Treatment of Asthma Exacerbations in the Pediatric Emergency Department

Treatment of Asthma
Exacerbations in the
Pediatric Emergency
Department
Five Important Questions
June 27th, 2014
Justin Davis, MD

Objectives
1. What is an asthma exacerbation?
2. How can one determine the severity?
3. What is “status asthmaticus”?
4. What is the role of various primary treatments?
5. What is the role of adjunctive/secondary treatments?

 Variety of triggers
 Airway hyper-responsiveness and inflammation
 Mucous plugging, V/Q mismatch
 Decrease in expiratory airflow
 Combination of symptoms – dyspnea, wheezing, chest
tightness
 Acute or subacute
 Can occur in someone with good control.
Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma; National Heart, Lung
and Blood Institute, National Asthma Education and Prevention Program; 2007 U.S. Department of
Health and Human Services

 Increasing prevalence of asthma (9.6% in 2009).
 Mortality lower in children.
 Hospitalization rate may be leveling off or declining.
 ICU care still increasing.
Koninckx, M, Buysse C., Hoog M. Management of
status asthmaticus in children. Paediatric Respiratory
Reviews 14 (2013) 78-85

2. Assessment & Severity
 Respiratory Rate
 Generally increased
 Not necessarily an indicator of severity
 Wheezes
 Typically expiratory
 If also inspiratory  more severe
 If absent  imminent respiratory failure
 Or inadequate exam

 Peak expiratory flow
(PEF) or Forced
Expiratory Volume (FEV1)
 Difficult if < 5-6 year old,
in the ED setting, severe
exacerbations
 Mild: >70% predicted (or
personal best)
 Severe: <40% predicted

 Work of breathing
 Scalene and SCM –
forceful inhalation
 Abdominals, internal
intercostals – forceful
expiration
 Indicates moderate to
severe exacerbation
 May not be present in
patients with imminent
respiratory arrest

 Pulse Oximetry
 Transient hypoxia relatively common after treatments.
 Initial borderline to mild hypoxia an indicator of moderate
to severe exacerbation.
 Hypoxia after one hour of treatment correlates with
increased risk of hospital admission
 PCO2
 Blood gas analysis rarely need for treatment of pediatric
asthma exacerbations

 Pulsus Paradoxus
 Inspiration  negative chest pressure  lower pulse pressure
 Expiration  positive chest pressure  higher pulse pressure
 < 10 mm Hg normal
 10-25 mm Hg  moderate
 25-40 mm Hg  severe
 Loss of pulsus paradoxus  respiratory failure
 Just like sudden loss of work of breathing in someone who is
still not moving air

 Red Flags
 Alteration in mental status
 Not necessarily completely unconscious
 Bradycardia
 Severity scores – why use them?
 Reliably + rapidly identify severity level
 Identify changes in clinical status
 Research purposes
 Protocols, pathways

2. Assessment & Severity – Asthma
Scores
Items in Score Validity Measures Reliability Measures
Asthma Severity Score (ASS)
(3)
Wheeze (0-3), Heart rate (0-
3), Accessory Muscle Use (0-
3)
1. Physician severity
judgment, 2. Oxygen
saturation, 3. PEFR
1. Interobserver reliability
Preschool Respiratory
Assessment Measure
(PRAM) (4)
Wheeze (0-3), Air entry (0-3),
Scalene contractions (0-2),
Suprasternal retractions (0-
2), oxygen saturation (0-2)
1. Resistance to forced
oscillation (RFO), 2. Clinician
and parent severity
judgment, 3. Change in score
correlation with change in
RFO
1. interobserver reliability, 2.
internal consistency
Pulmonary Index (PI) (5)
Wheeze (0-3), Repsiratory
Rate (0-3),
Inspiratory/Expiratory ratio
(0-3), Accessory Muscle Use
(0-3)
1. Spirometry, 2. ED
Disposition, 3. Change in
score with treatment during
ED course
Pulmonary Score (PS) (16)
Wheeze (0-3), Respiratory
rate (0-3),
Sternocleidomastoid use (0-
3)
1. PEFR, 2. Change in score
with treatment during ED
course
Pediatric Asthma Severity
Score (2)
Wheezing, Prolonged
Expiration, Work of
Breathing
1. PEFR, 2. Oxygen
Saturation, 3.
Responsiveness to
treatment, 4. Hospital
admission
1. interobserver reliability
good to excellent

3. What is status asthmaticus?
 Asthma Exacerbation
 Severe, Life-threatening
 Unresponsive to usual therapy
 Some definitions include more factors.

