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Emergent Management of

Pediatric Asthma: Myths & Pitfalls

Dan Nguyen, MDAssistant Professor of Emergency Medicine & Pediatrics

MCEP Critical Care Practice in the Emergency Department

March 22nd, 2018

Disclosures and Conflicts of Interest

• I have no conflicts of interest in relation to this presentation

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Learning Objectives

• Summarize the prevalence and financial impact of asthma in the pediatric population

• Prioritize a systematic approach for acute management

• Identify advanced treatment modalities

• Evaluate common pitfalls in management

Epidemiology

• 8.4% prevalence in US children– Rate of emergency care use 2-2.5 times higher in age <18 yrs

• Minorities disproportionately affected*– Mortality 4-5 times higher in black compared to white children

– Puerto Ricans have highest prevalence

– Role of allergen exposure

– Reliance on episodic/emergent care

– Decreased medication compliance

*Mayrides M, et al. “Ethnic Disparities in the Burden and Treatment of Asthma”. AAFA/National Pharmaceutical Council. 2005.

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Epidemiology

Wang LY, et al. “Direct and Indirect Cost of Asthma in School-age Children”. Preventing Chronic Disease. Jan 2005. Asthma Allergy Foundation of America, May 20015.The Express Scripts Lab. The 2014 Drug Trend Report. March 2015. http://lab.express-scripts.com/drug-trend/report/

• Annual health care cost for child with asthma: $1042

– Child without asthma $618

• Children with asthma miss 2.48 school days/year

$56 B$50.1 B

$5.9 B

Cost of Asthma

Pathophysiology

Reduce

Inflammation

Reverse

Obstruction

Correction of

Hypoxemia

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Bronchodilators

• Inhaled SABA (Albuterol)

• Ipratropium bromide

• Parental beta-agonists

• Magnesium sulfate

• Ketamine

Continuous vs. Intermittent

• Cochrane Database Systematic Review, 2003

– RCTs of continuous vs. intermittent inhaled beta-agonists in ED

– 8 trials

– Continuous treatments associated with greater improvement in spirometry and reduced rates of hospital admissions

*Carmargo CA, et al. “Continuous versus intermittent beta-agonists in the treatemnt of acute asthma”. Cochrane Database Systematic review. 2003 Oct 20;(4):CD001115.

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Inhaled SABA

• Goal = Administer 3 doses within the first hour

• Continuous vs. Intermittent– Similar outcomes and side effects

– Continuous less labor intensive

– Intermittent may be better tolerated by younger children

Recommendation

Continuous therapy for moderate to

severe asthma exacerbation

Nebulizer vs. MDI

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Nebulizer vs. MDI

• Meter-dosed Inhaler✖ Requires patient coordination and education

✖ Requires respiratory hold

✖ Requires spacer & mask

✔ Portability

✔ Treatment Time

✔ No external power source

✔ Cost in the community

• Nebulizer✖ Required to hold treatment over patient’s face (≈60 minutes)

✖Machine sanitation

✖Machine are not portable

✔ Passive administration

✔ Supplemental humidified oxygen

✔ Co-administration of other inhaled meds (ipratropium)

*Cates CJ, et al. “Holding chambers (spacer) versus nebulizers for beta-agonist treatment of acute asthma”. Cochrane Database Systematic review. 2014 Sept 13;(9):CD000052.

Nebulizer vs. MDI

*Cates CJ, et al. “Holding chambers (spacer) versus nebulizers for beta-agonist treatment of acute asthma”. Cochrane Database Systematic review. 2014 Sept 13;(9):CD000052.

Hospitalization Admission Rates

• Cochrane Database Systematic Review, 2014

– 39 Trials, 1897 children

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Nebulizer vs. MDIED Length of Stay

Heart Rate

Nebulizer vs. MDI

Recommendation

Nebulizers are equally as effective as MDI

*Cates CJ, et al. “Holding chambers (spacer) versus nebulisers for beta-agonist treatment of acute asthma”. Cochrane Database Systematic review. 2014 Sept 13;(9):CD000052.

• Cochrane Systematic Review, 2014

– Decreased admission rates

– Shorter ED Length of Stay

– Decreased Tachycardia

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A Word About Spacers

• Improved outcomes in children with asthma

Recommendation

All Children Need a

Spacer & Mask

• Corrects for poor coordination/technique

• Decreases oropharyngeal deposition

Levalbuterol

• Xopenex - Pure R-albuterol

• S-albuterol thought to be a weaker bronchoconstrictor

• Is it more effective?

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Levalbuterol

• Journal of Asthma, 2011

– 99 children, ED visits for mod/severe exacerbation

– 7.5 mg albuterol vs. 3.75 mg levalbuterol

• Further treatments given with same meds

• 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, et al. “Efficacy of Racemic Albuterol versus Levalbuterol used as a Continuous nebulization for the Treatment of Acute Asthma Exacerbations: A Randomized, Double-Blind, Clinical Trial”. Journal of Asthma. 2011 Mar; 48 (2):188-93.

Levalbuterol

• Pulmonary Pharm Therapeutics, 2013

– Large meta-analysis and systemic review

– 7 trials, 1625 patients

– Similar RR, SaO2, %ΔFEV1, Clinical Asthma Scores

– Levalbuterol should not be used over albuterol

Jat KR, et al. “Levalbuterol versus albuterol for acute asthma: a systematic review and meta-analysis”. Pulm Pharm Therapy. 2013 Apr; 26(2):239-48.

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Decreased Tachycardia?

• Journal of Ped Pharm Therapy, 2011

– Levalbuterol vs. Racemic Albuterol x 3 doses

– 50 patients

– No clinically significant difference in HR changes

• Annals of Pharmacotherapy, 2013

– Children with CHD, cardiomyopathy, or SVT

– 192 patients

– Equivalent increases in HR

*Bio LL, et al. “Comparison of levalbuterol and racemic albuterol based on cardiac adverse effects in children”. Journal of Ped Pharm Therapy. 2011 Jul-Sep; 16(3): 191-198.**Kelly A, et al. “Comparison of heart rate changes associated with levalbuterol and racemic albuterol in pediatric cardiology patients. Annals of Pharmacotherapy. 2013 May; 47(5): 644-50

Levalbuterol

• Does it cost more?

– YES! 4-5 x more expensive for equivalent neb nose

Recommendation

Racemic albuterol with rare exception

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Ipratropium Bromide

• Anticholinergic agent

• Impairs bronchial smooth muscle contraction

• Minimal systemic side effects

– Unable to cross from lung to systemic circulation

Ipratropium Bromide

• Additive effect with SABA*

– Improved spirometry measures

– Reduced risk of hospitalization

• No benefit to continuing as inpatient**

Recommendation

Combine ipratropium bromide (2-3 doses) with first

3 doses of albuterol given over 1st hr

*Rodrigo GJ, et al. Anticholinergic in the treatment of children and adults with acute asthma: a systematic review and meta-analysis”. Thorax. 2005 Sep; 60(9): 740-6. **Vezina K, et al. “Combined inhaled anticholinergics and short-acting beta2-agonists for initial treatment of acute asthma in children”. Cochrane Database Systematic Review. 2013 Aug 21;(8): CD000060.

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Parental Beta-Agonists

• Subcutaneous or Intramuscular

• Poor inspiratory air flow or cooperation (i.e. AMS)

• Given within minutes of arrival

• Dosing– Terbutaline: 0.01 mg/kg/dose (Max dose 0.4 mg)

– Epinephrine: 0.01 mg/kg/dose (Max dose 0.4 mg)

– Consider auto injectable epinephrine

Parenteral Beta-Agonists

• Pediatric Emergency Care, 2007

– Prospective RCT of IV Terbutaline

– 49 children in ICU

– Trend toward improved scores and shorter ICU stay, but not statistically significant

• Cochrane Review, 2012

– 3 studies, 157 children

– Limited evidence to support use of IV beta agonists

Bogie AL, et al. “Comparison of intravenous terbutaline versus normal saline in pediatric patients on continuous high-dose nebulized albuterol for status asthmaticus”. Pediatric Emergency Care. 2007 un; 23(6): 355-61.Travers AH, et al. “Addition of intravenous beta(2)-agonists to inhaled beta(2) agonists for acute asthma”. Cochrane Database Systematic Rev. 2012. Dec 12; 12: CD10179.

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Parental Beta-Agonists

• Increased side effects

– Dysrhythmias, myocardial ischemia, hypertension

• Reserved for critically ill, poorly responsive

• Consider repeated doses (x3) vs. infusion

• Discuss with ICU colleagues

Systemic Glucocorticoids

• Reduce airway edema and secretions

• Indicated in most children presenting to ED

– Any moderate or severe exacerbation

– Any mild exacerbation not responding to adequate home therapy

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Systemic Glucocorticoids

*Rowe BH, et al. “Early emergency department treatment of acute asthma with systemic corticosteroids”. Cochrane Database Systematic Review. 2001; (1):CD002178.

Forrest Plot: Any steroid vs. placebo, outcome hospital admission

Hospitalization Rates

Systemic Glucocorticoids

• The sooner the better!

• Early administration (within 1 hr) vs. placebo*

– Reduced admission rates

– NNT to prevent one admission = 8

*Rowe BH, et al. “Early emergency department treatment of acute asthma with systemic corticosteroids”. Cochrane Database Systematic Review. 2001; (1):CD002178.

NNT = 1 / [(159/426) – (209/418)] = 7.88 ≈ 8

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Systemic Glucocorticoids

• Prednisone vs. Dexamethasone vs. Methylprednisolone

(2mg/kg) (0.6 mg/kg) (2 mg/kg)

• Effects start in 1-3 hours, max effect at 4-8 hours

• Inhaled glucocorticoids?

– Thus far, no benefit in acute management

*Hendeles L, et al. “Are inhaled corticosteroids effective for acute exacerbation of asthma in children?”. Journal of Pediatrics. 2003; Feb; 142(2 Suppl): S26-32; discussion S32-3.Upham BD, et al. “Nebulized budesonide added to standard pediatric emergency department treatment of acute asthma: a randomized, double-blind trial. Acad Emerg Med 2011; 18:665-73.

Recommendation

Systemic steroids recommended to

non-responders to inhaled beta-agonists

Dexamethasone vs. Prednisone

• Pharmacokinetics

– 5-6 times more potent than prednisone

– 4-5 times longer half life

• Clinical

– Similar efficacy with less side effects (i.e. vomiting)*

– Single Dose or Two-Doses not inferior to predinsone**

– No increase in unscheduled medical evaluations

*Qureshi F, et al. “Comparative efficacy of oral dexamthasone versus oral prednisone in acute pediatric asthma”. Ped. Jul 2001; 139(1): 20-6.**Schwartz ES et al. “Is dexamethasone as effective as prednisone or prednisolone in the management of pediatric asthma exacerbations? ”. Annals of Emergency Medicine. Jan 2001; 65(1): 81-2.

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Dexamethasone vs Prednisone

• Increased Compliance

– Families prefer shorter duration*

– More palatable and preferred by pediatric patients**

• Economic Cost Savings***

– Less return visits

– Less admissions

*Williams KW, et al. “Parental preference for short- versus long-course corticosteroid therapy in children with asthma presenting to the pediatric emergency department”. Clinical Pediatrics. Jan 2013; 52(1): 30-4.**Hames H et al. “A palatability study of a flavored dexamethasone preparation versus prednisolone liquid in children ”. Canadian J ClinPharmacol. Winter 2008; 15(1): e95-8.***Andrews A et al. “A cost-effectiveness analysis of dexamthasone vs prednisone in pediatrics acute asthma exacerbation”. Acad Emerg Med. Aug. 2012; 19(8): 943-8.

Kitchen Sink

• Beta Agonists (naturally)

• Inhaled anticholingerics (useful in first hour)

• IV steroids (struggling to breath ≠ PO)

• Magnesium sulfate

• Heliox

• Ketamine

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Magnesium Sulfate

• Mechanism multifactorial

– Smooth muscle relaxation

• Blocks NMDA receptor-gated Ca channel

– Reduces inflammatory mediators

• Stabilizes T cells, inhibits mast cell degranulation

– Stimulates nitric oxide synthesis

– Rapid onset

Magnesium SulfateHospitalization Rates

Respiratory Function

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Magnesium Sulfate

• When added to SABA and steroids:– Improved pulmonary function

– Reduced inpatient hospitalization

– NO effect on SBP/DBP

• Dose: 25-75 mg/kg (max 2g) over 20 minutes

*Shan Z. et al. “Intravenous and nebulized magnesium sulfate for treating acute asthma in adults and children: a systematic review and meta-analysis” Respiratory Medicine. 2013 Mar; 107(3): 321-30.

Recommendation

Consider magnesium in severe exacerbations who

deteriorate despite initial therapy

Ketamine

• Bronchodilator effect

– Central catecholamine release

– Inhibition of vagal pathways anticholinergic effect on bronchial smooth muscle

• Medication of choice for sedation/analgesia required for endotracheal intubation in asthmatics

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Ketamine

• Utility in non-intubated children?

• Annals of Emergency medicine, 2005

– Double-blind, randomized, placebo-controlled trial

– 68 patients with continued mod-sever symptoms after initial conventional therapy

– No benefit

Allen JY, et al. “The efficacy of ketamine in pediatric emergency department patients who present with acute severe asthma”. Annals of Emergency Medicine. 2005 Jul; 46(1): 43-50.

Heliox

• Increases efficient laminar flow

• 70:30 or 80:20 mixture

Re =

Re = Reynolds Number

ρ = density

v = velocity

R = radius

η = viscosity

ρvr/η

η

*Gupta VK, et al. “Heliox administration in the pediatric intensive care unit: an evidence-based review”. Pediatric Critical Care Med. 2005; 6(2): 204-11.

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Heliox

• Benefits

– Better lung mechanics

– Improves albuterol delivery

– Few side effects/complications (inert gas)

• Drawback

– Expensive

– Contraindicated in hypoxia

– Few proven RCTs

– Does not treat causative issue

*Rodrigo GV, et al. “Heliox for the non-intubated acute asthma patients”. Cochrane Collaboration. 2010.

Common Pitfalls

• Intubation Risk

• Excessive IVF

• Elevated lactic acidosis

• Transient hypoxia with β-agonist

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Endotracheal Intubation

• Goal = DON’T INTUBATE

– ¼ of children intubation develop complications

• Pneumothorax

• Impaired Preload

• Cardiovascular Collapse

– Mechanical ventilation associated with increased mortality

Endotracheal Intubation

• Indications

– Apnea/Coma

– Worsening mental status

– Exhaustion

– Refractory hypoxemia

– Significant refractory respiratory acidosis (worsening despite maximal therapy)

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IV Hydration

IV Fluids Bolus???

Dehydration

- Thickened secretions

& mucous plugging

- Decreased preload

- CO = HR x Preload

Over-hydration

- Negative intrapleural

pressure

- Increased afterload

- Pulmonary Edema

Hydration Study

*Kantor DB, et al. “Fluid balance is associated with clinical outcomes and extravascular lung water in children with acute asthma exacerbation”. Am J Respir Crit Care Med. 2018 Jan 9.

• Am J Resp & Crit Care Medicine, 2018

– Retrospective cohort, Urban Children’s Hospital

– 1175 admitted asthmatic patients

– Positive fluid balance is associated with longer LOS, treatment duration, and oxygen utilization

– Prospective Validation Cohort (123 patients)

• Correlated with fluid balance (B-lines)

• Correlated with intrapleural pressure (Δ Peak Aortic Velocity)

– 1% fluid overload = 7 hours hospital LOS

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Retrospective Cohort

Prospective Observational Cohort

V/Q Mismatch

• β-agonist worsens V/Q mismatch

• Transient hypoxia (≈10 min)

*Rodrigo GJ, 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.

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Lactic Acidosis

• β-agonist derangement of glucose metabolism

• Increase Type B lactic acidosis

• Metabolic acidosis compensatory hyperventilation

• Common with severe asthmatics and continuous albuterol

Beyond the First Hour

Marked Improvement

• Observe at least one hour and reassess

No Improvement

• Consider other diagnoses

• Hospitalization (Inpatient vs. ICU)

• Escalate care (IV Mag sulfate, IV terbutaline, etc) vs. continuous inhaled therapy with albuterol

Partial Improvement

• Continued observation (more time for steroids to take action?)

• Consider further albuterol therapy (continuous vs frequent intermittent)

• Reassess for appropriate disposition

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Take Home Points

• Get steroids onboard early

– Decadron = Prednisone

• Duoneb x 3 in first hour

• MDI-Spacer = Nebulizer

• Advance therapies (continuous, magnesium, parental beta-agonist)

• Avoid pitfalls (V/Q mismatch, lactic acidosis, IVF)

References• Wang LY, et al. “Direct and Indirect Cost of Asthma in School-age Children”. Preventing Chronic Disease. Jan 2005.

• Mayrides M, et al. “Ethnic Disparities in the Burden and Treatment of Asthma”. AAFA/National Pharmaceutical Council. 2005.

• The Express Scripts Lab. The 2014 Drug Trend Report. March 2015. http://lab.express-scripts.com/drug-trend/report/

• Bousquet J, et al. “Uniform definition of asthma severity, control, and exacerbations: document presented for the World Health Organization Consultation on Severe Asthma”. Journal of Allergy and Clinical Immunology. Nov 2010. 126(5): 926-38.

• Singer AJ, et al. “A call for expanding the role of emergency physician in the care of patients with asthma”. Annals of Emergency Medicine. Mar 2005. 45(3): 295-8.

• Carrol CL, et al. “A modified pulmonary index score with predictive value for pediatric asthma exacerbation”. Annals of Allergy, Asthma, and Immunology. 2005 Mar; 94(3):355-9.

• Cates CJ, et al. “Holding chambers (spacer) versus nebulisers for beta-agonist treatment of acute asthma”. Cochrane Database Systematic review. 2014 Sept 13;(9):CD000052.

• Doan Q, et al. “Cost-effectiveness of meter-dose inhalers for asthma exacerbations in the pediatric emergency”. Pediatrics 2011. 127;(5): e1105-e1111.

• Castro-Rodriguez JA, et al. “Beta-agonists through meter-dose inhaler with valved holding chamber versus nebulizer for acute exacerbation of wheezing or asthma in children under 5 years of age: a systematic review with meta-analysis”. Journal of Pediatrics. 2004. 145: 172-7.

• Dolovich MB, et al. “ Device selection and outcomes of aerosol therapy: evidence-based guidelines: American College of Chest Physicians/American College of Asthma, Allergy, and Immunology”. Chest. Jan. 2005. 127(1): 335-71.

• Qureshi F, et al. “Clinical efficacy of racemic albuterol vs levalbuterol for the treatment of acute pediatric asthma”. Annals of EM. 2005 Jul; 46 (1):29-36.

• Jat KR, et al. “Levalbuterol versus albuterol for acute asthma: a systematic review and meta-analysis”. Pulm Pharm Therapy. 2013 Apr; 26(2):239-48.

• Bio LL, et al. “Comparison of levalbuterol and racemic albuterol based on cardiac adverse effects in children”. Journal of Ped Pharm Therapy. 2011 Jul-Sep; 16(3): 191-198.

• Kelly A, et al. “Comparison of heart rate changes associated with levalbuterol and racemic albuterol in pediatric cardiology patients. Annals of Pharmacotherapy. 2013 May; 47(5): 644-50

• Rodrigo GJ, et al. Anticholinergic in the treatment of children and adults with acute asthma: a systematic review and meta-analysis”. Thorax. 2005 Sep; 60(9): 740-6.

• Vezina K, et al. “Combined inhaled anticholinergics and short-acting beta2-agonists for initial treatment of acute asthma in children”. Cochrane Database Systematic Review. 2013 Aug 21;(8): CD000060.

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References• Bogie AL, et al. “Comparison of intravenous terbutaline versus normal saline in pediatric patients on continuous high-dose nebulized

albuterol for status asthmaticus”. Pediatric Emergency Care. 2007 un; 23(6): 355-61.

• Shan Z. et al. “Intravenous and nebulized magnesium sulfate for treating acute asthma in adults and children: a systematic review and meta-analysis” Respiratory Medicine. 2013 Mar; 107(3): 321-30.

• Allen JY, et al. “The efficacy of ketamine in pediatric emergency department patients who present with acute severe asthma”. Annals of Emergency Medicine. 2005 Jul; 46(1): 43-50.

• Rodrigo GV, et al. “Heliox for the non-intubated acute asthma patients”. Cochrane Collaboration. 2010.

• Rowe BH, et al. “Early emergency department treatment of acute asthma with systemic corticosteroids”. Cochrane Database Systematic Review. 2001; (1):CD002178.

• Hendeles L, et al. “Are inhaled corticosteroids effective for acute exacerbation of asthma in children?”. Journal of Pediatrics. 2003; Feb; 142(2 Suppl): S26-32; discussion S32-3.

• Qureshi F, et al. “Comparative efficacy of oral dexamthasone versus oral prednisone in acute pediatric asthma”. Ped. Jul 2001; 139(1): 20-6.

• Schwartz ES et al. “Is dexamethasone as effective as prednisone or prednisolone in the management of pediatric asthma exacerbations? ”. Annals of Emergency Medicine. Jan 2001; 65(1): 81-2.

• Williams KW, et al. “Parental preference for short- versus long-course corticosteroid therapy in children with asthma presenting to the pediatric emergency department”. Clinical Pediatrics. Jan 2013; 52(1): 30-4.

• Hames H et al. “A palatability study of a flavored dexamethasone preparation versus prednisolone liquid in children ”. Canadian J ClinPharmacol. Winter 2008; 15(1): e95-8.

• Andrews A et al. “A cost-effectiveness analysis of dexamthasone vs prednisone in pediatrics acute asthma exacerbation”. Acad EmergMed. Aug. 2012; 19(8): 943-8.

• Kantor DB, et al. “Fluid balance is associated with clinical outcomes and extravascular lung water in children with acute asthmaexacerbation”. Am J Respir Crit Care Med. 2018 Jan 9.

• Scarfone RJ, et al. “Emergency physicians’ prescribing of asthma controller medications”. Pediatrics. 2006 Mar; 117(3): 821-7.

• Lehman HK, et al. “Initiation of maintenance antiinflammatory medication in asthmatic children in pediatric emergency department. Pediatrics. 2006 Dec; 118(6): 2394-401.

Questions/Evaluation

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