Placebo | Nebulized epinephrine was associated with croup score improvement 30 min post-treatment (3 RCTs; standardized MD, -0.94; 95% CI, -1.37 to -0.51; I2 = 0%) and shorter LOS compared to placebo (1 RCT; MD, -32h; 95% CI, -59.1 to -4.9) There was no significant difference in croup scores between racemic and L-epinephrine administration after 30 min; L-epinephrine showed significant reduction compared to racemic epinephrine in 1 RCT after 2 hours posttreatment (standardized MD, 0.87; 95% CI, 0.09 to 1.65) | Nebulized epinephrine was associated with clinically and statistically significant reduction of croup symptoms 30 minutes posttreatment along with a shorter LOS. Analysis was limited to a small number of studies with small total population of evaluated patients |
| Randomized controlled trials |
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| Lee 201915 DB, RCT | N=84 children (6 months to 5 years) with moderate to severe croup | Low-dose (0.1 mg/kg) of 1:1000 nebulized L-epinephrine Conventional dose epinephrine (0.5 mg/kg) of 1:1000 nebulized L-epinephrine | Croup scores for both low and conventional dose nebulized epinephrine were significantly reduced from baseline (p<0.05), and there were no significant differences in score reduction between treatment groups (p=0.42) | Low-dose epinephrine was not inferior in croup score reduction to the conventional dose |
| Eghbali 20162 DB, RCT | N=174 children (6 months to 6 years) with mild to severe croup | Nebulized L-epinephrine Nebulized NS | There was a significant reduction in mean croup score in patients who received nebulized epinephrine compared to NS (p<0.009) | Nebulized epinephrine was superior to nebulized NS in reducing croup scores |
| da Silva 201218 DB, RCT | N=96 children with a PES score of ≥4 | Nebulized L-epinephrine (either 0.5 mL, 2.5 mL, or 5 mL) | There were no significant differences in PES score change among the 3 treatment groups, and the number of patients who clinically improved on treatment was not significant (p=0.54). Patients who received 5 mL of nebulized epinephrine had significantly increased SBP and DBP | Nebulized L-epinephrine at all studied doses displayed a lack of dose response, PES score change, and an increase in adverse side effects |
Conclusion
Nebulized epinephrine can be used for various indications including asthma, bronchospasm, croup, and suspected laryngeal/pharyngeal edema or stridor.3,4 However, it is important to note that there are limited recommendations for use of nebulized epinephrine in organizational guidelines, other than for pediatric cases of croup.11 Recently published systematic reviews and meta-analyses also have a lack of robust evidence for use of nebulized epinephrine due to significant heterogeneity and low-quality evidence, and more adequately powered and well-designed RCTs are needed to confirm efficacy and safety of nebulized epinephrine treatment.
References
- Epinephrine. AHFS Drug Information. Bethesda, MD: American Society of Health-System Pharmacists, Inc. Updated March 2, 2022.
- Eghbali A, Sabbagh A, Bagheri B, Taherahmadi H, Kahbazi M. Efficacy of nebulized L-epinephrine for treatment of croup: a randomized, double-blind study. Fundam Clin Pharmacol. 2016;30(1):70-75. doi:10.1111/fcp.12158
- Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc; 2022. Accessed October 11, 2022. http://online.lexi.com.
- Micromedex Solutions. Truven Health Analytics, Inc; 2022. Accessed October 11, 2022. http://www.micromedexsolutions.com/.
- Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention. Accessed 2022. https://ginasthma.org/wp-content/uploads/2022/07/GINA-Main-Report-2022-FINAL-22-07-01-WMS.pdf
- Expert Panel Working Group of the National Heart L, Blood Institute a, coordinated National Asthma E, et al. 2020 Focused updates to the asthma management guidelines: a report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group. J Allergy Clin Immunol. 2020;146(6):1217-1270. doi:10.1016/j.jaci.2020.10.003
- National Asthma E, Prevention P. Expert Panel Report 3 (EPR-3): Guidelines for the diagnosis and management of asthma-summary report 2007. J Allergy Clin Immunol. 2007;120(5 Suppl):S94-138. doi:10.1016/j.jaci.2007.09.043
- Muraro A, Worm M, Alviani C, et al. EAACI guidelines: Anaphylaxis (2021 update). Allergy. 2022;77(2):357-377. doi:10.1111/all.15032
- Shaker MS, Wallace DV, Golden DBK, et al. Anaphylaxis-a 2020 practice parameter update, systematic review, and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) analysis. J Allergy Clin Immunol. 2020;145(4):1082-1123. doi:10.1016/j.jaci.2020.01.017
- Sicherer SH, Simons FER, Section On A, Immunology. Epinephrine for first-aid management of anaphylaxis. Pediatrics. 2017;139(3). doi:10.1542/peds.2016-4006
- Kimberlin DW, Brady MT, Jackson MA, Long SS. Red Book 2018 : Report of the committee on infectious diseases. Vol Thirty-first edition. American Academy of Pediatrics; 2018. Accessed October 13, 2022. https://search.ebscohost.com/login.aspx?direct=true&db=nlebk&AN=1809323&site=ehost-live.
- Ralston SL, Lieberthal AS, Meissner HC, et al. Clinical practice guideline: the diagnosis, management, and prevention of bronchiolitis. Pediatrics. 2014;134(5):e1474-1502. doi:10.1542/peds.2014-2742
- Pereira RA, Oliveira de Almeida V, Zambrano M, Zhang L, Amantea SL. Effects of nebulized epinephrine in association with hypertonic saline for infants with acute bronchiolitis: A systematic review and meta-analysis. Health Sci Rep. 2022;5(3):e598. doi:10.1002/hsr2.598
- Bjornson C, Russell K, Vandermeer B, Klassen TP, Johnson DW. Nebulized epinephrine for croup in children. Cochrane Database Syst Rev. 2013(10):CD006619. doi:10.1002/14651858.CD006619.pub3
- Lee JH, Jung JY, Lee HJ, et al. Efficacy of low-dose nebulized epinephrine as treatment for croup: A randomized, placebo-controlled, double-blind trial. Am J Emerg Med. 2019;37(12):2171-2176. doi:10.1016/j.ajem.2019.03.012
- Elliott SA, Gaudet LA, Fernandes RM, et al. Comparative efficacy of bronchiolitis interventions in acute care: a network meta-analysis. Pediatrics. 2021;147(5). doi:10.1542/peds.2020-040816
- Baggott C, Hardy JK, Sparks J, et al. Epinephrine (adrenaline) compared to selective beta-2-agonist in adults or children with acute asthma: a systematic review and meta-analysis. Thorax. 2022;77(6):563-572. doi:10.1136/thoraxjnl-2021-217124
- da Silva PS, Fonseca MC, Iglesias SB, Junior EL, de Aguiar VE, de Carvalho WB. Nebulized 0.5, 2.5 and 5 ml L-epinephrine for post-extubation stridor in children: a prospective, randomized, double-blind clinical trial. Intensive Care Med. 2012;38(2):286-293. doi:10.1007/s00134-011-2408-9
Prepared by:
Faria Munir, PharmD, MS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy
November 2022
The information presented is current as October 20, 2022. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.