 Fatal and near-fatal asthma2
 Type 1(80%) – slow onset, progressive airway
obstruction, already using bronchodilators extensively,
more inflammation + mucous plugging
 Type 2 – sudden onset, more bronchoconstriction; higher
incidence of AMS, respiratory arrest, acidemia; rapid
deterioration but rapid recovery with treatment
Koninckx, M, Buysse C., Hoog M. Management of
status asthmaticus in children. Paediatric Respiratory
Reviews 14 (2013) 78-85

 Risk factors for asthma-related death?
 History: ICU, Intubation, 2 hospitalizations or 3 ED visits
in past year, any hospitalization in last month, > 2
canisters/month, lack of written asthma action plan
 Social- inner city, low socioeconomic status, substance
use
 Comorbidities – cardiac disease, psychiatric disease,
other chronic lung diseases

4. Primary Treatments
 Bronchodilation – inhaled beta agonists
 Anti-inflammatory – systemic corticosteroids
 Oxygen
 Rehydration prn
Wilkinson, M, Bullock B, Garcia-Filian P, Keahey L. Efficacy of Racemic Albuterol versus Levalbuterol
used as a Continuous Nebulization for the Treatment of Acute Asthma Exacerbations: A Randomized,
Double-Blind, Clinical Trial

4. Primary Treatments – Albuterol versus
Levalbuterol?
 Wilkinson 2011
 99 children, ED visits for moderate/severe exacerbation
 7.5 mg albuterol versus 3.75 mg levalbuterol
 Further treatments given with same med
 Standard care; Double-blinded
 After one hour, spirometry and asthma scores showed
greater improvement in albuterol group.
 No differences in side effects, HR, RR, SaO2
 No difference in admission rate
Wilkinson, M, Bullock B, Garcia-Filian P, Keahey L. Efficacy of Racemic Albuterol versus Levalbuterol
used as a Continuous Nebulization for the Treatment of Acute Asthma Exacerbations: A
Randomized, Double-Blind, Clinical Trial

4. Primary Treatments – Delivery Methods?
 Breathing Machine/Nebulizer/Jet
 Advantage: coordination not required, effective with tidal
breathing, ability to give high doses (continuous
nebulizer), ability to give supplemental O2
 Disadvantage: treatment time, sanitation, device
preparation
 Metered Dose Inhaler
 Advantage: treatment time, sanitation, preparation
 Disadvantage: coordination, ability to give high doses in
life threatening asthma

4. Primary Treatments – Nebs vs MDI?
 Cates et al. 2013
 Review of RCTs comparing MDI/spacer versus
nebulization in ED (39 trials, 1897 children, 729 adults)
 For children, mean length of ED stay was shorter with
MDI/spacer
 Spirometry, risk of admission not different
 Lower pulse and risk of tremor with MDI
 Many of the studies excluded severe exacerbations,
critically ill patients.
Cates CJ, Welsh EJ, Rowe BH. Holding chambers (spacers) versus nebulisers for beta-agonist
treatment of acute asthma. Cochrane Database of Systematic Reviews 2013, Issue 9. Art. No.:
CD000052. DOI: 10.1002/14651858.CD000052.pub3.

4. Primary Treatments – Neb vs. MDI?
 Duarte 2002
 196 children presenting with mild to moderate
exacerbations were randomized to either receive ED
treatment with a home-made non-valved spacer or a
nebulizer. Improvement in peak expiratory flow was the
same in both groups.
Duarte M, Camargos P. Efficacy and safety of a homemade non-valved spacer for bronchodilator therapy
in acute asthma. Acta Paediatrica 2002;91:909–13

 Sannier 2007
 79 children presenting with mild to moderate
exacerbations were randomized to receive ED treatment
with MDI and spacer or a nebulizer. Hospitalization rate,
asthma scores, peak flows, SaO2, respiratory rates and
other side effects were the same.
Sannier N, Timsit S, Cojocaru B, Leis A, Wille C, Garel D,et al.Metered-dose inhaler with spacer
versus nebulization for severe and potentially severe acute asthma treatment in the pediatric
emergency department. [French]. Revue Francaise d Allergologie et d Immunologie Clinique 2007;
Vol. 47, issue 2:64–71.

