Life-Threatening Asthma, Part 2:

Asthma remains a significant cause of morbidity and mortality throughout the world. Patients presenting with near-fatal asthma provide a unique population in which to study the variables that contribute to asthma-related mortality. By identifying high-risk patients, using objective and subjective measures to detect severe exacerbations, and initiating early medical intervention, we can reduce the morbidity and mortality of asthma.

On page 609, we reviewed the risk factors associated with life-threatening asthma. In this article, we focus on management strategies.

STANDARD THERAPIES

Standard therapies for severe asthma include β-agonists, oxygen, and corticosteroids (Table).

ß-Agonists. β-agonists remain first-line therapy for patients with exacerbations of any degree of severity (Figure 1).¹ These agents, with the exception of the long-acting formulations, induce bronchodilation with a rapid onset of action. Patients with life-threatening asthma may have significant bronchoconstriction, airway edema, and inflammation, and they may require high doses or repeated doses of β-agonists before they respond sufficiently.

Numerous studies have indicated that administration of β-agonists via metered-dose inhaler with spacer is as effective as nebulized treatments.^2,3 Evidence suggests that continuous nebulization may be beneficial in the most severe asthma exacerbations.⁴

Levalbuterol, an isomer of racemic albuterol, may play a role in managing refractory asthma,⁵ particularly in patients with ischemic heart disease or severe tachycardia. Levalbuterol is reported to have fewer side effects, since the bronchodilatory effects of albuterol result from activity of the R-isomer, while the side effects may result from the S-isomer.⁵ In a subset of patients with severe asthma, a dose-dependent relationship existed when higher doses of levalbuterol were used.⁶

Nebulized doses of levalbuterol range from 0.63 to 1.25 mg in adults, but a dose of 2.5 mg should be considered in those with severe asthma. One study demonstrated a dose-response curve with doses ranging from 0.31 to 2.5 mg in children with severe exacerbations.⁶

In European studies, intravenous β-agonists have not been shown to be more effective than inhaled β-agonists.^7,8 Although most patients respond to inhaled β-agonists, some may benefit from systemic treatment. Appel and asso-ciates⁹ performed a randomized controlled trial of patients with acute asthma. In this double-blind crossover study, patients with a peak expiratory flow rate (PEFR) of less than 150 L/min after standard therapy received either inhaled metaproterenol or subcutaneous epinephrine. At 120 minutes, 61% of those who received metaproterenol had improved PEFR, compared with 89% of those who received epinephrine.

Patients in whom initial therapy failed had symptoms for a significantly longer duration before presentation, which suggests that marked inflammation and mucous plugging may result in a suboptimal response to inhaled medications.⁹ The findings of this study do not clearly define the role of systemic β-agonists in the treatment of life-threatening asthma, but they suggest that a trial of subcutaneous β-agonists should be considered in patients who fail to respond to inhaled medications.

Epinephrine can be administered subcutaneously as 0.3 to 0.5 mg of a 1:1000 solution every 20 minutes to a maximum of 3 doses. Terbutaline, 0.25 to 0.5 mg, should be used in pregnant patients who require subcutaneous b-agonist treatment. Although there is some concern about using systemic β-agonists in older patients, Cydulka and associates¹⁰ showed that patients older than 40 years had minimal risk of side effects from subcutaneous epinephrine if they had no active angina and no history of myocardial infarction in the previous 6 months.

Systemic corticosteroids. Corticosteroids should be administered to all patients who present to the hospital with asthma unless PEFR or forced expiratory volume in 1 second (FEV₁) is at least 80% of predicted after 1 hour of treatment (Figure 2). Systemic corticosteroids decrease inflammation, increase the number and sensitivity of β-receptors, and inhibit the migration and function of eosinophils and neutrophils.¹¹

A meta-analysis of 700 articles with 30 randomized controlled trials demonstrated that corticosteroid administration in the emergency department (ED) reduced admission rates and decreased relapse rates at 7 to 10 days.¹² Oral therapy was equivalent to intravenous therapy. Corticosteroids were most effective in patients with severe asthma who were not receiving long-term corticosteroid therapy.

Because the maximum effect of corticosteroids is not seen until 4 to 6 hours after administration, this therapy should be instituted early (within 1 hour of presentation). The optimal dose remains controversial. Haskell and associates¹³ randomized patients with severe asthma to receive 125, 40, or 15 mg of methylprednisolone every 6 hours. Medium and high doses caused more significant improvement than did low doses. The high-dose group had a more rapid improvement in the first 24 to 36 hours of therapy.

