Nebulized epinephrine for croup in children

Abstract

Background

Croup is a common childhood illness characterized by barky cough, stridor, hoarseness and respiratory distress. Children with severe croup are at risk for intubation. Nebulized epinephrine may prevent intubation.

Objectives

To assess the efficacy (measured by croup scores, rate of intubation and health care utilization such as rate of hospitalization) and safety (frequency and severity of side effects) of nebulized epinephrine versus placebo in children with croup, evaluated in an emergency department (ED) or hospital setting.

Search methods

We searched CENTRAL 2013, Issue 6, MEDLINE (1966 to June week 3, 2013), EMBASE (1980 to July 2013), Web of Science (1974 to July 2013), CINAHL (1982 to July 2013) and Scopus (1996 to July 2013).

Selection criteria

Randomized controlled trials (RCTs) or quasi‐RCTs of children with croup evaluated in an ED or admitted to hospital. Comparisons were: nebulized epinephrine versus placebo, racemic nebulized epinephrine versus L‐epinephrine (an isomer) and nebulized epinephrine delivered by intermittent positive pressure breathing (IPPB) versus nebulized epinephrine without IPPB. Primary outcome was change in croup score post‐treatment. Secondary outcomes were rate and duration of intubation and hospitalization, croup return visit, parental anxiety and side effects.

Data collection and analysis

Two authors independently identified potentially relevant studies by title and abstract (when available) and examined relevant studies using a priori inclusion criteria, followed by methodological quality assessment. One author extracted data while the second checked accuracy. We use the standard methodological procedures expected by the Cochrane Collaboration.

Main results

Eight studies (225 participants) were included. In general, children included in the studies were young (average age less than two years in the majority of included studies). Severity of croup was described as moderate to severe in all included studies. Six studies took place in the inpatient setting, one in the ED and one setting was not specified. Six of the eight studies were deemed to have a low risk of bias and the risk of bias was unclear in the remaining two studies.

Nebulized epinephrine was associated with croup score improvement 30 minutes post‐treatment (three RCTs, standardized mean difference (SMD) ‐0.94; 95% confidence interval (CI) ‐1.37 to ‐0.51; I² statistic = 0%). This effect was not significant two and six hours post‐treatment. Nebulized epinephrine was associated with significantly shorter hospital stay than placebo (one RCT, MD ‐32.0 hours; 95% CI ‐59.1 to ‐4.9). Comparing racemic and L‐epinephrine, no difference in croup score was found after 30 minutes (SMD 0.33; 95% CI ‐0.42 to 1.08). After two hours, L‐epinephrine showed significant reduction compared with racemic epinephrine (one RCT, SMD 0.87; 95% CI 0.09 to 1.65). There was no significant difference in croup score between administration of nebulized epinephrine via IPPB versus nebulization alone at 30 minutes (one RCT, SMD ‐0.14; 95% CI ‐1.24 to 0.95) or two hours (SMD ‐0.72; 95% CI ‐1.86 to 0.42). None of the studies sought or reported data on adverse effects.

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 IPPB 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.

Plain language summary

Nebulized epinephrine for croup in children

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.

Background

Description of the condition

Croup (laryngotracheobronchitis) is a common respiratory illness of childhood, estimated to affect approximately three per cent of children under six years of age annually (Denny 1983; Johnson 2003). The clinical picture is characterized by the abrupt onset of a distinctive barky cough, which may be accompanied by stridor, hoarse voice and respiratory distress. Croup symptoms are often preceded by non‐specific symptoms such as cough, rhinorrhea and fever. The most common etiology is a viral infection, predominantly parainfluenza virus (Marx 1997).

Description of the intervention

While most children with croup have mild symptoms (defined as presence of a 'barky cough', no audible stridor at rest and no to mild chest wall indrawing) (Johnson 2001; Johnson 2003), a small minority have severe symptoms characterized by marked chest wall indrawing, agitation and lethargy (Johnson 2001; Johnson 2003). These children are at significant risk for intubation. Corticosteroids decrease both the frequency and duration of hospitalization and intubation (Kairys 1989; Russell 2011; Tibballs 1992). A systematic review of corticosteroids found that compared to placebo, corticosteroids significantly reduced six and 12‐hour croup scores, reduced length of hospital stay and reduced return visits (Russell 2011). However, corticosteroids take approximately 30 minutes after treatment to lessen respiratory distress (Dobrovoljac 2012). Consequently in children with the most severe symptoms, a therapy with a rapid rate of onset may lessen the need for intubation. The therapy most commonly used for this purpose is nebulized epinephrine. Children with moderate to severe croup are usually administered both epinephrine and corticosteroids concurrently to reduce respiratory distress while awaiting the effects of the corticosteroid treatment. Alternative therapies are mist and heliox (helium‐oxygen mixture) (Johnson 2005; Vorwerk 2010). However, recent evidence suggests that mist provides no significant clinical benefit (Moore 2007; Neto 2002; Scolnik 2006). Heliox has greater promise, but it is more cumbersome to use, and has little evidence of effectiveness (Johnson 2005).

How the intervention might work

Nebulized epinephrine has been widely used for more than 30 years, after the first report of its effectiveness in 1971 (Adair 1971). It is thought that epinephrine‐induced vasoconstriction decreases upper airway edema (Brown 2002; Johnson 2005; Kaditis 1998; Klassen 1999). A small number of randomized controlled trials (RCTs) have been published (Johnson 2005), along with one systematic review (Bjornson 2011).

Initial studies published in the 1970s and early 1980s suggested that epinephrine might be more effective when nebulized via IPPB (intermittent positive pressure breathing) than by nebulization alone. The use of IPPB has now fallen out of favor and it is no longer routinely used.

Clinical severity in children with croup can be determined by both direct measures (clinical scores, transcutaneous carbon dioxide concentrations, pulsus paradoxus, impedance plesmography, radiographic measurement of tracheal diameter) and indirect ones (rate and duration of intubation, rate and duration of hospitalization, rate of return to seek medical care for ongoing croup symptoms, sleep lost by parents, parental stress). Several objective techniques have been reported (Corkey 1981; Davis 1993; Fanconi 1990; Steele 1998), but none are easy to use, nor measure change across the full range of clinical severity. Consequently they have not been routinely used.

The most widely used direct measures of respiratory severity are different types of croup scores (Bourchier 1984; Corkey 1981; Downes 1975; Geelhoed 1995; Godden 1997; Husby 1993; Leipzig 1979; Massicotte 1973; Taussig 1975; von Muhlendahl 1982; Westley 1978). The Westley croup score has been shown to be reliable (Johnson 1998; Klassen 1994) and, to some extent, valid (Klassen 1994; Klassen 1995). None of the other croup scores, to our knowledge, have been assessed for either validity or reliability. On one hand, clinical scores are inevitably subjective at least to some degree, and may not represent truly significant clinical change. On the other hand, clinical scores are arguably more sensitive to change, and therefore more likely to detect smaller degrees of improvement.

Indirect measures of severity, such as health care utilization, are thought by many to capture significant clinical change better than clinical scores. Some would argue that if a treatment cannot be shown to reduce health care utilization, it is of no benefit.

We have chosen to assess and report both direct and indirect measures of clinical change, with the intent of allowing the reader to make their own judgement as to the relative merits of the different measures.

Why it is important to do this review

Croup is a common childhood illness and may result in presentation to the emergency department (ED) due to difficulty in breathing. Epinephrine has been used as a treatment option to reduce tracheal swelling for over 30 years. However, currently there is no systematic review examining the efficacy of this intervention.

Objectives

Primary objective

To assess the efficacy (measured by croup scores, rate of intubation and health care utilization such as rate of hospitalization) and safety (frequency and severity of side effects) of nebulized epinephrine versus placebo in children with croup, evaluated in an ED or hospital setting.

