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Asthmatic smooth muscle has increased shortening capacity and increased velocity of shortening74 that mandate treatment in the setting of an acute attack. Use of a β agonist by inhalation is preferred and should begin immediately regardless of prior use (Table 40-1).75 Large and frequent doses are needed in acute asthma because the dose-response curve and duration of action are adversely affected by airway narrowing. Fortunately, high doses are generally well tolerated. In one study, albuterol delivered by metered dose inhaler (MDI) and spacer to a total dose of 1600 μg over 90 minutes did not increase cardiovascular morbidity in well-oxygenated patients with acute asthma.76
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Albuterol is preferred over metaproterenol because of its greater β2 selectivity and longer duration of action.77,78 Some clinicians prefer metaproterenol or isoetharine for initial therapy, despite the tendency of these drugs to increase side effects, because of their faster onset of action.79
Levalbuterol is the R-isomer of racemic albuterol. Preclinical data demonstrate that the S-isomer has undesirable proinflammatory effects.80 The clinical relevance of these effects (particularly in those receiving high doses of the racemate) is under investigation. Clinical data do show that 1.25 mg levalbuterol increases FEV1 to a greater extent than 2.5 mg of the racemate in stable patients with FEV1 ≤60% of predicted.81 In acute asthma, an open-label study of 91 patients with an FEV1 of 20% to 55% of predicted, stratified into cohorts receiving 0.63 to 5 mg levalbuterol or 2.5 to 5 mg albuterol (three treatments in 1 hour), demonstrated faster onset of action and a greater degree of bronchodilation with levalbuterol.82 Results from a larger multicenter study are expected in the near future.
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Long-acting β agonists are not indicated in the initial treatment of acute asthma, but may be considered as add-on therapy in hospitalized patients. The addition of salmeterol to albuterol in hospitalized asthmatics is safe and improves FEV1 after 48 hours compared with placebo.83
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Subcutaneous administration is not indicated unless the patient is unable to carry out inhaled therapy (such as those with an altered mental status or cardiopulmonary arrest), and is associated with greater toxicity.84–86 Subcutaneous epinephrine, however, benefits some patients not responding to several hours of an inhaled β agonist.87 Known cardiac disease and age >40 years are relative contraindications to parenteral therapy,88 although older patients without recent myocardial ischemia or infarction tolerate subcutaneous epinephrine reasonably well. Intravenous infusion of β agonists is not recommended. Inhaled drug achieves greater airflow rates with lesser toxicity compared to intravenous drug.89–92 Combinations of inhaled and intravenous treatment have not been adequately studied.
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Inhaled β agonists are delivered equally well by MDI with spacer or hand-held nebulizer.93 Even in severe obstruction, four puffs of albuterol (0.36 mg) delivered by MDI with an InspirEase is as effective as 2.5 mg of albuterol by nebulization.94 MDIs with spacers are less expensive and able to achieve faster drug delivery times; hand-held nebulizers require fewer instructions, less supervision, and less coordination.
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The recommended initial dose is albuterol 2.5 mg by nebulization; three treatments can be given in the first hour depending on clinical response and side effects. A single high-dose treatment (e.g., 7.5 mg) is no better than multiple treatments (2.5 mg every 20 minutes 3 times), and causes more side effects.95 Depending on the study, there is either no difference in efficacy or toxicity between continuous or intermittently nebulized albuterol, or a slight benefit to continuous nebulization (at the same total dose per hour) in severe obstruction.96–98
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There are two dose response patterns to high and cumulative doses of albuterol. Approximately two-thirds of patients respond to inhaled albuterol in a dose-dependent fashion, generally allowing discharge home from the ED.99 In these patients 1.2 to 2.4 mg albuterol delivered by MDI and spacer or 5 to 7.5 mg by nebulizer in the first hour is effective. In the remaining one-third of patients, even in high doses, albuterol has minimal effect, presumably because of airway inflammation and mucus plugging.
