EVIDENCE-BASED CHILD HEALTH: A COCHRANE REVIEW JOURNALEvid.-Based Child Health 7:4: 1311–1354 (2012)Published online in Wi...
Evid.-Based Child Health 7:4: 1311–1354 (2012)                                              TABLE OF CONTENTSHEADER . . . ...
Evid.-Based Child Health 7:4: 1311–1354 (2012)[Intervention Review]Nebulized epinephrine for croup in childrenCandice Bjor...
Evid.-Based Child Health 7:4: 1311–1354 (2012)Main resultsEight studies (225 participants) were included. NE was associate...
Evid.-Based Child Health 7:4: 1311–1354 (2012)Johnson 1998). Consequently in children with the most severe              In...
Evid.-Based Child Health 7:4: 1311–1354 (2012)nebulized epinephrine delivered with intermittent positive pres-     Cochran...
Evid.-Based Child Health 7:4: 1311–1354 (2012)Data extraction and management                                          (NNT...
Evid.-Based Child Health 7:4: 1311–1354 (2012)Gardner 1973; Kristjansson 1994; Kuusela 1988; Westley 1978),          (11 m...
Evid.-Based Child Health 7:4: 1311–1354 (2012)        Figure 1. Risk of bias graph: review authors’ judgements about each ...
Evid.-Based Child Health 7:4: 1311–1354 (2012)   Figure 2. Risk of bias summary: review authors’ judgements about each ris...
Evid.-Based Child Health 7:4: 1311–1354 (2012)Allocation                                                                  ...
Evid.-Based Child Health 7:4: 1311–1354 (2012)Nebulized epinephrine with IPPB versus nebulized                        At 1...
Evid.-Based Child Health 7:4: 1311–1354 (2012)Waisman 1992 administered an identical 5 mg of L-epinephrine              te...
Evid.-Based Child Health 7:4: 1311–1354 (2012)Implications for research                                            The rev...
Evid.-Based Child Health 7:4: 1311–1354 (2012)     the treatment of moderate to severe croup. Journal of the       Klassen...
Evid.-Based Child Health 7:4: 1311–1354 (2012)Taussig 1975 {published data only}                                    Davis ...
Evid.-Based Child Health 7:4: 1311–1354 (2012)Johnson 2003                                                                ...
Evid.-Based Child Health 7:4: 1311–1354 (2012)CHARACTERISTICS OF STUDIESCharacteristics of included studies [ordered by st...
Evid.-Based Child Health 7:4: 1311–1354 (2012)Fernadez 1993Methods                                       Randomized, place...
Evid.-Based Child Health 7:4: 1311–1354 (2012)Fogel 1982      (Continued)Interventions                                 0.2...
Evid.-Based Child Health 7:4: 1311–1354 (2012)Gardner 1973      (Continued)Outcomes                                      C...
Evid.-Based Child Health 7:4: 1311–1354 (2012)Kristjansson 1994     (Continued)Notes                                      ...
Cochrane croup
Cochrane croup
Cochrane croup
Cochrane croup
Cochrane croup
Cochrane croup
Cochrane croup
Cochrane croup
Cochrane croup
Cochrane croup
Cochrane croup
Cochrane croup
Cochrane croup
Cochrane croup
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Cochrane croup
Cochrane croup
Cochrane croup
Cochrane croup
Cochrane croup
Cochrane croup
Cochrane croup
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  1. 1. 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 DWThis is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2011, Issue 2 http://www.thecochranelibrary.comNebulized epinephrine for croup in children (Review)Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  2. 2. Evid.-Based Child Health 7:4: 1311–1354 (2012) TABLE OF CONTENTSHEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1313ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1313PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1314BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1314OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1315METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1315RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1317 Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1319 Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1320DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1322AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1323ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1324REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1324CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1327DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1337 Analysis 1.1. Comparison 1 Nebulized epinephrine versus placebo, Outcome 1 Croup score (change baseline - 30 minutes). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1340 Analysis 1.2. Comparison 1 Nebulized epinephrine versus placebo, Outcome 2 Croup score (change baseline - 2 hours). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1341 Analysis 1.3. Comparison 1 Nebulized epinephrine versus placebo, Outcome 3 Croup score (change baseline - 6 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 Analysis 3.2. Comparison 3 Nebulized epinephrine with IPPB versus nebulized epinephrine without IPPB, Outcome 2 Croup score (change baseline - 2 hours). . . . . . . . . . . . . . . . . . . . . . . . 1350 Analysis 3.8. Comparison 3 Nebulized epinephrine with IPPB versus nebulized epinephrine without IPPB, Outcome 8 Intubation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1351APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1351HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1353CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1353DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1354DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . 1354INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1354Nebulized epinephrine for croup in children (Review) 1312Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  3. 3. Evid.