Secondary objectives

To assess the efficacy and severity of side effects of nebulized racemic epinephrine versus nebulized L‐epinephrine in children with croup evaluated in an ED or hospital setting and to assess the efficacy and severity of side effects of nebulized epinephrine delivered with intermittent positive pressure breathing (IPPB) versus nebulized epinephrine alone.

Methods

Criteria for considering studies for this review

Types of studies

Randomized controlled trials (RCTs) or quasi‐RCTs (Q‐RCTs) which compared the use of nebulized epinephrine to placebo, nebulized racemic epinephrine versus nebulized L‐epinephrine, and nebulized epinephrine delivered with intermittent positive pressure breathing (IPPB) versus nebulized epinephrine alone in children with croup.

Types of participants

Studies included children with a clinical diagnosis of croup (defined as acute onset of a 'barky cough' and stridor) whether evaluated in an ED or admitted to hospital.

Types of interventions

1. Nebulized epinephrine (either racemic or L‐epinephrine, or delivered with or without IPPB) versus placebo.

2. Nebulized racemic epinephrine versus L‐epinephrine.

3. Nebulized epinephrine delivered by IPPB versus nebulized epinephrine delivered without IPPB.

Types of outcome measures

Primary outcomes

1. Change in clinical croup scores following treatment.

Secondary outcomes

1. Rate and duration of intubation.

2. Rate and duration of hospitalization.

3. Rate of return to medical care for ongoing croup symptoms.

4. Improvement.

5. Parental anxiety.

6. Side effects such as hypertension.

7. Evidence of myocardial injury or cardiac arrhythmias.

We evaluated all studies that met the above criteria; we used no exclusion criteria.

Search methods for identification of studies

Electronic searches

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) 2013, Issue 6, part of The Cochrane Library, www.thecochranelibrary.com (accessed 3 July 2013), which contains the Cochrane Acute Respiratory Infections Group's Specialized Register, MEDLINE (1966 to June week 3, 2013), EMBASE (1980 to July 2013), Web of Science (1974 to July 2013), CINAHL (1982 to July 2013) and Scopus (1996 to July 2013).

We used the following search terms to search MEDLINE and CENTRAL. We combined the MEDLINE search with the Cochrane Highly Sensitive Search Strategy for identifying randomized trials in MEDLINE: sensitivity‐ and precision‐maximizing version (2008 revision) Ovid format (Lefebvre 2011). We adapted the search strategy to search EMBASE (see Appendix 2), CINAHL (see Appendix 3), Web of Science (see Appendix 4) and Scopus (see Appendix 5).

MEDLINE (Ovid)

1 exp Laryngitis/
 2 (croup or laryngit*).tw.
 3 laryngotracheit*.tw.
 4 (laryngotracheobronchit* or laryngo‐tracheo‐bronchit*).tw.
 5 (pseudocroup or pseudo‐croup).tw.
 6 or/1‐5
 7 Epinephrine/
 8 exp Adrenergic Agonists/
 9 exp Adrenal Cortex Hormones/
 10 epinephrin*.tw,nm.
 11 (adrenalin* or l‐adrenalin*).tw,nm.
 12 (adrenergic agonist* or adrenergic alpha‐agonist* or adrenergic beta‐agonist*).tw,nm.
 13 or/7‐12
 14 exp "Nebulizers and Vaporizers"/
 15 Aerosols/
 16 respiratory therapy/ or oxygen inhalation therapy/ or respiration, artificial/ or exp positive‐pressure respiration/
 17 (inhal* or vapor* or vapour* or atomiz* or atomis* or nebuliz* or nebulis* or spray* or mist* or aerosol*).tw.
 18 (positive‐pressure adj3 (breathing or respiration)).tw.
 19 ippb.tw.
 20 or/14‐19
 21 6 and 13 and 20

Searching other resources

We contacted experts in the field of acute respiratory infections to locate additional studies. There were no language or publication restrictions.

Data collection and analysis

Selection of studies

Two review authors (CB, KR) independently scanned abstracts from the initial search results to identify trials that broadly met the inclusion criteria. We then reviewed the full‐text articles of the selected trials and the same two review authors independently applied the inclusion criteria. We resolved differences by consensus.

Data extraction and management

We extracted data using a structured form that captures patient status (ED or inpatient, the author's description of their clinical severity), intervention and control characteristics (such as type of drug: racemic versus L‐epinephrine), dosage and method of administration (nebulization alone versus nebulized with intermittent positive pressure breathing (IPPB)). In addition, we collected data on the primary and secondary outcome measures if available: change from baseline clinical croup scores; rate and duration of intubation; rate and duration of hospitalization; and occurrence of hypertension, myocardial injury or cardiac arrhythmias. One review author (KR) extracted data and a second review author (CB) checked this for accuracy. If necessary, we extracted data from graphs or directly from the trial authors.

Assessment of risk of bias in included studies

Two review authors (CB, KR) independently assessed the quality of studies in three ways. We used more than one method since the relative merits of each remain controversial. First, we used the method outlined in the Cochrane Handbook for Systematic Reviews of Interventions that focuses on selection, performance, attrition and detection bias (Higgins 2011). Second, we classified concealment of allocation as being a high, low or unclear risk of bias (previously referred to as adequate, inadequate or unclear (Schulz 1995)). Lastly, we classified studies by who sponsored them: pharmaceutical company, other sources or not mentioned (Cho 1996). We resolved differences by consensus. We compared and reported the results from the three different classification methods.

Measures of treatment effect

With regard to continuous variables, we calculated the change from baseline measures if change from baseline measures were not reported directly. As needed, we performed variance imputations according to the work of Follmann (Follman 1992). We anticipated that different clinical croup scores would be reported. If this was the case, we used trial standardized mean differences (SMDs) for pooled estimates. (A treatment effect (difference between treatment means) divided by its measurement variation (for example, a pooled standard deviation) gives a SMD). We also anticipated that croup scores would be assessed at a variety of time periods. Because the treatment effect of epinephrine is rapid, we assessed change in croup score at 30 minutes, two hours and six hours. If a study did not assess change in croup scores at our time points of interest, we used the closest time point (for example, a 15‐minute change in croup score as used for the change in croup score at 30 minutes outcome). We expressed duration of intubation and hospitalization as MDs and calculated an overall MD.

For binary data (that is, intubation and hospitalization rates), we calculated risk ratios (RR). If zero events occurred in both groups, we derived risk differences (RD). If we found significant results, we calculated the number needed to treat to benefit (NNTB) or harm (NNTH). We reported the pooled baseline rates using the inverse variance method.

Unit of analysis issues

We calculated the change from baseline measures in cases where change from baseline measures were not reported directly (Corkey 1981; Fogel 1982; Waisman 1992; Westley 1978).

Dealing with missing data

Many variance imputations were performed according to the work of Follman 1992. The variance of a change from baseline measure was derived from the common variance of a single croup score assuming a correlation of 0.5 between pre‐ and post‐treatment scores (Corkey 1981; Fogel 1982; Westley 1978; Waisman 1992). We imputed variances from upper bound P values (Kristjansson 1994).

Assessment of heterogeneity

We assessed heterogeneity quantitatively with the I² statistic (Higgins 2002). The I² statistic indicates the per cent variability due to between‐study (or inter‐study) variability as opposed to within‐study (or intra‐study) variability. We considered an I² statistic greater than 50% to be large.

Assessment of reporting biases

If at least eight studies were found for our primary outcome we tested for publication bias. In addition to funnel plots, we used the rank correlation test (Begg 1994) and weighted regression (Egger 1997) for the detection of publication bias. We performed adjustment for publication bias in the pooled estimates using the trim and fill method. We used more than one method since the relative merits of the methods are not well established.

Data synthesis

For the analyses of all outcomes, we used a random‐effects model to combine treatment effects regardless of quantified heterogeneity. We considered a fixed‐effect model in sensitivity analyses.