We prefer using 125 mg of methylprednisolone every 6 hours for the first 24 to 48 hours in patients admitted to the ICU. The practice guidelines published by the NIH recommend prednisone, 120 to 180 mg/d in 3 or 4 divided doses (or the equivalent) for 48 hours, then 60 to 80 mg/d until PEFR reaches 70% of predicted or personal best.¹³ The guidelines also state that no advantage has been identified for higher doses or intravenous administration if GI absorption is normal.¹⁴

If patients improve on the NIH regimen, they may be switched to oral prednisone, 60 to 80 mg (1 mg/kg) per day. Treatment should be continued for 3 to 10 days, then discontinued without a taper if the patient is receiving inhaled corticosteroid therapy. Inhaled corticosteroids should be continued during systemic treatment to avoid rebound bronchoconstriction with discontinuation of systemic therapy.

Anticholinergics.

Ipratropium is effective in managing acute bronchospasm induced by β-blockers and monoamine oxidase inhibitors.

¹⁵

Patients with severe airway obstruction (FEV

₁

less than 50% of predicted) also benefit from ipratropium in combination with β-agonists. In such patients, the combined use of anticholinergics and β-agonists improves PEFR and FEV

₁

more than β-agonists alone and significantly decreases the risk of hospital admission.

^16,17

The onset of action of anticholinergics in patients with acute exacerbations of asthma is short, occurring within 1 minute, with peak effects within 20 minutes.¹⁵ Benefits may persist for up to 48 hours.¹⁶ Anticholinergic therapy should be continued until the patient stabilizes but should not be added to the patient's long-term asthma management regimen.

Be sure patients know how to use aerosol delivery devices. The correct use of both metered-dose inhalers with holding chambers (spacers) and dry powder inhalers is essential for optimal therapeutic results. The process should be taught before a patient is discharged from the hospital, and he or she should be provided with a handout that illustrates the correct technique.

The American College of Chest Physicians provides excellent free instructional handouts for all aerosol delivery devices on their Web site, www.chestnet.org. Instructions for dry powder inhalers can also be found in the CONSULTANT Health Guide, November 2005, page 1465.

Theophylline. This agent has not proved beneficial in the ED management of acute asthma in adults.¹⁸ In addition to bronchodilation, long-term use of theophylline may provide benefits such as decreased airway inflammation.¹⁵ Theophylline has a narrow therapeutic-to-toxic window, however; significant side effects, such as GI upset and tachycardia, can occur.

Studies of the use of theophylline in the ED have not demonstrated a significant reduction in time to recovery or decrease in hospital admission rates. Huang and associates¹⁹ found an improvement in FEV₁ at 3 to 48 hours when theophylline was administered with albuterol and corticosteroids to adults with asthma. In addition, numerous pediatric studies have demonstrated a benefit with the addition of theophylline in the treatment of status asthmaticus.

Two studies suggest that the-ophylline may have a role in the treatment of children with impending respiratory failure in whom aggressive therapy with inhaled bronchodilators has failed.²⁰ Ream and associates²¹ published results of a randomized controlled trial of aminophylline given with β-agonists, systemic corticosteroids, and anticholinergics in children admitted to the pediatric ICU because of asthma. Patients receiving theophylline had a more rapid improvement in their clinical asthma scores than those receiving placebo.

We recommend the addition of theophylline only in patients with poor or incomplete responses to therapy with β-agonists, oxygen, intravenous corticosteroids, and inhaled anticholinergics. Patients receiving long-term theophylline should have a baseline blood theophylline level measured before continuation of therapy. These patients may not require bolus dosing or intravenous administration of theophylline in the hospital.

OTHER THERAPIES

Magnesium sulfate. This agent inhibits calcium channel-mediated smooth muscle activity and reduces acetylcholine release. A dose of 1 to 2 g may be administered intravenously over 30 minutes. A Cochrane meta-analysis showed no improvement in PEFR or FEV₁ after administration of magnesium.²² A subgroup analysis suggested that patients with an FEV₁ of less than 30% at admission or less than 60% after 1 hour of treatment might benefit from 1 to 2 g of magnesium. Overall, the available data did not support the routine use of magnesium in status asthmaticus.

