ASTHMA-QUICK-RELIEF MEDICATIONS and MANAGING EXACERBATIONS


Quick-Relief Medications

Short-Acting Beta-Agonists
Anticholinergics

Systemic Corticosteroids

Magnesium Sulfate

Managing Exacerbations

 

QUICK-RELIEF MEDICATIONS

  1. Short-acting beta-agonists
  1. Produce bronchodilation within 5-15min of administration
  2. Treatment of choice for relief of acute sx and prevention of exercise-induced asthma
  3. Adverse effects
    1. Tachycardia, tremor, hypokalemia, hyperglycemia, QT prolongation with overdose
    2. Association with serious cardiovascular effects
      1. Use of inhaled beta-agonists was associated with sig. increased risk of (death or first CHF hospitalization) in a retrospective cohort study of 1,529 pts with CHF.  A dose-response relationship was observed: RR for CHF hospitalization was 1.4 for use of one canister of beta-agonist during the (1y) study period, 1.7 for use of two canisters, and 2.1 for use of 3 canisters, compared with no use. (Chest 123:1964, 2003--AFP)
      2. In a meta-analysis of 20 randomized trial of inhaled beta-agonists (including salmeterol) in treatment of asthma or COPD over mean 4.7mo f/u showed use of these medications to be associated with a RR of 2.5 (sig.) for any adverse cardiovascular event (most common = sinus tachycardia); no sig. diff. in risk of major cardiovacular events (Chest 125:2309, 2004--AFP)
    3. Non-beta-2-selective agents (isoproterenol, isoetharine, metaproterenol, epinephrine) may cause more cardiac stimulation than other beta-agonists
  4. Increasing use (including daily use, or > 1 canister/mo) or reduction in effect indicates inadequate control of asthma
  5. Dosing:
  1. Regularly scheduled use in pts without daily sx "neither harms nor benefits asthma control" & isn't recommended (see also NEJM 335:841, 1996-JW)
  2. May double usual dose for mild exacerbations
  3. Albuterol, bitolterol, pirbuterol, terbutaline MDI's: prior to exercise 2 puffs adult/1-2 puffs child; for relief of sx; 2 puffs TID-QID PRN (both adult/child)
  4. Albuterol nebulized: adult 1.25-5mg in 2-3cc saline; child 0.05mg/kg (min 1.25mg, max 2.5mg) in 2-3cc saline; both Q4-6h
  1. 5mg albuterol neb Q20min x 2 better than 2.5mg Q20min x 3 in terms of improvement in PEF and ability to be d/c'd from ER after 1 tx, in a randomized trial in 160 adults presenting w/an acute asthma attack and PEF < 40% normal (Am. J. Med 105:12, 1998--AFP)
  2. 169 adults with asthma exacerbation randomized to 7.5mg albuterol neb Q20min x 3 c/w 2.5mg Q20min x 3; no sig. diff. in post-tx FEV1, improvement in FEV1, or admission rate (Chest 115:92, 1999--AFP)
  3. May mix with cromolyn or ipratropium
  1. Levalbuterol nebulized (Xopenex) 0.63mg Q6-8h PRN
    1. Doubtful whether, as claimed, offers any less incidence of side f/x than racemic albuterol (Med. Let.. 41:51, 1999)
    2. 547 children 1-18yo presenting to an ED with acute asthma randomized to inhaled racemic albuterol 2.5mg vs. levalbuterol 1.25mg (max of 6 doses of either med within 2h). Levalbuterol group had sig. lower likelihood of hospital admission (36% vs. 45%) but no diffs. in length of ED or inpatient stay, # of neb treatments needed, need for O2 or ICU care, or evident side effects (J. Peds. 143:702, 2003--JW)
  2. Pirbuterol (Maxair) 200 mcg/spray
  1. Anticholinergics
  1. May take longer than inhaled beta-agonists to work, i.e. up to 30min
  2. Can be useful adjunct to beta-agonists in exacerbations for both adults and children--NHLBI guidelines recommend considering in severe exacerbations
    1. 434 children 2-18yo (mean age 8.3y) presenting with mod-severe asthma exacerbation (classified according to either PEF < 70% predicted, or Px) randomized to ipratropium 500ug neb x 2 vs. placebo (ipratropium 500mg nebs given along with 2nd & 3rd doses of albuterol nebs which were given Q20min in as many doses as needed; all kids getting 2nd dose of albuterol also got prednisone 2mg/kg PO); sig. less hospitalization in tx group (27% vs. 37%; subgroup of kids with moderate asthma exacerbation didn't have sig. lower hosp. rates) (NEJM 339:1030, 1998--JW & article itself)
    2. May improve bronchospasm better than albuterol alone and decrease risk of exacerbations when used in combination w/albuterol (2 puffs QID in a 3mo randomized study of 1,067 pts with "COPD" (Chest 115:635, 1999--JW)
    3. 356 pts with COPD randomized to combination Ipratropium-Albuterol MDI vs. Albuterol MDI. After 4wks of use, combination group had sig. better baseline FEV1 and sig. less wheezing and dyspnea (Arch. Int. Med. 159:156, 1999--AFP)
    4. 55 adults with acute asthma & PEFR < 200 randomized to albuterol + ipratropium nebs vs. albuterol + placebo; ipratropium group had sig. higher PEFR and lower rates of parenteral steroid use and hospitalization (11% vs. 36% for the latter) (Ann. Em. Med. 31:208--AFP)
    5. May reduce risk of hospitalization by 30% in one systematic review (BMJ 317:971, 1998--JW)