-Based Child Health 7:4: 1311–1354 (2012)[Intervention Review]Nebulized epinephrine for croup in childrenCandice Bjornson1 , Kelly F Russell2 , Ben Vandermeer3 , Tamara Durec4 , Terry P Klassen5 , David W Johnson11 Department of Pediatrics, Faculty of Medicine, University of Calgary, Alberta Children’s Hospital, Calgary, Canada. 2 Department ofPediatrics, 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-basedPractice Centre, Edmonton, Canada. 5 Manitoba Institute of Child Health, Winnipeg, CanadaContact 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.Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. ABSTRACTBackgroundCroup 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.ObjectivesTo evaluate the efficacy and safety of NE in children presenting to emergency department (ED) or admitted to hospital with croup.Search methodsWe 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 criteriaRandomized 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 analysisTwo 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.Nebulized epinephrine for croup in children (Review) 1313Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  4. 4. Evid.-Based Child Health 7:4: 1311–1354 (2012)Main resultsEight 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’ conclusionsNE 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 SUMMARYNebulized epinephrine for croup in childrenCroup 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.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 smallDescription of the condition minority have severe symptoms characterized by marked chestCroup (laryngotracheobronchitis) is a common respiratory illness wall indrawing, agitation and lethargy (Johnson 2001; Johnsonof 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; Tibballsbarky cough, which may be accompanied by stridor, hoarse voice 1992). A systematic review of corticosteroids found that comparedand respiratory distress. Croup symptoms are often preceded by to placebo, corticosteroids significantly reduced six and 12-hournon-specific symptoms such as cough, rhinorrhea and fever. The croup scores, reduced length of hospital stay, and reduced returnmost common etiology is a viral infection, predominantly parain- visits (Russell 2004). However, corticosteroids take an hour orfluenza virus (Marx 1997). more after treatment to lessen respiratory distress (Geelhoed 1995;Nebulized epinephrine for croup in children (Review) 1314Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  5. 5. Evid.-Based Child Health 7:4: 1311–1354 (2012)Johnson 1998). Consequently in children with the most severe Indirect measures of severity, such as health care utilization, aresymptoms, a therapy with a rapid rate of onset may lessen the need thought by many to capture significant clinical change better thanfor intubation. The therapy most commonly used for this purpose clinical scores. Some would argue that if a treatment cannot beis 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 toof the corticosteroid treatment. Alternative therapies are mist and make their own judgement as to the relative merits of the differentheliox (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 greaterpromise, but it is more cumbersome to use, and has little evidence Why it is important to do this reviewof 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 noHow the intervention might work systematic review examining the efficacy of this intervention.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; OBJECTIVESKlassen 1999). While a small number of randomized controlledtrials (RCTs) have been published (Johnson 2005), to date nosystematic review has been published. Primary objectiveInitial studies published in the 1970s and early 1980s suggestedthat 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 safetyalone. The use of IPPB has now fallen out of favor and it is no (frequency and severity of side effects) of nebulized epinephrinelonger routinely used. versus placebo in children with croup, evaluated in an emergencyClinical 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 nebulizedtion, rate of return to seek medical care for ongoing croup symp- racemic epinephrine versus nebulized L-epinephrine in childrentoms, 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 pressureacross 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 aredifferent types of croup scores (Bourchier 1984; Corkey 1981;Downes 1975; Geelhoed 1995; Godden 1997; Husby 1993; METHODSLeipzig 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 croup Criteria for considering studies for this reviewscores, 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- Types of studiesical 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, andNebulized epinephrine for croup in children (Review) 1315Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  6. 6. Evid.-Based Child Health 7:4: 1311–1354 (2012)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) andTypes 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/7-12Changes 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 noexclusion criteria. Searching other resources We contacted experts in the field of acute respiratory infections to locate additional studies. There were no language or publicationSearch methods for identification of studies restrictions.Electronic searches Data collection and analysisWe 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 studiesEMBASE (1980 to November 2010), Web of Science (1974 to Two review authors (CB, KR) independently scanned abstractsNovember 2010), CINAHL (1982 to November 2010) and Sco- from the initial search results to identify trials that broadly metpus (1996 to November 2010). the inclusion criteria. We then reviewed the full-text articles of theWe 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.Nebulized epinephrine for croup in children (Review) 1316Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  7. 7. Evid.