Cochrane croup

EVIDENCE-BASED CHILD HEALTH: A COCHRANE REVIEW JOURNALEvid.-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 2http://www.thecochranelibrary.com

Nebulized epinephrine for croup in children (Review)

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Evid.-Based Child Health 7:4: 1311–1354 (2012)

T A B L E O F C O N T E N T S

1313HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1313ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1314PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1314BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1315OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1315METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1317RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1319Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1320

1322DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1323AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1324ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1324REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1327CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . .1337DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Nebulized epinephrine versus placebo, Outcome 1 Croup score (change baseline - 30minutes). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1340

Analysis 1.2. Comparison 1 Nebulized epinephrine versus placebo, Outcome 2 Croup score (change baseline - 2hours). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1341

Analysis 1.3. Comparison 1 Nebulized epinephrine versus placebo, Outcome 3 Croup score (change baseline - 6hours). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1342

Analysis 1.4. Comparison 1 Nebulized epinephrine versus placebo, Outcome 4 Return visits and/or (re)admissions. 1343Analysis 1.5. Comparison 1 Nebulized epinephrine versus placebo, Outcome 5 Length of hospitalization in hours. 1344Analysis 1.7. Comparison 1 Nebulized epinephrine versus placebo, Outcome 7 Improvement. . . . . . . . 1345Analysis 2.1. Comparison 2 Nebulized racemic epinephrine versus L-epinephrine, Outcome 1 Croup score (change baseline

- 30 minutes). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1346Analysis 2.2. Comparison 2 Nebulized racemic epinephrine versus L-epinephrine, Outcome 2 Croup score (change baseline

- 2 hours). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1347Analysis 2.8. Comparison 2 Nebulized racemic epinephrine versus L-epinephrine, Outcome 8 Intubation. . . . 1348Analysis 3.1. Comparison 3 Nebulized epinephrine with IPPB versus nebulized epinephrine without IPPB, Outcome 1

Croup score (change baseline - 30 minutes). . . . . . . . . . . . . . . . . . . . . . . 1349Analysis 3.2. Comparison 3 Nebulized epinephrine with IPPB versus nebulized epinephrine without IPPB, Outcome 2

Croup score (change baseline - 2 hours). . . . . . . . . . . . . . . . . . . . . . . . 1350Analysis 3.8. Comparison 3 Nebulized epinephrine with IPPB versus nebulized epinephrine without IPPB, Outcome 8

Intubation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13511351APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1353HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1353CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . .1354DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1354DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . .1354INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1312Nebulized epinephrine for croup in children (Review)



[Intervention Review]

Nebulized epinephrine for croup in children

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

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

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.


A B S T R A C T

Background

Croup is a common childhood illness characterized by barky cough, stridor, hoarseness and respiratory distress. Children with severecroup 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 SpecializedRegister, MEDLINE (1966 to November Week 1, 2010), EMBASE (1980 to November 2010), Web of Science (1974 to November2010), 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. Comparisonswere: 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 andduration 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 studiesusing a priori inclusion criteria, followed by methodologic quality assessment. One author extracted data while the second checkedaccuracy. We performed standard statistical analyses.




Main results

Eight studies (225 participants) were included. NE was associated with croup score improvement 30 minutes post-treatment (threeRCTs, standardized mean difference (SMD) -0.94; 95% confidence interval (CI) -1.37 to -0.51; I2 statistic = 0%). This effect was notsignificant two and six hours post-treatment. NE was associated with significantly shorter hospital stay than placebo (one RCT, meandifference -32.0 hours; 95% CI -59.1 to -4.9). Comparing racemic and L-epinephrine, no difference in croup score was found after30 minutes (SMD 0.33; 95% CI -0.42 to 1.08). After two hours, L-epinephrine showed significant reduction compared with racemicepinephrine (one RCT, SMD 0.87; 95% CI 0.09 to 1.65). There was no significant difference in croup score between administrationof 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.

P L A I N L A N G U A G E S U M M A R Y

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 thevoice box (larynx). Although most cases of croup are mild and resolve on their own, occasionally the swelling can be severe enoughto cause difficulty in breathing. In these children, epinephrine (also called adrenaline) is a medication that is inhaled as a mist totemporarily 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, inhaledepinephrine improved croup symptoms in children at 30 minutes following treatment (three studies, 94 children). This treatmenteffect disappeared two hours after treatment (one study, 20 children). However, children’s symptoms did not become worse than priorto treatment. No study measured adverse events. This review is comprised of only eight studies and the number of included childrenwas small (225). Few studies examined similar outcomes, therefore data could often not be pooled and conclusions are based on oneor few studies.

B A C K G R O U N D

Description of the condition

Croup (laryngotracheobronchitis) is a common respiratory illnessof childhood, estimated to affect approximately 3% of childrenunder six years of age annually (Denny 1983; Johnson 2003). Theclinical picture is characterized by the abrupt onset of a distinctivebarky cough, which may be accompanied by stridor, hoarse voiceand respiratory distress. Croup symptoms are often preceded bynon-specific symptoms such as cough, rhinorrhea and fever. Themost common etiology is a viral infection, predominantly parain-fluenza virus (Marx 1997).

Description of the intervention

While most children with croup have mild symptoms (defined aspresence of a ’barky cough’, no audible stridor at rest, and no tomild chest wall indrawing) (Johnson 2001; Johnson 2003), a smallminority have severe symptoms characterized by marked chestwall indrawing, agitation and lethargy (Johnson 2001; Johnson2003). These children are at significant risk for intubation. Cor-ticosteroids decrease both the frequency and duration of hospi-talization and intubation (Kairys 1989; Russell 2004; Tibballs1992). A systematic review of corticosteroids found that comparedto placebo, corticosteroids significantly reduced six and 12-hourcroup scores, reduced length of hospital stay, and reduced returnvisits (Russell 2004). However, corticosteroids take an hour ormore after treatment to lessen respiratory distress (Geelhoed 1995;




Johnson 1998). Consequently in children with the most severesymptoms, a therapy with a rapid rate of onset may lessen the needfor intubation. The therapy most commonly used for this purposeis nebulized epinephrine. Children with moderate to severe croupare usually administered both epinephrine and corticosteroids con-currently to reduce respiratory distress while awaiting the effectsof the corticosteroid treatment. Alternative therapies are mist andheliox (helium-oxygen mixture) (Johnson 2005). However, recentevidence suggests that mist provides no significant clinical bene-fit (Moore 2006; Neto 2002; Scolnik 2006). Heliox has greaterpromise, but it is more cumbersome to use, and has little evidenceof effectiveness (Johnson 2005).

How the intervention might work

Nebulized epinephrine has been widely used for more than 30years, after the first report of its effectiveness in 1971 (Adair 1971).It is thought that epinephrine-induced vasoconstriction decreasesupper airway edema (Brown 2002; Johnson 2005; Kaditis 1998;Klassen 1999). While a small number of randomized controlledtrials (RCTs) have been published (Johnson 2005), to date nosystematic review has been published.Initial studies published in the 1970s and early 1980s suggestedthat epinephrine might be more effective when nebulized via IPPB(intermittent positive pressure breathing) than by nebulizationalone. The use of IPPB has now fallen out of favor and it is nolonger routinely used.Clinical severity in children with croup can be determined byboth direct measures (clinical scores, transcutaneous carbon diox-ide concentrations, pulsus paradoxus, impedance plesmography,radiographic measurement of tracheal diameter) and indirect ones(rate and duration of intubation, rate and duration of hospitaliza-tion, rate of return to seek medical care for ongoing croup symp-toms, sleep lost by parents, parental stress). Several objective tech-niques have been reported (Corkey 1981; Davis 1993; Fanconi1990; Steele 1998), but none are easy to use, nor measure changeacross the full range of clinical severity. Consequently they havenot been routinely used.The most widely used direct measure of respiratory severity aredifferent types of croup scores (Bourchier 1984; Corkey 1981;Downes 1975; Geelhoed 1995; Godden 1997; Husby 1993;Leipzig 1979; Massicotte 1973; Taussig 1975; von Muhlendahl1982; Westley 1978). The Westley croup score has been shownto be reliable (Johnson 1998; Klassen 1994) and, to some ex-tent, valid (Klassen 1994; Klassen 1995). None of the other croupscores, to our knowledge, have been assessed for either validity orreliability. On one hand, clinical scores are inevitably subjective atleast to some degree, and may not represent truly significant clin-ical change. On the other hand, clinical scores are arguably moresensitive to change, and therefore more likely to detect smallerdegrees of improvement.

Indirect measures of severity, such as health care utilization, arethought by many to capture significant clinical change better thanclinical scores. Some would argue that if a treatment cannot beshown to reduce health care utilization, it is of no benefit.We have chosen to assess and report both direct and indirect mea-sures of clinical change, with the intent of allowing the reader tomake their own judgement as to the relative merits of the differentmeasures.

Why it is important to do this review

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 reducetracheal swelling for over 30 years. However, currently there is nosystematic review examining the efficacy of this intervention.

O B J E C T I V E S

Primary objective

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

Secondary objectives

To assess the efficacy and severity of side effects of nebulizedracemic epinephrine versus nebulized L-epinephrine in childrenwith croup evaluated in an emergency department or hospital set-ting and to assess the efficacy and severity of side effects of neb-ulized epinephrine delivered with intermittent positive pressurebreathing (IPPB) versus nebulized epinephrine alone.

M E T H O D S

Criteria for considering studies for this review

Types of studies

Randomized controlled trials (RCTs) or quasi-RCTs (Q-RCTs)which compare the use of nebulized epinephrine to placebo, neb-ulized racemic epinephrine versus nebulized L-epinephrine, and




nebulized epinephrine delivered with intermittent positive pres-sure breathing (IPPB) versus nebulized epinephrine alone in chil-dren with croup.

Types of participants

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.

Types of interventions

1. Nebulized epinephrine (either racemic or L-epinephrine, ordelivered 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

Changes 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. Improvement5. 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 noexclusion criteria.

Search methods for identification of studies

Electronic searches

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),EMBASE (1980 to November 2010), Web of Science (1974 toNovember 2010), CINAHL (1982 to November 2010) and Sco-pus (1996 to November 2010).We used the following search terms to search MEDLINE andCENTRAL. We combined the MEDLINE search with the

Cochrane Highly Sensitive Search Strategy for identifying ran-domized trials in MEDLINE: sensitivity- and precision-maximiz-ing version (2008 revision) Ovid format (Lefebvre 2009). Weadapted the search strategy to search EMBASE (see Appendix 2),CINAHL (see Appendix 3), Web of Science (see Appendix 4) andScopus (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/1-57 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 adrenergicbeta-agonist*).tw,nm.13 or/7-1214 exp “Nebulizers and Vaporizers”/15 Aerosols/16 respiratory therapy/ or oxygen inhalation therapy/ or respira-tion, 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/14-1921 6 and 13 and 20

Searching other resources

We contacted experts in the field of acute respiratory infections tolocate additional studies. There were no language or publicationrestrictions.

Data collection and analysis

Selection of studies

Two review authors (CB, KR) independently scanned abstractsfrom the initial search results to identify trials that broadly metthe inclusion criteria. We then reviewed the full-text articles of theselected trials and the same two review authors independently ap-plied the inclusion criteria. We resolved differences by consensus.




Data extraction and management

We extracted data using a structured form that captures patientstatus (emergency department or inpatient, the author’s descrip-tion of their clinical severity), intervention and control character-istics (such as type of drug: racemic versus L-epinephrine), dosageand method of administration (nebulization alone versus nebu-lized with intermittent positive pressure breathing (IPPB)). In ad-dition, we collected data on the primary and secondary outcomemeasures if available: change from baseline clinical croup scores;rate and duration of intubation; rate and duration of hospitaliza-tion; and occurrence of hypertension, myocardial injury or car-diac arrhythmias. One review author (KR) extracted data and asecond 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 qualityof studies in three ways. We used more than one method sincethe relative merits of each remain controversial. First, we usedthe 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-cealment of allocation as adequate, inadequate or unclear (Schulz1995). Lastly, we classified studies by who sponsored them: phar-maceutical company, other sources or not mentioned (Cho 1996).We resolved differences by consensus. We compared and reportedthe results from the three different classification methods.

Measures of treatment effect

With regard to continuous variables, we calculated the changefrom baseline measures if change from baseline measures were notreported directly. As needed, we performed variance imputationsaccording to the work of Follmann (Follman 1992). We antici-pated that different clinical croup scores would be reported. If thiswas the case, we used trial standardized mean differences (SMDs)for pooled estimates. (A treatment effect (difference between treat-ment means) divided by its measurement variation (for example,a pooled standard deviation) gives a SMD). We also anticipatedthat croup scores would be assessed at a variety of time periods.Because the treatment effect of epinephrine is rapid, we assessedchange in croup score at 30 minutes, two hours and six hours. Ifa study did not assess change in croup scores at our time points ofinterest, we used the closest time point (for example, a 15-minutechange in croup score as used for the change in croup score at30 minutes outcome). We expressed duration of intubation andhospitalization as mean differences and calculated an overall meandifference.For binary data (that is, intubation and hospitalization rates), wecalculated risk ratios. If zero events occurred in both groups, wederived risk differences. If we found significant results, we cal-culated the number needed to treat to benefit (NNTB) or harm

(NNTH). We reported the pooled baseline rates using the inversevariance method.

Assessment of heterogeneity

We assessed heterogeneity quantitatively with the I2 statistic(Higgins 2002). The I2 statistic indicates the percent variabilitydue to between-study (or inter-study) variability as opposed towithin-study (or intra-study) variability. We considered an I2 valuegreater than 50% to be large. For the analyses of all outcomes,we used a random-effects model to combine treatment effects re-gardless of quantified heterogeneity. We considered a fixed-effectmodel in sensitivity analyses.We explored heterogeneity between studies using subgroup andsensitivity analyses performed on the primary outcome of thechange in clinical croup scores from baseline to 30 minutes and60 minutes. We considered the following subgroups: quality (thatis, the risk of bias, allocation concealment, funding, and simpleclassification of bias (low, moderate, or high)) and inpatient versusemergency department status.

Assessment of reporting biases

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

R E S U L T S

Description of studies

See: Characteristics of included studies; Characteristics of excludedstudies.

Results of the search

The electronic literature search identified 316 unique studies. Afterassessing the titles and, when available, the abstracts, we identified50 studies as being potentially relevant. Reviewing the referencelists of the included studies did not identify any additional studies.

Included studies

After applying the a priori inclusion criteria, eight of the 50 studiesmet the inclusion criteria. Three comparisons were examined: neb-ulized epinephrine versus placebo (Corkey 1981; Fernadez 1993;




Gardner 1973; Kristjansson 1994; Kuusela 1988; Westley 1978),nebulized racemic epinephrine versus L-epinephrine (Waisman1992) and nebulized epinephrine with IPPB versus nebulizedepinephrine without IPPB (Fogel 1982). All studies were random-ized placebo-controlled trials with the exception of the study com-paring nebulized epinephrine with and without IPPB, which wasa cross-over RCT. Seven studies were published in English and onein Spanish (Fernadez 1993). Studies tended to be small, rangingfrom 14 to 78 total participants per comparison.