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Data support the addition of ipratropium bromide to albuterol in acute asthma.100–106 Karpel and colleagues studied 384 patients randomized to nebulized albuterol 2.5 mg or albuterol 2.5 mg with ipratropium 0.5 mg at entry and at 45 minutes.107 At 45 minutes, there were more responders in the ipratropium group; however, the median change of FEV1 from baseline did not differ between groups, and by 90 minutes there was no difference between groups in the percentage of responders and median change in FEV1. There was no difference in the number of patients requiring additional ED or hospital treatment. Garrett and colleagues randomized 338 asthmatics to a single dose of nebulized ipratropium bromide 0.5 mg combined with salbutamol 3.0 mg, or salbutamol 3.0 mg alone.108 Mean FEV1 at 45 and 90 minutes was significantly higher with combined therapy. Lin and colleagues demonstrated that combination therapy resulted in greater improvement in PEFR than albuterol alone in 55 adult asthmatics.109 O'Driscoll and colleagues also demonstrated a benefit to combination therapy, particularly in patients with PEFR <140 L/min.110 In children, combination therapy decreases ED treatment time, albuterol dose requirements, and hospitalization rates.106,111,112
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To the contrary, Weber and colleagues performed a prospective, randomized, double-blind, placebo-controlled trial of 67 patients receiving combination albuterol and ipratropium bromide or albuterol alone by continuous nebulization for a maximum of 3 hours.113 Primary outcome measures were improvement in PEFR, hospital admission rates, and length of stay in the ED. All outcome measures favored combination therapy, but differences were not statistically significant. Fitzgerald and coworkers reported similar results.114 McFadden and colleagues showed no benefit in PEFR, admission rate, or ED length of stay with combination therapy used for the first hour.115 In children, Ducharme and Davis did not demonstrate benefit from combination therapy in their study of nearly 300 asthmatics with mild to moderate acute asthma.116
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The above studies demonstrating modest (or no) benefit to combination therapy generally used small doses of ipratropium bromide. Few trials have studied high and cumulative doses of both ipratropium bromide and albuterol. In one such study, Rodrigo and Rodrigo conducted a double-blind, randomized, prospective trial of albuterol and ipratropium bromide (120 μg of albuterol and 21 μg of ipratropium per puff, combined in one inhaler) vs. albuterol (120 μg per puff) and placebo in 180 patients with acute asthma.117 Four puffs were administered through an MDI with a spacer every 10 minutes for 3 hours. Combination therapy resulted in a 20.5% greater improvement in PEFR and a 48.1% greater improvement in FEV1 compared with albuterol alone. The rate of hospitalization decreased significantly, from 39% in the albuterol with placebo group to 20% with combination therapy. Subgroup analysis showed that patients most likely to benefit from high doses of ipratropium bromide were those with FEV1 <30% of predicted and symptoms for >24 hours prior to ED presentation.
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Overall, the data suggest an advantage in maximal bronchodilation response when high doses of ipratropium bromide and albuterol are combined in the emergency treatment of asthma. Combination therapy is recommended in any patient who is extremely ill on first presentation or not responding quickly (e.g., within 30 minutes) to albuterol alone.
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Systemic corticosteroids should be administered quickly to treat the inflammatory component of acute asthma. The data are mixed regarding benefit in the first few hours. McFadden's group demonstrated no differences in physiologic or clinical variables in the first 6 hours in 38 patients receiving hydrocortisone.118 Rodrigo and Rodrigo similarly showed that early administration of steroids did not improve spirometry in the first 6 hours.119 However, Littenberg and Gluck demonstrated that methylprednisolone 125 mg IV on arrival decreased admission rates compared to placebo,120 and Lin and colleagues demonstrated improved peak flows after 1 and 2 hours of solumedrol.121 A systematic review of 12 studies for the Cochrane Review demonstrated that corticosteroids within 1 hour of arrival in the ED reduced admissions.122 Use of early systemic steroids also reduces the number of relapses in the first 7 to 10 days and the risk of death.123–126 In hospitalized patients, systemic steroids speed the rate of improvement.127 Oral and intravenous routes are equally effective,128 but oral steroids should be avoided if there is concern regarding intubation.
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There is no clear dose-response relationship to steroids in acute asthma.129,130 In one meta-analysis by Manser and colleagues, there was no difference in clinical outcomes between low-dose corticosteroids (≤80 mg/d solumedrol or ≤400 mg/d hydrocortisone) and higher doses in the initial management of hospitalized asthmatics.131 Haskell and colleagues demonstrated that 125 mg IV methylprednisolone every 6 hours resulted in faster improvement compared to 40 mg every 6 hours, but there was no difference in peak improvement.132 Both doses were superior to 15 mg every 6 hours in terms of rate and absolute response. Emerman and Cydulka compared 500 mg and 100 mg of methylprednisolone and found no benefit to the higher dose.133
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The Expert Panel from the National Institutes of Health (NIH) recommends 120 to 180 mg per day of prednisone or methylprednisolone in three or four divided doses for 48 hours, then 60 to 80 mg/d until PEFR reaches 70% predicted or personal best.1 Prednisone is tapered at variable rates depending on a number of factors, including PEFR, the duration of high-dose therapy required to treat the acute exacerbation, and whether oral steroids had been used for maintenance therapy. Automatic tapering schedules are not recommended because patients may taper prematurely.
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Recent trials have demonstrated efficacy of inhaled corticosteroids in acute asthma. In children discharged from the ED, short-term use of budesonide, starting at a high-dose and tapered over 1 week, was as effective as a tapering course of oral prednisolone.134 Rodrigo and Rodrigo conducted a randomized, double-blind trial of the addition of flunisolide 1 mg or placebo to 400 μg salbutamol every 10 minutes for 3 hours in 94 ED subjects not receiving systemic steroids.135 They found that PEFR and FEV1 were approximately 20% higher in the flunisolide group, beginning at 90 minutes. McFadden suggests this benefit stems from steroid-induced vasoconstriction, decreasing airway wall edema, vascular congestion, and plasma exudation, and not anti-inflammatory effects.136 Recently Rodrigo and Rodrigo demonstrated therapeutic benefit from triple drug therapy (flunisolide, albuterol, and ipratropium bromide) in high doses in patients not receiving systemic steroids.137
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To the contrary, Guttman and colleagues found no benefit from the addition of beclomethasone 7 mg every 8 hours by MDI with spacer to nebulized salbutamol and systemic corticosteroid therapy.138 Further study demonstrated that beclomethasone (5 mg delivered by MDI) during the initial 4 hours of ER treatment did not confer added benefit to albuterol in adults with mild to moderately severe asthma.139
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Our view is that there is little benefit to the addition of inhaled steroids to high-dose β agonists and systemic corticosteroids in the management of acute asthma. Still, consideration should be given to the use of high-dose inhaled corticosteroids in refractory patients.
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There is no benefit to adding aminophylline to inhaled β agonists in the initial treatment of acute asthma.140 In a meta-analysis by Parameswaran and colleagues there was a trend toward higher PEFR at 12 and 24 hours, but at the cost of arrhythmias and vomiting.141 Others have reported a delayed benefit.142 In another recent meta-analysis in children, aminophylline was shown to improve FEV1 by 6 to 8 hours and provide sustained benefit for 24 hours.143 Nonbronchodilating properties of aminophylline may be useful in refractory cases. Anti-inflammatory effects and enhanced diaphragm function may explain one report that ED administration of aminophylline decreased hospitalizations, even when airflow rates were no different than placebo.144
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We rarely use aminophylline in refractory patients, but generally continue its use (after confirming a nontoxic serum concentration) in patients already taking theophylline. This approach is safe if attention is paid to serum drug levels and to factors that increase levels, such as congestive heart failure, ciprofloxacin, macrolide antibiotics, and cimetidine, and if the drug is discontinued in the presence of side effects.
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Three prospective trials failed to confirm a benefit to administering magnesium sulfate (MgSO4) to asthmatics in the ED.145–147 In 135 asthmatics randomized to 2 g MgSO4IV or placebo after 30 minutes and followed for 4 hours, admission rates and FEV1 were no different between magnesium-treated patients and controls.147 However, subgroup analysis revealed MgSO4 decreased admission rates and improved FEV1 in subjects with FEV1 <25% of predicted. Subsequently, a placebo-controlled, double-blind, randomized trial in 248 patients with FEV1 ≤30% showed a small but statistically significant increase in FEV1 after 240 minutes in the magnesium group, but no difference in hospitalization rates.148 Meta-analysis of 9 trials and 665 patients demonstrated nonsignificant improvements in peak flows and admission rates for all patients, but in those with severe exacerbations, MgSO4 increased FEV1 by nearly 10% compared to placebo, and decreased admissions.149 Additional evidence supporting benefit in severe disease comes from an uncontrolled study of five intubated asthmatics given magnesium.150 In this study, there was a fall in peak airway pressure (43 cm H2O to 32 cm H2O) after high doses of MgSO4 (10 to 20 g) were administered over 1 hour. Other investigators have suggested that gender may play a role in magnesium responsiveness, since estrogen augments the bronchodilator effect of magnesium.151 Routine use of MgSO4 is not justified, but MgSO4 is safe, inexpensive, and may be beneficial in severe exacerbations.
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Magnesium sulfate can also be administered by inhalation. Nannini and colleagues studied the effects of MgSO4 (225 mg) vs. saline as the vehicle for nebulized albuterol in a randomized, double-blind fashion.152 At 20 minutes, patients treated with MgSO4 and albuterol had a greater PEFR compared to the saline-albuterol group (134 ± 70 L/m vs. 86 ± 64 L/m). Hughes and colleagues have published similar data.153
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Leukotriene Modifiers
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Cysteinyl leukotrienes are elevated in asthmatic sputum compared to controls and higher in subjects studied within 48 hours of exacerbation.154 Preliminary data demonstrating benefit to a leukotriene receptor antagonist came from a double-blind, randomized trial of two doses (20 mg and 160 mg) of zafirlukast orally versus placebo in 641 asthmatics after 30 minutes of standard treatment.155 Zafirlukast 160 mg decreased admission rates, relapses, and treatment failures. In another double-blind, placebo-controlled study of 20 patients not receiving systemic steroids in an ED, oral montelukast 10 mg resulted in a trend toward a shorter duration of stay and higher peak flows, and fewer patients requiring aminophylline or steroids.156 In the most compelling trial to date, Camargo and colleagues randomized 201 acute asthmatics to standard therapy plus montelukast 7 mg or 14 mg IV or placebo.157 Montelukast improved FEV1 over the first 20 minutes (14.8% vs. 3.6% with placebo). Benefits were seen within 10 minutes and lasted for 2 hours; both treatment doses were equivalent. Montelukast also tended to result in less β-agonist use and fewer treatment failures.
