Cochrane croup

EVIDENCE-BASED CHILD HEALTH: A COCHRANE REVIEW JOURNAL
Evid.-Based Child Health 7:4: 1311–1354 (2012)
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ebch.1856

Nebulized epinephrine for croup in children (Review)

Bjornson C, Russell KF, Vandermeer B, Durec T, Klassen TP, Johnson DW

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2011, Issue 2
http://www.thecochranelibrary.com

Nebulized epinephrine for croup in children (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.


TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1313
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1313
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1314
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1314
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1315
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1315
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1317
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1319
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1320
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1322
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1323
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1324
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1324
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1327
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1337
Analysis 1.1. Comparison 1 Nebulized epinephrine versus placebo, Outcome 1 Croup score (change baseline - 30
minutes). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1340
hours). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1341
hours). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1342
Analysis 1.4. Comparison 1 Nebulized epinephrine versus placebo, Outcome 4 Return visits and/or (re)admissions. 1343
Analysis 1.5. Comparison 1 Nebulized epinephrine versus placebo, Outcome 5 Length of hospitalization in hours. 1344
Analysis 1.7. Comparison 1 Nebulized epinephrine versus placebo, Outcome 7 Improvement. . . . . . . . 1345
Analysis 2.1. Comparison 2 Nebulized racemic epinephrine versus L-epinephrine, Outcome 1 Croup score (change baseline
- 30 minutes). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1346
Analysis 2.2. Comparison 2 Nebulized racemic epinephrine versus L-epinephrine, Outcome 2 Croup score (change baseline
- 2 hours). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1347
Analysis 2.8. Comparison 2 Nebulized racemic epinephrine versus L-epinephrine, Outcome 8 Intubation. . . . 1348
Analysis 3.1. Comparison 3 Nebulized epinephrine with IPPB versus nebulized epinephrine without IPPB, Outcome 1
Croup score (change baseline - 30 minutes). . . . . . . . . . . . . . . . . . . . . . . 1349
Croup score (change baseline - 2 hours). . . . . . . . . . . . . . . . . . . . . . . . 1350
Intubation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1351
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1351
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1353
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1353
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1354
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . 1354
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1354

Nebulized epinephrine for croup in children (Review) 1312


[Intervention Review]

Nebulized epinephrine for croup in children

Candice Bjornson1 , Kelly F Russell2 , Ben Vandermeer3 , Tamara Durec4 , Terry P Klassen5 , David W Johnson1

1
Department of Pediatrics, Faculty of Medicine, University of Calgary, Alberta Children’s Hospital, Calgary, Canada. 2 Department of
Pediatrics, University of Alberta, Edmonton, Canada. 3 Department of Pediatrics, Alberta Research Centre for Child Health Evidence
& University of Alberta Evidence-based Practice Centre, Edmonton, Canada. 4 Aberhart Centre One, Room 9418, Evidence-based
Practice Centre, Edmonton, Canada. 5 Manitoba Institute of Child Health, Winnipeg, Canada

Contact address: Candice Bjornson, Department of Pediatrics, Faculty of Medicine, University of Calgary, Alberta Children’s Hospital,
2888 Shaganappi Trail NW, Calgary, Alberta, T3B 6A8, Canada. candice.bjornson@albertahealthservices.ca.

Editorial group: Cochrane Acute Respiratory Infections Group.
Publication status and date: New, published in Issue 2, 2011.
Review content assessed as up-to-date: 14 November 2010.

Citation: Bjornson C, Russell KF, Vandermeer B, Durec T, Klassen TP, Johnson DW. Nebulized epinephrine for croup in children.
Cochrane Database of Systematic Reviews 2011, Issue 2. Art. No.: CD006619. DOI: 10.1002/14651858.CD006619.pub2.


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 (NE) may prevent intubation.

Objectives

To evaluate the efﬁcacy and safety of NE in children presenting to emergency department (ED) or admitted to hospital with croup.

Search methods

We searched CENTRAL (The Cochrane Library 2010, Issue 4), containing the Cochrane Acute Respiratory Infections Group’s Specialized
Register, MEDLINE (1966 to November Week 1, 2010), EMBASE (1980 to November 2010), Web of Science (1974 to November
2010), CINAHL (1982 to November 2010) and Scopus (1996 to November 2010).