Nebulized epinephrine versus placebo

Four studies took place in an inpatient setting, one in an out-patient setting, and one did not specify setting. In general, chil-dren within the studies were young (average age two years or lessin two studies, two to three years in two studies, and not spec-ified in two studies). Severity of croup in the majority of en-rolled children was judged to be moderate or moderate to severein all six studies. There was minor variance between studies in thetype 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 of2.25% racemic epinephrine per 5 kg 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 vali-dated. The Westley 17-point croup score incorporates assessmentof 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-validated croup scores as outcome measures, with total possiblepoints ranging from six to 12 points.

Nebulized racemic epinephrine versus L-epinephrine

We identified a single study suitable for inclusion, of 66 childrenin an inpatient setting (Waisman 1992). Average age was young

(11 months) and baseline severity of croup on study admission wasmoderate. The doses of racemic epinephrine and L-epinephrinewere 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 theprimary outcome measure.

Nebulized epinephrine with IPPB versus nebulized

epinephrine without IPPB

We identified a single study suitable for inclusion, of 14 chil-dren in an inpatient setting (Fogel 1982). Average age was young(1.9 years), and baseline severity of croup on study admission wasmoderate. The dose of racemic epinephrine used was 0.25 ml of2.25%. The IPPB pressure used was 15 cm to 17 cm of waterand two hours after the first treatment, cross-over to the othergroup occurred. A modified 16-point croup score based upon thevalidated Westley croup score (level of consciousness, four points;color, four points; stridor, three points; air entry, two points; andchest wall retractions, three points) was utilized as the primaryoutcome measure.

Excluded studies

We excluded a total of 42 studies. The exact reason for exclusionis provided in the Characteristics of excluded studies table.

Risk of bias in included studies

Six of the eight studies were deemed to have a low risk of bias andthe risk of bias was unclear in the remaining two studies (Fernadez1993; Kuusela 1988). Half of the studies reported adequate con-cealment of allocation (Fernadez 1993; Kuusela 1988; Waisman1992; Westley 1978). Only one study reported a funding source(Kristjansson 1994). The results from the various quality indica-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

Allocation concealment was adequate in three of the studies (Fernadez 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 wasblinded (Gardner 1973; Westley 1978).

Incomplete outcome data

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

Selective reporting

All but two studies (Fogel 1982; Waisman 1992) reported a pri-mary 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


There were six studies (183 participants) that reported data com-paring nebulized epinephrine versus placebo. Four (109 partici-pants) of these six studies took place in an inpatient setting, whileone (54 participants) took place in an outpatient setting, and one(20 participants) did not specify the setting. While six studies wereincluded in this section, no more than three were included in anyparticular analysis.

Primary outcome: croup score

Since all studies used different systems in their croup scoring,we used SMDs to synthesize the data. Three studies showed thatepinephrine had a statistically significant smaller croup score thanplacebo after 30 minutes (SMD -0.94; 95% CI -1.37 to -0.51; I2 statistic = 0%) (Analysis 1.1). The change in croup score wasalmost identical for the two studies that looked at inpatients (SMD-0.82; 95% CI -1.47 to -0.17; I2 statistic = 0%) (Analysis 1.1.1)and the one study that looked at outpatients (SMD -1.03; 95%

CI -1.60 to -0.46) (Analysis 1.1.2). Heterogeneity was negligiblein these comparisons.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 statisticallysignificant.

Secondary outcomes

There were two studies that reported length of hospital stay (inhours), one each in the inpatient and outpatient settings. The in-patient study showed children on epinephrine spent a statisticallysignificant smaller amount of time in the hospital than placeboparticipants in the hospital (MD -32.00; 95% CI -59.14 to -4.86)(Analysis 1.5.1), while the outpatient study had a much smallerand non-significant difference (MD -1.80; 95% CI -4.07 to 0.47)(Analysis 1.5.2). We did not combine these two studies as wewould not expect similar hospital stays between inpatients andoutpatients.Two studies counted the number of participants that had signif-icant improvement. Improvement was defined in one study as adecrease in the croup score of greater that 2 or more points (2/10 total points) (Gardner 1973), and in the other study as a de-crease in the croup score of greater than 2 or more points (2/15) (Kristjansson 1994). The combined risk ratio (RR) did favorepinephrine but it was not statistically significant (RR 1.46; 95%CI 0.82 to 2.60; I2 statistic = 17%) (Analysis 1.7). Heterogeneitywas moderate.The only other outcome of interest that was reported by any of thestudies was return visits, which was reported by one study. How-ever, that study reported no re-admissions in either the epinephrineor the placebo group, thus we computed no statistics. No studyreported rate and duration of intubation, or parental anxiety.

Nebulized racemic epinephrine versus L-epinephrine

Waisman 1992 (28 participants) compared nebulized racemicepinephrine versus L-epinephrine in an outpatient setting. Therewas no significant difference in croup score between the two typesof epinephrine after 30 minutes (SMD 0.33; 95% CI -0.42 to1.08) (Analysis 2.1.2) but after two hours, L-epinephrine showedsignificant reduction over racemic epinephrine (SMD 0.87; 95%CI 0.09 to 1.65) (Analysis 2.2.2 ).The only other outcome reported was intubation, where theracemic group had an intubation rate of 3/16 and the L-epinephrine group had a rate of 0/14, which was a non-significantdifference (RD 0.19; 95% CI -0.03 to 0.40) (Analysis 2.8).






Fogel 1982 (14 participants) compared nebulized epinephrinewith IPPB versus nebulized epinephrine without IPPB in an in-patient setting. After 30 minutes, there was no significant differ-ence in croup score between the two groups (SMD -0.72; 95%CI -1.86 to 0.42) (Analysis 3.1.1), while at two hours there was alarger, still non-significant difference (SMD -0.14; 95% CI -1.24to 0.95) (Analysis 3.2.1).The only other outcome reported in this study was that of intu-bation. However, both groups had zero intubations, thus we com-puted no statistics.

Subgroup, sensitivity and publication bias analysis

Since none of our analyses contained more than three studies, nofurther analysis exploring heterogeneity or publication bias couldbe conducted.

D I S C U S S I O N

Summary of main results

Nebulized epinephrine has become standard management, espe-cially in North America, for the treatment of moderate and severecroup. Nebulized epinephrine is typically administered to a childwith moderate or severe upper airway obstruction in either anemergency department or inpatient setting. Though widely usedin clinical practice, our search identified only six relevant clinicaltrials comparing nebulized epinephrine to placebo that includeda total of 183 subjects (Corkey 1981; Fernadez 1993; Gardner1973; Kristjansson 1994; Kuusela 1988; Westley 1978).


Primary outcome: croup score

Data from this review have shown that, compared to placebo, neb-ulized racemic epinephrine effectively improves croup symptomsas measured by clinical croup scores in children 30 minutes fol-lowing treatment. Three trials assessed croup score at 30 minutes(Corkey 1981; Kristjansson 1994; Westley 1978). Although thenumber of children was small (94 participants), the pooled dataindicated a moderate to large reduction in croup score as com-pared with placebo (Cohen 1969). All three trials favored racemicepinephrine over placebo and the magnitude of benefit was similarand consistent between studies and in both inpatient and outpa-tient settings.

At 120 minutes following treatment, the mean difference in croupscore was similar in both racemic epinephrine and placebo groupsin the single, small (20 participants) study (Westley 1978). Al-though the observed clinical benefit of epinephrine had essentiallydissipated at 120 minutes, there was no evidence, on average, tosuggest that there was an increase or worsening of croup score, ascompared to pre-treatment or baseline in the group of childrentreated with epinephrine.Two studies (69 participants) assessed croup score at six hours fol-lowing treatment in an inpatient setting (Fernadez 1993; Kuusela1988) and found no difference in croup score between the neb-ulized racemic epinephrine and placebo groups. This is not sur-prising given the relatively brief duration of action of nebulizedepinephrine and is also consistent with the finding of no differencein croup score at the 120-minute assessment.

Secondary outcomes

In a single inpatient study, hospital stay was shorter among thosetreated with nebulized racemic epinephrine group as comparedwith placebo (Kuusela 1988). The mean difference of 32 hours wasboth statistically and clinically significant. Confidence intervalswere 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 forthe shorter hospital stay in the epinephrine group. Length of stayin the outpatient setting was assessed in one study and it was simi-lar between epinephrine and placebo groups (Kristjansson 1994).Equal proportions of children (52% and 58% in the racemicepinephrine and placebo groups, respectively) received concomi-tant corticosteroid treatment. No difference in length of stay isconsistent with resolution of clinical effect by two hours after treat-ment.We chose to report the outcome proportion of patients improvedeven though we had not pre-specified it as a secondary outcomebecause one study (Gardner) did not report the actual croup scorevalues, only the proportion of children whose croup score hadimproved by two or more points versus those which had not.

Racemic epinephrine versus L-epinephrine

A small, methodologically sound study comparing nebulizedracemic epinephrine with L-epinephrine in the outpatient settingshowed no difference in croup score 30 minutes following treat-ment (Waisman 1992). By 120 minutes, there was a statisticallysignificant result showing L-epinephrine to have a longer durationof benefit than racemic epinephrine.Racemic epinephrine is composed of equal proportions of D-and L-isomers of epinephrine and was originally used to treatcroup because it was hypothesized that racemic epinephrine wouldcause fewer cardiovascular side effects than L-epinephrine. L-epinephrine is the type of epinephrine routinely used for other in-dications 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 1:1000epinephrine) and found no statistically significant differences incardiovascular side effects between the two drugs. In addition, it isnow known that only L-epinephrine is pharmacologically active;the R-isomer has no activity (Westfall 2009).



One study of good methodological quality found that nebulizedepinephrine with IPPB was similar to nebulized epinephrine with-out IPPB in the inpatient setting (Fogel 1982). However, thisstudy was small and not designed to show equivalence. Nonethe-less, given the technical challenges of IPPB and no evidence ofsuperiority, routine use of nebulized epinephrine without IPPBseems justified.

Safety of nebulized epinephrine

Though none of the clinical trials reported significant adverseevents associated with nebulized epinephrine, the small total num-ber of study subjects and rarity of adverse events provides insuf-ficient data to conclude that the use of nebulized epinephrine isuniversally safe. Further, none of these trials assessed the effective-ness or safety of epinephrine when administered repeatedly in arow. A single case report of ventricular tachycardia and myocardialinfarction in a previously healthy child who received three dosesof nebulized epinephrine in one hour raises concerns about po-tential cardiac toxicity (Butte 1999). While this case is of concern,given the widespread use of epinephrine over several decades, itseems unlikely, however, that one or even two nebulized doses ofepinephrine poses significant risk to a child.

Overall completeness and applicability ofevidence

The number of relevant studies was small, as were total numbersof study subjects. Studies assessed a wide range of outcomes andfew studies examined the same outcomes, thus most outcomescontained data from very few or even single studies. Timing ofoutcome measures also varied between studies. Finally, co-inter-ventions (for example, corticosteroid administration) were not ex-plicitly described for some studies. There were too few studies in-cluded to formally assess publication bias.We did not search for articles which included co-treatment withcorticosteroids, as the question of whether adjunct epinephrinetherapy provides additional benefit to corticosteroid treatmentalone 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 ofairway obstruction on presentation; epinephrine is used to provide

temporary relief of airway obstructive symptoms and, thus, thereis not a strong rationale for the use of epinephrine in children withmild croup.

Quality of the evidence

The majority of the studies were at low risk of bias and half of thestudies reported adequately concealed patient allocation methods.While all studies were double-blind and the majority of the studiesreported their primary outcome, several studies reported a loss tofollow 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 multipledatabases, contacted experts in the field, and applied no languageor publication restrictions to minimize the chance of bias due tomissing published studies or non-English language studies. Thisreview did contain one Spanish language study. As none of ouranalyses contained more than three studies, no further analysisexploring heterogeneity or publication bias could be performed.Thus, the possibility of publication bias cannot be ruled out.

Agreements and disagreements with otherstudies or reviews

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

A U T H O R S ’ C O N C L U S I O N S

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 at30 minutes post-treatment.

• There is no evidence to suggest that croup symptoms, onaverage, worsen after the treatment effect of nebulizedepinephrine dissipates.

• Five out of six epinephrine versus placebo trials have usedracemic epinephrine. There is only one small, good quality trialcomparing racemic epinephrine versus L-epinephrine and itprovides reasonable evidence that L-epinephrine is at least aseffective as racemic epinephrine if this drug for some reason isnot available.

• The addition of IPPB did not appear to improve the clinicaleffect 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 carriedout.

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

A C K N O W L E D G E M E N T S

The review authors wish to thank the following people for com-menting on the draft protocol: Josephine Wai Leng Chow, GaryGeelhoed, Joe Luria, Max Bulsara and Juan Lozano. We wish tothank the following people for commenting on the draft review:Jiaan-Der Wang, Shweta Bansal, Chris Vorwerk, Aroonwan Preut-thipan, Teresa Neeman and Inge Axelsson.

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

R E F E R E N C E S

References to studies included in this review

Corkey 1981 {published data only}Corkey C, Barker G, Edmonds J, Mok P, Newth C.Radiographic tracheal diameter measurements in acuteinfectious croup: an objective scoring system. Critical Care

Medicine 1981;9:587–90.

Fernadez 1993 {published data only}Fernandez MA, Gonzalez SE, Etxefarria RI, Urcelay EI, DiezAM, Ciriza WM, et al.Randomized double-blind study oftreatment of croup with adrenaline and/or dexamthasone inchildren. Anales Espandoles de Pediatria 1993;38(1):29–32.

Fogel 1982 {published data only}Fogel JM, Berg IJ, Gerber MA, Sherter CB. Racemicepinephrine in the treatment of croup: nebulization aloneversus nebulization with intermittent positive pressurebreathing. Journal of Pediatrics 1982;101(6):1028–31.

Gardner 1973 {published data only}Gardner HG, Powell KR, Roden VJ, Cherry JD. Theevaluation of racemic epinephrine in the treatment ofinfectious croup. Pediatrics 1973;52(1):52–5.

Kristjansson 1994 {published data only}Kristjansson S, Berg-Kelly K, Winso E. Inhalation ofracemic adrenaline in the treatment of mild and moderatelysevere croup. Clinical symptom score and oxygen saturationmeasurements for evaluation of treatment effects. Acta

Paediatrica 1994;83(11):1156–60.

Kuusela 1988 {published data only}Kuusela AL, Vesikari T. A randomized double-blind,placebo-controlled trial of dexamethasone and racemicepinephrine in the treatment of croup. Acta Paediatrica

Scandinavica 1988;77(1):99–104.

Waisman 1992 {published data only}Waisman Y, Klein BL, Boenning DA, Young GM,Chamberlain JM, O’Donnel R, et al.Prospective randomizeddouble-blind study comparing L-epinephrine and racemicepinephrine aerosols in the treatment of laryngotracheitis(croup). Pediatrics 1992;89(2):302–6.

Westley 1978 {published data only}Westley C, Ross C, Brooks J. Neublized racemic epinephrineby IPPB for the treatment of croup: a double-blind study.American Journal of Diseases of Children 1978;132:484–7.

References to studies excluded from this review

Annonymous 1996 {published data only}Annonymous. Inhaled budesonide and adrenaline forcroup. Drug and Therapeutics Bulletin 1996;34(3):22–4.

Banac 2005 {published data only}Banac S, Palcieevski G, Roziemanici V, Ahel V.Administration of nebulized L-epinephrine in children withcroup. Medicina 2005;41(3):242–5.

Bass 1978 {published data only}Bass JW. Croup - IPPD and/or racemic epinephrine therapy.Pediatrics 1978;61(1):148–9.

Bass 1980 {published data only}Bass JW. Corticosteroids and racemic epinephrine withIPPD in the treatment of croup. Journal of Pediatrics 1980;96(1):173–4.

Beaudry 1983 {published data only}Beaudry PH, Laussig LM, Bureau M. Efficacy of racemicepinephrine in croup. Journal of Pediatrics 1983;103(4):661–2.

Brown 2002 {published data only}Brown J. The management of croup. British Medical

Bulletin 2002;61:189–202.

Celis 1978 {published data only}Celis PA, Frias VJ, Aragon JG, Eternod GJ, Serafin FJ.Evaluation of racemic epinephrine with intermittentpositive pressure in the treatment of acute infectionslaryngotracheitis. Boletin Medico del Hospital Infantile de

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Cherry 1974 {published data only}Cherry JD, Powell KR, Gardner HG, Roden VJ. Letter:Racemic epinephrine in croup. Pediatrics 1974;53(2):290–1.

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Cristaldi 2001 {published data only}Cristaldki A, Villani A, Bifano M, Cavaliere GF, CristaldiS, Turbacci M, et al.[Osturzione acuta delle alte vierespiratorie]. Rivista Italiana Di Pediatria 2001;27(4):462–5.

Cronin 1996 {published data only}Cronin M, Diedericks R. Steroids in the management ofcroup - nebulized adrenaline is also useful. BMJ 1996;312(7029):510.

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Ellis 1974 {published data only}Ellis EF, Taylor JC, Lefkowit MS. Racemic epinephrine incroup (continued). Pediatrics 1974;53(2):291–2.

Fitzgerald 1996 {published data only}Fitzgerald D, Mellis C, Johnson M, Allen H, Cooper P,Asperen P. Nebulized budesonide is as effective as adrenalinein moderately severe croup. Pediatrics 1996;97(5):722–5.

Fogel 1983 {published data only}Fogel JM, Berg IJ, Gerber MA, Sherter CB. Efficacy inracemic epinephrine in croup - reply. Journal of Pediatrics

1983;103(4):662.

Ghosh 2001 {published data only}Ghosh A, Morton R. Nebulized epinephrine orcorticosteroids in croup. Emergency Medicine Journal 2001;18(2):119.

Gilligan 2005 {published data only}Gilligan P, Shepherd M, Lumsden G, Law H, BrenchleyJ, Kitching G, et al.SOCRATES 4 (synopsis of Cochranereviews applicable to emergency services). Emergency

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Gonzalez 1984 {published data only}Gonzalez ER, Burke TG. Review of the status ofintermittent positive pressure breathing therapy. Drug

Intelligence & Clinical Pharmacy 1984;18(12):974–6.

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Journal of Emergency Medicine 1996;14(1):104–6.

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of Pediatrics 1983;103(4):661.

Kunkel 1996 {published data only}Kunkle NC, Baker MD. Use of racemic epinephrine,dexamethasone, and mist in the outpatient management ofcroup. Pediatric Emergency Care 1996;12(3):156–9.

Ledwith 1995 {published data only}Ledwith CA, Shea LM, Mauro RD. Safety and efficacy ofnebulized racemic epinephrine in conjunction with oraldexamethasone and mist in the outpatient treatment ofcroup. Annals of Emergency Medicine 1995;25(3):331–7.

Lenney 1978 {published data only}Lenney W, Milner AD. Treatment of acute viral croup.Archives of Disease in Childhood 1978;53(9):704–6.

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Remington 1986 {published data only}Remington S, Meakin G. Nebulized adrenaline 1-1000 inthe treatment of croup. Anaesthesia 1986;41(9):923–6.

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Singer 1976 {published data only}Singer OP, Wilson WJ. Laryngotracheobronchitis - 2 yearsexperience with racemic epinephrine. Canadian Medical

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Taussig 1975 {published data only}Taussig L, Castro O, Beaudry P, Fox W, Bureau M.Treatment of laryngotracheobronchitis (croup): use ofintermittent positive-pressure breathing and racemicepinephrine. American Journal of Diseases of Children 1975;129:790–3.

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C H A R A C T E R I S T I C S O F S T U D I E S

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 randomizationDefinition of croup: upper respiratory tract infections, often with fever, followed by theonset 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 mLof distilled water IPPB (n = 8) or 4 mL of placebo with IPPB (n = 6)The IPPB flow rate was 10 L/min, 100% oxygenTreatment 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?All outcomes

Low risk Nurse was the only one who knew studydrug

Incomplete outcome data addressed?All outcomes

Unclear risk No missing data

Free of selective reporting? Unclear risk Details not reported

Free of other bias? Low risk




Fernadez 1993

Methods Randomized, placebo-controlled trialNo withdrawals

Participants All participants (children) hospitalized because of croup symptoms (unclear if spasmodiccroup was excluded)

Interventions 0.5 mg/kg of nebulized L-epinephrine (containing 5 mg L-epinephrine) (n = 15) orplacebo (n = 17) (delivered via nebulization alone)At least half of the children received IM dexamethasone but it is unclear which treatmentthey received first

Outcomes Croup score (8 points: stridor 0 to 2 points, respiratory distress 0 to 2 points, cough 0to 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-labeledby the pharmacy


Low risk Nurses were not told which vial was used


Unclear risk Details not reported


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 trialNo withdrawals

Participants 14 children admitted to hospital with persistent inspiratory stridor at rest after 20 to 30minutes of mist therapy. Children remained in a mist tent during the study period andreceived supplemental oxygen as indicatedDefinition 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 cmTwo 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 to4 points, stridor 0 to 3 points, air entry 0 to 2 points, retractions 0 to 3 points) at 30,60, 90 and 120 minutesHeart rateRespiratory rateSupplemental oxygenIntubationAdverse reactions

Notes IPPB: intermittent positive pressure breathing

Risk of bias


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



Low risk Patient and evaluator did not known


Low risk Data were complete

Free of selective reporting? Low risk


Gardner 1973


Participants 20 children with moderate croup (unclear if spasmodic croup was excluded) - inpatientor outpatient status not reportedCo-interventions were not reported

Interventions 0.5 mL of 2.25% racemic epinephrine (containing 5 mg L-epinephrine) in 3.5 mL ofsaline (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 croupscore assessment not reportedImprovementAdditional treatment of study drug

Notes -

Risk of bias



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




Low risk Pre-selected outcomes are not reported

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


Kristjansson 1994


Participants 54 children presenting to the emergency department with moderate croup (unclear ifspasmodic 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 vianebulization alone)

Outcomes Croup score (15 points: inspiratory stridor 0 to 3 points, retractions 0 to 3 points, airentry 0 to 3 points, cyanosis 0 to 3 points, state of consciousness 0 to 3 points) at 30and 120 minutesRespiratory rateHeart rateLength of stayAdditional treatmentBetamethasone treatmentRe-admission




Kristjansson 1994 (Continued)

Notes -

Risk of bias







Unclear risk Five additional patients were not includedbecause protocols were incomplete - detailsnot reported



Kuusela 1988

Methods Randomized, double-blind, placebo-controlled trial78 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 withspasmodic 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 IPPBNebulization was repeated at 2 hours

Outcomes Dyspnea score (0 to 3 points)Cough score (0 to 3 points) at 6, 12, 24 and 48 hoursLength of staypH day 1PCO2 day 1Base deficit

Notes PCO2: partial pressure of carbon dioxide

Risk of bias






Kuusela 1988 (Continued)