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Heliox is a mixture of 20% oxygen and 80% helium (30%:70% and 40%:60% mixtures are also available). As the percentage of helium decreases, so does the benefit of breathing this gas blend. Concentrations of helium less than 60% are ineffective, precluding its use in significant hypoxemia. Heliox is slightly more viscous than air, but significantly less dense, resulting in a more than threefold increase in kinematic viscosity (the ratio of gas viscosity to gas density) compared to air. Theoretically, this property decreases the driving pressure required for gas flow by two mechanisms. First, for any level of turbulent flow, breathing low-density gas decreases the pressure gradient required for flow. Second, heliox decreases the Reynolds number, favoring conversion of turbulent flow to laminar flow.158 Heliox does not treat bronchospasm or airway wall inflammation.
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Heliox promptly improves dyspnea, work of breathing, and arterial blood gases in upper airway obstruction.159 Benefits have also been reported in acute asthma. In adults treated in an ED, an 80:20 mix delivered by tight-fitting face mask increased PEFR and decreased PP, suggesting improved airway resistance and work of breathing.160 Similar results have been published in children.161 Other studies have failed to demonstrate benefit.162–164 In a recent meta-analysis by Rodrigo and colleagues of four randomized trials and 288 patients, the authors concluded that the evidence does not support the use of heliox in nonintubated asthmatics in the ED.165 However, methodologic differences between studies limit the ability to draw conclusions.
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If heliox is effective, it may give time for concurrent therapies to work, and thereby avert the need for intubation in some cases. Of theoretical concern is the potential for heliox to mask worsening airflow obstruction, so there is less time (and no margin for error) to control the airway when intubation is required.
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Whether heliox augments the bronchodilator effect of inhaled β agonists compared to delivery in air (presumably due to low-density gas facilitating albuterol deposition) is unclear. Data are available demonstrating benefit to heliox as a driving gas,166 but there are also data to the contrary.167
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Because viruses trigger most infectious exacerbations of asthma and bacterial pneumonia is rare, there is likely no role for antibiotics in treating acute asthma. Antibiotics are frequently prescribed for an increase in sputum volume and purulence. However, purulence may reflect an abundance of eosinophils, not polymorphonuclear leukocytes. The importance of Mycoplasma pneumoniae in acute asthma is unknown. A recent study by Lieberman using paired serology demonstrated evidence for mycoplasma infection in 18% of patients hospitalized for acute asthma.168 In their 2002 update, the Expert Panel from the NIH did not recommend the use of antibiotics in asthma exacerbation unless there was fever with purulent sputum, evidence for pneumonia, or suspected bacterial sinusitis.169 In a separate review of the literature, Graham and associates recently selected 2 out of 128 possible studies adequate for review, concluding that the role of antibiotics is difficult to assess.170
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Noninvasive Positive Pressure Ventilation
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Noninvasive positive pressure ventilation (NPPV) by face mask is an option for patients with hypercapneic respiratory failure who do not require intubation. Continuous positive airway pressure (CPAP) helps overcome the adverse effects of PEEPi and decreases the inspiratory work of breathing.171 Bronchial dilation also occurs during CPAP.172 Advantages of NPPV over intubation include decreased need for sedation and paralysis, decreased incidence of nosocomial pneumonia, decreased incidence of otitis and sinusitis, and improved patient comfort.173 Disadvantages include increased risk of aspiration when there is gastric insufflation, skin necrosis, and diminished control of ventilatory status compared with invasive ventilation. Data regarding the efficacy of NPPV in acute asthma are limited. In one study174 of 21 acute asthmatics with a mean PEFR of 144 L/min, nasal CPAP of 5 or 7.5 cm H2O decreased respiratory rate and dyspnea compared to placebo. In another study,175 Meduri and colleagues reported their observational experience with NPPV during 17 episodes of acute severe asthma. NPPV was achieved using a loose-fitting full-face mask with initial settings of 0 cm H2O CPAP and 10 cm H2O pressure support ventilation. CPAP was increased to 3 to 5 cm H2O and pressure support was titrated to achieve an exhaled tidal volume of ≥7 mL/kg and a respiratory rate of <25/min. The average duration of NPPV was 16 hours. NPPV generally improved dyspnea, HR, RR, and blood gases. Two NPPV-treated patients required intubation for worsening PaCO2. There were no NPPV complications.