Director, Pediatric Allergy & Immunology Acute Asthma: 2009 Update Heather Lemon-Mulé, MD Director, Pediatric Allergy & Immunology St. Barnabas Hospital July 28, 2009

Definition of Asthma A chronic inflammatory disease of the lungs characterized by reversible airway obstruction and airway hyper-reactivity Acute asthma exacerbations are paroxysmal episodes of wheeze, cough, tachypnea, dyspnea, hypoxia, respiratory failure

Etiology of Acute Exacerbations Viral agents identified in >80% of pediatric asthma exacerbations and >50% of adult asthma exacerbations Rhinovirus is identified in>65% of wheezing episodes caused by URIs Peaks in hospital admissions for asthma correlate with RV seasons (spring and fall) With use of RT-PCR as a supplement to viral culture viruses detected in >80% of pediatric asthma exacerbations. When URI is suspected cause of asthma exacerbation, viral agent identified >90% of the time so clinical judgement is quite sensitiive

Acute Asthma Etiology Pediatric Inf Disease Journal 2009: PICU admissions for 43 pts with LRTI; 30 specimens with identifiable infectious agent;

Etiology of Acute Asthma Exacerbations Allergen exposure (aeroallergen) Exercise Atypical bacteria GERD Sinusitis ASA/NSAID ingestion (AERD)

Pathophysiology Asthma historically has been considered the prototypic atopic disease triggered by allergen exposure Acute phase is triggered by allergen binding to IgE molecules bound to the FcEpsilon receptor on the mast cell surface in a sensitized individual Allergen binding and cross-linking of t he IgE receptors sends a powerful stimulus for mast cell degranulation Upon dgranulation is the release of pre-formed and newly synthesized mediators including histamine, proteases, leukotrienes as well as various pro-inflammatory cytokines and chemokines Histamine and leukotrienes are both powerful agents of bronchoconstriction and histamine also promotes increased mucus production and viscosity leading to mucus plugging Pro-inflamatory cytokines and chemokines initiate the chronic phase leading to recruitment of various cells, including eosinophils, lymphocytes, macrophages and to a lesser extent neutrophils Wth prolonged and uncontrolled inflammation airway remodelling occurs; this is a result of fibroblast activation with collegen and other extracellular matric protein deposition as well as airway smooth muscle hyperplasia/hypertrophy and mucus gland hyperplasia The end result of remodelling is loss of lung function essentially leading from a lung disease charactierized by reversible airway obstruction to one with irreversible airway obstruction.

Pathophysiology: Virus-Induced Wheezing The pathophysiology of viral-induced wheezing is different. Viral infections induce neutrophilic inflammation but also increased levels of eosinophils, CD4 and CD8 T-cells and mast cells through increased expression of pro-inflammatory cytokines and chemokines. Viral infection also results in increased mucus secretion as well as respiratory epithelium shedding and release of mediators from neutrophils ans eosinophils that lead to bronchocontriction

Pathophysiology of Acute Asthma Evidence of neutrophil degranulation and LDH levels are independent predictors of exacerbation severity. RV infection leads to early release of IP-10 which is INF-γ-induced protein 10 (IP-10) and asthmatic pts have increased serum levels of IP-10 in response to Rv infection as compared with non-asthmatic controls; IP-10 levels correlate with airflow obstruction and high levels are associated with decreased bronchdilator response to B-agonists. RV infection also leads to increases expression of IL-6, IL-8, IL-16, eotaxin and RANTES which promote influx of other inflammatory cells as well, including eosinophils. RV viral loads correlate with exacerbation severity.

Pathophysiology: Virus-Induced Wheezing This slide shows the role of eosinophils in viral-induced asthma exacerbations.

RV in Asthma: Innate Immune Defect? Interferons are anti-viral proteins produced in the innate immune response to viral infections IFN-β induces apoptosis in infected cells; decreased production of IFN-β in asthmatics allows increased viral replication Asthmatics also have decreased production of IFN-α and IFN-λ RV has garnered a lot of interest over past decade b/c it really seems to pick out the asthmatics, specifically those who develop persistent atopic asthma. There is increasing evidence that asthmatic patients (those with classica atopic asthma) are particularly susceptible to viral respiratory infections and RV especially because of an innate immune defect

Allergy and Viral Infections: Synergy? Murray et al (Thorax 2006) showed allergen-exposed, atopic asthmatic children at greater risk for hospital admission with LRT viral infections Similar findings in adult asthmatic patients (BMJ 2002) Likely due to increased chronic airway inflammation in atopic asthmatic patients; asthmatics have increased expression of ICAM1 (this protein is upregulated in allergic inflammation and allows for leukocyte/lymphocyte adhesion to endothelium and transmigration into lung tissue); ICAM-1 is the binding receptor for RV and therefore at risk for more severe RV infections (greater infection rate and possibly innate immune defect)

Allergen Sensitization and Exposure Exposure to seasonal allergens implicated in sudden asthma-related deaths Alternaria sp exposure is associated with exacerbations and a 200-fold increased risk for respiratory arrest HDM, cat and CR sensitization are RF for emergency treatment Grass pollen sensitization (“thunderstorm asthma”) is associated with asthma exacerbation epidemics No question that allergen exposure in an atopic asthmatic can trigger asthma exacerbations including life-threatening exacerbations

Role of Atypical Bacteria? Cunningham et al (Eur Respir J 1998) showed strong correlation between C. pneumoniae-specific IgA in NLF and asthma exacerbation frequency in children Wark et al (Eur Respir J 2002) found 38% of adults treated in ED for asthma exacerbations had serologic evidence of C. pneumoniae reactivation and greater lower airway inflammation Both studies had high viral detection rates (85% and 76%) These studies suggest that viral infections allow for C. pneumoniae reactivation possibly increasing the severity of the exacerbation

Role of Atypical Bacteria? Johnston et al (NEJM 2006) performed RDBPCT with telithromycin in adult asthmatics experiencing acute exacerbations >50% of patients had serologic evidence of infection but only 3 by PCR assay (C. pneumoniae) Telithromycin treated patients had improved symptom scores, but not lung function compared with placebo Unclear whether improvement due to antibacterial properties vs. immunomodulating properties Improvement noted in patients with and without evidence of infection with atypical organisms Improvement in telithromycin group statistically significant but of questionable clinical significance

Differential Diagnosis of Acute Asthma Bronchiolitis (and other viral PNAs) Croup Bacterial Pneumonia (typical or atypical) Foreign Body Vocal Cord Dysfunction Allergic Reaction Panic Attack Congestive Heart Failure Pertussis CF exacerbation

Determining Exacerbation Severity Clinical signs and symptoms Objective measurements (functional assessment) Implications for management

Signs and Symptoms of Acute Asthma Mild Moderate Severe Impending Respiratory Arrest Breathlessness While walking At rest (Infants – softer, shorter cry, difficulty feeding) At rest (Infants – stops feeding) Can lie down Prefers sitting Sits upright Talks in Sentences Phrases Words Unable to speak Alertness May be agitated Often agitated Usually agitated Drowsy or confused Signs Respiratory Rate Often increased Usually increased Increased May be decreased Use of Accessory Muscles Usually not Commonly Usually Paradoxical thoracoabdominal movement Wheeze Often only end expiratory Throughout expiration Throughout inhalation/expiration Absence of wheeze Heart Rate Usually normal Often Bradycardic Pulsus paradoxus Absent (<10 mm Hg) May be present (10-25 mm Hg) Often Present (20-40 mm Hg) (>25 mm Hg adult) Absence suggests respiratory muscle fatigue Modified from NAEPP Guidelines 2007

Determining Severity: PEF Symptoms & Signs Initial PEF (or FEV1) Clinical Course Mild Dyspnea only with activity (infants: tachypnea only and does not interfere with feeding) PEF ≥70% predicted or personal best Prompt relief with SABA; Usually cared for at home; Oral steroids usually not required Moderate Dyspnea interferes with or limits activity (may interfere with infant feeding) PEF 40-69% predicted or personal best Requires office/ED visit; Relief from frequent inhaled SABA; Oral steroids often required; sx last 1-2 days after Rx initiated Severe Dyspnea at rest; interferes with conversation (and infant feeding) PEF <40% predicted or personal best Usually requires ED visit and hospitalization; partial relief from SABA; oral steroids required; sx last >3 days after Rx initiated; adjunctive therapies helpful Life Threatening Too dyspneic to speak; perspiring PEF < 25% predicted or personal best Requires ED/hospitalization and probable ICU; poor response to SABA; IV steroids required; adjunctive therapies helpful