Allocation concealment? Low risk Sequentially numbered




Unclear risk Six patients not analyzed but details notreported



Waisman 1992

Methods Randomized, double-blind controlled trial3 children were withdrawn

Participants 66 children hospitalized due to symptoms suggestive of moderate croup (spasmodiccroup was excluded). All children were received mist therapy prior to randomizationCroup suggestive symptoms: acute laryngitis, laryngotracheobronchitis and laryngitiswith stridor

Interventions 2.25% racemic epinephrine (n = 16) or 5 mL of 1:1000 L-epinephrine (n = 15) (eachcontaining 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 minutesRespiratory rateDexamethasone treatmentSupplemental oxygenIntubation

Notes -

Risk of bias


Adequate sequence generation? Low risk Table of random numbers

Allocation concealment? Low risk Pharmacy-controlled randomization


Low risk Identical vials blinded to patient and inves-tigator




Waisman 1992 (Continued)


Low risk 3 patients were not included because of in-tubation (n = 2) and tracheal stenosis (n =1)

Free of selective reporting? Unclear risk Primary outcome not reported


Westley 1978

Methods Randomized, double-blind, placebo-controlled trial3 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 minutesin a humidity mist room (unclear if spasmodic croup was excluded). All children receivedcontinuous room temperature mist and no supplemental oxygen was given except duringIPPB treatment and 4 children received antibiotics

Interventions 0.5 mL of 2.25% racemic epinephrine (containing 5 mg L-epinephrine) (n = 10) ornebulized 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 5points, stridor 0 to 2 points, air entry 0 to 2 points, retractions 0 to 3 points) at 10, 30,and 120 minutesPulseRespiratory rate

Notes -

Risk of bias


Adequate sequence generation? Low risk Table of random numbers

Allocation concealment? Low risk Prepared identical bottles


Low risk Identical bottles and code unknown to in-vestigators


Low risk Missing data for 3 patients because IPPBmachine broke






IM = intramuscularIPPB = intermittent positive pressure breathingPCO2 = partial pressure of carbon dioxide

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Annonymous 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

Dardick 1974 Not a RCT

Dunman 2005 Compares cool mist and intramuscular dexamethasone versus nebulized L-epinephrine and intramusculardexamethasone versus nebulized L-epinephrine and nebulized budesonide

Ellis 1974 Not a RCT

Fitzgerald 1996 Compares L-epinephrine versus budesonide

Fogel 1983 Not a RCT

Ghosh 2001 Not a RCT

Gilligan 2005 Not a RCT

Gonzalez 1984 Not a RCT




(Continued)

Heisinge 1974 Not a RCT

Jones 1996 Not a RCT

Klassen 1997 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

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 adminis-tered)

Taussig 1976 Not a RCT

Thomas 1998 Not a RCT

Thompson 1974 Not a RCT

Weber 2001 Compared epinephrine to heliox

Zach 1981 Not a RCT

RCT = randomized controlled trial




D A T A A N D A N A L Y S E S

Comparison 1. Nebulized epinephrine versus placebo

Outcome or subgroup titleNo. ofstudies

No. ofparticipants 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 - 2hours)

1 20 Std. Mean Difference (IV, Random, 95% CI) -0.15 [-1.03, 0.73]

2.1 Inpatient 1 20 Std. Mean Difference (IV, Random, 95% CI) -0.15 [-1.03, 0.73]2.2 Outpatient 0 0 Std. Mean Difference (IV, Random, 95% CI) Not estimable


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) Not estimable3.3 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 Return visits and/or(re)admissions

1 54 Risk Difference (M-H, Random, 95% CI) Not estimable

4.1 Inpatient 0 0 Risk Difference (M-H, Random, 95% CI) Not estimable4.2 Outpatient 1 54 Risk Difference (M-H, Random, 95% CI) Not estimable

5 Length of hospitalization inhours

2 Mean Difference (IV, Random, 95% CI) Subtotals only

5.1 Inpatient 1 37 Mean Difference (IV, Random, 95% CI) -32.0 [-59.14, -4.86]5.2 Outpatient 1 54 Mean Difference (IV, Random, 95% CI) -1.80 [-4.07, 0.47]

6 Hospitalization 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable7 Improvement 2 74 Risk Ratio (M-H, Random, 95% CI) 1.46 [0.82, 2.60]

7.1 Inpatient 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable7.2 Outpatient 1 54 Risk Ratio (M-H, Random, 95% CI) 1.83 [0.96, 3.50]7.3 Setting not reported 1 20 Risk Ratio (M-H, Random, 95% CI) 1.0 [0.42, 2.40]

8 Length of intubation 0 0 Mean Difference (IV, Random, 95% CI) Not estimable8.1 Inpatient 0 0 Mean Difference (IV, Random, 95% CI) Not estimable8.2 Outpatient 0 0 Mean Difference (IV, Random, 95% CI) Not estimable

9 Intubation 0 0 Risk Difference (M-H, Random, 95% CI) Not estimable9.1 Inpatient 0 0 Risk Difference (M-H, Random, 95% CI) Not estimable9.2 Outpatient 0 0 Risk Difference (M-H, Random, 95% CI) Not estimable

10 Parental anxiety 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable10.1 Inpatient 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable10.2 Outpatient 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable

11 Adverse events 0 0 Risk Difference (M-H, Random, 95% CI) Not estimable11.1 Hypertension 0 0 Risk Difference (M-H, Random, 95% CI) Not estimable11.2 Myocardial injury 0 0 Risk Difference (M-H, Random, 95% CI) Not estimable11.3 Cardial arrhythmia 0 0 Risk Difference (M-H, Random, 95% CI) Not estimable11.4 Pallor 0 0 Risk Difference (M-H, Random, 95% CI) Not estimable11.5 Sustained tachycardia 0 0 Risk Difference (M-H, Random, 95% CI) Not estimable11.6 Tremor 0 0 Risk Difference (M-H, Random, 95% CI) Not estimable




Comparison 2. Nebulized racemic epinephrine versus L-epinephrine




1 28 Std. Mean Difference (IV, Random, 95% CI) 0.33 [-0.42, 1.08]

1.1 Inpatient 0 0 Std. Mean Difference (IV, Random, 95% CI) Not estimable1.2 Outpatient 1 28 Std. Mean Difference (IV, Random, 95% CI) 0.33 [-0.42, 1.08]


1 28 Std. Mean Difference (IV, Random, 95% CI) 0.87 [0.09, 1.65]

2.1 Inpatient 0 0 Std. Mean Difference (IV, Random, 95% CI) Not estimable2.2 Outpatient 1 28 Std. Mean Difference (IV, Random, 95% CI) 0.87 [0.09, 1.65]

3 Return visits and/or (re)admissions





4.1 Inpatient 0 0 Mean Difference (IV, Random, 95% CI) Not estimable4.2 Outpatient 0 0 Mean Difference (IV, Random, 95% CI) Not estimable

5 Hospitalization 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable6 Improvement 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable

6.1 Inpatient 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable6.2 Outpatient 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable


8 Intubation 1 30 Risk Difference (M-H, Random, 95% CI) 0.19 [-0.03, 0.40]8.1 Inpatient 0 0 Risk Difference (M-H, Random, 95% CI) Not estimable8.2 Outpatient 1 30 Risk Difference (M-H, Random, 95% CI) 0.19 [-0.03, 0.40]






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









3 Return visits and/or (re)admissions





4.1 Inpatient 0 0 Mean Difference (IV, Random, 95% CI) Not estimable4.2 Outpatient 0 0 Mean Difference (IV, Random, 95% CI) Not estimable

5 Hospitalization 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable6 Improvement 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable

6.1 Inpatient 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable6.2 Outpatient 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable


8 Intubation 1 14 Risk Difference (M-H, Random, 95% CI) Not estimable8.1 Inpatient 1 14 Risk Difference (M-H, Random, 95% CI) Not estimable8.2 Outpatient 0 0 Risk Difference (M-H, Random, 95% CI) Not estimable






Analysis 1.1. Comparison 1 Nebulized epinephrine versus placebo, Outcome 1 Croup score (change

baseline - 30 minutes).