Subgroup analysis and investigation of heterogeneity

We explored heterogeneity between studies using subgroup and sensitivity analyses performed on the primary outcome of the change in clinical croup scores from baseline to 30 minutes and 60 minutes. We considered the following subgroups: quality (that is, the risk of bias, allocation concealment, funding and simple classification of bias (low, moderate or high)) and inpatient versus ED status.

Sensitivity analysis

There were not enough studies in any one meta‐analysis to perform any meaningful sensitivity analyses.

Results

Description of studies

Results of the search

For the 2011 Cochrane Review, the electronic literature search identified 316 unique studies. After assessing the titles and, when available, the abstracts, we identified 50 studies as being potentially relevant. Reviewing the reference lists of the included studies did not identify any additional studies.

The electronic literature search performed in July 2013 identified 23 studies, one of which was a duplicate, leaving 22 unique studies. After assessing the titles and the abstracts for each of these 22 studies, we identified no new relevant studies.

Included studies

After applying the a priori inclusion criteria, eight of the 50 studies met the inclusion criteria. Three comparisons were examined: nebulized epinephrine versus placebo (Corkey 1981; Fernandez 1993; Gardner 1973; Kristjansson 1994; Kuusela 1988; Westley 1978), nebulized racemic epinephrine versus L‐epinephrine (Waisman 1992) and nebulized epinephrine with IPPB versus nebulized epinephrine without IPPB (Fogel 1982). All studies were randomized, placebo‐controlled trials with the exception of the study comparing nebulized epinephrine with and without IPPB, which was a cross‐over RCT. Seven studies were published in English and one in Spanish (Fernandez 1993). Studies tended to be small, ranging from 14 to 78 total participants per comparison.   

Nebulized epinephrine versus placebo

Four studies took place in an inpatient setting, one in an outpatient setting and one did not specify setting. In general, children within the studies were young (average age two years or less in two studies, two to three years in two studies and not specified in two studies). Severity of croup in the majority of enrolled children was judged to be moderate or moderate to severe in all six studies. There was minor variance between studies in the type of epinephrine used (racemic epinephrine in five studies, L‐epinephrine in one study) and dose of racemic epinephrine used (0.5 ml of 2.25% racemic epinephrine in three studies, 0.5 mg/kg of 2.25% racemic epinephrine in two studies, and 0.25 ml of 2.25% racemic epinephrine per five kilograms of body weight in one study). Epinephrine was administered via IPPB in two of the six studies. One study (Westley 1978) used a croup score which has been validated. The Westley 17‐point croup score incorporates assessment of level of consciousness (five points), cyanosis (five points), stridor (two points), air entry (two points) and chest wall retractions (three points). The remaining five studies used a variety of non‐validated croup scores as outcome measures, with total possible points ranging from six to 12 points.

Nebulized racemic epinephrine versus L‐epinephrine  

We identified a single study suitable for inclusion, of 66 children in an inpatient setting (Waisman 1992). Average age was young (11 months) and baseline severity of croup on study admission was moderate. The doses of racemic epinephrine and L‐epinephrine were 0.5 ml of 2.25% and 5 ml of 1:1000 dilution, respectively. A non‐validated 10‐point croup score (inspiratory breath sounds, two points; stridor, two points; cough, two points, retractions/nasal flaring, two points; cyanosis, two points) was utilized as the primary outcome measure.

Nebulized epinephrine with IPPB versus nebulized epinephrine without IPPB

We identified a single study suitable for inclusion, of 14 children in an inpatient setting (Fogel 1982). Average age was young (1.9 years) and baseline severity of croup on study admission was moderate. The dose of racemic epinephrine used was 0.25 ml of 2.25%. The IPPB pressure used was 15 cm to 17 cm of water and two hours after the first treatment, cross‐over to the other group occurred. A modified 16‐point croup score based upon the validated Westley croup score (level of consciousness, four points; color, four points; stridor, three points; air entry, two points; and chest wall retractions, three points) was utilized as the primary outcome measure.     

Excluded studies

We excluded a total of 50 studies. The exact reason for exclusion is provided in the Characteristics of excluded studies table.

Risk of bias in included studies

In the original review, we assessed methodological quality using the Jadad scale and concealment of allocation. No studies were added to this update. However, the conclusions concerning methodological quality were revised to reflect the 'Risk of bias' tool. We deemed six of the eight studies to have a low risk of bias and the risk of bias was unclear in the remaining two studies (Fernandez 1993; Kuusela 1988). Half of the studies were reported to be of low risk of bias due to adequate concealment of allocation (Fernandez 1993; Kuusela 1988; Waisman 1992; Westley 1978). Only one study reported a funding source (Kristjansson 1994). The results from the various quality indicators are pictorially displayed in Figure 1 and Figure 2.

1.

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

2.

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

Allocation

Allocation concealment was adequate in three of the studies (Fernandez 1993; Kuusela 1988; Waisman 1992), inadequate in two (Corkey 1981; Westley 1978) and unclear in three (Fogel 1982; Gardner 1973; Kristjansson 1994).

Blinding

All trials were double‐blind. Two studies did not report who was blinded (Gardner 1973; Westley 1978).

Incomplete outcome data

Four studies reported losses to follow‐up (Kuusela 1988; Kristjansson 1994; Waisman 1992; Westley 1978). However, only one study explained the losses to follow‐up (Waisman 1992).

Selective reporting

All but two studies (Fogel 1982; Waisman 1992) reported a primary outcome (6/8; 75%).

Other potential sources of bias

Two studies conducted an intention‐to‐treat (ITT) analysis (Corkey 1981; Fogel 1982).

Effects of interventions

Nebulized epinephrine versus placebo

There were six studies (183 participants) that reported data comparing nebulized epinephrine versus placebo. Four (109 participants) of these six studies took place in an inpatient setting, while one (54 participants) took place in an outpatient setting and one (20 participants) did not specify the setting. While six studies were included in this section, no more than three were included in any particular analysis.

Primary outcome

1. Croup score

Since all studies used different systems in their croup scoring, we used standardized mean differences (SMDs) to synthesize the data. Three studies showed that epinephrine had a statistically significant smaller croup score than placebo after 30 minutes (SMD ‐0.94; 95% confidence interval (CI) ‐1.37 to ‐0.51; I² statistic = 0%) (Analysis 1.1). The change in croup score was almost identical for the two studies that looked at inpatients (SMD ‐0.82; 95% CI ‐1.47 to ‐0.17; I² statistic = 0%) (Analysis 1.1) and the one study that looked at outpatients (SMD ‐1.03; 95% CI ‐1.60 to ‐0.46) (Analysis 1.1). Heterogeneity was negligible in these comparisons.

1.1. Analysis.

Comparison 1 Nebulized epinephrine versus placebo, Outcome 1 Croup score (change baseline ‐ 30 minutes).

There were also data on croup score after two hours (SMD ‐0.15; 95% CI ‐1.03 to 0.73; one study) (Analysis 1.2) and six hours (SMD ‐0.60; 95% CI ‐1.50 to 0.30; two studies; I² statistic = 70%) (Analysis 1.3). Neither of these estimates was statistically significant.

1.2. Analysis.

Comparison 1 Nebulized epinephrine versus placebo, Outcome 2 Croup score (change baseline ‐ 2 hours).

1.3. Analysis.

Comparison 1 Nebulized epinephrine versus placebo, Outcome 3 Croup score (change baseline ‐ 6 hours).

Secondary outcomes

1. Rate and duration of intubation

Not reported.

2. Rate and duration of hospitalization

There were two studies that reported length of hospital stay (in hours), one each in the inpatient and outpatient settings. The inpatient study showed children on epinephrine spent a statistically significant smaller amount of time in the hospital than placebo participants in the hospital (MD ‐32.00; 95% CI ‐59.14 to ‐4.86) (Analysis 1.4), while the outpatient study had a much smaller and non‐significant difference (MD ‐1.80; 95% CI ‐4.07 to 0.47) (Analysis 1.4). We did not combine these two studies as we would not expect similar hospital stays between inpatients and outpatients.

1.4. Analysis.

Comparison 1 Nebulized epinephrine versus placebo, Outcome 4 Length of hospitalization in hours.

3. Rate of return to medical care for ongoing croup symptoms

Return visits were reported by one study. However, that study reported no re‐admissions in either the epinephrine or the placebo group, thus we computed no statistics.

4. Improvement

Two studies counted the number of participants that had significant improvement. Improvement was defined in one study as a decrease in the croup score of greater that two or more points (2/10 total points) (Gardner 1973) and in the other study as a decrease in the croup score of greater than two or more points (2/15) (Kristjansson 1994). The combined risk ratio (RR) did favor epinephrine but it was not statistically significant (RR 1.46; 95% CI 0.82 to 2.60; I² statistic = 17%) (Analysis 1.6). Heterogeneity was moderate.

1.6. Analysis.

Comparison 1 Nebulized epinephrine versus placebo, Outcome 6 Improvement.

5. Parental anxiety

Not reported.

6. Side effects such as hypertension

Not reported.

7. Evidence of myocardial injury or cardiac arrhythmias

Not reported.

Nebulized racemic epinephrine versus L‐epinephrine

Primary outcome

1. Croup score

Waisman 1992 (28 participants) compared nebulized racemic epinephrine versus L‐epinephrine in an outpatient setting. There was no significant difference in croup score between the two types of epinephrine after 30 minutes (SMD 0.33; 95% CI ‐0.42 to 1.08) (Analysis 2.1) but after two hours, L‐epinephrine showed significant reduction over racemic epinephrine (SMD 0.87; 95% CI 0.09 to 1.65) (Analysis 2.2).

2.1. Analysis.

Comparison 2 Nebulized racemic epinephrine versus L‐epinephrine, Outcome 1 Croup score (change baseline ‐ 30 minutes).

2.2. Analysis.

Comparison 2 Nebulized racemic epinephrine versus L‐epinephrine, Outcome 2 Croup score (change baseline ‐ 2 hours).

Secondary outcomes

Rate and duration of intubation. The racemic epinephrine group had an intubation rate of 3/16 and the L‐epinephrine group had a rate of 0/14, which was a non‐significant difference (RD 0.19; 95% CI ‐0.03 to 0.40) (Analysis 2.3).

2.3. Analysis.

Comparison 2 Nebulized racemic epinephrine versus L‐epinephrine, Outcome 3 Intubation.

1. Rate and duration of intubation

Not reported.

2. Rate of return to medical care for ongoing croup symptoms

Not reported.

3. Improvement

Not reported.

4. Parental anxiety

Not reported.

5. Side effects such as hypertension

Not reported.

6. Evidence of myocardial injury or cardiac arrhythmias

Not reported.

Nebulized epinephrine with intermittent positive pressure breathing (IPPB) versus nebulized epinephrine without IPPB

Primary outcome

1. Croup score

Fogel 1982 (14 participants) compared nebulized epinephrine with IPPB versus nebulized epinephrine without IPPB in an inpatient setting. After 30 minutes, there was no significant difference in croup score between the two groups (SMD ‐0.72; 95% CI ‐1.86 to 0.42) (Analysis 3.1), while at two hours there was a larger, still non‐significant difference (SMD ‐0.14; 95% CI ‐1.24 to 0.95) (Analysis 3.2).

3.1. Analysis.

Comparison 3 Nebulized epinephrine with IPPB versus nebulized epinephrine without IPPB, Outcome 1 Croup score (change baseline ‐ 30 minutes).

3.2. Analysis.

Comparison 3 Nebulized epinephrine with IPPB versus nebulized epinephrine without IPPB, Outcome 2 Croup score (change baseline ‐ 2 hours).

Secondary outcomes

1. Rate and duration of intubation

Intubation was reported as an outcome. However, both groups had zero intubations, thus we computed no statistics.

2. Rate of return to medical care for ongoing croup symptoms

Not reported.

3. Improvement

Not reported.

4. Parental anxiety

Not reported.

5. Side effects such as hypertension

Not reported.

6. Evidence of myocardial injury or cardiac arrhythmias

Not reported.

Subgroup, sensitivity and publication bias analysis

Since none of our analyses contained more than three studies, no further analysis exploring heterogeneity or publication bias could be conducted.

Discussion

Summary of main results

Nebulized epinephrine has become standard management, especially in North America, for the treatment of moderate and severe croup. Nebulized epinephrine is typically administered to a child with moderate or severe upper airway obstruction in either an emergency department (ED) or inpatient setting. Though widely used in clinical practice, our search identified only six relevant clinical trials comparing nebulized epinephrine to placebo that included a total of 183 participants (Corkey 1981; Fernandez 1993; Gardner 1973; Kristjansson 1994; Kuusela 1988; Westley 1978).

Nebulized epinephrine versus placebo

Primary outcome: croup score

Data from this review have shown that, compared to placebo, nebulized racemic epinephrine effectively improves croup symptoms as measured by clinical croup scores in children 30 minutes following treatment. Three trials assessed croup score at 30 minutes (Corkey 1981; Kristjansson 1994; Westley 1978). Although the number of children was small (94 participants), the pooled data indicated a moderate to large reduction in croup score as compared with placebo (Cohen 1988). All three trials favored racemic epinephrine over placebo and the magnitude of benefit was similar and consistent between studies and in both inpatient and outpatient settings.   

At 120 minutes following treatment, the mean difference in croup score was similar in both racemic epinephrine and placebo groups in the single, small (20 participants) study (Westley 1978). Although the observed clinical benefit of epinephrine had essentially dissipated at 120 minutes, there was no evidence, on average, to suggest that there was an increase or worsening of croup score, as compared to pre‐treatment or baseline in the group of children treated with epinephrine.      

Two studies (69 participants) assessed croup score at six hours following treatment in an inpatient setting (Fernandez 1993; Kuusela 1988) and found no difference in croup score between the nebulized racemic epinephrine and placebo groups. This is not surprising given the relatively brief duration of action of nebulized epinephrine and is also consistent with the finding of no difference in croup score at the 120‐minute assessment.

Secondary outcomes

In a single inpatient study, hospital stay was shorter among those treated with nebulized racemic epinephrine group as compared with placebo (Kuusela 1988). The mean difference of 32 hours was both statistically and clinically significant. Confidence intervals were wide, however, reflecting the small study size. Also, corticosteroid was administered to eight of 37 participants and the breakdown by treatment group was not provided. This could account for the shorter hospital stay in the epinephrine group. Length of stay in the outpatient setting was assessed in one study and it was similar between epinephrine and placebo groups (Kristjansson 1994). Equal proportions of children (52% and 58% in the racemic epinephrine and placebo groups, respectively) received concomitant corticosteroid treatment. No difference in length of stay is consistent with resolution of clinical effect by two hours after treatment.

We chose to report the outcome proportion of patients improved even though we had not pre‐specified it as a secondary outcome because one study (Gardner) did not report the actual croup score values, only the proportion of children whose croup score had improved by two or more points versus those which had not.           

Racemic epinephrine versus L‐epinephrine

A small, methodologically sound study comparing nebulized racemic epinephrine with L‐epinephrine in the outpatient setting showed no difference in croup score 30 minutes following treatment (Waisman 1992). By 120 minutes, there was a statistically significant result showing L‐epinephrine to have a longer duration of benefit than racemic epinephrine.  

Racemic epinephrine is composed of equal proportions of D‐ and L‐isomers of epinephrine and was originally used to treat croup because it was hypothesized that racemic epinephrine would cause fewer cardiovascular side effects than L‐epinephrine. L‐epinephrine is the type of epinephrine routinely used for other indications in medicine in either 1:1000 or 1:10,000 concentrations. Waisman 1992 administered an identical 5 mg of L‐epinephrine (0.5 ml of 2.25% racemic epinephrine versus 5.0 ml of 1:1000 epinephrine) and found no statistically significant differences in cardiovascular side effects between the two drugs. In addition, it is now known that only L‐epinephrine is pharmacologically active; the R‐isomer has no activity (Westfall 2009).

Nebulized epinephrine with IPPB versus nebulized epinephrine without IPPB

One study of good methodological quality found that nebulized epinephrine with IPPB was similar to nebulized epinephrine without IPPB in the inpatient setting (Fogel 1982). However, this study was small and not designed to show equivalence. Nonetheless, given the technical challenges of IPPB and no evidence of superiority, routine use of nebulized epinephrine without IPPB seems justified. 

Safety of nebulized epinephrine

Though none of the clinical trials reported significant adverse events associated with nebulized epinephrine, the small total number of participants and rarity of adverse events provides insufficient data to conclude that the use of nebulized epinephrine is universally safe. Further, none of these trials assessed the effectiveness or safety of epinephrine when administered repeatedly in a row. A single case report of ventricular tachycardia and myocardial infarction in a previously healthy child who received three doses of nebulized epinephrine in one hour raises concerns about potential cardiac toxicity (Butte 1999). While this case is of concern, given the widespread use of epinephrine over several decades, it seems unlikely, however, that one or even two nebulized doses of epinephrine poses significant risk to a child.     

Overall completeness and applicability of evidence

The number of relevant studies was small, as were total numbers of participants. Studies assessed a wide range of outcomes and few studies examined the same outcomes, thus most outcomes contained data from very few or even single studies. Timing of outcome measures also varied between studies. Finally, co‐interventions (for example, corticosteroid administration) were not explicitly described for some studies. There were too few studies included to formally assess publication bias. 

We did not search for articles which included co‐treatment with corticosteroids, as the question of whether adjunct epinephrine therapy provides additional benefit to corticosteroid treatment alone will be addressed in a separate Cochrane Review. 

Finally, none of the studies included children with mild croup. However, mild croup is defined as minimal to no symptoms of airway obstruction on presentation; epinephrine is used to provide temporary relief of airway obstructive symptoms and, thus, there is not a strong rationale for the use of epinephrine in children with mild croup. 

Quality of the evidence

The majority of the studies were at low risk of bias and half of the studies reported adequately concealed patient allocation methods. While all studies were double‐blind and the majority of the studies reported their primary outcome, several studies reported a loss to follow‐up and few studies conducted an intention‐to‐treat analysis.

Potential biases in the review process

We undertook a broad and extensive search strategy of multiple databases, contacted experts in the field and applied no language or publication restrictions to minimize the chance of bias due to missing published studies or non‐English language studies. This review did contain one Spanish language study. As none of our analyses contained more than three studies, no further analysis exploring heterogeneity or publication bias could be performed. Thus, the possibility of publication bias cannot be ruled out. 

Agreements and disagreements with other studies or reviews

We did not identify any other relevant studies or systematic reviews in publication. 

Authors' conclusions

Implications for practice.

• Nebulized epinephrine may be used to treat obstructive airway symptoms associated with moderate to severe croup.     

• The clinical effect of nebulized epinephrine is apparent at 30 minutes post‐treatment.

• There is no evidence to suggest that croup symptoms, on average, worsen after the treatment effect of nebulized epinephrine dissipates.    

• Five out of six epinephrine versus placebo trials have used racemic epinephrine. There is only one small, good quality trial comparing racemic epinephrine versus L‐epinephrine and it provides reasonable evidence that L‐epinephrine is at least as effective as racemic epinephrine if this drug for some reason is not available.

• The addition of IPPB did not appear to improve the clinical effect of epinephrine as compared with nebulization alone.

Implications for research.

• Surveillance and reporting of adverse events associated with the administration of nebulized epinephrine should be carried out.

• Additional studies of interest might focus on health care utilization as an outcome.  

What's new

Date	Event	Description
3 July 2013	New citation required but conclusions have not changed	No new trials were included in this update. We excluded seven new trials (Danen 2011; da Silva 2012; de Benedictis 2012; Frazier 2010; Kline‐Krammes 2012; Pitluk 2011; Zoorob 2011) and our conclusions remain unchanged.
3 July 2013	New search has been performed	Searches conducted.

History

Protocol first published: Issue 3, 2007
 Review first published: Issue 2, 2011

Date	Event	Description
11 September 2008	Amended	Converted to new review format.

Appendices

Appendix 1. Glossary of terms

Rhinorrhea ‐ runny nose.

Stridor ‐ noisy breathing heard on inspiration.

Nebulized epinephrine alone ‐ epinephrine delivered by inhalation with a mask, a holding chamber for the medication, and attached tube through which oxygen flows. The flow of oxygen through the liquid medication creates droplets which are then breathed in by the child.

Nebulized epinephrine delivered with intermittent positive pressure breathing (IPPB) ‐ epinephrine delivered via nebulizer under intermittent pressure.

Intubation ‐ the placement of a breathing tube in children with severe breathing difficulties.

Pulsus paradoxus ‐ an exaggeration of the normal variation in the pulse during respiration, in which the pulse becomes weaker as one inhales and stronger as one exhales.

Impedance plesmography ‐ a technique for measuring paradoxical breathing. This type of breathing occurs in young children with severe respiratory distress. Typically, in well people the abdomen and chest expand and contract in a synchronized fashion with respiration. Children compensate for narrowing of their upper airway by increasing their work of breathing, which increases intrapleural pressure and the rate of airflow through the upper airway. With greater increases in pleural pressure, during inspiration, young children's compliant chest wall begins to collapse as the abdomen protrudes, owing to diaphragmatic contraction. The severity of paradoxical breathing can be measured using a device called respiratory inductance plethysmograph, which measures the phase angle. A decrease in phase angle equates to a reduction in the severity of paradoxical breathing.

Appendix 2. EMBASE.com search strategy

#18 #14 AND #176815 Nov 2010
 #17 #15 OR #1682006715 Nov 2010
 #16 random*:ab,ti OR placebo*:ab,ti OR factorial*:ab,ti OR crossover*:ab,ti OR 'cross over':ab,ti OR 'cross‐over':ab,ti OR assign*:ab,ti OR allocat*:ab,ti OR volunteer*:ab,ti OR ((singl* OR doubl*) NEAR/2 (blind* OR mask*)):ab,ti 
 #15 'randomized controlled trial'/exp OR 'single blind procedure'/exp OR 'double blind procedure'/exp OR 'crossover procedure'/exp 
 #14 #3 AND #9 AND #13 
 #13 #10 OR #11 OR #12 
 #12 'positive‐ pressure breathing':ab,ti OR 'positive‐pressure respiration':ab,ti OR ippb:ab,ti 
 #11 inhal*:ab,ti OR vapor*:ab,ti OR vapour*:ab,ti OR atomiz*:ab,ti OR atomis*:ab,ti OR nebuliz*:ab,ti OR nebulis*:ab,ti OR spray*:ab,ti OR mist*:ab,ti OR aerosol*:ab,ti 
 #10 'nebulizer'/exp OR 'aerosol'/de OR 'artificial ventilation'/de OR 'intermittent positive pressure ventilation'/de OR 'positive end expiratory pressure'/exp OR 'oxygen therapy'/de 
 #9 #4 OR #5 OR #6 OR #7 OR #8 
 #8 'adrenal cortex hormone':ab,ti OR 'adrenal cortex hormones':ab,ti OR '17‐ketosteroid':ab,ti OR '17‐ketosteroids':ab,ti OR 'hydroxycorticosteroid':ab,ti OR 'hydroxycorticosteroids':ab,ti 
 #7 'corticosteroid'/exp OR '17 oxosteroid'/de 
 #6 adrenalin*:ab,ti OR 'l‐adrenalin':ab,ti OR 'l‐adrenaline':ab,ti OR epinephrin*:ab,ti OR 'adrenergic agonist':ab,ti OR 'adrenergic agonists':ab,ti OR 'adrenergic alpha‐agonist':ab,ti OR 'adrenergic alpha‐agonists':ab,ti OR 'adrenergic beta‐agonist':ab,ti OR 'adrenergic beta‐agonists':ab,ti 
 #5 'adrenergic receptor stimulating agent'/exp 
 #4 'adrenalin'/de 
 #3 #1 OR #2 
 #2 laryngit*:ab,ti OR croup:ab,ti OR laryngotracheobronchit*:ab,ti OR 'laryngo‐tracheo‐bronchitis':ab,ti OR laryngotracheit*:ab,ti OR pseudocroup:ab,ti OR 'pseudo‐croup':ab,ti 
 #1 'laryngitis'/de OR 'croup'/de OR 'laryngotracheobronchitis'/de OR 'pseudocroup'/de

