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Nebulized epinephrine for croup in children

  1. Candice Bjornson1,*,
  2. Kelly Russell2,
  3. Ben Vandermeer3,
  4. Terry P Klassen4,
  5. David W Johnson1

Editorial Group: Cochrane Acute Respiratory Infections Group

Published Online: 10 OCT 2013

Assessed as up-to-date: 3 JUL 2013

DOI: 10.1002/14651858.CD006619.pub3


How to Cite

Bjornson C, Russell K, Vandermeer B, Klassen TP, Johnson DW. Nebulized epinephrine for croup in children. Cochrane Database of Systematic Reviews 2013, Issue 10. Art. No.: CD006619. DOI: 10.1002/14651858.CD006619.pub3.

Author Information

  1. 1

    Faculty of Medicine, University of Calgary, Alberta Children's Hospital, Department of Pediatrics, Calgary, Alberta, Canada

  2. 2

    University of Manitoba, Department of Pediatrics and Child Health, Winnipeg, Manitoba, Canada

  3. 3

    University of Alberta, Department of Pediatrics, Edmonton, Alberta, Canada

  4. 4

    Manitoba Institute of Child Health, Winnipeg, Manitoba, Canada

*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.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 10 OCT 2013

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Characteristics of included studies [ordered by study ID]
Corkey 1981

MethodsRandomized, placebo-controlled trial. No withdrawals


Participants14 children hospitalized with acute infectious croup (spasmodic croup was excluded). No child received either antibiotics or steroid therapy prior to randomization
Definition of croup: upper respiratory tract infections, often with fever, followed by the onset of inspiratory stridor and barking cough in 24 to 72 hours


Interventions0.5 mL of 2.25% of racemic epinephrine (containing 5 mg L-epinephrine) with 3.5 mL of distilled water IPPB (n = 8) or 4 mL of placebo with IPPB (n = 6)
The IPPB flow rate was 10 L/min, 100% oxygen
Treatment was repeated if clinical score did not improve after 15 minutes


OutcomesCroup 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


NotesIPPB: intermittent positive pressure breathing


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom numbers table

Allocation concealment (selection bias)Unclear riskDetails not reported

Blinding (performance bias and detection bias)
All outcomes
Low riskNurse was the only one who knew study drug

Blinding of participants and personnel (performance bias)
All outcomes
Low riskNurse was the only one who knew study drug

Blinding of outcome assessment (detection bias)
All outcomes
Low riskNurse was the only one who knew study drug. Outcome assessors were unable to distinguish treatment solutions on basis of smell or other characteristics

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo missing data

Selective reporting (reporting bias)Unclear riskDetails not reported

Other biasLow risk

Fernandez 1993

MethodsRandomized, placebo-controlled trial
No withdrawals


ParticipantsAll participants (children) hospitalized because of croup symptoms (unclear if spasmodic croup was excluded)


Interventions0.5 mg/kg of nebulized L-epinephrine (containing 5 mg L-epinephrine) (n = 15) or placebo (n = 17) (delivered via nebulization alone)

At least half of the children received IM dexamethasone but it is unclear which treatment they received first


OutcomesCroup score (8 points: stridor 0 to 2 points, respiratory distress 0 to 2 points, cough 0 to 2 points, cyanosis 0 to 2 points) at baseline, 6, 12, 18 and 24 hours


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDetails not reported

Allocation concealment (selection bias)Low riskVials were pre-numbered and labeled by the pharmacy

Blinding (performance bias and detection bias)
All outcomes
Low riskNurses were not told which vial was used

Blinding of participants and personnel (performance bias)
All outcomes
Low riskVial were pre-numbered and labeled by the pharmacy; treating personnel did not know which study treatment was used

Blinding of outcome assessment (detection bias)
All outcomes
Low riskDetails not reported, but assessors would not know which study treatment vial was used

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDetails not reported

Selective reporting (reporting bias)Unclear riskDetails not reported

Other biasHigh riskAuthors measured croup score in 6-hour intervals and measurements were treated separately instead of as repeated measures

Fogel 1982

MethodsCross-over, randomized controlled trial
No withdrawals


Participants14 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)


Interventions0.25 mL of 2.25% racemic nebulized epinephrine diluted to 1:8 with isotonic saline (n = 5) or the same dose of nebulized racemic epinephrine with IPPB (n = 9)
IPPB pressure was 15 to 17 cm
2 hours after first treatment, children were then crossed over to the other treatment