Review: Nebulized epinephrine for croup in children

Comparison: 1 Nebulized epinephrine versus placebo

Outcome: 1 Croup score (change baseline - 30 minutes)

Study or subgroup Epinephrine Placebo

Std.Mean

Difference Weight

Std.Mean

Difference

N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

1 Inpatient

Corkey 1981 10 -2 (2.06) 10 -0.1 (1.76) 21.1 % -0.95 [ -1.89, -0.01 ]

Westley 1978 10 -2.2 (1.64) 10 -1 (1.67) 22.4 % -0.69 [ -1.60, 0.21 ]

Subtotal (95% CI) 20 20 43.5 % -0.82 [ -1.47, -0.17 ]Heterogeneity: Tau2 = 0.0; Chi2 = 0.15, df = 1 (P = 0.70); I2 =0.0%

Test for overall effect: Z = 2.46 (P = 0.014)

2 Outpatient

Kristjansson 1994 25 -2.7 (1.88) 29 -1.1 (1.14) 56.5 % -1.03 [ -1.60, -0.46 ]

Subtotal (95% CI) 25 29 56.5 % -1.03 [ -1.60, -0.46 ]Heterogeneity: not applicable


Total (95% CI) 45 49 100.0 % -0.94 [ -1.37, -0.51 ]Heterogeneity: Tau2 = 0.0; Chi2 = 0.38, df = 2 (P = 0.83); I2 =0.0%


-10 -5 0 5 10

Favours epinephrine Favours placebo





baseline - 2 hours).



Outcome: 2 Croup score (change baseline - 2 hours)


Std.Mean

Difference Weight

Std.Mean

Difference


1 Inpatient

Westley 1978 10 -0.6 (1.64) 10 -0.3 (2.19) 100.0 % -0.15 [ -1.03, 0.73 ]

Subtotal (95% CI) 10 10 100.0 % -0.15 [ -1.03, 0.73 ]Heterogeneity: not applicable


2 Outpatient

Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]Heterogeneity: not applicable

Test for overall effect: not applicable

Total (95% CI) 10 10 100.0 % -0.15 [ -1.03, 0.73 ]Heterogeneity: not applicable


-4 -2 0 2 4






baseline - 6 hours).





Std.Mean

Difference Weight

Std.Mean

Difference


1 Inpatient

Fernadez 1993 15 -2.4 (1.5) 17 -2.2 (1.2) 25.1 % -0.14 [ -0.84, 0.55 ]

Kuusela 1988 16 2 (0.4) 21 2.5 (0.5) 24.9 % -1.06 [ -1.76, -0.36 ]

Subtotal (95% CI) 31 38 50.0 % -0.60 [ -1.50, 0.30 ]Heterogeneity: Tau2 = 0.30; Chi2 = 3.34, df = 1 (P = 0.07); I2 =70%


2 Outpatient



3 IPPB administration

Kuusela 1988 16 2 (0.4) 21 2.5 (0.5) 24.9 % -1.06 [ -1.76, -0.36 ]



4 No IPPB administration

Fernadez 1993 15 -2.4 (1.5) 17 -2.2 (1.2) 25.1 % -0.14 [ -0.84, 0.55 ]



Total (95% CI) 62 76 100.0 % -0.60 [ -1.12, -0.08 ]Heterogeneity: Tau2 = 0.16; Chi2 = 6.68, df = 3 (P = 0.08); I2 =55%


-2 -1 0 1 2





Analysis 1.4. Comparison 1 Nebulized epinephrine versus placebo, Outcome 4 Return visits and/or

(re)admissions.



Outcome: 4 Return visits and/or (re)admissions

Study or subgroup Epinephrine PlaceboRisk

Difference WeightRisk

Difference

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Inpatient

Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]Total events: 0 (Epinephrine), 0 (Placebo)

Heterogeneity: not applicable


2 Outpatient

Kristjansson 1994 0/25 0/29 100.0 % 0.0 [ -0.07, 0.07 ]

Subtotal (95% CI) 25 29 100.0 % 0.0 [ -0.07, 0.07 ]Total events: 0 (Epinephrine), 0 (Placebo)



Total (95% CI) 25 29 100.0 % 0.0 [ -0.07, 0.07 ]Total events: 0 (Epinephrine), 0 (Placebo)



-0.5 -0.25 0 0.25 0.5





Analysis 1.5. Comparison 1 Nebulized epinephrine versus placebo, Outcome 5 Length of hospitalization in

hours.



Outcome: 5 Length of hospitalization in hours

Study or subgroup Epinephrine PlaceboMean

Difference WeightMean

Difference


1 Inpatient

Kuusela 1988 16 59 (43) 21 91 (40) 100.0 % -32.00 [ -59.14, -4.86 ]



2 Outpatient

Kristjansson 1994 25 11.5 (4.07) 29 13.3 (4.44) 100.0 % -1.80 [ -4.07, 0.47 ]



-100 -50 0 50 100





Analysis 1.7. Comparison 1 Nebulized epinephrine versus placebo, Outcome 7 Improvement.



Outcome: 7 Improvement

Study or subgroup Epinephrine Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Inpatient




2 Outpatient

Kristjansson 1994 17/29 8/25 62.2 % 1.83 [ 0.96, 3.50 ]




3 Setting not reported

Gardner 1973 5/10 5/10 37.8 % 1.00 [ 0.42, 2.40 ]




Total (95% CI) 39 35 100.0 % 1.46 [ 0.82, 2.60 ]Total events: 22 (Epinephrine), 13 (Placebo)

Heterogeneity: Tau2 = 0.03; Chi2 = 1.20, df = 1 (P = 0.27); I2 =17%


0.1 0.2 0.5 1 2 5 10

Favours placebo Favours ephinephrine




Analysis 2.1. Comparison 2 Nebulized racemic epinephrine versus L-epinephrine, Outcome 1 Croup score

(change baseline - 30 minutes).


Comparison: 2 Nebulized racemic epinephrine versus L-epinephrine


Study or subgroup Racemic epinephrine L-epinephrine

Std.Mean

Difference Weight

Std.Mean

Difference


1 Inpatient



2 Outpatient

Waisman 1992 14 -2.28 (1.39) 14 -2.84 (1.88) 100.0 % 0.33 [ -0.42, 1.08 ]

Subtotal (95% CI) 14 14 100.0 % 0.33 [ -0.42, 1.08 ]Heterogeneity: not applicable


Total (95% CI) 14 14 100.0 % 0.33 [ -0.42, 1.08 ]Heterogeneity: not applicable


-4 -2 0 2 4

Favours racemic epi Favours L-epi




Analysis 2.2. Comparison 2 Nebulized racemic epinephrine versus L-epinephrine, Outcome 2 Croup score

(change baseline - 2 hours).




Study or subgroup Racemic epinephine L-epinephrine

Std.Mean

Difference Weight

Std.Mean

Difference


1 Inpatient



2 Outpatient

Waisman 1992 14 -0.65 (1.19) 14 -2.2 (2.14) 100.0 % 0.87 [ 0.09, 1.65 ]



Total (95% CI) 14 14 100.0 % 0.87 [ 0.09, 1.65 ]Heterogeneity: not applicable


-4 -2 0 2 4

Favours racemic epi Favours L-epi




Analysis 2.8. Comparison 2 Nebulized racemic epinephrine versus L-epinephrine, Outcome 8 Intubation.