-Based Child Health 7:4: 1311–1354 (2012)Data extraction and management (NNTH). We reported the pooled baseline rates using the inverseWe 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 heterogeneityistics (such as type of drug: racemic versus L-epinephrine), dosageand method of administration (nebulization alone versus nebu- We assessed heterogeneity quantitatively with the I2 statisticlized with intermittent positive pressure breathing (IPPB)). In ad- (Higgins 2002). The I2 statistic indicates the percent variabilitydition, we collected data on the primary and secondary outcome due to between-study (or inter-study) variability as opposed tomeasures if available: change from baseline clinical croup scores; within-study (or intra-study) variability. We considered an I2 valuerate 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-effectsecond 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 andAssessment of risk of bias in included studies 60 minutes. We considered the following subgroups: quality (thatTwo review authors (CB, KR) independently assessed the quality is, the risk of bias, allocation concealment, funding, and simpleof studies in three ways. We used more than one method since classification of bias (low, moderate, or high)) and inpatient versusthe 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 biasescealment of allocation as adequate, inadequate or unclear (Schulz If at least eight studies were found for our primary outcome we1995). Lastly, we classified studies by who sponsored them: phar- tested for publication bias. In addition to funnel plots, we usedmaceutical 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 performedthe 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 effectWith regard to continuous variables, we calculated the changefrom baseline measures if change from baseline measures were notreported directly. As needed, we performed variance imputations RESULTSaccording 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- Description of studiesment means) divided by its measurement variation (for example, See: Characteristics of included studies; Characteristics of excludeda 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 assessedchange in croup score at 30 minutes, two hours and six hours. If Results of the searcha study did not assess change in croup scores at our time points of The electronic literature search identified 316 unique studies. Afterinterest, we used the closest time point (for example, a 15-minute assessing the titles and, when available, the abstracts, we identifiedchange in croup score as used for the change in croup score at 50 studies as being potentially relevant. Reviewing the reference30 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 meandifference.For binary data (that is, intubation and hospitalization rates), we Included studiescalculated risk ratios. If zero events occurred in both groups, we After applying the a priori inclusion criteria, eight of the 50 studiesderived 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;Nebulized epinephrine for croup in children (Review) 1317Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  8. 8. Evid.-Based Child Health 7:4: 1311–1354 (2012)Gardner 1973; Kristjansson 1994; Kuusela 1988; Westley 1978), (11 months) and baseline severity of croup on study admission wasnebulized racemic epinephrine versus L-epinephrine (Waisman moderate. The doses of racemic epinephrine and L-epinephrine1992) 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 thea cross-over RCT. Seven studies were published in English and one primary outcome measure.in Spanish (Fernadez 1993). Studies tended to be small, rangingfrom 14 to 78 total participants per comparison. Nebulized epinephrine with IPPB versus nebulized epinephrine without IPPBNebulized 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 youngpatient setting, and one did not specify setting. In general, chil- (1.9 years), and baseline severity of croup on study admission wasdren within the studies were young (average age two years or less moderate. The dose of racemic epinephrine used was 0.25 ml ofin 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 waterified in two studies). Severity of croup in the majority of en- and two hours after the first treatment, cross-over to the otherrolled children was judged to be moderate or moderate to severe group occurred. A modified 16-point croup score based upon thein 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; andepinephrine 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 of2.25% racemic epinephrine per 5 kg of body weight in one study). Excluded studiesEpinephrine 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 exclusiondated. 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 studiesvalidated croup scores as outcome measures, with total possible Six of the eight studies were deemed to have a low risk of bias andpoints 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; WaismanNebulized racemic epinephrine versus L-epinephrine 1992; Westley 1978). Only one study reported a funding sourceWe 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.Nebulized epinephrine for croup in children (Review) 1318Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  9. 9. Evid.-Based Child Health 7:4: 1311–1354 (2012) Figure 1. Risk of bias graph: review authors’ judgements about each risk of bias item presented as percentages across all included studies.Nebulized epinephrine for croup in children (Review) 1319Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  10. 10. Evid.-Based Child Health 7:4: 1311–1354 (2012) Figure 2. Risk of bias summary: review authors’ judgements about each risk of bias item for each included study.Nebulized epinephrine for croup in children (Review) 1320Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  11. 11. Evid.-Based Child Health 7:4: 1311–1354 (2012)Allocation CI -1.60 to -0.46) (Analysis 1.1.2). Heterogeneity was negligibleAllocation 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 hoursGardner 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.BlindingAll trials were double-blind. Two studies did not report who wasblinded (Gardner 1973; Westley 1978). Secondary outcomes There were two studies that reported length of hospital stay (inIncomplete 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 statisticallyKristjansson 1994; Waisman 1992; Westley 1978). However, only significant smaller amount of time in the hospital than placeboone 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 weAll but two studies (Fogel 1982; Waisman 1992) reported a pri- would not expect similar hospital stays between inpatients andmary outcome (6/8; 75%). outpatients. Two studies counted the number of participants that had signif- icant improvement. Improvement was defined in one study as aOther 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 favorEffects 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 theNebulized 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 epinephrineparing nebulized epinephrine versus placebo. Four (109 partici- or the placebo group, thus we computed no statistics. No studypants) 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 wereincluded in this section, no more than three were included in any Nebulized racemic epinephrine versus L-epinephrineparticular analysis. Waisman 1992 (28 participants) compared nebulized racemic epinephrine versus L-epinephrine in an outpatient setting. TherePrimary outcome: croup score was no significant difference in croup score between the two typesSince all studies used different systems in their croup scoring, of epinephrine after 30 minutes (SMD 0.33; 95% CI -0.42 towe used SMDs to synthesize the data. Three studies showed that 1.08) (Analysis 2.1.2) but after two hours, L-epinephrine showedepinephrine 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 thealmost 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-significantand 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 for croup in children (Review) 1321Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  12. 12. Evid.-Based Child Health 7:4: 1311–1354 (2012)Nebulized epinephrine with IPPB versus nebulized At 120 minutes following treatment, the mean difference in croupepinephrine without IPPB score was similar in both racemic epinephrine and placebo groupsFogel 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 essentiallypatient setting. After 30 minutes, there was no significant differ- dissipated at 120 minutes, there was no evidence, on average, toence in croup score between the two groups (SMD -0.72; 95% suggest that there was an increase or worsening of croup score, asCI -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 childrenlarger, 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; Kuuselabation. 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 differenceSubgroup, sensitivity and publication bias analysis in croup score at the 120-minute assessment.Since none of our analyses contained more than three studies, nofurther analysis exploring heterogeneity or publication bias could Secondary outcomesbe 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 intervalsDISCUSSION 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 forSummary 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 racemiccroup. 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 isemergency 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 improveda total of 183 subjects (Corkey 1981; Fernadez 1993; Gardner even though we had not pre-specified it as a secondary outcome1973; 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-epinephrinePrimary outcome: croup score A small, methodologically sound study comparing nebulizedData from this review have shown that, compared to placebo, neb- racemic epinephrine with L-epinephrine in the outpatient settingulized 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 statisticallylowing 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 treatpared with placebo (Cohen 1969). All three trials favored racemic croup because it was hypothesized that racemic epinephrine wouldepinephrine 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.Nebulized epinephrine for croup in children (Review) 1322Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  13. 13. Evid.-Based Child Health 7:4: 1311–1354 (2012)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 withepinephrine) and found no statistically significant differences in mild croup.cardiovascular 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). Quality of the evidence The majority of the studies were at low risk of bias and half of theNebulized 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 toOne 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, thisstudy 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 processsuperiority, routine use of nebulized epinephrine without IPPB We undertook a broad and extensive search strategy of multipleseems 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. ThisSafety of nebulized epinephrine review did contain one Spanish language study. As none of ourThough none of the clinical trials reported significant adverse analyses contained more than three studies, no further analysisevents 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 isuniversally safe. Further, none of these trials assessed the effective-ness or safety of epinephrine when administered repeatedly in a Agreements and disagreements with otherrow. A single case report of ventricular tachycardia and myocardial studies or reviewsinfarction in a previously healthy child who received three dosesof nebulized epinephrine in one hour raises concerns about po- We did not identify any other relevant studies or systematic reviewstential cardiac toxicity (Butte 1999). While this case is of concern, in publication.