OutcomesModified Westley croup score (16 points: level of consciousness 0 to 4 points, color 0 to 4 points, stridor 0 to 3 points, air entry 0 to 2 points, retractions 0 to 3 points) at 30, 60, 90 and 120 minutes
Heart rate
Respiratory rate
Supplemental oxygen
Intubation
Adverse reactions


NotesIPPB: intermittent positive pressure breathing


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDetails not reported - prospectively randomized

Allocation concealment (selection bias)Unclear riskDetails not reported

Blinding (performance bias and detection bias)
All outcomes
Low riskPatient and evaluator did not know

Blinding of participants and personnel (performance bias)
All outcomes
Low riskPatient and evaluator did not know. The respiratory therapist was the only person who knew which study group the participant was in. The delivery of the study intervention was via the same apparatus in both groups

Blinding of outcome assessment (detection bias)
All outcomes
Low riskThe evaluator did not know

Incomplete outcome data (attrition bias)
All outcomes
Low riskData were complete

Selective reporting (reporting bias)Low risk

Other biasLow risk

Gardner 1973

MethodsRandomized, placebo-controlled trial. No withdrawals


Participants20 children with moderate croup (unclear if spasmodic croup was excluded) - inpatient or outpatient status not reported
Co-interventions were not reported


Interventions0.5 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)


OutcomesCroup score (10 points: cough score 0 to 2 points, anxiety/air hunger 0 to 2 points, stridor 0 to 2 points, retractions 0 to 2 points, cyanosis 0 to 2 points); timing of croup score assessment not reported
Improvement
Additional treatment of study drug


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDetails not reported

Allocation concealment (selection bias)Unclear riskUsed numbered vials but did not describe how they were allocated

Blinding (performance bias and detection bias)
All outcomes
Unclear riskDetails not reported

Blinding of participants and personnel (performance bias)
All outcomes
Low riskAuthors reported that placebo and racemic epinephrine solutions were indistinguishable by smell or appearance

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDetails not reported

Incomplete outcome data (attrition bias)
All outcomes
Low riskPre-selected outcomes are not reported

Selective reporting (reporting bias)Unclear riskMethods do not include sufficient details to adequately assess

Other biasLow risk

Kristjansson 1994

MethodsRandomized, placebo-controlled trial. No withdrawals


Participants54 children presenting to the ED with moderate croup (unclear if spasmodic croup was excluded). No co-interventions were given prior to randomization


Interventions0.5 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)


OutcomesCroup score (15 points: inspiratory stridor 0 to 3 points, retractions 0 to 3 points, air entry 0 to 3 points, cyanosis 0 to 3 points, state of consciousness 0 to 3 points) at 30 and 120 minutes
Respiratory rate
Heart rate
Length of stay
Additional treatment
Betamethasone treatment
Re-admission


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDetails not reported

Allocation concealment (selection bias)Unclear riskDetails not reported

Blinding (performance bias and detection bias)
All outcomes
Unclear riskDetails not reported

Blinding of participants and personnel (performance bias)
All outcomes
Low riskAuthors reported that placebo and racemic epinephrine solutions were indistinguishable by smell and solubility

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDetails not reported

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk5 additional patients were not included because protocols were incomplete - details not reported

Selective reporting (reporting bias)Unclear riskDetails not reported

Other biasLow risk

Kuusela 1988

MethodsRandomized, double-blind, placebo-controlled trial
78 children were enrolled and 72 were treated and evaluated by the protocol


Participants78 children admitted with moderate croup (70 children's symptoms were consistent with spasmodic croup). All children were placed in a humid room


Interventions0.25 mL per 5 kg body weight of 2.25% solution of nebulized racemic epinephrine (containing 2.5 mg L-epinephrine) (n = 16) or placebo (n = 21) via IPPB
Nebulization was repeated at 2 hours


OutcomesDyspnea score (0 to 3 points)
Cough score (0 to 3 points) at 6, 12, 24 and 48 hours
Length of stay
pH day 1
PCO2 day 1
Base deficit


NotesPCO2: partial pressure of carbon dioxide


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDetails not reported

Allocation concealment (selection bias)Low riskSequentially numbered

Blinding (performance bias and detection bias)
All outcomes
Unclear riskDetails not reported

Blinding of participants and personnel (performance bias)
All outcomes
Low riskAuthors reported that placebo and racemic epinephrine solutions were indistinguishable by smell or appearance and were identically packaged