Selection criteria

Randomized controlled trials (RCTs) or quasi-RCTs of children with croup evaluated in an ED or admitted to hospital. Comparisons
were: NE versus placebo, racemic NE versus L-epinephrine (an isomer), and NE delivered by intermittent positive pressure breathing
(IPPB) versus NE 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 methodologic quality assessment. One author extracted data while the second checked
accuracy. We performed standard statistical analyses.


Main results

Eight studies (225 participants) were included. NE 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. NE was associated with significantly shorter hospital stay than placebo (one RCT, mean
difference -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 NE 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).

Authors’ conclusions

NE is associated with clinically and statistically significant transient reduction of symptoms of croup 30 minutes post-treatment.
Evidence does not favor racemic epinephrine or LE, or IPPB over simple nebulization.

PLAIN LANGUAGE SUMMARY

Nebulized epinephrine for croup in children

Croup is a common childhood illness that is usually 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. 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. This review is comprised of only eight studies and the number of included children
was small (225). Few studies examined similar outcomes, therefore data could often not be pooled and conclusions are based on one
or few studies.

BACKGROUND 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
Description of the condition minority have severe symptoms characterized by marked chest
Croup (laryngotracheobronchitis) is a common respiratory illness wall indrawing, agitation and lethargy (Johnson 2001; Johnson
of childhood, estimated to affect approximately 3% of children 2003). These children are at significant risk for intubation. Cor-
under six years of age annually (Denny 1983; Johnson 2003). The ticosteroids decrease both the frequency and duration of hospi-
clinical picture is characterized by the abrupt onset of a distinctive talization and intubation (Kairys 1989; Russell 2004; Tibballs
barky cough, which may be accompanied by stridor, hoarse voice 1992). A systematic review of corticosteroids found that compared
and respiratory distress. Croup symptoms are often preceded by to placebo, corticosteroids significantly reduced six and 12-hour
non-specific symptoms such as cough, rhinorrhea and fever. The croup scores, reduced length of hospital stay, and reduced return
most common etiology is a viral infection, predominantly parain- visits (Russell 2004). However, corticosteroids take an hour or
fluenza virus (Marx 1997). more after treatment to lessen respiratory distress (Geelhoed 1995;



Johnson 1998). Consequently in children with the most severe Indirect measures of severity, such as health care utilization, are
symptoms, a therapy with a rapid rate of onset may lessen the need thought by many to capture significant clinical change better than
for intubation. The therapy most commonly used for this purpose clinical scores. Some would argue that if a treatment cannot be
is nebulized epinephrine. Children with moderate to severe croup shown to reduce health care utilization, it is of no benefit.
are usually administered both epinephrine and corticosteroids con- We have chosen to assess and report both direct and indirect mea-
currently to reduce respiratory distress while awaiting the effects sures of clinical change, with the intent of allowing the reader to
of the corticosteroid treatment. Alternative therapies are mist and make their own judgement as to the relative merits of the different
heliox (helium-oxygen mixture) (Johnson 2005). However, recent measures.
evidence suggests that mist provides no significant clinical bene-
fit (Moore 2006; Neto 2002; Scolnik 2006). Heliox has greater
promise, but it is more cumbersome to use, and has little evidence Why it is important to do this review
of effectiveness (Johnson 2005).
Croup is a common childhood illness and may result in presen-
tation to the emergency department due to difficulty in breath-
ing. Epinephrine has been used as a treatment option to reduce
tracheal swelling for over 30 years. However, currently there is no
How the intervention might work systematic review examining the efficacy of this intervention.
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; OBJECTIVES
Klassen 1999). While a small number of randomized controlled
trials (RCTs) have been published (Johnson 2005), to date no
systematic review has been published. Primary objective
Initial studies published in the 1970s and early 1980s suggested
that epinephrine might be more effective when nebulized via IPPB To assess the efficacy (measured by croup scores, rate of intubation
(intermittent positive pressure breathing) than by nebulization and health care utilization such as rate of hospitalization) and safety
alone. The use of IPPB has now fallen out of favor and it is no (frequency and severity of side effects) of nebulized epinephrine
longer routinely used. versus placebo in children with croup, evaluated in an emergency
Clinical severity in children with croup can be determined by department or hospital setting.
both direct measures (clinical scores, transcutaneous carbon diox-
ide concentrations, pulsus paradoxus, impedance plesmography,
radiographic measurement of tracheal diameter) and indirect ones Secondary objectives
(rate and duration of intubation, rate and duration of hospitaliza- To assess the efficacy and severity of side effects of nebulized
tion, rate of return to seek medical care for ongoing croup symp- racemic epinephrine versus nebulized L-epinephrine in children
toms, sleep lost by parents, parental stress). Several objective tech- with croup evaluated in an emergency department or hospital set-
niques have been reported (Corkey 1981; Davis 1993; Fanconi ting and to assess the efficacy and severity of side effects of neb-
1990; Steele 1998), but none are easy to use, nor measure change ulized epinephrine delivered with intermittent positive pressure
across the full range of clinical severity. Consequently they have breathing (IPPB) versus nebulized epinephrine alone.
not been routinely used.
The most widely used direct measure of respiratory severity are
different types of croup scores (Bourchier 1984; Corkey 1981;
Downes 1975; Geelhoed 1995; Godden 1997; Husby 1993;
METHODS
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 ex-
tent, valid (Klassen 1994; Klassen 1995). None of the other croup Criteria for considering studies for this review
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 clin- Types of studies
ical change. On the other hand, clinical scores are arguably more Randomized controlled trials (RCTs) or quasi-RCTs (Q-RCTs)
sensitive to change, and therefore more likely to detect smaller which compare the use of nebulized epinephrine to placebo, neb-
degrees of improvement. ulized racemic epinephrine versus nebulized L-epinephrine, and