 Batra 1997
 Children presenting to the ED with an asthma
exacerbation (any severity) were randomized to MDI
versus nebulizer.
 No difference in outcomes between the two groups
 Clinical assessments at 20, 40 and 60 minutes
 Hospital admission rate
Batra V, Sethi G, Sachdev H. Comparative efficacy of jet nebuliser and metered dose inhaler with
spacer device in the treatment of acute asthma. Indian Pediatrics 1997;34:497–503

 Breath Actuated Nebulizer
 There are different types, but Aeroeclipse® seems to be
most well studies in pediatric ED
 Higher percentage of respiratory range partciles.
 Works best with mouthpiece, mask can be used as well.
 No studies comparing with MDI.
 Can be manually activated.
 Early non-randomized study showed favorable results
but had several limitations.1
1. Titus MO, Eady M, King L, Bowman M. Effectiveness of a
Breath-Actuated Nebulizer Device on Asthma Care in the
Pediatric Emergency Department. Clin Pediatr 2012 51: 1150-
1154

 Breath Actuated Nebulizer (BAN), Sabato 2011
 149 children presenting to the ED with mild to severe asthma
exacerbations were randomized to use either the Aeroeclipse® breath-
actuated nebulizer or standard nebulizer.
 BAN group had greater improvement in symptom score and
respiratory rate, lower hospital admission rate.
 No difference in adverse effects.
 Older patients & those with more severe symptoms were more likely to
have greater improvement with BAN.
 There were patients as young as 6 months of age who were able to
breath-actuate. A greater percentage of the BAN patients accepted
their aerosol treatments.
 Potential confounders: masks in the BAN group had better seal; BAN
group likely received higher actual dose of albuterol.
Sabato K, Ward P, Hawk W, et al. Randomized controlled trial of
a breath-actuated nebulizer in pediatric asthma patients in the
emergency department. Respir Care. 2011;56:761-770.

4. Primary Treatments – continuous versus
intermittent treatments
 Per most recent NHLBI guidelines, either is acceptable.
 Camargo et al. 2003
 Review of randomized controlled trials evaluating continuous versus intermittent
inhaled beta-agonists in the emergency setting.
 Eight trials were included in the analysis.
 Continuous treatments were associated with greater improvement in spirometry
and reduced rates of hospital admissions.
Camargo CA, Spooner CH, Rowe BH. Continuous versus intermittent beta-
agonists in the treatment of acute asthma. Cochrane Database Syst Rev.
2003; (4): CD001115

4. Primary Treatments – Atrovent
 Anticholinergic
 Causes bronchodilation without inhibiting mucociliary clearance (unlike
atropine)
 May be helpful in the ED setting in terms of greater improvement in
symptom scores and spirometry.1
 Effect is additive to inhaled beta-agonists. Not really helpful on its own.
Kline-Krammes S, Patel NH, Robinson S. Childhood Asthma: A Guide for Pediatric Emergency
Medicine Providers. Emerg Med Clin N Am 31

4. Primary Treatments – Steroids?
 Start as early as possible
 Effect starts in 1-3 hours, maximum effect at 4-8 hours
 PO or IV
 Can avoid steroids for mild exacerbations with complete
response to initial beta agonist treatment
 +/-5 day course of orapred or prednisone frequently given
 Two day course of dexamethasone likely just as effective.1
Expert Panel Report 3: Guidelines for the Diagnosis and
Management of Asthma; National Heart, Lung and Blood
Institute, National Asthma Education and Prevention Program;
2007 U.S. Department of Health and Human Services
1. Qureshi F, Zaritsky A, Poirier MP. Comparative efficacy of oral
dexamethasone versus oral prednisone in acute pediatric
asthma. J Pediatr 2001; 139(1):20–6.