Determining Severity: Functional Assessment Mild Moderate Severe Subset: Life-Threatening PEF (% predicted or personal best) ≥70 40-69 or response lasts < 2 ours <40 <25 (may not be needed or pt may not be capable) PaO2 (on RA) and/or PaCO2 Normal (test usually not required) <42 mm Hg (test usually not required) ≥ 60 mm Hg (test usually not required) <60 mm Hg: possible cyanosis ≥ 42 mm Hg: possible respiratory failure SaO2 (on RA) at sea level >95% 90-95% <90%

RF for Asthma-Related Death: Asthma History Previous severe exacerbations (especially history of ETI or ICU admission) ≥2 admissions for asthma within previous 12 months ≥3 ED visits for asthma within previous 12 months Hospitalization or ED visit within past month Use of >2 canisters of SABA/month Difficulty perceiving asthma symptoms or severity of exacerbations

Other RF for Asthma-Related Death Social: low SES or inner city residence, illicit drug use or other major psychosocial problems Comorbidities: cardiovascular disease, other chronic lung disease, chronic psychiatric disease

Special Consideration: Infants Infants high-risk group for respiratory failure Greater peripheral airway resistance Fewer collateral channels of ventilation Further extension of airway smooth muscle into the peripheral airways Less elastic recoil Mechanical disadvantage of the diaphragm Ventilation/perfusion characteristics promote hypoxemia more readily than older children/adults

Special Consideration: Infants Use of accessory muscles, inspiratory/expiratory wheezing, paradoxical breathing, cyanosis and RR>60 suggest serious distress SaO2<90% also sign of serious distress; SaO2<92% after 1 hour of treatment good indicator of need for hospitalization Assessment largely determined by PE findings rather than objective measurements Response to SABA can be variable; lack of response can be an indicator for admission

Initial Assessment: Brief History Time of onset and any potential causes of current exacerbation Severity of symptoms, especially compared with previous exacerbations, and response to any already given treatments All current medications and time of last dose, especially of asthma medications Any prior episodes of respiratory insufficiency due to asthma Other potentially complicating illness Estimate of number of previous unscheduled office visits, ED visits, and hospitalizations for asthma, particularly within the past year (loss of consciousness or intubation and mechanical ventilation) especially other pulmonary or cardiac disease or diseases that may be aggravated by systemic corticosteroid therapy (such as diabetes, peptic ulcer, hypertension, and psychosis).

Initial Assessment: Physical Examination Assess the severity of the exacerbation: overall patient status, including level of alertness, fluid status, and presence of cyanosis, respiratory distress, and wheezing Identify possible complications Rule out upper airway obstruction Clues to the presence of alternative reasons for dyspnea include dysphonia, inspiratory stridor, monophonic wheezing loudest over the central airway, normal values for PaO2, and unexpectedly complete resolution of airflow obstruction with intubation. Wheezing can be an unreliable indicator of obstruction; in rare cases, extremely severe obstruction may be accompanied by a “silent chest” (Shim and Williams 1980). Complications: (ex. pneumonia, pneumothorax, pneumomediastinum); although rare, these will influence management of the asthma exacerbation. When upper airway obstruction is suspected, further evaluation is indicated by flow-volume curves and by referral for laryngoscopy Both intrathoracic and extrathoracic central airway obstruction can cause severe dyspnea and may be diagnosed as asthma. ♦ Causes include upper airway foreign bodies, epiglottitis, organic diseases of the larynx, vocal cord dysfunction, and extrinsic and intrinsic tracheal narrowing

Laboratory Studies: Indications CXR: obtain if complicating process suspected CBC: consider for patients with suspected serious bacterial infections ABG: indicated in patients suspected of hypoventilation, severe distress or FEV1 or PEF ≤25% predicted or personal best after initial treatment VBG: PCO2>45 mmHg may serve as a screening test but cannot substitute for an ABG Serum electrolytes generally not indicated unless patient at risk for electrolyte disturbances Most patients presenting with acute asthma do not require investigations CXR: indicated if suspect CHF, PNA, pneumothorax, pneumonmediastinum, lobar atelectasis CBC: asthma exacerbations can be associated with modest leukocytosis and corticosteroids cause neutrophil demargination with 1-2 hours of administration (mature PMNs not bands) ABG: respiratory drive increased in patients with asthma exacerbations so normal PCO2 of 40 mm Hg indicates severe airflow obstruction and heightened risk of respiratory failure Electrolytes: frequent SABA administration can lead to transient decreases in K, Mg and PO4; patients at risk for clinical symptoms include patients taking diuretics and those with pre-existing cardiac disease

Treatment Goals Correction of hypoxemia Rapid reversal of airflow obstruction Reduction of likelihood of relapse or recurrence of exacerbation

This is the algorithm for home management of asthma exacerbations. Assess Severity Patients at high risk for a fatal attack require immediate medical attention after initial treatment. Symptoms and signs suggestive of a more serious exacerbation such as marked breathlessness, inability to speak more than short phrases, use of accessory muscles, or drowsiness should result in initial treatment while immediately consulting with a clinician. Less severe signs and symptoms can be treated initially with assessment of response to therapy and further steps as listed below. If available, measure PEF—values of 50–79% predicted or personal best indicate the need for quick-relief mediation. Depending on the response to treatment, contact with a clinician may also be indicated. Values below 50% indicate the need for immediate medical care. Initial Treatment Inhaled SABA: up to two treatments 20 minutes apart of 2–6 puffs by MDI+ VHC or nebulizer treatments. Good Response: No wheezing or dyspnea (assess tachypnea in young children). PEF ≥80% predicted or personal best. Contact clinician for follow-up instructions/management May continue inhaled SABA every 3–4 hours for 24–48 hours. Consider short course of oral systemic corticosteroids for high-risk patients Incomplete Response: Persistent wheezing and dyspnea (tachypnea). PEF 50–79% predicted or personal best. Add oral systemic corticosteroid. Continue inhaled SABA. Contact clinician urgently (this day) for further instruction. Poor Response: Marked wheezing and dyspnea. PEF <50% predicted or personal best. Repeat inhaled SABA immediately. If distress is severe and nonresponsive to initial treatment: —Call your doctor AND —PROCEED TO ED; —Consider calling 9–1–1 (ambulance transport). To ED This is the algorithm for home management of asthma exacerbations. Modified from NAEPP Guidelines 2007

Modified from NAEPP Guidelines 2007 Initial Assessment Brief history, physical examination , PEF or FEV1, oxygen saturation, and other tests as indicated. Mild-to-Moderate (FEV1 or PEF ≥40%) Oxygen to achieve SaO2 ≥90% SABA up to 3 doses in first hour Oral CS if no immediate response or recently took oral CS or high-risk patient Severe (FEV1 or PEF <40%) SABA + ipratropium q20min or continuously for 1h; Oral CS Impending or Actual Respiratory Arrest Intubation and mechanical ventilation (FiO2 1.0) Nebulized SABA + ipratropium; consider adjunct therapies; Intravenous CS Repeat Assessment Symptoms, physical examination, PEF, O2 saturation, other tests as needed Moderate Exacerbation Physical exam: moderate symptoms; FEV1 or PEF 40–69% Inhaled SABA q1h; Oral CS Continue treatment 1–3 hours if improvement; make admit decision in <4 hours Severe Exacerbation Physical exam: severe symptoms at rest, accessory muscle use, chest retractions; FEV1 or PEF <40%. History: high-risk patient. No improvement after initial treatment: Oxygen, Nebulized SABA + ipratropium, hourly or continuous; consider adjunct therapies, Oral CS Good Response (FEV1 or PEF ≥70%) Response sustained 1 hr after last SABA Physical exam: normal; no distress Incomplete Response (FEV1 or PEF 40–69%) Mild-to-moderate symptoms Poor Response (FEV1 or PEF <40%) PCO2 ≥42 mm Hg Physical exam: symptoms severe, drowsiness, confusion Individualized decision re: hospitalization Discharge Home Continue inhaled SABA. Continue course of oral CS. Consider initiation of an ICS. Patient education: − Review medications, including inhaler technique. − Review/initiate action plan. − Recommend close medical follow-up Admit to Hospital Ward Oxygen Inhaled SABA Systemic (oral or intravenous) CS Consider adjunct therapies Monitor vital signs, FEV1 or PEF, SaO2 Admit to Hospital Intensive Care Inhaled SABA hourly or continuously Intravenous CS Possible intubation and mechanical ventilation Improve Continue treatment with inhaled SABAs. Continue course of oral CS Continue on or consider initiating ICS. Patient education (e.g., review meds, including inhaler technique, environmental control measures; review/initiate action plan; recommend close medical follow-up. Schedule follow-up appointment with PMD and/or asthma specialist in 1–4 weeks. This is the treatment algorithm for management of exacerbations in the ED. PE as well as FEV1/PEF measurements if capable determines severity: auscultation, use of accessory muscles, heart rate, respiratory rate Modified from NAEPP Guidelines 2007