nebulized epinephrine delivered with intermittent positive pres- Cochrane Highly Sensitive Search Strategy for identifying ran-
sure breathing (IPPB) versus nebulized epinephrine alone in chil- domized trials in MEDLINE: sensitivity- and precision-maximiz-
dren with croup. ing version (2008 revision) Ovid format (Lefebvre 2009). We
adapted the search strategy to search EMBASE (see Appendix 2),
CINAHL (see Appendix 3), Web of Science (see Appendix 4) and
Types of participants Scopus (see Appendix 5).
Studies including children with a clinical diagnosis of croup (de-
fined as acute onset of a ’barky cough’ and stridor) whether eval-
uated in an emergency department or admitted to hospital. MEDLINE (Ovid)
1 exp Laryngitis/
2 (croup or laryngit*).tw.
Types of interventions
3 laryngotracheit*.tw.
1. Nebulized epinephrine (either racemic or L-epinephrine, or 4 (laryngotracheobronchit* or laryngo-tracheo-bronchit*).tw.
delivered with or without IPPB) versus placebo. 5 (pseudocroup or pseudo-croup).tw.
2. Nebulized racemic epinephrine versus L-epinephrine. 6 or/1-5
3. Nebulized epinephrine delivered by IPPB versus nebulized 7 Epinephrine/
epinephrine delivered without IPPB. 8 exp Adrenergic Agonists/
9 exp Adrenal Cortex Hormones/
10 epinephrin*.tw,nm.
Types of outcome measures 11 (adrenalin* or l-adrenalin*).tw,nm.
12 (adrenergic agonist* or adrenergic alpha-agonist* or adrenergic
beta-agonist*).tw,nm.
Primary outcomes 13 or/7-12
Changes in clinical croup scores following treatment. 14 exp “Nebulizers and Vaporizers”/
15 Aerosols/
16 respiratory therapy/ or oxygen inhalation therapy/ or respira-
Secondary outcomes tion, artificial/ or exp positive-pressure respiration/
1. Rate and duration of intubation. 17 (inhal* or vapor* or vapour* or atomiz* or atomis* or nebuliz*
2. Rate and duration of hospitalization. or nebulis* or spray* or mist* or aerosol*).tw.
3. Rate of return to medical care for ongoing croup symptoms. 18 (positive-pressure adj3 (breathing or respiration)).tw.
4. Improvement 19 ippb.tw.
5. Parental anxiety. 20 or/14-19
6. Side effects such as hypertension. 21 6 and 13 and 20
7. Evidence of myocardial injury or cardiac arrhythmias.
We evaluated all studies that met the above criteria; we used no
exclusion criteria. Searching other resources
We contacted experts in the field of acute respiratory infections to
locate additional studies. There were no language or publication
Search methods for identification of studies restrictions.

Electronic searches Data collection and analysis
We searched the Cochrane Central Register of Controlled Trials
(CENTRAL) (The Cochrane Library 2010, Issue 4), which con-
tains the Cochrane Acute Respiratory Infections Group’s Special-
ized Register, MEDLINE (1966 to November Week 1, 2010), Selection of studies
EMBASE (1980 to November 2010), Web of Science (1974 to Two review authors (CB, KR) independently scanned abstracts
November 2010), CINAHL (1982 to November 2010) and Sco- from the initial search results to identify trials that broadly met
pus (1996 to November 2010). the inclusion criteria. We then reviewed the full-text articles of the
We used the following search terms to search MEDLINE and selected trials and the same two review authors independently ap-
CENTRAL. We combined the MEDLINE search with the plied the inclusion criteria. We resolved differences by consensus.