Appendix 3. CINAHL search (EBSCO)

S15 S4 and S13
 S14 S4 and S13
 S13 S9 and S12
 S12 S10 or S11
 S11 TI (inhal* or vapor* or vapour* or atomiz* or atomis* or nebuliz* or nebulis* or spray* or mist* or aerosol*) or AB (inhal* or vapor* or vapour* or atomiz* or atomis* or nebuliz* or nebulis* or spray* or mist* or aerosol*)
 S10 (MH "Nebulizers and Vaporizers")
 S9 S5 or S6 or S7 or S8
 S8 TI (epinephrine or adrenaline or adrenergic agonist*) or AB (epinephrine or adrenaline or adrenergic agonist*)
 S7 (MH "Adrenal Cortex Hormones")
 S6 (MH "Adrenergic Agonists")
 S5 (MH "Epinephrine+")
 S4 S1 or S2 or S3
 S3 TI (laryngotracheobronchit* or laryngotracheit* or pseudocroup or psuedo‐croup) or AB (laryngotracheobronchit* or laryngotracheit* or pseudocroup or psuedo‐croup)
 S2 TI croup or AB croup
 S1 (MH "Laryngitis+")

Appendix 4. Web of Science search strategy (Thomson Reuters)

# 6	67	#5 AND #4 Databases=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH, CCR‐EXPANDED, IC Timespan=All Years
# 5	1,410,273	Topic=(random* or placebo* or allocat* or crossover* or "cross over" or ((singl* or doubl*) NEAR/1 blind*)) OR Title=(trial) Databases=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH, CCR‐EXPANDED, IC Timespan=All Years
# 4	112	#3 AND #2 AND #1 Databases=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH, CCR‐EXPANDED, IC Timespan=All Years
# 3	583,070	Topic=(nebuli* or vapor* or vapour* or inhal* or atomis* or atomiz* or spray* or mist* or aerosol* or (positive‐pressure NEAR/3 (breathing or respiration)) or ippb) Databases=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH, CCR‐EXPANDED, IC Timespan=All Years
# 2	44,458	Topic=(epinephrin* or adrenalin* or (adrenergic* NEAR/2 agonist*) or "adrenal cortex hormone" or "adrenal cortex hormones") Databases=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH, CCR‐EXPANDED, IC Timespan=All Years
# 1	2,985	Topic=(laryngit* or croup or laryngotracheit* or laryngotracheobronchit* or "laryngo‐tracheo‐bronchitis" or pseudocroup or "pseudo‐croup") Databases=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH, CCR‐EXPANDED, IC Timespan=All Years

Appendix 5. Scopus search strategy

((TITLE‐ABS‐KEY(laryngit* OR croup OR laryngotracheit* OR laryngotracheobronchit* OR "laryngo‐tracheo‐bronchitis" OR pseudocroup OR "pseudo‐croup") AND SUBJAREA(mult OR agri OR bioc OR immu OR neur OR phar OR mult OR medi OR nurs OR vete OR dent OR heal)) AND (TITLE‐ABS‐KEY(epinephrin* OR adrenalin* OR "adrenergic agonist" OR "adrenergic agonists" OR "adrenal cortex hormone" OR "adrenal cortex hormones") AND SUBJAREA(mult OR agri OR bioc OR immu OR neur OR phar OR mult OR medi OR nurs OR vete OR dent OR heal)) AND (TITLE‐ABS‐KEY(nebuli* OR vapor* OR vapour* OR inhal* OR atomis* OR atomiz* OR spray* OR mist* OR aerosol* OR ippb OR "positive‐pressure breathing" OR "positive‐pressure respiration") AND SUBJAREA(mult OR agri OR bioc OR immu OR neur OR phar OR mult OR medi OR nurs OR vete OR dent OR heal))) AND ((TITLE‐ABS‐KEY(random* OR placebo* OR allocat* OR crossover* OR "cross over" OR (singl* W/1 blind*) OR (doubl* W/1 blind*)) AND SUBJAREA(mult OR agri OR bioc OR immu OR neur OR phar OR mult OR medi OR nurs OR vete OR dent OR heal)) OR (TITLE(trial) AND SUBJAREA(mult OR agri OR bioc OR immu OR neur OR phar OR mult OR medi OR nurs OR vete OR dent OR heal)))

Data and analyses

Comparison 1. Nebulized epinephrine versus placebo.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Croup score (change baseline ‐ 30 minutes)	3	94	Std. Mean Difference (IV, Random, 95% CI)	‐0.94 [‐1.37, ‐0.51]
1.1 Inpatient	2	40	Std. Mean Difference (IV, Random, 95% CI)	‐0.82 [‐1.47, ‐0.17]
1.2 Outpatient	1	54	Std. Mean Difference (IV, Random, 95% CI)	‐1.03 [‐1.60, ‐0.46]
2 Croup score (change baseline ‐ 2 hours)	1		Std. Mean Difference (IV, Random, 95% CI)	Totals not selected
2.1 Inpatient	1		Std. Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
2.2 Outpatient	0		Std. Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
3 Croup score (change baseline ‐ 6 hours)	2	138	Std. Mean Difference (IV, Random, 95% CI)	‐0.60 [‐1.12, ‐0.08]
3.1 Inpatient	2	69	Std. Mean Difference (IV, Random, 95% CI)	‐0.60 [‐1.50, 0.30]
3.2 Outpatient	0	0	Std. Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
3.3 IPPB administration	1	37	Std. Mean Difference (IV, Random, 95% CI)	‐1.06 [‐1.76, ‐0.36]
3.4 No IPPB administration	1	32	Std. Mean Difference (IV, Random, 95% CI)	‐0.14 [‐0.84, 0.55]
4 Length of hospitalization in hours	2		Mean Difference (IV, Random, 95% CI)	Totals not selected
4.1 Inpatient	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
4.2 Outpatient	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
5 Return visits and/or (re)admissions	1		Risk Difference (M‐H, Random, 95% CI)	Totals not selected
5.1 Inpatient	0		Risk Difference (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
5.2 Outpatient	1		Risk Difference (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
6 Improvement	2	74	Risk Ratio (M‐H, Random, 95% CI)	1.46 [0.82, 2.60]
6.1 Inpatient	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
6.2 Outpatient	1	54	Risk Ratio (M‐H, Random, 95% CI)	1.83 [0.96, 3.50]
6.3 Setting not reported	1	20	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.42, 2.40]

1.5. Analysis.

Comparison 1 Nebulized epinephrine versus placebo, Outcome 5 Return visits and/or (re)admissions.