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. AUTHORS’ CONCLUSIONSOverall completeness and applicability of Implications for practice • Nebulized epinephrine may be used to treat obstructiveevidence 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 atof study subjects. Studies assessed a wide range of outcomes and 30 minutes post-treatment.few studies examined the same outcomes, thus most outcomescontained data from very few or even single studies. Timing of • There is no evidence to suggest that croup symptoms, onoutcome measures also varied between studies. Finally, co-inter- average, worsen after the treatment effect of nebulizedventions (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 usedcluded to formally assess publication bias. racemic epinephrine. There is only one small, good quality trialWe did not search for articles which included co-treatment with comparing racemic epinephrine versus L-epinephrine and itcorticosteroids, as the question of whether adjunct epinephrine provides reasonable evidence that L-epinephrine is at least astherapy provides additional benefit to corticosteroid treatment effective as racemic epinephrine if this drug for some reason isalone 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 clinicalairway obstruction on presentation; epinephrine is used to provide effect of epinephrine as compared with nebulization alone.Nebulized epinephrine for croup in children (Review) 1323Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  14. 14. Evid.-Based Child Health 7:4: 1311–1354 (2012)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, Garythe administration of nebulized epinephrine should be carried Geelhoed, Joe Luria, Max Bulsara and Juan Lozano. We wish toout. 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 extractingACKNOWLEDGEMENTS appropriate data. REFERENCESReferences to studies included in this review Westley 1978 {published data only} Westley C, Ross C, Brooks J. Neublized racemic epinephrineCorkey 1981 {published data only} by IPPB for the treatment of croup: a double-blind study. Corkey C, Barker G, Edmonds J, Mok P, Newth C. American Journal of Diseases of Children 1978;132:484–7. Radiographic tracheal diameter measurements in acute References to studies excluded from this review infectious croup: an objective scoring system. Critical Care Medicine 1981;9:587–90. Annonymous 1996 {published data only} Annonymous. Inhaled budesonide and adrenaline forFernadez 1993 {published data only} croup. Drug and Therapeutics Bulletin 1996;34(3):22–4. Fernandez MA, Gonzalez SE, Etxefarria RI, Urcelay EI, Diez AM, Ciriza WM, et al.Randomized double-blind study of Banac 2005 {published data only} treatment of croup with adrenaline and/or dexamthasone in Banac S, Palcieevski G, Roziemanici V, Ahel V. children. Anales Espandoles de Pediatria 1993;38(1):29–32. Administration of nebulized L-epinephrine in children with croup. Medicina 2005;41(3):242–5.Fogel 1982 {published data only} Bass 1978 {published data only} Fogel JM, Berg IJ, Gerber MA, Sherter CB. Racemic Bass JW. Croup - IPPD and/or racemic epinephrine therapy. epinephrine in the treatment of croup: nebulization alone Pediatrics 1978;61(1):148–9. versus nebulization with intermittent positive pressure Bass 1980 {published data only} breathing. Journal of Pediatrics 1982;101(6):1028–31. Bass JW. Corticosteroids and racemic epinephrine withGardner 1973 {published data only} IPPD in the treatment of croup. Journal of Pediatrics 1980; Gardner HG, Powell KR, Roden VJ, Cherry JD. The 96(1):173–4. evaluation of racemic epinephrine in the treatment of Beaudry 1983 {published data only} infectious croup. Pediatrics 1973;52(1):52–5. Beaudry PH, Laussig LM, Bureau M. Efficacy of racemic epinephrine in croup. Journal of Pediatrics 1983;103(4):Kristjansson 1994 {published data only} 661–2. Kristjansson S, Berg-Kelly K, Winso E. Inhalation of Brown 2002 {published data only} racemic adrenaline in the treatment of mild and moderately Brown J. The management of croup. British Medical severe croup. Clinical symptom score and oxygen saturation Bulletin 2002;61:189–202. measurements for evaluation of treatment effects. Acta Paediatrica 1994;83(11):1156–60. Celis 1978 {published data only} Celis PA, Frias VJ, Aragon JG, Eternod GJ, Serafin FJ.Kuusela 1988 {published data only} Evaluation of racemic epinephrine with intermittent Kuusela AL, Vesikari T. A randomized double-blind, positive pressure in the treatment of acute infections placebo-controlled trial of dexamethasone and racemic laryngotracheitis. Boletin Medico del Hospital Infantile de epinephrine in the treatment of croup. Acta Paediatrica Mexico 1978;35(4):59–607. Scandinavica 1988;77(1):99–104. Cherry 1974 {published data only}Waisman 1992 {published data only} Cherry JD, Powell KR, Gardner HG, Roden VJ. Letter: Waisman Y, Klein BL, Boenning DA, Young GM, Racemic epinephrine in croup. Pediatrics 1974;53(2): Chamberlain JM, O’Donnel R, et al.Prospective randomized 290–1. double-blind study comparing L-epinephrine and racemic Choi 1999 {published data only} epinephrine aerosols in the treatment of laryngotracheitis Choi B, Song K, Shim J, Hong S. Prospective randomized (croup). Pediatrics 1992;89(2):302–6. study comparing L-epinephrine and budesonide aerosols inNebulized epinephrine for croup in children (Review) 1324Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  15. 15. Evid.-Based Child Health 7:4: 1311–1354 (2012) the treatment of moderate to severe croup. Journal of the Klassen 1997 {published data only} Korean Pediatric Society 1999;42(1):40–6. Klassen TP. Advances in the treatment of bronchiolitis andCressman 1994 {published data only} laryngitis. Pediatric Clinics of North America 1997;44(1): Cressman WR, Myer CM. Diagnosis and management of 249. croup and epiglottitis. Pediatric Clinics of North America Koren 1983 {published data only} 1994;41(2):265–76. Koren G. Efficacy of racemic epinephrine in croup. Journal of Pediatrics 1983;103(4):661.Cristaldi 2001 {published data only} Cristaldki A, Villani A, Bifano M, Cavaliere GF, Cristaldi Kunkel 1996 {published data only} S, Turbacci M, et al.