Inhaled SABA Onset of action within 5 minutes Peak effect in 30-60 minutes Duration of action 4-6 hours Promote bronchodilation by smooth muscle relaxation May be given intermittently or continuously (nebulized) First line therapy for the relief of asthma symptoms are the inhaled SAB2A B2-specific

Inhaled SABAs Medication Children ≤ 12 years old Children > 12 years old Comments Albuterol nebulizer solution (0.63 mg/3 ml, 1.25 mg/3 ml, 2.5 mg/3 ml, 5 mg/ml) 0.15 mg/kg (min of 2.5 mg) q20mins for 3 doses then 0.15-0.3 mg/kg (max 10 mg) q1-4h prn OR 0.5 mg/kg/hr continuous nebulization 2.5-5 mg q20mins for 3 doses then 2.5-10 mg q1-4h prn OR 10-15 mg/hr continuously Dilute aerosols to minimum of 3 ml; gas flow at 6-8 L/min. Albuterol MDI (90 mcg/puff) 4-8 puffs q20min for 3 doses then q1-4h prn; use VHC; add mask in children <4 years old 4-8 puffs q20min up to 4 doses then q1-4h prn MDI plus VHC equally efficacious as nebulized therapy in mild-moderate exacerbations Levalbuterol nebulizer solution (0.63 mg/3 ml, 1.25 mg/0.5 mL, 1.25 mg/3 mL) 0.075 mg/kg (min dose 1.25 mg) q20min for 3 doses then 0.075-0.15 mg/kg up to 5 mg q1-4h prn 1.25-2.5 mg q20min for 3 doses then 1.25-5 mg q1-4h prn Comparable efficacy to albuterol; not evaluated by continuous nebulization Levalbuterol MDI (45 mcg/puff) Same as albuterol MDI dosing Albuterol also comes in an oral preparation but this is generally not indicated, especially in the acute asthma setting due to it’s delay in onset and increased systemic side-effects.

Modified from NAEPP Guidelines 2007 Initial Assessment Brief history, physical examination , PEF or FEV1, oxygen saturation, and other tests as indicated. Mild-to-Moderate (FEV1 or PEF ≥40%) Oxygen to achieve SaO2 ≥90% SABA up to 3 doses in first hour Oral CS if no immediate response or recently took oral CS or high-risk patient Severe (FEV1 or PEF <40%) SABA + ipratropium q20min or continuously for 1h; Oral CS Impending or Actual Respiratory Arrest Intubation and mechanical ventilation (FiO2 1.0) Nebulized SABA + ipratropium; consider adjunct therapies; Intravenous CS Repeat Assessment Symptoms, physical examination, PEF, O2 saturation, other tests as needed Moderate Exacerbation Physical exam: moderate symptoms; FEV1 or PEF 40–69% Inhaled SABA q1h; Oral CS Continue treatment 1–3 hours if improvement; make admit decision in <4 hours Severe Exacerbation Physical exam: severe symptoms at rest, accessory muscle use, chest retractions; FEV1 or PEF <40%. History: high-risk patient. No improvement after initial treatment: Oxygen, Nebulized SABA + ipratropium, hourly or continuous; consider adjunct therapies, Oral CS Good Response (FEV1 or PEF ≥70%) Response sustained 1 hr after last SABA Physical exam: normal; no distress Incomplete Response (FEV1 or PEF 40–69%) Mild-to-moderate symptoms Poor Response (FEV1 or PEF <40%) PCO2 ≥42 mm Hg Physical exam: symptoms severe, drowsiness, confusion Individualized decision re: hospitalization Discharge Home Continue inhaled SABA. Continue course of oral CS. Consider initiation of an ICS. Patient education: − Review medications, including inhaler technique. − Review/initiate action plan. − Recommend close medical follow-up Admit to Hospital Ward Oxygen Inhaled SABA Systemic (oral or intravenous) CS Consider adjunct therapies Monitor vital signs, FEV1 or PEF, SaO2 Admit to Hospital Intensive Care Inhaled SABA hourly or continuously Intravenous CS Possible intubation and mechanical ventilation Improve Continue treatment with inhaled SABAs. Continue course of oral CS Continue on or consider initiating ICS. Patient education (e.g., review meds, including inhaler technique, environmental control measures; review/initiate action plan; recommend close medical follow-up. Schedule follow-up appointment with PMD and/or asthma specialist in 1–4 weeks. For the treatment of severe exacerbations the NAEPP guidelines recommend the addition of inhaled ipratropium to SABA treatments Modified from NAEPP Guidelines 2007