4. Primary Treatments – Inhaled Steroids?
 Edmonds et al. 2012a
 Review of studies comparing ICS added to usual care for
ED treatment of asthma exacerbations.
 ICS versus systemic steroids
 ICS + systemic steroids versus systemic steroids alone
 ICS versus placebo (no systemic steroids)
 Patients given ICS less likely to be admitted to hospital &
had small improvements in spirometry compared with
patients not given systemic steroids.
 No significant improvement in pulmonary function,
symptom scores or admission rates when given in
addition to systemic steroids.
Emonds ML, Milan SJ, Camargo Jr CA, Pollack CV, Rowe BH. Early use of inhaled corticosteroids in the
emergency department treatment of acute asthma. Cochrane Database of Systematic Reviews 2012, Issue 12.
Art. No.: D002308

 Singhi et al. 1999
 60 children presenting to an urban pediatric ED with a
moderate exacerbation were randomized to receive either
budesonide 400 mcg or placebo at half hour intervals for
three doses.
 Children in the intervention group showed greater
improvements in RR, PEFR, and symptom scores.
Singhi SC, Banerjee S, Nanjundaswamy HM. Inhaled
Budesonide in Acute Asthma. J. Paediatr. Child Health
1999; 35; 483-487

 Scarfone et al. 1995
moderate exacerbation were randomized to receive oral
prednisone or 1.5 mg/kg nebulized dexamethasone.
 Dexamethasone group had improvement in:
 Discharge home within 2 hours
 Unplanned return visits within 48 hours
 Improvement more pronounced in those treated with
mouthpiece versus face mask.
Scarfone RJ, Loiselle JM, Wiley JF, et al. Nebulized dexamethasone versus oral prednisone in
the emergency treatment of asthmatic children. Ann Emerg Med 1995; 26:480–486

 Macias 2003
moderate exacerbation were randomized to receive either
inhaled triamcinolone (in ED and after discharge) or oral
steroids.
 Lower hospitalization and unscheduled return rate in
inhaled steroid group.
 No placebo control.
Macias CG, Felner EI, Gan V. Inhaled Corticosteroids May be Superior to Systemic Corticosteroids in
Children with Moderate-to-Severe Acute Asthma. Pediatric Asthma, Allergy and Immunology 2003;
16(3): 121-128

 Schuh 2000
 100 children presenting to the ED with a severe asthma
exacerbation (FEV1 less than 60% of predicted) were
randomized to either receive 2 mg of inhaled fluticasone
via MDI/spacer or 2mg/kg of prednisone.
 FEV1 increased by twice as much in the oral steroid
group after four hours. The hospitalization rate for
children treated with fluticasone was three-fold higher.
Schuh S, Reisman J, Alshehri M, Dupuis A, Corey M, Arseneault R, Alothman G, Tennis O, Canny G. A
comparison of inhaled fluticasone and oral prednisone for children with severe acute asthma. N Engl J
Med 2000;343(10):689–94.

 Upham 2011
 180 children presenting to the ED with a moderate to
severe asthma exacerbation were randomized to either
receive 2 mg of inhaled budesonide or placebo along with
usual care (including systemic steroids).
 No change change in symptom scores at 2 hours. No
difference in hospitalization rates.
Upham BD, Mollen CJ, Scarfone RJ, Seiden J, Chew A, Zorc JJ. Nebulized budesonide added to standard
pediatric emergency department treatment of acute asthma: a randomized, double-blind trial. Acad Emerg
Med 2011;18: 665–73.

4. Primary Treatments – Oxygen?
 Guidelines recommend oxygen as needed to achief
normal SaO2.
 Supplemental O2 likely more important in children.
 Oxygen has mild bronchodilatory effect.
 Hyperoxia not necessary.
Rodrigo GJ, Rodriquez Verde M, Peregalli V, et al. Effects of
short-term 28% and 100% oxygen on PaCO2 and peak
expiratory flow rate in acute asthma: a randomized trial. Chest
2003;124(4):1312–7.

4. Primary Treatments – Fluids?
 Patients with severe exacerbations are often
dehydrated and have increased ongoing insensible
losses.
 PO rehydration preferable but not always possible.
 Extensive variation in practice.

4. Primary Treatments – Not Indicated?
 Mucolytics
 Chest physical therapy

5. Secondary Treatments?
 Magnesium Sulfate
 Helium
 IV Beta Agonists
 IV Methylxanthines
 IV LRTAs

5. Secondary Treatments – Magnesium
Sulfate?
 Calcium antagonism
 Relaxation of smooth muscle
 Anti-inflammatory
 Risks
 Hypotension
 Can be given iv or inhaled.