Heliox is a combination of helium and oxygen at typical ratios of 60:40 or 70:30; it provides a less dense, more viscous medium than air. This gas decreases turbulent flow through constricted airways. Case reports suggest that heliox might increase distal airway delivery of β-agonists, decrease pulsus paradoxus and the work of breathing, and decrease peak airway pressures and PaCO₂ in intubated patients.¹⁷

Four randomized controlled trials failed to show improvement in pulmonary function or hospital admissions with heliox. One study, however, showed that heliox with a helium-to-oxygen ratio of 80:20 delivered via non-rebreather mask led to significant improvements in pulmonary function over the first 3 hours of treatment.²³

Inhaled corticosteroids. The role of inhaled corticosteroids in the treatment of severe asthma remains under investigation. Although inhaled corticosteroids have been shown to be of benefit when added to b-agonist therapy for acute asthma, the additive benefit in combination with systemic corticosteroids remains unproved.⁴ Current data support the continued use of inhaled corticosteroids after hospital discharge,²⁴ but no clear evidence exists that inhaled corticosteroids are safe for use without systemic therapy for life-threatening asthma.

Leukotriene antagonists and leukotriene synthesis inhibitors may play a role in the management of acute life-threatening asthma.⁵ These agents may complement the anti-inflammatory effects of systemic corticosteroids in patients with severe asthma exacerbations.⁵ A randomized controlled clinical trial published in 1999 demonstrated a decrease in the need for hospital admission among patients with acute asthma treated with zafirlukast.²⁵ Further studies are needed to confirm the role of leukotriene antagonists in near-fatal asthma.

Mechanical ventilation. Arterial blood gas values alone should not be used to determine the need for mechanical ventilation. The overall clinical status of the patient and rate of decline or improvement in dyspnea, tachypnea, tachycardia, and objective measures of airflow are the most important determinants of the need for artificial ventilatory support. Maffei and colleagues²⁶ found that the need for early initiation of mechanical ventilation was a marker for near-fatal asthma and did not necessarily represent a simple failure of preintubation asthma management. Thus, physicians should assess the patient's clinical condition and, if ventilatory support is indicated, institute this therapy early and under elective conditions in the appropriate clinical setting.

If mechanical ventilation is required, nasal intubation should be avoided because of the increased incidence of sinusitis and nasal polyps in patients with asthma.²⁷ Permissive hypercapnia is a ventilatory strategy often favored in patients with asthma. This strategy minimizes lung hyperinflation by providing adequate time to exhale alveolar gas while allowing PaCO₂ to rise if necessary to achieve this goal.²⁷ In general, hypercapnia can be tolerated as long as PaCO₂ does not rise above 90 mm Hg and does not change acutely.²⁶

Studies have shown that noninvasive mechanical ventilation has some benefit in preventing progression of respiratory failure in a subset of asthmatic patients who had rapid progression, although the studies are small.²⁶ For example, in a comparison of 11 asthmatic patients who were placed on mechanical ventilation and 22 who were treated with noninvasive ventilation, only 3 of the latter required intubation.²⁸ In responders, PaCO₂ tends to decrease quickly after institution of therapy.²⁷

Thus, noninvasive mechanical ventilation can be considered in patients with severe asthma exacerbations if respiratory failure is not thought to be imminent, but there is concern that mechanical ventilation may eventually be required. Close monitoring and a low threshold for intubation are warranted in such patients.

References:

REFERENCES:
1. Smith D, Riel J, Tilles I, et al. Intravenous epinephrine in life-threatening asthma. Ann Emerg Med. 2003;41:706-711.
2. Newhouse MT. Emergency department management of life-threatening asthma. Are nebulizers obsolete? Chest. 1993;103:661-663.
3. Idris AH, McDermott MF, Raucci JC, et al. Emergency department treatment of severe asthma. Metered-dose inhaler plus holding chamber is equivalent in effectiveness to nebulizer. Chest. 1993;103: 665-672.
4.Rowe BH, Edmonds ML, Spooner CH, Camargo CA. Evidence-based treatments for acute asthma. Respir Care. 2001;46:1380-1390.
5. Varon J, Marik PE. Managing acute severe asthma: what therapies to try, and when. J Respir Dis. 2003;24:67-76.
6. Milgrom H, Skoner DP, Bensch G, et al. Low-dose levalbuterol in children with asthma: safety and efficacy in comparison with placebo and racemic albuterol. J Allergy Clin Immunol. 2001; 108:938-945.
7. O'Connell MB, Iber C. Continuous intravenous terbutaline infusions for adult patients with status asthmaticus. Ann Allergy. 1990;64:213-218.
8. Lawford P, Jones BJ, Milledge JS. Comparison of intravenous and nebulised salbutamol in initial treatment of severe asthma. Br Med J. 1978;1:84.
9. Appel D, Karpel JP, Sherman M. Epinephrine improves expiratory flow rates in patients with asthma who do not respond to inhaled metaproterenol sulfate. J Allergy Clin Immunol. 1989;84:90-98.
10. Cydulka R, Davison R, Grammer L, et al. The use of epinephrine in the treatment of older adult asthmatics. Ann Emerg Med. 1988;17:322-326.
11. Peters JI, Rossrucker J. Current concepts in managing status asthmaticus. J Respir Dis. 1992; 13:829-849.
12.Rowe BH, Keller JL, Oxman AD. Effectiveness of steroid therapy in acute exacerbations of asthma: a meta-analysis. Am J Emerg Med. 1992;10:301-310.
13. Haskell RJ, Wong BM, Hansen JE. A double-blind, randomized clinical trial of methylprednisolone in status asthmaticus. Arch Intern Med. 1983;143: 1324-1327.
14.National Asthma Education and Prevention Program Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma. Bethesda, Md: National Heart, Lung, and Blood Institute, National Institutes of Health; 1997. NIH publication 97-4051.
15.Levy BD, Kitch B, Fanta CH. Medical and ventilatory management of status asthmaticus. Intensive Care Med. 1998;24:105-117.
16.Rodrigo GJ, Rodrigo C. First-line therapy for adult patients with acute asthma receiving a multiple-dose protocol of ipratropium bromide plus albuterol in the emergency department. Am J Respir Crit Care Med. 2000;161:1862-1868.
17. Rodrigo GJ, Castro-Rodriguez JA. Anticholinergics in the treatment of children and adults with acute asthma: a systematic review with meta-analysis. Thorax. 2005;60:740-746.
18. Corbridge TC, Hall JB. The assessment and management of adults with status asthmaticus. Am J Respir Crit Care Med. 1995;151:1296-1316.
19. Huang D, O'Brien RG, Harman E, et al. Does aminophylline benefit adults admitted to the hospital for an acute exacerbation of asthma? Ann Intern Med. 1993;119:1155-1160.
20. Self TH, Redmond AM, Nguyen WT. Reassessment of theophylline use for severe asthma exacer-bation: is it justified in critically ill hospitalized pa-tients? J Asthma. 2002;39:677-686.
21. Ream RS, Loftis LL, Albers GM. Efficacy of IV theophylline in children with severe status asthmaticus. Chest. 2001;119:1480-1488.
22. Rowe BH, Bretzlaff JA, Bourdon C, et al. Magnesium sulfate for treating exacerbations of acute asthma in the emergency department. Cochrane Database Syst Rev. 2000;(2):CD001490.
23. Kress JP, Noth I, Gehlbach BK, et al. The utility of albuterol nebulized with heliox during acute asthma exacerbations. Am J Respir Crit Care Med. 2002; 165:1317-1321.
24. Edmonds ML, Camargo CA, Saunders LD, et al. Inhaled steroids for acute asthma following emergency department discharge. Cochrane Database Syst Rev. 2000;(3):CD002316.
25.Silverman RA, Miller CJ, Chen Y. Zafirlukast reduces relapses and treatment failures after an acute asthma episode. Chest. 1999;166:296S.
26. Maffei FA, Van der Jagt EW, Powers KS, et al. Duration of mechanical ventilation in life-threatening pediatric asthma: description of an acute asphyxial subgroup. Pediatrics. 2004;114:762-767.
27. Rodrigo GJ, Rodrigo C, Hall JB. Acute asthma in adults. Chest. 2004;125:1081-1102.
28. Fernandez MM, Villagra A, Blanch L, Fernandez R. Non-invasive mechanical ventilation in status asthmaticus. Intensive Care Med. 2001;27:486-492.

EVIDENCE-BASED MEDICINE

• Rodrigo GJ, Castro-Rodriguez JA. Anticholinergics in the treatment of children and adults with acute asthma: a systematic review with meta-analysis. Thorax. 2005;60:740-746.

• Rowe BH, Edmonds ML, Spooner CH, Camargo CA. Evidence-based treatments for acute asthma. Respir Care. 2001;46:1380-1390.

RELEVANT GUIDELINES

• National Asthma Education and Prevention Program Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma. Bethesda, Md: National Heart, Lung, and Blood Institute, National Institutes of Health; 1997. NIH Publication 97-4051. Available at www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm.