Nebulized Epinephrine for Croup in Children

This week, as part of the Child Health Emergency Medicine Social Media Campaign, we are highlighting a Cochrane summary on nebulized epinephrine for croup in children. This review was selected for the TREKK Evidence Repository on croup.

Key Messages:


Related TREKK Resources:

Cochrane Summary:

Croup is a common childhood illness which primarily affects those between the ages of six months and three years, with a peak annual incidence in the second year of life of nearly five per cent. Males and females are affected equally. Croup is most often caused by a viral infection. Symptoms of croup include a hoarse voice, a ‘barking’ cough and noisy breathing. These symptoms are the result of swelling that occurs in the area of the windpipe (trachea) just below the voice box (larynx). Although most cases of croup are mild and resolve on their own, occasionally the swelling can be severe enough to cause difficulty in breathing. In these children, epinephrine (also called adrenaline) is a medication that is inhaled as a mist to temporarily shrink the swollen area in the trachea.

This review looked at trials of inhaled epinephrine for the treatment of children with croup and is comprised of only eight studies with 225 participants. Of the eight included studies, six were assessed as having low risk of bias and two as unclear risk of bias (based upon assessment of adequate random sequence generation, allocations concealment, blinding of participants and personnel, blinding of outcome assessment, completeness of outcome data, and selective reporting). Studies assessed a variety of outcome measures and few studies examined the same outcomes; therefore, most outcomes contained data from a maximum of three studies, and in some cases only single studies.

Compared to no medication, inhaled epinephrine improved croup symptoms in children at 30 minutes following treatment (three studies, 94 children). This treatment effect disappeared two hours after treatment (one study, 20 children). However, children’s symptoms did not become worse than prior to treatment. No study measured adverse events.

The evidence is current to July 2013.

Authors’ Conclusions:

Nebulized epinephrine is associated with clinically and statistically significant transient reduction of symptoms of croup 30 minutes post-treatment. Evidence does not favor racemic epinephrine or L-epinephrine, or intermittent positive pressure breathing over simple nebulization. The authors note that data and analyses were limited by the small number of relevant studies and total number of participants and thus most outcomes contained data from very few or even single studies.

Check Out the Full Cochrane Systematic Review Below:

Bjornson, C., Russell, K., Vandermeer, B., Klassen, T.P., Johnson, D.W. (2013). Nebulized epinephrine for croup in children. Cochrane Database Syst Rev, 10, CD006619. doi: 10.1002/14651858.CD006619.pub3


This post is part of a weekly blog series highlighting pediatric emergency medicine (PEM) focused Cochrane summaries and other key resources selected by TREKK.

Published by arrangement with John Wiley & Sons.

To wheeze or not to wheeze?


According to the World Health Organization, an estimated 235 million people worldwide suffer from asthma and it is the most common chronic disease among children (WHO 2014). Asthma is a non-communicable condition that affects the airways, often leading to wheezing, coughing and problems breathing. Beta-2-agonists are commonly prescribed to relax the airways and relieve symptoms of asthma. Short-acting beta-2-agonists (SABAs), such as salbutamol, are typically recommended as first line treatment to open the airways. Children with regular symptoms of asthma include an inhaled corticosteroid (ICS) as add-on to the SABA, aimed at preventing long-term damage due to inflammation in their lungs. Increasing severity or exacerbations can be addressed with the addition of a regular long-acting beta-2-agonist (LABA), such as formoterol or salmeterol, to ICS therapy.

A Cochrane overview (Cates 2012) examined the safety of regular formoterol or salmeterol, alone (monotherapy) or as combination therapy with an ICS, in children with asthma. Six reviews and two additional recent trials were included in the overview, for a total of 21 trials on 7474 children aged 4 to 17 years. The assessment of safety was done through direct (randomized evidence from trials) and indirect (testing for differences between pooled results of different trials) comparisons of formoterol and salmeterol:

  • Formoterol vs. placebo
  • Salmeterol vs. placebo
  • Formoterol + ICS vs. ICS
  • Salmeterol + ICS vs. ICS
  • Formoterol vs. salmeterol
  • Formoterol + ICS vs. salmeterol + ICS

The results…

  • Serious adverse events: The included reviews defined serious adverse event as any untoward medical occurrence that at any dose: a) results in death; b) is life threatening; c) requires inpatient hospitalization or prolongation of existing hospitalization; d) results in persistent or significant disability/incapacity; or e) is a congenital anomaly/birth defect. All therapies were associated with an increased odds of children having a serious adverse event (SAE), but this was only statistically significant for formoterol monotherapy. Similarly, there was an increase in the odds of children having asthma-related SAEs with both formoterol and salmeterol monotherapy. One child died of a sub-arachnoid hemorrhage while on formoterol monotherapy.
  • Monotherapy vs. combination therapy: No significant difference was found between monotherapy (LABA vs. placebo) and combination therapy (LABA + ICS vs. ICS); however, the ICS control arm had fewer SAEs than the placebo control arm, indicating key differences between the trials.
  • Formoterol vs. salmeterol: No significant difference was found in comparative safety.

Strengths and Limitations:

  • Overall quality of the included reviews was high
  • There are no trials randomizing children to monotherapy versus combination therapy, so the interpretation of the safety interaction with ICS is based on indirect comparisons
  • Adverse event reporting may not capture the whole picture (e.g. AEs related to medications vs. asthma, poor reporting in journals)
  • Children younger than 4 years old were not included in any of the studies

Take-home message:

Trial data in adolescents and adults with asthma have shown an increase in the risk of death from regular salmeterol monotherapy. The Food and Drug Administration (FDA) found significant increased risk of serious asthma events for children on LABA monotherapy and made recommendations to restrict LABAs to combination ICS/LABA therapy only.

Dr. Chris Cates, coordinating editor of the Cochrane Airways Group and first author of the overview, states:

“All we can say is that combination therapy looks safer than using formoterol or salmeterol on their own but may still carry a small additional risk of a serious adverse event. Children on combination therapy should still be carefully monitored and seek help promptly if their asthma gets worse.”

Source: Wikimedia Commons

Source: Wikimedia Commons


Cates, C. J., Stovold, E., Wieland, S., Oleszczuk, M., Thomson, D., & Becker, L. (2012). The Cochrane Library and safety of regular long‐acting beta2‐agonists in children with asthma: an overview of reviews. Evidence‐Based Child Health: A Cochrane Review Journal, 7(6), 1798-1806.]

Overview of the safety of regular formoterol or salmeterol in children with asthma. (2012). Cochrane Podcast.

World Health Organization 2014.