Data extraction and management (NNTH). We reported the pooled baseline rates using the inverse
We extracted data using a structured form that captures patient variance method.
status (emergency department or inpatient, the author’s descrip-
tion of their clinical severity), intervention and control character-
Assessment of heterogeneity
istics (such as type of drug: racemic versus L-epinephrine), dosage
and method of administration (nebulization alone versus nebu- We assessed heterogeneity quantitatively with the I2 statistic
lized with intermittent positive pressure breathing (IPPB)). In ad- (Higgins 2002). The I2 statistic indicates the percent variability
dition, we collected data on the primary and secondary outcome due to between-study (or inter-study) variability as opposed to
measures if available: change from baseline clinical croup scores; within-study (or intra-study) variability. We considered an I2 value
rate and duration of intubation; rate and duration of hospitaliza- greater than 50% to be large. For the analyses of all outcomes,
tion; and occurrence of hypertension, myocardial injury or car- we used a random-effects model to combine treatment effects re-
diac arrhythmias. One review author (KR) extracted data and a gardless of quantified heterogeneity. We considered a fixed-effect
second review author (CB) checked this for accuracy. If necessary, model in sensitivity analyses.
we extracted data from graphs or directly from the trial authors. 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
Assessment of risk of bias in included studies 60 minutes. We considered the following subgroups: quality (that
Two review authors (CB, KR) independently assessed the quality is, the risk of bias, allocation concealment, funding, and simple
of studies in three ways. We used more than one method since classification of bias (low, moderate, or high)) and inpatient versus
the relative merits of each remain controversial. First, we used emergency department status.
the method outlined in the Cochrane Handbook for Systematic Re-
views of Interventions that focuses on selection, performance, attri-
tion and detection bias (Higgins 2009). Second, we classified con- Assessment of reporting biases
cealment of allocation as adequate, inadequate or unclear (Schulz If at least eight studies were found for our primary outcome we
1995). Lastly, we classified studies by who sponsored them: phar- tested for publication bias. In addition to funnel plots, we used
maceutical company, other sources or not mentioned (Cho 1996). the rank correlation test (Begg 1994) and weighted regression (
We resolved differences by consensus. We compared and reported Egger 1997) for the detection of publication bias. We performed
the results from the three different classification methods. 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.
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
RESULTS
according to the work of Follmann (Follman 1992). We antici-
pated 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 treat- Description of studies
ment means) divided by its measurement variation (for example, See: Characteristics of included studies; Characteristics of excluded
a pooled standard deviation) gives a SMD). We also anticipated studies.
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 Results of the search
a study did not assess change in croup scores at our time points of The electronic literature search identified 316 unique studies. After
interest, we used the closest time point (for example, a 15-minute assessing the titles and, when available, the abstracts, we identified
change in croup score as used for the change in croup score at 50 studies as being potentially relevant. Reviewing the reference
30 minutes outcome). We expressed duration of intubation and lists of the included studies did not identify any additional studies.
hospitalization as mean differences and calculated an overall mean
difference.
For binary data (that is, intubation and hospitalization rates), we Included studies
calculated risk ratios. If zero events occurred in both groups, we After applying the a priori inclusion criteria, eight of the 50 studies
derived risk differences. If we found significant results, we cal- met the inclusion criteria. Three comparisons were examined: neb-
culated the number needed to treat to benefit (NNTB) or harm ulized epinephrine versus placebo (Corkey 1981; Fernadez 1993;



Gardner 1973; Kristjansson 1994; Kuusela 1988; Westley 1978), (11 months) and baseline severity of croup on study admission was
nebulized racemic epinephrine versus L-epinephrine (Waisman moderate. The doses of racemic epinephrine and L-epinephrine
1992) and nebulized epinephrine with IPPB versus nebulized were 0.5 ml of 2.25% and 5 ml of 1:1000 dilution, respectively.
epinephrine without IPPB (Fogel 1982). All studies were random- A non-validated 10-point croup score (inspiratory breath sounds,
ized placebo-controlled trials with the exception of the study com- two points; stridor, two points; cough, two points, retractions/
paring nebulized epinephrine with and without IPPB, which was nasal flaring, two points; cyanosis, two points) was utilized as the
a cross-over RCT. Seven studies were published in English and one primary outcome measure.
in Spanish (Fernadez 1993). Studies tended to be small, ranging
from 14 to 78 total participants per comparison.
Nebulized epinephrine with IPPB versus nebulized
epinephrine without IPPB
Nebulized epinephrine versus placebo We identified a single study suitable for inclusion, of 14 chil-
Four studies took place in an inpatient setting, one in an out- dren in an inpatient setting (Fogel 1982). Average age was young
patient setting, and one did not specify setting. In general, chil- (1.9 years), and baseline severity of croup on study admission was
dren within the studies were young (average age two years or less moderate. The dose of racemic epinephrine used was 0.25 ml of
in two studies, two to three years in two studies, and not spec- 2.25%. The IPPB pressure used was 15 cm to 17 cm of water
ified in two studies). Severity of croup in the majority of en- and two hours after the first treatment, cross-over to the other
rolled children was judged to be moderate or moderate to severe group occurred. A modified 16-point croup score based upon the
in all six studies. There was minor variance between studies in the validated Westley croup score (level of consciousness, four points;
type of epinephrine used (racemic epinephrine in five studies, L- color, four points; stridor, three points; air entry, two points; and
epinephrine in one study), and dose of racemic epinephrine used chest wall retractions, three points) was utilized as the primary
(0.5 ml of 2.25% racemic epinephrine in three studies, 0.5 mg/ outcome measure.
kg of 2.25% racemic epinephrine in two studies, and 0.25 ml of
2.25% racemic epinephrine per 5 kg of body weight in one study).
Excluded studies
Epinephrine was administered via IPPB in two of the six studies.
One study (Westley 1978) used a croup score which has been vali- We excluded a total of 42 studies. The exact reason for exclusion
dated. The Westley 17-point croup score incorporates assessment is provided in the Characteristics of excluded studies table.
of level of consciousness (five points), cyanosis (five points), stri-
dor (two points), air entry (two points) and chest wall retractions
(three points). The remaining five studies used a variety of non- Risk of bias in included studies
validated croup scores as outcome measures, with total possible Six of the eight studies were deemed to have a low risk of bias and
points ranging from six to 12 points. the risk of bias was unclear in the remaining two studies (Fernadez
1993; Kuusela 1988). Half of the studies reported adequate con-
cealment of allocation (Fernadez 1993; Kuusela 1988; Waisman
Nebulized racemic epinephrine versus L-epinephrine 1992; Westley 1978). Only one study reported a funding source
We identified a single study suitable for inclusion, of 66 children (Kristjansson 1994). The results from the various quality indica-
in an inpatient setting (Waisman 1992). Average age was young tors are pictorially displayed in Figure 1 and Figure 2.



Figure 1. Risk of bias graph: review authors’ judgements about each risk of bias item presented as
percentages across all included studies.



Figure 2. Risk of bias summary: review authors’ judgements about each risk of bias item for each included
study.



Allocation
CI -1.60 to -0.46) (Analysis 1.1.2). Heterogeneity was negligible
Allocation concealment was adequate in three of the studies ( in these comparisons.
Fernadez 1993; Kuusela 1988; Waisman 1992), inadequate in two There were also data on croup score after two hours (SMD -0.15;
(Corkey 1981; Westley 1978) and unclear in three (Fogel 1982; 95% CI -1.03 to 0.73; one study) (Analysis 1.2) and six hours
Gardner 1973; Kristjansson 1994). (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.
Blinding
All trials were double-blind. Two studies did not report who was
blinded (Gardner 1973; Westley 1978).
Secondary outcomes
There were two studies that reported length of hospital stay (in
Incomplete outcome data hours), one each in the inpatient and outpatient settings. The in-
Four studies reported losses to follow up (Kuusela 1988; patient study showed children on epinephrine spent a statistically
Kristjansson 1994; Waisman 1992; Westley 1978). However, only significant smaller amount of time in the hospital than placebo
one study explained the losses to follow up (Waisman 1992). participants in the hospital (MD -32.00; 95% CI -59.14 to -4.86)
(Analysis 1.5.1), while the outpatient study had a much smaller
and non-significant difference (MD -1.80; 95% CI -4.07 to 0.47)
Selective reporting (Analysis 1.5.2). We did not combine these two studies as we
All but two studies (Fogel 1982; Waisman 1992) reported a pri- would not expect similar hospital stays between inpatients and
mary outcome (6/8; 75%). outpatients.
Two studies counted the number of participants that had signif-
icant improvement. Improvement was defined in one study as a
Other potential sources of bias decrease in the croup score of greater that 2 or more points (2/
Two studies conducted an intention-to-treat (ITT) analysis ( 10 total points) (Gardner 1973), and in the other study as a de-
Corkey 1981; Fogel 1982). crease in the croup score of greater than 2 or more points (2/
15) (Kristjansson 1994). The combined risk ratio (RR) did favor
Effects of interventions epinephrine but it was not statistically significant (RR 1.46; 95%
CI 0.82 to 2.60; I2 statistic = 17%) (Analysis 1.7). Heterogeneity
was moderate.
The only other outcome of interest that was reported by any of the
Nebulized epinephrine versus placebo
studies was return visits, which was reported by one study. How-
There were six studies (183 participants) that reported data com- ever, that study reported no re-admissions in either the epinephrine
paring nebulized epinephrine versus placebo. Four (109 partici- or the placebo group, thus we computed no statistics. No study
pants) of these six studies took place in an inpatient setting, while reported rate and duration of intubation, or parental anxiety.
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
Nebulized racemic epinephrine versus L-epinephrine
particular analysis.
Waisman 1992 (28 participants) compared nebulized racemic
epinephrine versus L-epinephrine in an outpatient setting. There
Primary outcome: croup score was no significant difference in croup score between the two types
Since all studies used different systems in their croup scoring, of epinephrine after 30 minutes (SMD 0.33; 95% CI -0.42 to
we used SMDs to synthesize the data. Three studies showed that 1.08) (Analysis 2.1.2) but after two hours, L-epinephrine showed
epinephrine had a statistically significant smaller croup score than significant reduction over racemic epinephrine (SMD 0.87; 95%
placebo after 30 minutes (SMD -0.94; 95% CI -1.37 to -0.51; I CI 0.09 to 1.65) (Analysis 2.2.2 ).
2 statistic = 0%) (Analysis 1.1). The change in croup score was The only other outcome reported was intubation, where the
almost identical for the two studies that looked at inpatients (SMD racemic group had an intubation rate of 3/16 and the L-
-0.82; 95% CI -1.47 to -0.17; I2 statistic = 0%) (Analysis 1.1.1) epinephrine group had a rate of 0/14, which was a non-significant
and the one study that looked at outpatients (SMD -1.03; 95% difference (RD 0.19; 95% CI -0.03 to 0.40) (Analysis 2.8).



Nebulized epinephrine with IPPB versus nebulized At 120 minutes following treatment, the mean difference in croup
epinephrine without IPPB score was similar in both racemic epinephrine and placebo groups
Fogel 1982 (14 participants) compared nebulized epinephrine in the single, small (20 participants) study (Westley 1978). Al-
with IPPB versus nebulized epinephrine without IPPB in an in- though the observed clinical benefit of epinephrine had essentially
patient setting. After 30 minutes, there was no significant differ- dissipated at 120 minutes, there was no evidence, on average, to
ence in croup score between the two groups (SMD -0.72; 95% suggest that there was an increase or worsening of croup score, as
CI -1.86 to 0.42) (Analysis 3.1.1), while at two hours there was a compared to pre-treatment or baseline in the group of children
larger, still non-significant difference (SMD -0.14; 95% CI -1.24 treated with epinephrine.
to 0.95) (Analysis 3.2.1). Two studies (69 participants) assessed croup score at six hours fol-
The only other outcome reported in this study was that of intu- lowing treatment in an inpatient setting (Fernadez 1993; Kuusela
bation. However, both groups had zero intubations, thus we com- 1988) and found no difference in croup score between the neb-
puted no statistics. ulized racemic epinephrine and placebo groups. This is not sur-
prising given the relatively brief duration of action of nebulized
epinephrine and is also consistent with the finding of no difference
Subgroup, sensitivity and publication bias analysis in croup score at the 120-minute assessment.
Since none of our analyses contained more than three studies, no
further analysis exploring heterogeneity or publication bias could Secondary outcomes
be conducted.
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
DISCUSSION were wide, however, reflecting the small study size. Also, corticos-
teroid was administered to eight of 37 participants and the break-
down by treatment group was not provided. This could account for
Summary of main results the shorter hospital stay in the epinephrine group. Length of stay
in the outpatient setting was assessed in one study and it was simi-
Nebulized epinephrine has become standard management, espe- lar between epinephrine and placebo groups (Kristjansson 1994).
cially in North America, for the treatment of moderate and severe Equal proportions of children (52% and 58% in the racemic
croup. Nebulized epinephrine is typically administered to a child epinephrine and placebo groups, respectively) received concomi-
with moderate or severe upper airway obstruction in either an tant corticosteroid treatment. No difference in length of stay is
emergency department or inpatient setting. Though widely used consistent with resolution of clinical effect by two hours after treat-
in clinical practice, our search identified only six relevant clinical ment.
trials comparing nebulized epinephrine to placebo that included We chose to report the outcome proportion of patients improved
a total of 183 subjects (Corkey 1981; Fernadez 1993; Gardner even though we had not pre-specified it as a secondary outcome
1973; Kristjansson 1994; Kuusela 1988; Westley 1978). 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.
Nebulized epinephrine versus placebo