Blinding of outcome assessment (detection bias)
All outcomes
Low riskCode was not available to investigators until end of study

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk6 patients not analyzed but details not reported

Selective reporting (reporting bias)Unclear riskDetails not reported

Other biasLow risk

Waisman 1992

MethodsRandomized, double-blind controlled trial
3 children were withdrawn


Participants66 children hospitalized due to symptoms suggestive of moderate croup (spasmodic croup was excluded). All children were received mist therapy prior to randomization
Croup suggestive symptoms: acute laryngitis, laryngotracheobronchitis and laryngitis with stridor


Interventions2.25% racemic epinephrine (n = 16) or 5 mL of 1:1000 L-epinephrine (n = 15) (each containing 5 mg L-epinephrine and delivered via nebulization alone)


OutcomesCroup score (10 points: inspiratory breath sounds 0 to 2 points, stridor 0 to 2 points, cough 0 to 2 points, retractions/nasal flaring 0 to 2 points, cyanosis 0 to 2 points) at 5, 15, 30, 60, 90 and 120 minutes
Respiratory rate
Dexamethasone treatment
Supplemental oxygen
Intubation


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskTable of random numbers

Allocation concealment (selection bias)Low riskPharmacy-controlled randomization

Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical vials blinded to patient and investigator

Blinding of participants and personnel (performance bias)
All outcomes
Low riskIdentical vials blinded to participant and personnel

Blinding of outcome assessment (detection bias)
All outcomes
Low riskDrug code broken only after the last participant completed the study

Incomplete outcome data (attrition bias)
All outcomes
Low risk3 participants were not included because of intubation (n = 2) and tracheal stenosis (n = 1)

Selective reporting (reporting bias)Unclear riskPrimary outcome not reported

Other biasLow risk

Westley 1978

MethodsRandomized, double-blind, placebo-controlled trial
3 children were withdrawn due to mechanical failure in the IPPB machine


Participants23 children admitted with moderate croup and inspiratory stridor after 15 to 30 minutes in a humidity mist room (unclear if spasmodic croup was excluded). All children received continuous room temperature mist and no supplemental oxygen was given except during IPPB treatment and 4 children received antibiotics


Interventions0.5 mL of 2.25% racemic epinephrine (containing 5 mg L-epinephrine) (n = 10) or nebulized saline with IPPB (n = 10)
IPPB pressure was 10 cm and increased to 15 cm within the first minute


OutcomesWestley croup score (17 points: level of consciousness 0 to 5 points, cyanosis 0 to 5 points, stridor 0 to 2 points, air entry 0 to 2 points, retractions 0 to 3 points) at 10, 30, and 120 minutes
Pulse
Respiratory rate


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskTable of random numbers

Allocation concealment (selection bias)Low riskPrepared identical bottles

Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical bottles and code unknown to investigators

Blinding of participants and personnel (performance bias)
All outcomes
Low riskIdentical bottles and code unknown to investigators or participants

Racemic epinephrine and placebo reported to be identical in smell

Blinding of outcome assessment (detection bias)
All outcomes
Low riskEvaluators of outcome were not aware of which intervention the participant had received at time of evaluation

Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing data for 3 participants because IPPB machine broke

Selective reporting (reporting bias)Unclear riskDetails not reported

Other biasLow risk

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Anonymous 1996Not a RCT

Banac 2005There is no comparison group. All children were treated with L-epinephrine

Bass 1978Not a RCT

Bass 1980Not a RCT

Beaudry 1983Not a RCT

Brown 2002Not a RCT

Celis 1978Not a RCT

Cherry 1974Not a RCT

Choi 1999Children were randomized to L-epinephrine or nebulized budesonide

Cressman 1994Not a RCT

Cristaldi 2001Not a RCT

Cronin 1996Not a RCT

da Silva 2012Compares 3 doses of epinephrine in children with post-extubation stridor

Danen 2011Not a RCT

Dardick 1974Not a RCT

de Benedictis 2012Not a RCT

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

Ellis 1974Not a RCT

Fitzgerald 1996Compares L-epinephrine versus budesonide

Fogel 1983Not a RCT

Frazier 2010Not a RCT

Ghosh 2001Not a RCT

Gilligan 2005Not a RCT

Gonzalez 1984Not a RCT

Heisinge 1974Not a RCT

Jones 1996Not a RCT

Klassen 1997Not a RCT

Kline-Krammes 2012Not a RCT

Koren 1983Not a RCT

Kunkel 1996Not a RCT

Ledwith 1995Not a RCT

Lenney 1978Not a RCT

Loriette 1997Not a RCT

Niggermann 1995Not a RCT

Osmond 2002Not a RCT

Pitluk 2011Not a RCT

Preutthipan 2005Compares 2 doses of epinephrine in children with post-intubation croup