[Osturzione acuta delle alte vie Kunkle NC, Baker MD. Use of racemic epinephrine, respiratorie]. Rivista Italiana Di Pediatria 2001;27(4): dexamethasone, and mist in the outpatient management of 462–5. croup. Pediatric Emergency Care 1996;12(3):156–9.Cronin 1996 {published data only} Ledwith 1995 {published data only} Cronin M, Diedericks R. Steroids in the management of Ledwith CA, Shea LM, Mauro RD. Safety and efficacy of croup - nebulized adrenaline is also useful. BMJ 1996;312 nebulized racemic epinephrine in conjunction with oral (7029):510. dexamethasone and mist in the outpatient treatment of croup. Annals of Emergency Medicine 1995;25(3):331–7.Dardick 1974 {published data only} Dardick KR. Racemic epinephrine in croup. Pediatrics Lenney 1978 {published data only} 1974;53(2):290. Lenney W, Milner AD. Treatment of acute viral croup. Archives of Disease in Childhood 1978;53(9):704–6.Dunman 2005 {published data only} Dunman M, Ozdemir D, Atasever S. Nebulised L- Loriette 1997 {published data only} epinephrine and steroid combination in the treatment of Loriette Y, Poirier V, Labbel A. [Laryngites aiguel’s]. Revue moderate to severe croup. Clinical Drug Investigation 2005; Internationale de Pediatrie 1997;278:10–2. 25(3):183–9. Niggermann 1995 {published data only}Ellis 1974 {published data only} Niggerman B, Wahn U. Micronephrin, adrenaline Ellis EF, Taylor JC, Lefkowit MS. Racemic epinephrine in medihaler aerosol and the use of nebulized steroids for croup (continued). Pediatrics 1974;53(2):291–2. laryngitis. Monatsschrift Kinderheilkunde 1995;143(12): 1259–60.Fitzgerald 1996 {published data only} Osmond 2002 {published data only} Fitzgerald D, Mellis C, Johnson M, Allen H, Cooper P, Osmond M. Croup. Clinical Evidence 2002;8:319–29. Asperen P. Nebulized budesonide is as effective as adrenaline in moderately severe croup. Pediatrics 1996;97(5):722–5. Preutthipan 2005 {published data only} Preutthipan A, Poomthavorn P, Sumanapisan A, ChinratFogel 1983 {published data only} B, Thasuntia S, Plitponkarnpim A, et al.A prospective, Fogel JM, Berg IJ, Gerber MA, Sherter CB. Efficacy in randomized double-blind study in children comparing two racemic epinephrine in croup - reply. Journal of Pediatrics doses of nebulized L-epinephrine in postintubation croup. 1983;103(4):662. Journal of the Medical Association of Thailand 2005;88(4):Ghosh 2001 {published data only} 508–12. Ghosh A, Morton R. Nebulized epinephrine or Remington 1986 {published data only} corticosteroids in croup. Emergency Medicine Journal 2001; Remington S, Meakin G. Nebulized adrenaline 1-1000 in 18(2):119. the treatment of croup. Anaesthesia 1986;41(9):923–6.Gilligan 2005 {published data only} Rygnestad 2001 {published data only} Gilligan P, Shepherd M, Lumsden G, Law H, Brenchley Rygnestad T, Skogvoll E. Treatment of pseudocroup with J, Kitching G, et al.SOCRATES 4 (synopsis of Cochrane racemic adrenaline. Tidsskrift For Den Norske Laegeforening reviews applicable to emergency services). Emergency 2001;12(10):1263–4. Medicine Journals 2005;22(2):126–7. Singer 1976 {published data only}Gonzalez 1984 {published data only} Singer OP, Wilson WJ. Laryngotracheobronchitis - 2 years Gonzalez ER, Burke TG. Review of the status of experience with racemic epinephrine. Canadian Medical intermittent positive pressure breathing therapy. Drug Association Journal 1976;115(2):132–4. Intelligence & Clinical Pharmacy 1984;18(12):974–6. Skolnik 1989 {published data only}Heisinge 1974 {published data only} Skolnik NS. Treatment of croup. A critical review. American Heisinge DH. Epinephrine in croup. Pediatrics 1974;53(2): Journal of Disease of Children 1989;143(9):1045–9. 290. Steele 1998 {published data only}Jones 1996 {published data only} Steele DW, Santucci KA, Wright RO, Natarajan R, Jones JS, Hendricks J. Racemic epinephrine in the treatment McQuillen KK, Jay GD. Pulsus paradoxus: an objective of laryngotracheitis: can relapse be prevented?. American measure of severity in croup. 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  16. 16. Evid.-Based Child Health 7:4: 1311–1354 (2012)Taussig 1975 {published data only} Davis 1993 Taussig L, Castro O, Beaudry P, Fox W, Bureau M. Davis, Cooper D, Mitchell I. The measurement of Treatment of laryngotracheobronchitis (croup): use of thoraco-abdominal asynchrony in infants with severe intermittent positive-pressure breathing and racemic laryngotracheobronchitis. Chest 103;103:1842–8. epinephrine. American Journal of Diseases of Children 1975; Denny 1983 129:790–3. Denny F, Murphy T, Clyde W, Collier A, Henderson F.Taussig 1976 {published data only} Croup: an 11-year study in a pediatric practice. Pediatrics Taussig LM. Treatment of croup - reply. American Journal 1983;71(6):871–6. of Disease of Children 1976;130(3):336–7. Downes 1975Thomas 1998 {published data only} Downes J, Raphael R. Pediatric intensive care. Anesthesiology Thomas LP, Friedland LR. The cost-effective use of 1975;43:238–50. nebulized racemic epinephrine in the treatment of croup. Egger 1997 American Journal of Emergency Medicine 1998;16(1):87–9. Egger M, Davey Smith G, Schneider M, Minder C. BiasThompson 1974 {published data only} in meta-analysis detected by a simple, graphical test. BMJ Thompson RS. Racemic epinephrine in croup. Pediatrics 1997;315(7109):629–34. 