Racemic epinephrine versus L-epinephrine
Primary outcome: croup score A small, methodologically sound study comparing nebulized
Data from this review have shown that, compared to placebo, neb- racemic epinephrine with L-epinephrine in the outpatient setting
ulized racemic epinephrine effectively improves croup symptoms showed no difference in croup score 30 minutes following treat-
as measured by clinical croup scores in children 30 minutes fol- ment (Waisman 1992). By 120 minutes, there was a statistically
lowing treatment. Three trials assessed croup score at 30 minutes significant result showing L-epinephrine to have a longer duration
(Corkey 1981; Kristjansson 1994; Westley 1978). Although the of benefit than racemic epinephrine.
number of children was small (94 participants), the pooled data Racemic epinephrine is composed of equal proportions of D-
indicated a moderate to large reduction in croup score as com- and L-isomers of epinephrine and was originally used to treat
pared with placebo (Cohen 1969). All three trials favored racemic croup because it was hypothesized that racemic epinephrine would
epinephrine over placebo and the magnitude of benefit was similar cause fewer cardiovascular side effects than L-epinephrine. L-
and consistent between studies and in both inpatient and outpa- epinephrine is the type of epinephrine routinely used for other in-
tient settings. dications in medicine in either 1:1000 or 1:10,000 concentrations.



Waisman 1992 administered an identical 5 mg of L-epinephrine temporary relief of airway obstructive symptoms and, thus, there
(0.5 ml of 2.25% racemic epinephrine versus 5.0 ml of 1:1000 is not a strong rationale for the use of epinephrine in children with
epinephrine) and found no statistically significant differences in mild croup.
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). Quality of the evidence
The majority of the studies were at low risk of bias and half of the
Nebulized epinephrine with IPPB versus nebulized studies reported adequately concealed patient allocation methods.
epinephrine without IPPB While all studies were double-blind and the majority of the studies
reported their primary outcome, several studies reported a loss to
One study of good methodological quality found that nebulized
follow up and few studies conducted an intention-to-treat analysis.
epinephrine with IPPB was similar to nebulized epinephrine with-
out IPPB in the inpatient setting (Fogel 1982). However, this
study was small and not designed to show equivalence. Nonethe-
less, given the technical challenges of IPPB and no evidence of Potential biases in the review process
superiority, routine use of nebulized epinephrine without IPPB We undertook a broad and extensive search strategy of multiple
seems justified. 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
Safety of nebulized epinephrine
review did contain one Spanish language study. As none of our
Though none of the clinical trials reported significant adverse analyses contained more than three studies, no further analysis
events associated with nebulized epinephrine, the small total num- exploring heterogeneity or publication bias could be performed.
ber of study subjects and rarity of adverse events provides insuf- Thus, the possibility of publication bias cannot be ruled out.
ficient data to conclude that the use of nebulized epinephrine is
universally safe. Further, none of these trials assessed the effective-
ness or safety of epinephrine when administered repeatedly in a Agreements and disagreements with other
row. A single case report of ventricular tachycardia and myocardial studies or reviews
infarction in a previously healthy child who received three doses
of nebulized epinephrine in one hour raises concerns about po- We did not identify any other relevant studies or systematic reviews
tential cardiac toxicity (Butte 1999). While this case is of concern, in publication.
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.
AUTHORS’ CONCLUSIONS