Remington 1986Not a RCT

Rygnestad 2001Not a RCT

Singer 1976Not a RCT

Skolnik 1989Not a RCT

Steele 1998Compares children with croup to healthy controls

Taussig 1975All children received mist therapy and were randomized to epinephrine or no treatment (no placebo administered)

Taussig 1976Not a RCT

Thomas 1998Not a RCT

Thompson 1974Not a RCT

Vorwerk 2010Not a RCT

Weber 2001Compared epinephrine to heliox

Zach 1981Not a RCT

Zoorob 2011Not a RCT

 
Comparison 1. Nebulized epinephrine versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Croup score (change baseline - 30 minutes)394Std. Mean Difference (IV, Random, 95% CI)-0.94 [-1.37, -0.51]

    1.1 Inpatient
240Std. Mean Difference (IV, Random, 95% CI)-0.82 [-1.47, -0.17]

    1.2 Outpatient
154Std. Mean Difference (IV, Random, 95% CI)-1.03 [-1.60, -0.46]

 2 Croup score (change baseline - 2 hours)1Std. Mean Difference (IV, Random, 95% CI)Totals not selected

    2.1 Inpatient
1Std. Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

   2.2 Outpatient
0Std. Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

 3 Croup score (change baseline - 6 hours)2138Std. Mean Difference (IV, Random, 95% CI)-0.60 [-1.12, -0.08]

    3.1 Inpatient
269Std. Mean Difference (IV, Random, 95% CI)-0.60 [-1.50, 0.30]

   3.2 Outpatient
00Std. Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    3.3 IPPB administration
137Std. Mean Difference (IV, Random, 95% CI)-1.06 [-1.76, -0.36]

    3.4 No IPPB administration
132Std. Mean Difference (IV, Random, 95% CI)-0.14 [-0.84, 0.55]

 4 Length of hospitalization in hours2Mean Difference (IV, Random, 95% CI)Totals not selected

    4.1 Inpatient
1Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    4.2 Outpatient
1Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

 5 Return visits and/or (re)admissions1Risk Difference (M-H, Random, 95% CI)Totals not selected

   5.1 Inpatient
0Risk Difference (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    5.2 Outpatient
1Risk Difference (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 6 Improvement274Risk Ratio (M-H, Random, 95% CI)1.46 [0.82, 2.60]

   6.1 Inpatient
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    6.2 Outpatient
154Risk Ratio (M-H, Random, 95% CI)1.83 [0.96, 3.50]

    6.3 Setting not reported
120Risk Ratio (M-H, Random, 95% CI)1.0 [0.42, 2.40]

 
Comparison 2. Nebulized racemic epinephrine versus L-epinephrine

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Croup score (change baseline - 30 minutes)1Std. Mean Difference (IV, Random, 95% CI)Totals not selected

   1.1 Inpatient
0Std. Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    1.2 Outpatient
1Std. Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

 2 Croup score (change baseline - 2 hours)1Std. Mean Difference (IV, Random, 95% CI)Totals not selected

   2.1 Inpatient
0Std. Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    2.2 Outpatient
1Std. Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

 3 Intubation1Risk Difference (M-H, Random, 95% CI)Totals not selected

   3.1 Inpatient
0Risk Difference (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    3.2 Outpatient
1Risk Difference (M-H, Random, 95% CI)0.0 [0.0, 0.0]

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

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Croup score (change baseline - 30 minutes)1Std. Mean Difference (IV, Random, 95% CI)Totals not selected

    1.1 Inpatient
1Std. Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

   1.2 Outpatient
0Std. Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

 2 Croup score (change baseline - 2 hours)1Std. Mean Difference (IV, Random, 95% CI)Totals not selected

    2.1 Inpatient
1Std. Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

   2.2 Outpatient
0Std. Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

 3 Intubation1Risk Difference (M-H, Random, 95% CI)Totals not selected

    3.1 Inpatient
1Risk Difference (M-H, Random, 95% CI)0.0 [0.0, 0.0]

   3.2 Outpatient
0Risk Difference (M-H, Random, 95% CI)0.0 [0.0, 0.0]