1974;53(2):292. Fanconi 1990Weber 2001 {published data only} Fanconi S, Burger R, Maurer H, Uehlinger J, Ghelfi D, Weber JE, Chudnofsky CR, Younger JG, Larkin GL, Boczar Muhlemann C. Transcutaneous carbon dioxide pressure for M, Wilkerson MD, et al.A randomized comparison of monitoring patients with severe croup. Journal of Pediatrics helium-oxygen mixture (Heliox) and racemic epinephrine 1990;117:701–5. for the treatment of moderate to severe croup. Pediatrics Follman 1992 2001;107(6):E96. Follmann D, Elliott P, Suh I, Cutler J. Variance imputationZach 1981 {published data only} for overviews of clinical trials with continuous response. Zach M. Simple nebulization of racemic epinephrine in Journal of Clinical Epidemiology 1992;45(7):769–73. the treatment of acute laryngitis (croup). Monatsschrift Geelhoed 1995 Kinderheilkunde 1981;129(3):168–70. Geelhoed G, Macdonald W. Oral and inhaled steroids in croup: a randomized placebo-controlled trial. PediatricAdditional references Pulmonology 1995;20:355–61.Adair 1971 Godden 1997 Adair J, Ring W, Jordan W, Elwyn R. Ten-year Godden CW, Campbel MJ, Hussey M, Cogswell JJ. Double- experience with IPPB in the treatment of acute blind placebo controlled trial of nebulised budesonide for laryngotracheobronchitis. Anesthesia and Analgesia 1971;50 croup. Archives of Disease in Childhood 1997;76:155–8. (4):649–55. Higgins 2002Begg 1994 Higgins JP, Thompson SG. Quantifying heterogeneity in a Begg CB, Mazumdar M. Operating characteristics of a rank meta-analysis. Statistics in Medicine 2002;21(11):1539–58. correlation test for publication bias. Biometrics 1994;50(4): Higgins 2009 1088–101. Higgins JPT, Green S (editors). Cochrane Handbook forBourchier 1984 Systematic Reviews of Interventions Version 5.0.2 [updated Bourchier D, Dawson K, Fergusson D. Humidification in September 2009]. The Cochrane Collaboration, 2008. viral croup: a controlled trial. Australian Paediatric Journal Available from www.cochrane-handbook.org. 1984;20:289–91. Husby 1993Brown 2002 Husby S, Agertoft L, Mortensen S, Pedersen D. Treatment Brown J. The management of croup. British Medical of croup with nebulised steroid (budesonide): a double Bulletin 2002;61:189–202. blind, placebo-controlled study. Archives of Disease inButte 1999 Childhood 1993;68:352–5. Butte M, Nguyen B, Hutchison T, Wiggins J, Ziegler J. Johnson 1998 Pediatric myocardial infarction after racemic epinephrine Johnson D, Jacobson S, Edney P, Hadfield P, Mundy administration. Journal of Pediatrics 1999;104:e9. M, Schuh S. A comparison of nebulized budesonide,Cho 1996 intramuscular dexamethasone, and placebo for moderately Cho MK, Bero LA. The quality of drug studies published in severe croup. New England Journal of Medicine 1998;339 symposium proceedings. Annals of Internal Medicine 1996; (8):498–503. 124(5):485–9. Johnson 2001Cohen 1969 Johnson D, Williamson J. Croup: duration of symptoms Cohen J. Statistical power analysis for the behavioral science. and impact on family functioning. Poster presentation. New York: Academic Press, 1969. Pediatric Research 2001;49:83A.Nebulized epinephrine for croup in children (Review) 1326Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  17. 17. Evid.-Based Child Health 7:4: 1311–1354 (2012)Johnson 2003 de la methyl–presnisolone dans le traitement]. L’union Johnson D, Williamson J. Health care utilization by Medicale du Canada 1973;102:2064–72. children with croup in Alberta. Pediatric Research 2003;53: Moore 2006 110A. Moore M, Little P. Humidified air inhalation for treatingJohnson 2005 croup. Cochrane Database of Systematic Reviews 2006, Issue Johnson D. Croup. Clinical Evidence 2005;14:310–27. 3. [DOI: 10.1002/14651858.CD002870.pub2.]Kaditis 1998 Neto 2002 Kaditis A, Wald E. Viral croup: current diagnosis and Neto G, Kentab O, Klassen T, Osmond M. A randomized treatment. Pediatric Infectious Disease Journal 1998;17(9): controlled trial of mist in the acute treatment of moderate 827–34. croup. Academic Emergency Medicine 2002;9(9):873–9.Kairys 1989 Kairys S, Olmstead EM, O’Connor G. Steroid treatment Russell 2004 of laryngotracheitis: a meta-analysis of the evidence from Russell K, Wiebe N, Ausejo Segura M, Johnson DW, randomized trials. Pediatrics 1989;83(5):683–93. Hartling L, Klassen TP. Glucocorticoids for croup. CochraneKlassen 1994 Database of Systematic Reviews 2004, Issue 1. [DOI: Klassen T, Feldman M, Watters L, Sutcliffe T, Rowe P. 10.1002/14651858.CD001955.pub2] Nebulized budesonide for children with mild-to-moderate Schulz 1995 croup. New England Journal of Medicine 1994;331:285–9. Schulz KF, Chalmers I, Hayes RJ, Altman DG. EmpiricalKlassen 1995 evidence of bias. Dimensions of methodological quality Klassen T, Rowe P. The croup score as an evalutative associated with estimates of treatment effects in controlled instrument in clinical trials [abstract]. Archives of Pediatrics trials. JAMA 1995;273(5):408–12. & Adolescent Medicine 1995;149:60. Scolnik 2006Klassen 1999 Scolnik D, Coates AL, Stephens D, Da Silva Z, Lavine E, Klassen T. Croup: a current perspective. Pediatric Clinics of Schuh S. Controlled delivery of high vs low humidity vs mist North America 1999;46(6):1167–78. therapy for croup in emergency departments: a randomizedLefebvre 2009 controlled trial. JAMA 2006;295(11):1274–80. Lefebvre C, Manheimer E, Glanville J. Chapter 6: Searching Steele 1998 for studies. In: Higgins JPT, Green S (editors). Cochrane Steele DW, Santucci KA, Wright RO, Natarajan R, Handbook for Systematic Reviews of Interventions. McQuillen KK, Jay GD. Pulsus paradoxus: an objective Version 5.0.2 [updated September 2009]. The Cochrane measure of severity in croup. American Journal of Respiratory Collaboration, 2008. Available from www.cochrane- and Critical Care Medicine 1998;157:331–4. handbook.org. Tibballs 1992Leipzig 1979 Tibballs J, Shann F, Landau L. Placebo-controlled trial Leipzig B, Oski F, Cummings C, Stockman J, Swender P. A of prednisolone in children intubated with croup. Lancet prospective randomized study to determine the efficacy of 1992;340(8822):745–8. steroids in treatment of croup. Journal of Pediatrics 1979; 94:194–6. von Muhlendahl 1982Marx 1997 von Muhlendahl K, Kahn D, Spohr H, Dressler F. Steroid 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:Massicotte 1973 Goodman, Gilman editor(s). The Pharmacological Basis of Massicotte P, Tetreault L. Evaluation of methyl-prednisolone Therapeutics. McGraw Hill Companies, 2009. ∗ in the treatment of acute laryngitis in children [Evaluation Indicates the major publication for the studyNebulized epinephrine for croup in children (Review) 1327Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  18. 