Overall completeness and applicability of Implications for practice
• Nebulized epinephrine may be used to treat obstructive
evidence
airway symptoms associated with moderate to severe croup.
The number of relevant studies was small, as were total numbers
• The clinical effect of nebulized epinephrine is apparent at
of study subjects. Studies assessed a wide range of outcomes and
30 minutes post-treatment.
few studies examined the same outcomes, thus most outcomes
contained data from very few or even single studies. Timing of • There is no evidence to suggest that croup symptoms, on
outcome measures also varied between studies. Finally, co-inter- average, worsen after the treatment effect of nebulized
ventions (for example, corticosteroid administration) were not ex- epinephrine dissipates.
plicitly described for some studies. There were too few studies in-
• Five out of six epinephrine versus placebo trials have used
cluded to formally assess publication bias.
racemic epinephrine. There is only one small, good quality trial
We did not search for articles which included co-treatment with
comparing racemic epinephrine versus L-epinephrine and it
corticosteroids, as the question of whether adjunct epinephrine
provides reasonable evidence that L-epinephrine is at least as
therapy provides additional benefit to corticosteroid treatment
effective as racemic epinephrine if this drug for some reason is
alone will be addressed in a separate Cochrane Review.
not available.
Finally, none of the studies included children with mild croup.
However, mild croup is defined as minimal to no symptoms of • The addition of IPPB did not appear to improve the clinical
airway obstruction on presentation; epinephrine is used to provide effect of epinephrine as compared with nebulization alone.



Implications for research The review authors wish to thank the following people for com-
• Surveillance and reporting of adverse events associated with menting on the draft protocol: Josephine Wai Leng Chow, Gary
the administration of nebulized epinephrine should be carried Geelhoed, Joe Luria, Max Bulsara and Juan Lozano. We wish to
out. thank the following people for commenting on the draft review:
Jiaan-Der Wang, Shweta Bansal, Chris Vorwerk, Aroonwan Preut-
• Additional studies of interest might focus on health care
thipan, Teresa Neeman and Inge Axelsson.
utilization as an outcome.

We also thank Alberto Nettel-Aguirre for assessing the Spanish ar-
ticle for inclusion, assessing methodological quality and extracting
ACKNOWLEDGEMENTS appropriate data.

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Marx A, Torok TJ, Holman RC, Clarke MJ, treatment of pseudo-croup. Helvetica Paediatrica Acta 1982;
Anderson LJ. Pediatric hospitalizations for croup 37:431–6.
(laryngotracheobronchitis): biennial increases associated Westfall 2009
with human parainfluenza virus 1 epidemics. Journal of Westfall TC, Westfall DP, Brunton LL, Lazo JS, Parker
Infectious Diseases 1997;176(6):1423–7. KL. Chapter 10. Adrenergic agonists and antagonists. In:
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∗
in the treatment of acute laryngitis in children [Evaluation Indicates the major publication for the study



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

Adequate sequence generation? Low risk Random numbers table

Allocation concealment? Unclear risk Details not reported

Blinding? Low risk Nurse was the only one who knew study
All outcomes drug

Incomplete outcome data addressed? Unclear risk No missing data
All outcomes

Free of selective reporting? Unclear risk Details not reported

Free of other bias? Low risk



Fernadez 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


Adequate sequence generation? Unclear risk Details not reported

Allocation concealment? Low risk Vials were pre-numbered and non-labeled
by the pharmacy

Blinding? Low risk Nurses were not told which vial was used
All outcomes

Incomplete outcome data addressed? Unclear risk Details not reported
All outcomes


Free of other bias? High risk Authors measured croup score in 6-hour in-
tervals and measurements were treated sep-
arately 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)



Fogel 1982 (Continued)

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
Two 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


Adequate sequence generation? Unclear risk Details not reported - prospectively ran-
domized


Blinding? Low risk Patient and evaluator did not known
All outcomes

Incomplete outcome data addressed? Low risk Data were complete
All outcomes

Free of selective reporting? Low risk


Gardner 1973


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)



Gardner 1973 (Continued)

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



Allocation concealment? Unclear risk Used numbered vials but not described
how they were allocated

Blinding? Unclear risk Details not reported
All outcomes

Incomplete outcome data addressed? Low risk Pre-selected outcomes are not reported
All outcomes

Free of selective reporting? Unclear risk Methods do not include sufﬁcient details
to adequately assess


Kristjansson 1994


Participants 54 children presenting to the emergency department 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



Kristjansson 1994 (Continued)

Notes -

Risk of bias




Blinding? Unclear risk Details not reported
All outcomes

Incomplete outcome data addressed? Unclear risk Five additional patients were not included
All outcomes because protocols were incomplete - details
not reported



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




Cochrane croup

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