5. Secondary Treatments – Nebulized
Magnesium Sulfate?
 Powel 2012
 Review of RCT comparing nebulized Magnesium Sulfate
versus standard care.
 16 trials (7 adult, 4 child, 3 both)
 No improvement in pulmonary function (3 studies)
 No advantage in terms of hospital admission (4
studies)
 No serious adverse events
Powell C, Dwan K, Milan SJ, Beasley R, Hughes R, Knopp-Sihota JA, Rowe BH. Inhaled
magnesium sulfate in the treatment of acute asthma. Cochrane Database of Systematic Reviews
2012, Issue 12. Art. No.: CD003898. DOI: 10.1002/14651858.CD003898.pub5.

5. Secondary Treatments – Nebulized
Magnesium Sulfate?
 MANETIC Clinical Trial
 Multi-center trial in the UK
 508 children presenting to 30 different emergency
departments with severe exacerbations were randomized
to receive 2.5 ml (151 mg) of nebulized magnesium
sulfate versus placebo in addition to standard care.
 Children in MS group had sustained improvements in
symptom scores. Larger effect noted in those with more
severe symptoms. No differences in other outcomes; no
difference in adverse events.
Powell C, Kolamunnage-Dona R, Lowe J, Boland A, Petrou S, Doull I, et al.MAGNEsium Trial In Children
(MAGNETIC): a randomised, placebo controlled trial and economic evaluation of nebulised magnesium sulphate in
acute severe asthma in children. Health Technol Assess 2013;17(45)

5. Secondary Treatments – IV Magnesium
Sulfate?
 Guidelines suggest usage in patients who have
moderate to severe exacerbations not responsive to
initial albuterol treatment.
 Most common ED use
 Initial treatment of patients with severe or life-threatening
asthma.
 Subsequent use in patients who don’t improve after first
hour of therapy.
Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma; National Heart,
Lung and Blood Institute, National Asthma Education and Prevention Program; 2007 U.S.
Department of Health and Human Services

Sulfate?
 Mohammed 2007
 Systematic review of randomized and quasi-
randomized trials of iv magnesium (15 studies, 5
pediatric)
 Adults – improvement in respiratory function, no effect on
hospital admission
 Children – improvement in respiratory function and
reduction in hospital admission
Mohammed S, goodacre S. Intravensou and nebulized
Magnesium Sulphate for acute asthma: systematic
review and meta-analysis. Emerg Med J 2007; 24:
823-830

Sulfate –Early Use?
 Ciarallo 2000
 Thirty children who presented to two emergency
departments with moderate to severe exacerbations
received either 40 mg/kg IV Magnesium versus
Placebo.
 Mg group had greater improvement in spirometry and
were more likely to be discharged home (8/16 versus
0/14).
 Children < 6 yo excluded.
Ciarallo L, Brousseau D, Reinert S. Higher-dose intravenous
magnesium therapy for children with moderate to severe acute
asthma. Arch Pediatr Adolesc Med 2000;154:979–83.Gurkon 1999

Sulfate –Early Use?
 Torres 2012
 143 children presenting to an ED in Argentina were
randomized to receive Magnesium Sulfate versus
standard care in the first hour of treatment.
 Not clear if blinded.
 33% in the control group required mechanical
ventilation compared with 5% in the intervention group.
Torres S, Sticco N, Bosch JJ, Iolster T, Siaba A, Rocca RM, Schnitzler E. Effectiveness of magnesium
sulfate as initial treatment of acute severe asthma in children, conducted in a tertiary-level university
hospital: a randomized, controlled trial. Arch Argent Pediatr 2012 Aug; 110(4): 291-6

Sulfate –Late Use?
 Scarfone 2000
 54 children who presented to the ED with a moderate
to severe exacerbation were randomized to either
receive magnesium sulfate (75 mg/kg) or placebo after
an initial albuterol treatment and IV solumedrol.
 The mean change in pulmonary index score over the
following two hours was not different in both groups.
 No difference in hospitalization rate.
Scarfone RJ, Loiselle JM, Joffe MD, et al. A randomized trial of magnesium in the emergency
department treatment of children with asthma. Ann Emerg Med2000;36:572–8

5. Secondary Treatments – Helium?
 Colorless, odorless, less dense
 Improved CO2 diffusion
 Promotes laminar flow, higher flow rate even in
turbulent flow conditions
 If not using premixed tanks, care must be taken to
avoid giving hypoxic gas mixture.
 Higher thermal conduction
Gupta VK, Cheifetz IM. Heliox administration in the pediatric intensive care unit: an evidence-based
review. Pediatr Crit Care Med 2005;6(2):204–11.