Comparison 2. Nebulized racemic epinephrine versus L‐epinephrine.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Croup score (change baseline ‐ 30 minutes)	1		Std. Mean Difference (IV, Random, 95% CI)	Totals not selected
1.1 Inpatient	0		Std. Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
1.2 Outpatient	1		Std. Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
2 Croup score (change baseline ‐ 2 hours)	1		Std. Mean Difference (IV, Random, 95% CI)	Totals not selected
2.1 Inpatient	0		Std. Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
2.2 Outpatient	1		Std. Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
3 Intubation	1		Risk Difference (M‐H, Random, 95% CI)	Totals not selected
3.1 Inpatient	0		Risk Difference (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.2 Outpatient	1		Risk Difference (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 3. Nebulized epinephrine with IPPB versus nebulized epinephrine without IPPB.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Croup score (change baseline ‐ 30 minutes)	1		Std. Mean Difference (IV, Random, 95% CI)	Totals not selected
1.1 Inpatient	1		Std. Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
1.2 Outpatient	0		Std. Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
2 Croup score (change baseline ‐ 2 hours)	1		Std. Mean Difference (IV, Random, 95% CI)	Totals not selected
2.1 Inpatient	1		Std. Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
2.2 Outpatient	0		Std. Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
3 Intubation	1		Risk Difference (M‐H, Random, 95% CI)	Totals not selected
3.1 Inpatient	1		Risk Difference (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.2 Outpatient	0		Risk Difference (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

3.3. Analysis.

Comparison 3 Nebulized epinephrine with IPPB versus nebulized epinephrine without IPPB, Outcome 3 Intubation.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Corkey 1981.

Methods	Randomized, placebo‐controlled trial. No withdrawals
Participants	14 children hospitalized with acute infectious croup (spasmodic croup was excluded). No child received either antibiotics or steroid therapy prior to randomization Definition of croup: upper respiratory tract infections, often with fever, followed by the onset of inspiratory stridor and barking cough in 24 to 72 hours
Interventions	0.5 mL of 2.25% of racemic epinephrine (containing 5 mg L‐epinephrine) with 3.5 mL of distilled water IPPB (n = 8) or 4 mL of placebo with IPPB (n = 6) The IPPB flow rate was 10 L/min, 100% oxygen Treatment was repeated if clinical score did not improve after 15 minutes
Outcomes	Croup score (6‐point score: stridor 1 to 3 points and recession 1 to 3 points) at post‐treatment (15 or 30 minutes) Change in tracheal diameter
Notes	IPPB: intermittent positive pressure breathing
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random numbers table
Allocation concealment (selection bias)	Unclear risk	Details not reported
Blinding (performance bias and detection bias) All outcomes	Low risk	Nurse was the only one who knew study drug
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Nurse was the only one who knew study drug
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Nurse was the only one who knew study drug. Outcome assessors were unable to distinguish treatment solutions on basis of smell or other characteristics
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	No missing data
Selective reporting (reporting bias)	Unclear risk	Details not reported
Other bias	Low risk

Fernandez 1993.

Methods	Randomized, placebo‐controlled trial No withdrawals
Participants	All participants (children) hospitalized because of croup symptoms (unclear if spasmodic croup was excluded)
Interventions	0.5 mg/kg of nebulized L‐epinephrine (containing 5 mg L‐epinephrine) (n = 15) or placebo (n = 17) (delivered via nebulization alone) At least half of the children received IM dexamethasone but it is unclear which treatment they received first
Outcomes	Croup score (8 points: stridor 0 to 2 points, respiratory distress 0 to 2 points, cough 0 to 2 points, cyanosis 0 to 2 points) at baseline, 6, 12, 18 and 24 hours
Notes	—
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Details not reported
Allocation concealment (selection bias)	Low risk	Vials were pre‐numbered and labeled by the pharmacy
Blinding (performance bias and detection bias) All outcomes	Low risk	Nurses were not told which vial was used
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Vial were pre‐numbered and labeled by the pharmacy; treating personnel did not know which study treatment was used
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Details not reported, but assessors would not know which study treatment vial was used
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Details not reported
Selective reporting (reporting bias)	Unclear risk	Details not reported
Other bias	High risk	Authors measured croup score in 6‐hour intervals and measurements were treated separately instead of as repeated measures

Fogel 1982.

Methods	Cross‐over, randomized controlled trial No withdrawals
Participants	14 children admitted to hospital with persistent inspiratory stridor at rest after 20 to 30 minutes of mist therapy. Children remained in a mist tent during the study period and received supplemental oxygen as indicated Definition of croup: inspiratory stridor at rest (unclear if spasmodic croup was excluded)
Interventions	0.25 mL of 2.25% racemic nebulized epinephrine diluted to 1:8 with isotonic saline (n = 5) or the same dose of nebulized racemic epinephrine with IPPB (n = 9) IPPB pressure was 15 to 17 cm 2 hours after first treatment, children were then crossed over to the other treatment
Outcomes	Modified Westley croup score (16 points: level of consciousness 0 to 4 points, color 0 to 4 points, stridor 0 to 3 points, air entry 0 to 2 points, retractions 0 to 3 points) at 30, 60, 90 and 120 minutes Heart rate Respiratory rate Supplemental oxygen Intubation Adverse reactions
Notes	IPPB: intermittent positive pressure breathing
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Details not reported ‐ prospectively randomized
Allocation concealment (selection bias)	Unclear risk	Details not reported
Blinding (performance bias and detection bias) All outcomes	Low risk	Patient and evaluator did not know
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Patient and evaluator did not know. The respiratory therapist was the only person who knew which study group the participant was in. The delivery of the study intervention was via the same apparatus in both groups
Blinding of outcome assessment (detection bias) All outcomes	Low risk	The evaluator did not know
Incomplete outcome data (attrition bias) All outcomes	Low risk	Data were complete
Selective reporting (reporting bias)	Low risk
Other bias	Low risk

Gardner 1973.

Methods	Randomized, placebo‐controlled trial. No withdrawals
Participants	20 children with moderate croup (unclear if spasmodic croup was excluded) ‐ inpatient or outpatient status not reported Co‐interventions were not reported
Interventions	0.5 mL of 2.25% racemic epinephrine (containing 5 mg L‐epinephrine) in 3.5 mL of saline (n = 10) or 4.0 mL of saline (n = 10) (delivered via nebulization alone)
Outcomes	Croup score (10 points: cough score 0 to 2 points, anxiety/air hunger 0 to 2 points, stridor 0 to 2 points, retractions 0 to 2 points, cyanosis 0 to 2 points); timing of croup score assessment not reported Improvement Additional treatment of study drug
Notes	—
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Details not reported
Allocation concealment (selection bias)	Unclear risk	Used numbered vials but did not describe how they were allocated
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Details not reported
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Authors reported that placebo and racemic epinephrine solutions were indistinguishable by smell or appearance
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Details not reported
Incomplete outcome data (attrition bias) All outcomes	Low risk	Pre‐selected outcomes are not reported
Selective reporting (reporting bias)	Unclear risk	Methods do not include sufficient details to adequately assess
Other bias	Low risk

Kristjansson 1994.

Methods	Randomized, placebo‐controlled trial. No withdrawals
Participants	54 children presenting to the ED with moderate croup (unclear if spasmodic croup was excluded). No co‐interventions were given prior to randomization
Interventions	0.5 mg/kg of 2.25% racemic epinephrine (containing 0.25 mg/kg of L‐epinephrine) diluted with 0.9% saline solution up to 2 mL (n = 25) or placebo (n = 29) (delivered via nebulization alone)
Outcomes	Croup score (15 points: inspiratory stridor 0 to 3 points, retractions 0 to 3 points, air entry 0 to 3 points, cyanosis 0 to 3 points, state of consciousness 0 to 3 points) at 30 and 120 minutes Respiratory rate Heart rate Length of stay Additional treatment Betamethasone treatment Re‐admission
Notes	—
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Details not reported
Allocation concealment (selection bias)	Unclear risk	Details not reported
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Details not reported
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Authors reported that placebo and racemic epinephrine solutions were indistinguishable by smell and solubility
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Details not reported
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	5 additional patients were not included because protocols were incomplete ‐ details not reported
Selective reporting (reporting bias)	Unclear risk	Details not reported
Other bias	Low risk

Kuusela 1988.