Inhaled Anticholinergics Medication Children ≤12 yo Children >12 yo Comments Ipratropium bromide Nebulized solution (0.25 mg/ml) 0.25-0.5 mg q20min for 3 doses, then prn 0.5 mg q20min for 3 doses then prn Added to SABA during severe exacerbations; no proven benefit for mild/moderate exacerbations; no proven benefit once patient hospitalized MDI (18 mcg/puff) 4-8 puffs q20min prn up to 3 hours 8 puffs q20min prn up to 3 hours Children should use VHC; studies have examined MDI up to 3 hours only Ipratropium bromide with albuterol Nebulized solution (each vial contains 0.5 mg ipratropium and 2.5 mg albuterol) 1.5-3 ml q20min for 3 doses then prn 3 ml q20min for up to 3 doses then prn Reserved for first 3 hours of treatment of severe exacerbations; no proven benefit once patient hospitalized Ipratropium bromide with albuterol MDI (18 mcg ipratropium and 90 mcg albuterol per puff) Children should use VHC; indications as above

Systemic Corticosteroids Prednisone/Methylprednisolone/Prednisolone Children ≤ 12 yo: 1-2 mg/kg/day (max 60 mg/day) for 3-10 days until PEF is 70% predicted or personal best Children >12 yo: 40-80 mg/day for 3-10 days until PEF is 70% predicted or personal best Outpatient burst 1-2 mg/kg/day for 3-10 days Tapers not required for courses less than 1 week; 10 day courses do no need to be tapered if patients taking ICS chronically

Preschool Wheezers: The Great CS Debate Panickar et al (NEJM 2009) performed RDBPCT comparing oral prednisolone to placebo in 687 children between ages of 10 and 60 months Majority of children experienced mild-moderate wheezing Primary outcome was length of hospitalization; secondary outcomes were PRAM score, albuterol use and 7-day symptom scores PRAM pre=school respiratory assessmetnt measure

Preschool Wheezers: The Great CS Debate Prednisolone no better than placebo for any outcome Study strengths: RDBPCT, large number of patients, use of standardized scoring (PRAM), majority of patients with viral wheezer phenotype Limitations: possibly under-dosing of prednisolone for a significant number of patients, lack of data on subjects refusing participation, no provision of age of patients at high-risk for persistent asthma, no viral studies Prednisone was also no better than placebo in subjects at high risk for the devlopemnt of persistent wheezing (atopic asthma) Underdosing: 10 mg for children <2, 20 mg for older children would often work out to <1 mg/kg/day PRAM- preschool respiratory assessment measure; validated against lung function measurements

Preschool Wheezers: The Great CS Debate Several other studies have found contradictory results, particularly in patients at high-risk for the development of atopic asthma (positive API) Recent study found reduced rate of relapse in subjects infected with RV when treated with prednisolone as compared to placebo Study by Ducharme et al (NEJM 2009) showed decreased exacerbation severity in subjects treated with high-dose inhaled fluticasone at the onset of a URI-induced exacerbation API:>4 wheezing episodes, parental h/o asthma, personal h/o physician-diagnosed AD Minor: sensitization to food or aeroallergen, eosinophilia, wheezing without a cold Ducharme study: used use of rescue oral CS as primary endpoint (surrogate for exacerbation severity) Other studies have also shown intermittent use of inhaled CS and LTRA reduce symptoms during a URI-induced exacerbation