18. Evid.-Based Child Health 7:4: 1311–1354 (2012)CHARACTERISTICS OF STUDIESCharacteristics of included studies [ordered by study ID]Corkey 1981Methods Randomized, placebo-controlled trial. No withdrawalsParticipants 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 hoursInterventions 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 minutesOutcomes 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 diameterNotes IPPB: intermittent positive pressure breathingRisk of biasBias Authors’ judgement Support for judgementAdequate sequence generation? Low risk Random numbers tableAllocation concealment? Unclear risk Details not reportedBlinding? Low risk Nurse was the only one who knew studyAll outcomes drugIncomplete outcome data addressed? Unclear risk No missing dataAll outcomesFree of selective reporting? Unclear risk Details not reportedFree of other bias? Low riskNebulized epinephrine for croup in children (Review) 1328Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  19. 19. Evid.-Based Child Health 7:4: 1311–1354 (2012)Fernadez 1993Methods Randomized, placebo-controlled trial No withdrawalsParticipants 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 firstOutcomes 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 hoursNotes -Risk of biasBias Authors’ judgement Support for judgementAdequate sequence generation? Unclear risk Details not reportedAllocation concealment? Low risk Vials were pre-numbered and non-labeled by the pharmacyBlinding? Low risk Nurses were not told which vial was usedAll outcomesIncomplete outcome data addressed? Unclear risk Details not reportedAll outcomesFree of selective reporting? Unclear risk Details not reportedFree of other bias? High risk Authors measured croup score in 6-hour in- tervals and measurements were treated sep- arately instead of as repeated measuresFogel 1982Methods Cross-over, randomized controlled trial No withdrawalsParticipants 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)Nebulized epinephrine for croup in children (Review) 1329Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  20. 20. Evid.-Based Child Health 7:4: 1311–1354 (2012)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 treatmentOutcomes 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 reactionsNotes IPPB: intermittent positive pressure breathingRisk of biasBias Authors’ judgement Support for judgementAdequate sequence generation? Unclear risk Details not reported - prospectively ran- domizedAllocation concealment? Unclear risk Details not reportedBlinding? Low risk Patient and evaluator did not knownAll outcomesIncomplete outcome data addressed? Low risk Data were completeAll outcomesFree of selective reporting? Low riskFree of other bias? Low riskGardner 1973Methods Randomized, placebo-controlled trial. No withdrawalsParticipants 20 children with moderate croup (unclear if spasmodic croup was excluded) - inpatient or outpatient status not reported Co-interventions were not reportedInterventions 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)Nebulized epinephrine for croup in children (Review) 1330Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  21. 21. Evid.-Based Child Health 7:4: 1311–1354 (2012)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 drugNotes -Risk of biasBias Authors’ judgement Support for judgementAdequate sequence generation? Unclear risk Details not reportedAllocation concealment? Unclear risk Used numbered vials but not described how they were allocatedBlinding? Unclear risk Details not reportedAll outcomesIncomplete outcome data addressed? Low risk Pre-selected outcomes are not reportedAll outcomesFree of selective reporting? Unclear risk Methods do not include sufficient details to adequately assessFree of other bias? Low riskKristjansson 1994Methods Randomized, placebo-controlled trial. No withdrawalsParticipants 54 children presenting to the emergency department with moderate croup (unclear if spasmodic croup was excluded). No co-interventions were given prior to randomizationInterventions 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-admissionNebulized epinephrine for croup in children (Review) 1331Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  22. 22. Evid.-Based Child Health 7:4: 1311–1354 (2012)Kristjansson 1994 (Continued)Notes -Risk of biasBias Authors’ judgement Support for judgementAdequate sequence generation? Unclear risk Details not reportedAllocation concealment? Unclear risk Details not reportedBlinding? Unclear risk Details not reportedAll outcomesIncomplete outcome data addressed? Unclear risk Five additional patients were not includedAll outcomes because protocols were incomplete - details not reportedFree of selective reporting? Unclear risk Details not reportedFree of other bias? Low riskKuusela 1988Methods Randomized, double-blind, placebo-controlled trial 78 children were enrolled and 72 were treated and evaluated by the protocolParticipants 78 children admitted with moderate croup (70 children’s symptoms were consistent with spasmodic croup). All children were placed in a humid roomInterventions 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 hoursOutcomes 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 deficitNotes PCO2 : partial pressure of carbon dioxideRisk of biasBias Authors’ judgement Support for judgementAdequate sequence generation? Unclear risk Details not reportedNebulized epinephrine for croup in children (Review) 1332Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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