5. Secondary Treatments – Helium?
 Guidelines say it “can be considered” for use in asthma
exacerbations.
 Potential uses
 As a “rescue” treatment early in therapy until conventional
therapies have had maximal effect
 For air delivery in intubated patients, especially early in
illness
 For delivery of aerosols

5. Secondary Treatments – Helium Rescue
therapy?
 Kudukis 1997
 Double-blind, RCT of 18 children with status asthmaticus
showed improvement in pulsus paradoxus, peak
expiratory flow and dyspnea scores in patients treated
with 15 minutes of 80:20 Heliox.
 Carter 1996
 Double-blind, RCT of 11 children with status asthmaticus
showed small improvements in peak flows in patients
treated with 70:30 heliox but no improvement in other
outcomes. Patients had already been treated for at least
six hours prior to enrollment.
Kudukis TM, Manthous CA, Schmidt GA, et al: Inhaled helium–
oxygen revisited: effect of inhaled helium– oxygen during the
treatment of status asthmaticus in children. J Pediatr 1997;
130:217–224
Carter ER, Webb CR, Moffitt DR: Evaluation of heliox in children
hospitalized with acute severe asthma. A randomized crossover
trial.Chest 1996; 109:1256–1261

5. Secondary Treatments – Helium in
children intubated due to asthma?
 Abd-Allah 2003
 Retrospective review of 28 intubated patients using
helium concentrations from 32 to 74%.
 With similar ventilator settings, PIP was significantly
decreased with heliox treatment.
 CO2 and pH also improved with heliox treatment. .
Abd-Allah SA, Rogers MS, Terry M, et al: Helium–oxygen therapy for pediatric acute severe asthma
requiring mechanical ventilation. Pediatr Crit Care Med 2003; 4:353–357

5. Secondary Treatments – Helium for
delivery of aerosol treatments?
 Results promising in adults.
 Conflicting results in children.
 Rivera 20006
 41 children in the ED with moderate to severe
exacerbations were randomized to receive initial albuterol
driven by heliox or usual care.
 No difference between groups in symptom scores after 20
minutes, admission rate, or rate of intubation.
Rivera ML, Kim TY, Stewart GM, Minasyan L, Brown L. Albuterol nebulized in heliox
in the initial ED treatment of pediatric asthma: a blinded, randomized controlled trial.
Am J Emerg Med 2006;24(1):38–42.

5. Secondary Treatments – Helium for
delivery of aerosol treatments?
 Kim 2005
 30 children in the ED with moderate to severe exacerbations were
randomized to receive, after an initial 5mg albuterol neb and oral
steroids, continuous albuterol by heliox or oxygen.
 Blinded video assessments, provider and patient not blinded.
 The mean change in pulmonary index over the subsequent four
hours was almost twice as much in the heliox group.
 More patients in the heliox group were discharged from the
hospital within 12 hours.
 No difference in rate of discharge from ED, PICU admission.
Kim IK, Phrampus E, Venkataraman S, Pitetti R, Saville A, Corcoran T, Gracely E, Funt N, Thompson A.
Helium/oxygen-driven albuterol nebulization in the treatment of children with moderate to severe asthma
exacerbations: a randomized, controlled trial. Pediatrics 2005;116(5):1127–33.

5. Secondary Treatments – iv beta
agonists?
 Selective agents – terbutaline, bedoradrine (IV)
 Non-selective agents – epinephrine
 Travers 2012
 Systematic review of RCTs of iv beta agonists for asthma
in the acute setting. Three pediatric studies identified.
 Limited evidence from RCTs to support use of IV beta
agonists.
Travers AH, Milan SJ, Jones AP, Camargo CA, Rowe BH. Addition of intravenous beta(2)-agonists to
inhaled beta(2) agonists for acute asthma. Cochrane Database Syst Rev. 2012 Dec 12; 12: CD010179

agonists?
 Browne 1997
 Children presenting to the ED with a severe asthma
exacerbation who did not improve after an initial albuterol
treatment were randomized to receive 15 mcg/kg iv
salbutamol or saline placebo in addition to standard care.
 Outcomes
 Recovery time (time until able to space treatments)
 4 hours in intervention group versus 11.5 hours in control group
 Time until discharge criteria met – 9.7 hours earlier in
intervention group
Browne GJ, Penna AS, Phung X, Soo M. Randomised trial of intravenous salbutamol in
early management of acute severe asthma in children. The Lancet. 1997; Vol. 349, 301-
305

agonists?
 Bogie 2007
 49 children with asthma between age 2-17 who required ICU
admission (but not intubation) were randomized to receive IV
terbutaline versus placebo in addition to standard care.
 Standard care included continuous albuterol up to 20 mg/hr,
steroids, fluid bolus. Aminophylline given for non-responders
(more given in intervention group). No patients received
magnesium. Some patients in both groups received inhaled or
subcutaneous terbutaline in ED prior to enrollment in the PICU.
 Improvements noted in severity scores, duration of continuous
nebs, and ICU stay were present but not statistically significant.
Browne GJ, Penna AS, Phung X, Soo M. Randomised trial of intravenous salbutamol in early
management of acute severe asthma in children. The Lancet. 1997; Vol. 349, 301-305

agonists?
 Nowak 2010 and Matsuda 2012
 Bedoradrine is a newer selective beta-2 agonist.
 A phase two clinical trial published in 2012 in Journal of Asthma
showed improvements in FEV1 versus placebo.1
 A related poster presentation of a randomized, placebo-controlled
study of the drug (added to standard of care) showed reduced
hospitalization rates and improved FEV1.
2. Nowak R, Iwaki Y, Matsuda K, Johnson K. Reduced Hospital
Admission and Improved Pulmonary Function following
Intravenous MN-221 (Bedoradrine), a Novel Highly Selective
Beta2-Adrenergic Receptor Agonist, Adjunctive to Standard of
Care in Severe Acute Exacerbation of Asthma.
1. Matsuda K, Makhay M, Johnson K and Iwaki Y. Evaluation of
Bedoradrine Sulfate (MN-221), a Novel, Highly Selective Beta2-
Adrenergic Receptor Agonist for the Treatment of Asthma via
Intravenous infusion. Journa of Asthma 2012; 49(10): 1071–
1078

5. Secondary Treatments – Intravenous
Leukotriene Receptor Antagonists
 Evidence exists in adult literature that iv administrating may be
effective in acute severe asthma. Pediatric Studies appear to be
lacking.
Camargo CA, Smithline HA, Malice MP, et al. A randomized
controlled trial of intravenous montelukast in acute asthma. Am J
Respir Crit Care Med 2003; 167(4):528–33.

5. Secondary Treatments –
Methylxanthines
 Not recommend by guidelines for routine treatment of acute
asthma in children.
 Recent systematic review of adult studies showed no evidence
reduced hospitalization rate, improved severity scores, or other
outcomes. Significant amount of vomiting and arrhythmias not
uncommon.1
 Meta-analysis in children from 2005 including 7 trials showed
statistically significant (but maybe not clinically significant)
improvement in spirometry when added to usual care but no
improvement in other outcomes. Methylxanthines led to a three-
fold increased risk of vomiting (but not arrythmias).2
1. Nair P, Milan SJ,Rowe BH. Addition of intravenous
aminophylline to inhaled beta(2)-agonists in adults with acute
asthma. Cohcrane Database Syst Review. 2012 Dec 12: 12
CD002742
2. Mitra A, Bassler, Goodman K, Lasserson TJ, Ducharme FM.
Intravenous Aminophylline for acute severe asthma in children
over two years receiving inhaled bronchodilators. Cochrane
Database Syst Rev 2005 Apr 18; (2): CD 001276

5. Secondary Treatments – Ketamine
 Case studies and observational studies have shown promising
results.1
 One RCT in children did not show improvement in outcomes.2
1. Jat KR, Chawla D. Ketamine for management of
acute exacerbations of asthma in children. Cochrane
Database of Systematic Reviews 2012, Issue 11. Art.
No.: CD009293. DOI:
10.1002/14651858.CD009293.pub2.
2. Allen JY, Macias CG. The efficacy of ketamine in
pediatric emergency department patients who present
with acute severe asthma. Annals of Emergency
Medicine 2005;46(1): 43–50.

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