Systemic Corticosteroids: Summary Always indicated for patients with severe exacerbations Generally not indicated for patients with mild exacerbations unless high-risk for asthma-related death Indicated for patients with moderate exacerbations if no immediate response to SABA treatment or high-risk for asthma-related death

Modified from NAEPP Guidelines 2007 Initial Assessment Brief history, physical examination , PEF or FEV1, oxygen saturation, and other tests as indicated. Mild-to-Moderate (FEV1 or PEF ≥40%) Oxygen to achieve SaO2 ≥90% SABA up to 3 doses in first hour Oral CS if no immediate response or recently took oral CS or high-risk patient Severe (FEV1 or PEF <40%) SABA + ipratropium q20min or continuously for 1h; Oral CS Impending or Actual Respiratory Arrest Intubation and mechanical ventilation (FiO2 1.0) Nebulized SABA + ipratropium; consider adjunct therapies; Intravenous CS Repeat Assessment Symptoms, physical examination, PEF, O2 saturation, other tests as needed Moderate Exacerbation Physical exam: moderate symptoms; FEV1 or PEF 40–69% Inhaled SABA q1h; Oral CS Continue treatment 1–3 hours if improvement; make admit decision in <4 hours Severe Exacerbation Physical exam: severe symptoms at rest, accessory muscle use, chest retractions; FEV1 or PEF <40%. History: high-risk patient. No improvement after initial treatment: Oxygen, Nebulized SABA + ipratropium, hourly or continuous; consider adjunct therapies, Oral CS Good Response (FEV1 or PEF ≥70%) Response sustained 1 hr after last SABA Physical exam: normal; no distress Incomplete Response (FEV1 or PEF 40–69%) Mild-to-moderate symptoms Poor Response (FEV1 or PEF <40%) PCO2 ≥42 mm Hg Physical exam: symptoms severe, drowsiness, confusion Individualized decision re: hospitalization Discharge Home Continue inhaled SABA. Continue course of oral CS. Consider initiation of an ICS. Patient education: − Review medications, including inhaler technique. − Review/initiate action plan. − Recommend close medical follow-up Admit to Hospital Ward Oxygen Inhaled SABA Systemic (oral or intravenous) CS Consider adjunct therapies Monitor vital signs, FEV1 or PEF, SaO2 Admit to Hospital Intensive Care Inhaled SABA hourly or continuously Intravenous CS Possible intubation and mechanical ventilation Improve Continue treatment with inhaled SABAs. Continue course of oral CS Continue on or consider initiating ICS. Patient education (e.g., review meds, including inhaler technique, environmental control measures; review/initiate action plan; recommend close medical follow-up. Schedule follow-up appointment with PMD and/or asthma specialist in 1–4 weeks. This is the treatment algorithm for management of exacerbations in the ED. PE as well as FEV1/PEF measurements if capable determines severity: auscultation, use of accessory muscles, heart rate, respiratory rate Modified from NAEPP Guidelines 2007

Magnesium Sulfate (IV) Meta-analyses (adult and peds studies) show that hospitalization rates decreased when MgSO4 added to conventional Rx for severe exacerbations Dose 25-75 mg/kg up to 2 g NAEPP recommendation: “consider in patients with life-threatening exacerbations and patients who remain in the severe category after 1 hour of intensive conventional therapy” Severe exacerbations: PF<40%; no apparent value for pts with mild/moderate exacerbations Not all studies have shown positive effect Nebulized MgSO4 has shown some improvement in lung function in several trials but not adequate evidence to date

Heliox Theoretical benefit for improving gas exchange because of helium’s low density Studies contradictory Three studies (1 peds, 2 adult) showed improvement in subjects experiencing moderate-severe exacerbations treated with Heliox-driven SABA treatments when compared to subjects receiving O2-driven SABA treatments Discrepancies may be due to small sample sizes as well as failure to account for the different effect of heliox vs. oxygen on respirable mass (did not increase gas flow rate with heliox treatments).