Outcome: 8 Intubation

Study or subgroup Racemic epinephrine L-epiephrineRisk


Difference

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Inpatient

Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]Total events: 0 (Racemic epinephrine), 0 (L-epiephrine)



2 Outpatient

Waisman 1992 3/16 0/14 100.0 % 0.19 [ -0.03, 0.40 ]

Subtotal (95% CI) 16 14 100.0 % 0.19 [ -0.03, 0.40 ]Total events: 3 (Racemic epinephrine), 0 (L-epiephrine)



Total (95% CI) 16 14 100.0 % 0.19 [ -0.03, 0.40 ]Total events: 3 (Racemic epinephrine), 0 (L-epiephrine)



-10 -5 0 5 10

Favours racemic- epi Favours L-epi




Analysis 3.1. Comparison 3 Nebulized epinephrine with IPPB versus nebulized epinephrine without IPPB,

Outcome 1 Croup score (change baseline - 30 minutes).


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


Study or subgroup IPPB epinephrine No IPPB epinephrine

Std.Mean

Difference Weight

Std.Mean

Difference


1 Inpatient

Fogel 1982 9 -3.6 (2.26) 5 -3.3 (1.02) 100.0 % -0.14 [ -1.24, 0.95 ]



2 Outpatient





-4 -2 0 2 4

Favours IPPB epi Favours no IPPB epi





Outcome 2 Croup score (change baseline - 2 hours).




Study or subgroup IPPB epinephine No IPPB epinephrine

Std.Mean

Difference Weight

Std.Mean

Difference


1 Inpatient

Fogel 1982 9 -1.2 (2.1) 5 0.2 (1.02) 100.0 % -0.72 [ -1.86, 0.42 ]



2 Outpatient





-10 -5 0 5 10

Favours IPPB epi Favours no IPPB epi





Outcome 8 Intubation.



Outcome: 8 Intubation

Study or subgroup Epinephrine PlaceboRisk


Difference

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Inpatient

Fogel 1982 0/5 0/9 100.0 % 0.0 [ -0.26, 0.26 ]

Subtotal (95% CI) 5 9 100.0 % 0.0 [ -0.26, 0.26 ]Total events: 0 (Epinephrine), 0 (Placebo)



2 Outpatient




Total (95% CI) 5 9 100.0 % 0.0 [ -0.26, 0.26 ]Total events: 0 (Epinephrine), 0 (Placebo)



-0.5 -0.25 0 0.25 0.5

Favours IPPB Favours no IPPB

A P P E N D I C E S

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 attachedtube through which oxygen flows. The flow of oxygen through the liquid medication creates droplets which are then breathed in bythe child.Nebulized epinephrine delivered with intermittent positive pressure breathing (IPPB) - epinephrine delivered via nebulizer underintermittent 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 oneinhales and stronger as one exhales.Impedance plesmography - a technique for measuring paradoxical breathing. This type of breathing occurs in young children with severerespiratory 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 andthe rate of airflow through the upper airway. With greater increases in pleural pressure, during inspiration, young children’s compliantchest wall begins to collapse as the abdomen protrudes, owing to diaphragmatic contraction. The severity of paradoxical breathing canbe measured using a device called respiratory inductance plethysmograph, which measures the phase angle. A decrease in phase angleequates to a reduction in the severity of paradoxical breathing.

Appendix 2. EMBASE search strategy (Ovid)

1. exp laryngitis/ or exp croup/2. (laryngitis or croup or laryngotracheobronchitis or laryngo-tracheo-bronchitis).mp. or laryngotracheitis.tw,sh. [mp=title, subjectheading word, registry word, abstract, trade name/generic name]3. 1 or 24. exp adrenalin/ or exp epinephrine/5. (adrenalin$ or epinephrine).mp. [mp=title, subject heading word, registry word, abstract, trade name/generic name]6. 51-42-3.rn.7. exp adrenergic agonist$/ or exp adrenergic alpha-agonist$/ or exp adrenergic beta-agonist$/8. (adrenergic agonist$ or adrenergic alpha-agonist$ or adrenergic beta-agonist$).mp. [mp=title, subject heading word, registry word,abstract, trade name/generic name]9. (racemic adrenalin$ or l-adrenalin$).mp. [mp=title, subject heading word, registry word, abstract, trade name/generic name]10. (adrenalin$ and isomer$).mp. [mp=title, subject heading word, registry word, abstract, trade name/generic name]11. exp CORTICOSTEROID/ or exp 17 OXOSTEROID/ or HYDROXYCORTICOSTEROID/12. (adrenal cortex hormones or 17-ketosteroids or hydroxycorticosteroids).mp. [mp=title, subject heading word, registry word, abstract,trade name/generic name]13. or/4-1214. exp nebulizer/ or exp medical nebulizer/ or exp vaporizer/ or exp aerosol/15. exp artificial ventilation/16. (nebuli$ or vapo#ri$ or medical nebuli#er$ or aerosol$ or artificial ventilation).mp.17. (positive-pressure breathing or positive-pressure respiration).mp.18. (intermittent positive-pressure breathing or IPPB or intermittent positive-pressure respiration).mp.19. or/14-1820. 13 and 1921. 3 and 2022. exp randomized controlled trial$/23. randomized controlled trial$.pt.24. randomi#ed controlled trial$.ti,ab.25. quasi-randomi#ed controlled trial$.ti,ab.26. randomi#ed.ab.27. placebo?.ab.28. clinical trials/29. randomly.ab.30. trial.ti.31. or/22-3032. animals/33. humans/34. 32 not (32 and 33)35. 31 not 3436. 21 and 35




Appendix 3. CINAHL search (EBSCO)

S15 S4 and S13S14 S4 and S13S13 S9 and S12S12 S10 or S11S11 TI (inhal* or vapor* or vapour* or atomiz* or atomis* or nebuliz* or nebulis* or spray* or mist* or aerosol*) or AB (inhal* orvapor* 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 S8S8 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 S3S3 TI (laryngotracheobronchit* or laryngotracheit* or pseudocroup or psuedo-croup) or AB (laryngotracheobronchit* or laryngotra-cheit* or pseudocroup or psuedo-croup)S2 TI croup or AB croupS1 (MH “Laryngitis+”)

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

Topic=(laryngit* or croup or laryngotracheit* or laryngotracheobronchit* or pseudocroup or pseudo-croup) AND Topic=(epinephrineor adrenaline or adrenergic agonist* or adrenal cortex hormone*) ANDTopic=(nebuliz* or nebulis* or vapour* or vapor* or inhal* or atomiz* or atomis* or spray* or mist* or aerosol*)

Appendix 5. Scopus search strategy

(TITLE-ABS-KEY(croup OR laryngit* OR laryngotracheit* OR laryngotracheobronchit* OR pseudocroup OR pseudo-croup) ANDTITLE-ABS-KEY((epinephrine OR adrenaline OR adrenergic agonist* OR adrenal cortex hormone*) AND(nebuliz* OR nebulis* OR vapour* OR vapor* OR atomiz* OR atomis* OR inhal* OR spray* OR mist* OR aerosol*)))

H I S T O R Y

Protocol first published: Issue 3, 2007

Review first published: Issue 2, 2011

Date Event Description

11 September 2008 Amended Converted to new review format.




C O N T R I B U T I O N S O F A U T H O R S

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

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

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

Tamara Durec (TD) critically reviewed this protocol. She developed and executed the literature search. She critically reviewed drafts ofthe review.

Terry Klassen (TK) critically reviewed this 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 thereview’s results and critically reviewed the discussion and conclusions.

D E C L A R A T I O N S O F I N T E R E S T

None known.

D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W

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

I N D E X T E R M SMedical Subject Headings (MeSH)

Adrenergic alpha-Agonists [∗therapeutic use]; Adrenergic beta-Agonists [∗therapeutic use]; Croup [∗drug therapy]; Epinephrine[∗administration & dosage]; Nebulizers and Vaporizers; Randomized Controlled Trials as Topic

MeSH check words

Child; Humans



Cochrane croup

Health & Medicine

Transcript of Cochrane croup