    6. A meta-analysis of 10 randomized trials involving 1,377 adults with acute asthma comparing inhaled beta-agonists with vs. without inhaled ipratropium showed sig. improvement in measures of pulmonary function and decreases in hospitalization rates (JABFP 13:55, 2000--JW, AFP)
  1. Can cause blurry vision if sprayed into the eyes
  2. May increase intraocular pressure in pts with glaucoma
  3. Ipratropium bromide (Atrovent)
  1. HFA 17 mcg/spray 2-4 puffs for adults; 1-2 puffs for kids; Q6h
  2. Available in combination MDI w/albuterol (Combivent)
  3. Neb 0.25-0.5mg for adults; 0.25mg for kids; Q6h
  1. Tiotropium (Spiriva)
    1. Longer duration of action than ipratropium--Can be given QD
    2. Ass'd with sig. better FEV1 than placebo in a 13wk trial of 470 smokers w/COPD (Chest 118:1294, 2000--JW)
    3. See also under Maintenance Medications for Asthma
  1. Systemic Corticosteroids
  1. For mod-severe exacerbations (for mild, can just double dose of inhaled steroids) or if h/o severe exacerbations
    1. In a study in 69 children 5-17yo presenting to an ED with mild-moderate asthma exacerbation (FEV1 50-79% predicted) randomized to inhaled steroids (fluticasone 2000ug then 500ug BID x 10 doses) vs. oral steroids (prednisolone 2mg/kg then 1mg/kg QD x 5d), the oral steroid-gropu had sig. greater improvement in FEV1 at 4h (Peds 118:644, 2006--JW)
  2. Some experts advise having pts keep some at home to use at start of exacerbations
  3. Dosing guidelines
    1. "Burst" administration (several days) to reduce duration/severity of exacerbations (prednisone or methylprednisolone 40-60mg/d (or 1-2mg/kg/d max 60mg/d for kids) x 3-10d
    2. Continue until pt reaches 80% of their personal best PEFR or until sx resolve; us. 3-10d. No evidence to support tapering vs. just discontinuing.
    3. Oral vs. parenteral--efficacy probably similar
      1. 66 children hospitalized with acute asthma randomized to PO prednisone 2mg/kg BID up to 120mg/d vs. IV methylprednisolone 1mg/kg QID max 60mg/d; PO & IV placebos were used as appropriate. No sig. diff. in mean hospital stay, time on steroids, or improvement in PEFR; however, the pred. group required sig. less time on supplemental O2 (J. All. Clin. Immunol. 103:586, 1999--JW)
      2. Dexamethasone acetate (not the same as the more common Dex. phosphate; persists in circulation for 1-3wks!) 1.7mg/kg IM x 1 was ass'd with similar rates of clinical improvement over 5d f/u c/w prednisone 2mg/kg QD x 5d in a randomized trial of children 6mo-7yo presenting with a mild-mod asthma exacerbation (J. Peds. 136:298, 2000--JW)
      3. In a study in 180 pts 18-45yo being discharged from a hospital ED after treatment for an asthma exacerbation randomized to methylprednisolone 160mg IM vs. methylprednisolone PO tapering over 8d, incidence of need for unscheduled care in the 10d after d/c was not sig. diff. in the two groups (Chest 126:362, 2005--AFP)
    4. Oral Dexamethasone x 2d vs. oral Prednisone x 5d--the former better tolerated & equally effective in a randomized trial of 533 children 2-18yo presenting to an ER with acute asthma and requiring > 1 dose inhaled albuterol.  Doses used were prednisone 2mg/kg/d max 60mg on day 1 then 1mg/kg/d x 4d and Dexamethasone 0.6mg/kg/d max 16mg x 2d (J. Peds. 139:20, 2001--JW)
  4. See under "Corticosteroids" for more information on dosing/avoiding side effects
  1. Inhaled Corticosteroids as a "quick-relief" medication-likely not effective
    1. In a study in 288 pts 6-18yo with mild persistent asthma, all on inhaled albuterol PRN, randomized to inhaled beclomethasone as a "controller" treatment (40ug BID), beclomethasone 80ug with every rescue dose of inhaled albuterol, both, or neither, over 44wks, incidence of an asthma exacerbation requiring oral steroids was sig. lower in the groups with daily beclamethasone c/w placebo (28% and 31% vs. 49%); no sig. diff. between "rescue" beclamethasone alone and placebo ("TREXA" trial; Lancet 377:650, 2011-JW)
  2. In a study in 288 pts 6-18yo with mild persistent asthma, all on inhaled albuterol PRN, randomized to inhaled beclomethasone as a "controller" treatment (40ug BID), beclomethasone 80ug with every rescue dose of inhaled albuterol, both, or neither, over 44wks, incidence of an asthma exacerbation requiring oral steroids was sig. lower in the groups with daily beclamethasone c/w placebo (28% and 31% vs. 49%); no sig. diff. between "rescue" beclamethasone alone and placebo ("TREXA" trial; Lancet 377:650, 2011-JW)
  3. Magnesium Sulfate--For acute exacerbations; see link for details
  4. Comparisons among quick-relief medications
    1. In a study in 3,394 pts > 12yo with asthma x > 6mos and at least one severe exacerbation randomized to prescriptions for rescue therapy for inhaled terbutaline, inhaled formoterol, or inhaled budesonide/formoterol (all used BID inhaled budesonide/formoterol), over 12mo f/u, the incidence of severe exacerbation was sig. less in the budesonide/formoterol pts than in the formoterol-only or terbutalien pts (19% vs. 29% and 37%, respectively) (Lancet 368:744, 2006--AFP)

 

MANAGING EXACERBATIONS

  1. Early initiation of treatment is key! Written action plan is helpful for this
  2. Can often be managed at home if mild and pt is sophisticated
  3. Initial functional assessment
  1. General appearance, RR, skin color, use of accessory mm., lung exam
  2. PEFR
  3. O2 %sat
  4. CXR
  5. ABG; note that PCO2 should be low (should be hyperventilating)
  6. Consider upper airway obstruction, esp. In kids
  7. In infants, RR > 60 and/or sat < 91% "indicate serious distress"; lack of response to inhaled beta-agonists is an indication for hospitalization
  1. Supplemental O2 to correct hypoxemia (may need mechanical ventilation for this)
  2. Rapid reversal of airflow obstruction
  1. Inhaled beta-agonists; can give Q20-30min or even continuously; duration of action is not precisely known
    1. Continuous vs. intermittent albuterol nebs in pts with severe asthma exacerbation: In a randomized trial in 42 adults with acute severe asthma randomized to continuous vs. intermittent (Q20min x 3 then Q1y x 5) albuterol neb, total dose being equal, there was no sig. diff. in PEFR, clinical severity, or admission rates in the two groups (Ann. Emerg. Med. 36:198, 2000--JW)
    2. Delivery by Metered-Dose Inhaled (MDI) with spacer vs. nebulizer
      1. In a study in children < 2yo presenting to an ED with wheezing randomized to albuterol via MDI w/spacer and face mask vs. nebulizer Q20min, the MDI recipients had lower incidence of hospital admission, additional treatments, or steroids (Arch. Ped. Adol. Med. 157:76, 2003--AFP)
      2. In adults, MDI w/spacer has been shown to be as effective as nebulizer for delivering inhaled short-acting beta-agonists
  2. Inhaled cholinergics e.g. ipratropium--NHLBI guidelines recommend considering in severe exacerbations; no benefit in combination c/w albuterol alone in a placebo-controlled randomized trial of 210 children 1-18yo admitted to hospital for status asthmaticus; outcomes included length of hosp. stay, need for additional therapy, & adverse effects  (J. Peds. 138:51, 2001--JW)
  3. Systemic Corticosteroids (click on link for details of use in asthma exacerbations)
  4. Inhaled Corticosteroids
    1. In a study in 58 children with acute asthma exacerbations randomized to prednisone 2mg/kg/d x 7d vs. flunisolide 4 puffs BID x 7d, there were no sig. differences at 3d or 7d in symptom severity or PEFR measurements (Chest 124:790, 2003--AFP)
    2. 390 adult pts with persistent asthma on daily inhaled steroids taught to do home monitoring of sx and peak flow and instructed, when PEFR declined > 15% or sx worsened, to add an additional MDI containing a corticosteroid (to produce a doubling of dose) or placebo x 14d. Over 12mos, no sig. diff. between groups in likelihood of needing oral prednisolone, lowest peak flow recorded, rise in symptom scores, highest symptom score recorded, or time to recovery for peak flow and symptom scores. (Lancet 363:271, 2004--abst)
    3. In a systematic review of 17 randomized studies of inhaled corticosteroids (vs. either placebo or systemic corticosteroids) in treatment of asthma exacerbation in the ED with effectiveness evaluated 1-4h after initiating therapy, inhaled steroids were associated with higher incidence of discharge from ED 2-3h after tx than both placebo and systemic-corticosteroid recipients. (Chest 130:1301, 2006--AFP)
  5. Theophylline and aminophylline are probably not useful
  6. Magnesium Sulfate-Shown to reduce incidence of hospitalization
    1. 31 kids, mean age 11, who presented to ER with acute asthma and PEF < 60% predicted after 3 albuterol nebs, randomized to MgSO4 25mg/kg IV vs. placebo. Mg group had sig. more improved PEF and FEV1. 4 of the 15 Mg-treated kids discharged from ED as opposed to 1 of 16 placebo-treated kids. No adverse effects or BP differences between 2 groups (J. Peds 129:809, 1996-JW)
    2. 30 kids 6-17yo with mod-severe asthma exacerbations randomized to usual tx + MgSO4 (40mg/kg up to max 2g) vs. usual tx + placebo; at 20min, MgSO4 recipients had sig. greater FEV1 & FVC as well as sig. lower admission rates (50% vs. 100%); no sig. side effets noted (Arch. Ped. Adol. Med. 154:979, 2000--JW)
    3. In a meta-analysis of 7 randomized trials (5 adult, 2 pediatric) involving 668 pts, MgSO4 ass'd with sig. lower risk fo admission (OR 0.1) and sig. higher PEFR and FEV1 in pts with severe asthma , but not for those with moderate asthma (Ann. Emerg. Med. 36:181, 2000--JW)
    4. In a randomized trial in 248 adults presenting to an ED with a severe asthma exacerbation (FEV1 < 31% predicted) randomized to MGSO4 2g IV vs. placebo in addition to "standard" care (including inhaled bronchodilators & IV steroids), mean FEV1 at 4h was sig. higher in Mg group but admission rates were no different (Chest 122:489, 2002--JW)
    5. 52 pts 16-65yo presenting to an emergency department with an asthma exacerbation with FEV1 < 50% predicted despite a single treatment with inhaled albuterol 2.5mg randomized to (nebulized albuterol 2.5mg vs. albuterol 2.5mg + isotonic (250mmol/L) MgSO4) Q30min x 3; all pts also received hydrocortisone 100mg IV.  Decision to hospitalize was made by pre-established criteria.  At end of the 3 treatments, MgSO4 group had sig. higher gains in FEV1 (0.72L vs. 0.35L) and sig. lower incidence of hospitalization (43% vs. 71%) (Lancet 361:2114, 2003--AFP)
  7. Nitric oxide--Has been used successfully in uncontrolled trials in kids with severe asthma requiring mechanical ventilation, not responding to standard management (continuous neb for 5-22h--J. Peds. 137:119, 2000--JW)
  1. Leukotriene Modifiers for acute asthma
    1. In a study in 641 pts with asthma exacerbations presenting to an ED, all with FEV1 < 70% predicted on presentation and 25min after a single albuterol neb, randomized to zafirlukast 160mg PO in the ED then 20mg BID x 28d vs. placebo, the zafirlukast recipients were sig. less likely to receive "extended care" in the ED and also had more rapid symptomatic improvement (Chest 126:1480, 2005--AFP)
    2. In a study in 130 children 2-17yo with mild-to-moderate asthma presenting to an ED with acute asthma, all treated with at least 1 dose of oral prednisone and inhaled (albuterol + ipratropium) randomized to 5d of (oral steroids vs. montelukast), treatment failure (unscheduled medical visit, hospitalization, or addition of systemic corticosteroids within 8d after discharge) was sig. more likely in montelukast group (22% vs. 8%) (J. Peds. 155:795, 2009-JW)
  2. Note that infants and young children may become vol. Depleted due to increased RR and decreased PO intake; consider IV fluid administration
  3. Chest PT is generally not beneficial
  4. Reduce likelihood of recurrence by stepping-up Rx
  5. Monitor lung function and sx closely