Leukotriene Receptor Antagonists RT showed significant improvement in pulmonary function within 10 minutes of administration of IV montelukast to patients with moderate-severe exacerbations Oral montelukast does not take effect before 90 minutes from time of administration

Systemic β2 Agonists Medication Children<12 yo Children ≥12 yo Comments Epinephrine 1:1000 (1 mg/ml) 0.01 mg/kg up to 0.3-0.5 mg sq q20min for 3 doses 0.3-0.5 mg sq q20min for up to 3 doses No proven benefit over aerosol Terbutaline (1 mg/ml) 0.01 mg/kg sq q20min for up to 3 doses then q2-6h prn 0.25 mg sq q20min for up to 3 doses

When to Intubate Signs of impending respiratory failure: Inability to speak Altered mental status Worsening fatigue Significant and prolonged retractions PCO2 ≥ 42 mm Hg Theoretical benefit of ketamine as a premedication for ETI has not born out in studies (limited data)

Assessing Response to Treatment Serial physical examinations Serial FEV1 or PEF Serial pulse oximetry measurements Signs and symptom scores FEV1/PEF maneuvers almost impossible for children <5 yo Study by Gorelick et al found that only 65% of children 5-18 yo could perform these tests adequately during exacerbation

Predicting Need for Hospitalization Kelly et al (Respir Med 2004) showed that severity assessment at 1hour after initial treatment with SABA was better predictor of need for hospitalization than initial assessment After 1hour if meets criteria for severe exacerbation >86% chance of hospitalization; if moderate after 1 hour >84% chance of hospitalization; if mild then only 18% chance of hospitalization SaO2 <92-94% at 1 hour better predictor of need to hospitalize than initial SaO2

Modified from NAEPP Guidelines 2007 Initial Assessment Brief history, physical examination , PEF or FEV1, oxygen saturation, and other tests as indicated. Mild-to-Moderate (FEV1 or PEF ≥40%) Oxygen to achieve SaO2 ≥90% SABA up to 3 doses in first hour Oral CS if no immediate response or recently took oral CS or high-risk patient Severe (FEV1 or PEF <40%) SABA + ipratropium q20min or continuously for 1h; Oral CS Impending or Actual Respiratory Arrest Intubation and mechanical ventilation (FiO2 1.0) Nebulized SABA + ipratropium; consider adjunct therapies; Intravenous CS Repeat Assessment Symptoms, physical examination, PEF, O2 saturation, other tests as needed Moderate Exacerbation Physical exam: moderate symptoms; FEV1 or PEF 40–69% Inhaled SABA q1h; Oral CS Continue treatment 1–3 hours if improvement; make admit decision in <4 hours Severe Exacerbation Physical exam: severe symptoms at rest, accessory muscle use, chest retractions; FEV1 or PEF <40%. History: high-risk patient. No improvement after initial treatment: Oxygen, Nebulized SABA + ipratropium, hourly or continuous; consider adjunct therapies, Oral CS Good Response (FEV1 or PEF ≥70%) Response sustained 1 hr after last SABA Physical exam: normal; no distress Incomplete Response (FEV1 or PEF 40–69%) Mild-to-moderate symptoms Poor Response (FEV1 or PEF <40%) PCO2 ≥42 mm Hg Physical exam: symptoms severe, drowsiness, confusion Individualized decision re: hospitalization Discharge Home Continue inhaled SABA. Continue course of oral CS. Consider initiation of an ICS. Patient education: − Review medications, including inhaler technique. − Review/initiate action plan. − Recommend close medical follow-up Admit to Hospital Ward Oxygen Inhaled SABA Systemic (oral or intravenous) CS Consider adjunct therapies Monitor vital signs, FEV1 or PEF, SaO2 Admit to Hospital Intensive Care Inhaled SABA hourly or continuously Intravenous CS Possible intubation and mechanical ventilation Improve Continue treatment with inhaled SABAs. Continue course of oral CS Continue on or consider initiating ICS. Patient education (e.g., review meds, including inhaler technique, environmental control measures; review/initiate action plan; recommend close medical follow-up. Schedule follow-up appointment with PMD and/or asthma specialist in 1–4 weeks. Once the patient is hospitalized treatment is continued with O2, SABA q1-4h as needed or continuously if severe and systemic CS. Adjunct therapies may be continues as well but there is no proven benefit of continuing ipratropium treatments once patiets are admitted. Modified from NAEPP Guidelines 2007

Plan for Discharge Provide patients written instructions regarding dose, frequency and correct use of medications Consider initiating or continue with ICS Schedule follow-up appointment with PMD or asthma specialist within 4 weeks Moderate exacerbations can have some sx for 1-2 days after initial treatment; severe exacerbations may be prolonged >3 days