Methods	Randomized, double‐blind, placebo‐controlled trial 78 children were enrolled and 72 were treated and evaluated by the protocol
Participants	78 children admitted with moderate croup (70 children's symptoms were consistent with spasmodic croup). All children were placed in a humid room
Interventions	0.25 mL per 5 kg body weight of 2.25% solution of nebulized racemic epinephrine (containing 2.5 mg L‐epinephrine) (n = 16) or placebo (n = 21) via IPPB Nebulization was repeated at 2 hours
Outcomes	Dyspnea score (0 to 3 points) Cough score (0 to 3 points) at 6, 12, 24 and 48 hours Length of stay pH day 1 PCO2 day 1 Base deficit
Notes	PCO2: partial pressure of carbon dioxide
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Details not reported
Allocation concealment (selection bias)	Low risk	Sequentially numbered
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Details not reported
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Authors reported that placebo and racemic epinephrine solutions were indistinguishable by smell or appearance and were identically packaged
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Code was not available to investigators until end of study
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	6 patients not analyzed but details not reported
Selective reporting (reporting bias)	Unclear risk	Details not reported
Other bias	Low risk

Waisman 1992.

Methods	Randomized, double‐blind controlled trial 3 children were withdrawn
Participants	66 children hospitalized due to symptoms suggestive of moderate croup (spasmodic croup was excluded). All children were received mist therapy prior to randomization Croup suggestive symptoms: acute laryngitis, laryngotracheobronchitis and laryngitis with stridor
Interventions	2.25% racemic epinephrine (n = 16) or 5 mL of 1:1000 L‐epinephrine (n = 15) (each containing 5 mg L‐epinephrine and delivered via nebulization alone)
Outcomes	Croup score (10 points: inspiratory breath sounds 0 to 2 points, stridor 0 to 2 points, cough 0 to 2 points, retractions/nasal flaring 0 to 2 points, cyanosis 0 to 2 points) at 5, 15, 30, 60, 90 and 120 minutes Respiratory rate Dexamethasone treatment Supplemental oxygen Intubation
Notes	—
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Table of random numbers
Allocation concealment (selection bias)	Low risk	Pharmacy‐controlled randomization
Blinding (performance bias and detection bias) All outcomes	Low risk	Identical vials blinded to patient and investigator
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Identical vials blinded to participant and personnel
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Drug code broken only after the last participant completed the study
Incomplete outcome data (attrition bias) All outcomes	Low risk	3 participants were not included because of intubation (n = 2) and tracheal stenosis (n = 1)
Selective reporting (reporting bias)	Unclear risk	Primary outcome not reported
Other bias	Low risk

Westley 1978.

Methods	Randomized, double‐blind, placebo‐controlled trial 3 children were withdrawn due to mechanical failure in the IPPB machine
Participants	23 children admitted with moderate croup and inspiratory stridor after 15 to 30 minutes in a humidity mist room (unclear if spasmodic croup was excluded). All children received continuous room temperature mist and no supplemental oxygen was given except during IPPB treatment and 4 children received antibiotics
Interventions	0.5 mL of 2.25% racemic epinephrine (containing 5 mg L‐epinephrine) (n = 10) or nebulized saline with IPPB (n = 10) IPPB pressure was 10 cm and increased to 15 cm within the first minute
Outcomes	Westley croup score (17 points: level of consciousness 0 to 5 points, cyanosis 0 to 5 points, stridor 0 to 2 points, air entry 0 to 2 points, retractions 0 to 3 points) at 10, 30, and 120 minutes Pulse Respiratory rate
Notes	—
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Table of random numbers
Allocation concealment (selection bias)	Low risk	Prepared identical bottles
Blinding (performance bias and detection bias) All outcomes	Low risk	Identical bottles and code unknown to investigators
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Identical bottles and code unknown to investigators or participants Racemic epinephrine and placebo reported to be identical in smell
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Evaluators of outcome were not aware of which intervention the participant had received at time of evaluation
Incomplete outcome data (attrition bias) All outcomes	Low risk	Missing data for 3 participants because IPPB machine broke
Selective reporting (reporting bias)	Unclear risk	Details not reported
Other bias	Low risk

ED = emergency department
 IM = intramuscular
 IPPB = intermittent positive pressure breathing
 PCO₂ = partial pressure of carbon dioxide

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Anonymous 1996	Not a RCT
Banac 2005	There is no comparison group. All children were treated with L‐epinephrine
Bass 1978	Not a RCT
Bass 1980	Not a RCT
Beaudry 1983	Not a RCT
Brown 2002	Not a RCT
Celis 1978	Not a RCT
Cherry 1974	Not a RCT
Choi 1999	Children were randomized to L‐epinephrine or nebulized budesonide
Cressman 1994	Not a RCT
Cristaldi 2001	Not a RCT
Cronin 1996	Not a RCT
da Silva 2012	Compares 3 doses of epinephrine in children with post‐extubation stridor
Danen 2011	Not a RCT
Dardick 1974	Not a RCT
de Benedictis 2012	Not a RCT
Dunman 2005	Compares cool mist and intramuscular dexamethasone versus nebulized L‐epinephrine and intramuscular dexamethasone versus nebulized L‐epinephrine and nebulized budesonide
Ellis 1974	Not a RCT
Fitzgerald 1996	Compares L‐epinephrine versus budesonide
Fogel 1983	Not a RCT
Frazier 2010	Not a RCT
Ghosh 2001	Not a RCT
Gilligan 2005	Not a RCT
Gonzalez 1984	Not a RCT
Heisinge 1974	Not a RCT
Jones 1996	Not a RCT
Klassen 1997	Not a RCT
Kline‐Krammes 2012	Not a RCT
Koren 1983	Not a RCT
Kunkel 1996	Not a RCT
Ledwith 1995	Not a RCT
Lenney 1978	Not a RCT
Loriette 1997	Not a RCT
Niggermann 1995	Not a RCT
Osmond 2002	Not a RCT
Pitluk 2011	Not a RCT
Preutthipan 2005	Compares 2 doses of epinephrine in children with post‐intubation croup
Remington 1986	Not a RCT
Rygnestad 2001	Not a RCT
Singer 1976	Not a RCT
Skolnik 1989	Not a RCT
Steele 1998	Compares children with croup to healthy controls
Taussig 1975	All children received mist therapy and were randomized to epinephrine or no treatment (no placebo administered)
Taussig 1976	Not a RCT
Thomas 1998	Not a RCT
Thompson 1974	Not a RCT
Vorwerk 2010	Not a RCT
Weber 2001	Compared epinephrine to heliox
Zach 1981	Not a RCT
Zoorob 2011	Not a RCT

RCT = randomized controlled trial

Differences between protocol and review

'Improvement' was measured in several studies, therefore it was added to the secondary outcomes.

Contributions of authors

Candice Bjornson (CB) critically reviewed the protocol. She selected articles based on their abstract, reviewed and included articles based on their full text and determined whether the studies met this review's inclusion/exclusion criteria, and checked data extracted from included articles for accuracy and completeness. She also analyzed and interpreted the review's results, and drafted the discussion and conclusions.

Kelly Russell (KR) reviewed and selected articles based on their abstract, reviewed and included articles based on their full text as to whether they meet this review's inclusion/exclusion criteria, and checked data extracted from included articles for accuracy and completeness. She also critically reviewed drafts of the review.

Ben Vandermeer (BV) critically reviewed the protocol, focusing on data analysis. He analyzed and interpreted the review's results. He also critically reviewed drafts of the review.

Terry Klassen (TK) critically reviewed the protocol and critically reviewed drafts of the review.

David Johnson (DJ) conceived the idea of a systematic review on this topic and wrote the protocol. He analyzed and interpreted the review's results and critically reviewed the discussion and conclusions.

Declarations of interest

None known.

New search for studies and content updated (no change to conclusions)