Five Developments in Asthma Care

The emergency management of acute asthma exacerbations currently revolves around the inhaled b-agonist albuterol, along with systemic corticosteroids. Several other therapies may confer benefits, particularly in very ill asthma patients.

Sir William Osler identified the causes of asthma as bronchial muscle spasm, mucosal swelling, and bronchial inflammation more than a century ago.¹ Therapy for asthma, however, has varied widely over the intervening years. The emergency management of acute asthma exacerbations currently revolves around the inhaled b-agonist albuterol, along with systemic corticosteroids.² Several other therapies may confer benefits, particularly in very ill asthma patients. These include ipratropium bromide, lev-albuterol, magnesium sulfate, and helium-oxygen mixtures for the hospital treatment of acute asthma attacks.

Ipratropium bromide is a nonsympathomimetic bronchodilator that acts by competitively inhibiting cholinergic receptors to reduce vagally mediated bronchoconstriction. It may also decrease mucosal secretion.² It is clearly a beneficial addition to first-line therapy for acute asthma exacerbations. The addition of ipratropium to albuterol nebulizations can increase peak expiratory flow rates (PEFR) by more than 20%, with greater benefits for patients with worse airway obstruction.³ The response varies from patient to patient as a result of variability in airway parasympathetic innervation, but it has been reproduced in both pediatric and adult patients.^1,3,4 Use of this drug also appears to decrease the likelihood of hospital admission for patients seen in the emergency department.³ The effects of ipratropium are synergistic with albuterol, so current asthma management guidelines² suggest the addition of ipratropium to the first three inhaled b-agonist treatments. This drug is the treatment of choice for patients with bronchospasm triggered by b-blocker administration.²

Treatment with b2-Agonists
b2-Agonists decrease muscle spasm and increase airway diameter by relaxing bronchial smooth muscle. They also beneficially inhibit inflammatory mediator release, enhance mucociliary clearance, and inhibit cholinergic neurotransmission.¹ Inhaled albuterol is the most common short-acting b-agonist. Albuterol is a racemic agent, actually composed of equal proportions of two mirror-image molecules called lev-albuterol and dex-albuterol. The two albuterol molecules have dramatically different properties. Lev-albuterol produces rapid bronchodilation, while dex-albuterol provides none. In fact, the dex-albuterol isomer actually appears to worsen bronchoconstriction and spasm in asthma by increasing intracellular calcium, heightening airway hyperresponsiveness, and enhancing inflammatory effects. Dex-albuterol is also metabolized more slowly than lev-albuterol, perhaps taking up to 10 times as long; this prolongs the duration of adverse effects, compared with benefits, when treatments are repeated.⁵

Lev-albuterol is now marketed for nebulization. The drug provides bronchodilation equivalent to that produced by larger doses of racemic albuterol, with 0.63 mg of lev-albuterol and 2.5 mg of racemic albuterol creating similar lung-function change.⁵ The exact role of lev-albuterol is yet to be determined, and the drug is too new to appear in current guidelines. Some studies,^5,6 however, suggest that the use of lev-albuterol in lieu of racemic albuterol may decrease rates of admission from the emergency department to the hospital and may reduce sympathetic side effects, such as anxiety and tachycardia. Emergency department lengths of stay, number of treatments, number of admissions to intensive care, and oxygen requirements have not yet been shown to vary with the form of albuterol used. In addition, the benefits of treating inpatients are less clear, and there has been no demonstrated benefit associated with the use of lev-albuterol in settings outside the hospital.^6-8

Lev-albuterol is more expensive than racemic albuterol, and it also requires more expensive administration via nebulization, as no metered-dose inhaler (MDI) is available. The best clinical role for lev-albuterol thus remains unclear. Two suggestions^6,9,10 have been made; the first is to use the agent only for patients who require nebulizer treatment instead of MDI delivery and who also have a history of adverse effects attributed to traditional albuterol, and the second is to use lev-albuterol in the emergency department but not on inpatient floors.

MDI Delivery
Although it is very common, in emergency settings, to deliver inhaled medications via oxygen-powered nebulizers, it has been well established¹¹ that delivery via MDI with a spacer chamber is less expensive and at least equally effective in the treatment of both adults and children, provided proper technique is used. To date, the MEDLINE-indexed literature does not show a clinical benefit for nebulized medication administration compared with MDI. Some studies^12-14 have shown improved pulmonary function with MDI use, with decreases in wheezing and sympathetic side effects, emergency department time and admissions, and relapse rates. Patients treated with MDIs versus nebulizers have decreases in total emergency department costs of up to 33%.¹³

Magnesium Sulfate
After a period of uncertainty, magnesium sulfate has now been clearly shown to be a beneficial adjunct to treatment of the most severe cases of asthma. The intravenous administration of 2 g of magnesium sulfate to adult patients, or 25 to 100 mg/kg to pediatric patients, improves pulmonary function when added to standard treatment for the most severely ill asthma patients (those with an initial PEFR of less than 25% of the predicted value).^1,15-17 The exact mechanism of action of magnesium in asthma is unclear. Magnesium in the body is primarily an intracellular cation and is essential for the activation of over 300 enzymes, for nearly all hormonal reactions, and for the activity of adenylate cyclase. It also functions as a calcium-channel blocker.¹⁸ The beneficial effect is believed to be related to some combination of calcium antagonism and adenylate cyclase activation. Magnesium also has been shown to potentiate the effects of b-agonists. Although magnesium is clearly useful for very ill asthma patients, it is also obvious that the routine use of magnesium for all asthma patients is not beneficial.^15,16 A possibility currently under investigation is that the nebulized administration of magnesium may be as effective as intravenous administration in appropriately selected patients.¹⁹

Helium-Oxygen Mixtures
Helium-oxygen mixtures are widely used in the treatment of upper-airway disease. There is interest in using helium-oxygen mixtures to treat patients with acute asthma exacerbations. Gas flow in the upper airways is largely laminar and behaves according to the Hagen-Poiseuille law, varying according to gas viscosity, tube length, tube radius, and pressure gradient. At bifurcations and in constricted, inflamed, or secretion-filled airways, however, airflow is turbulent, as it may also be at the most distal airways. Turbulent airflow is more sluggish than laminar flow, and turbulent airflow varies with gas density (laminar airflow does not). Helium has a lower density than air, so helium-oxygen mixtures could conceivably decrease airway resistance and work of breathing by increasing airflow in small and diseased airways.

Helium-oxygen mixtures generally contain 60% to 80% helium. Case reports and small series^20,21 have shown increased PEFR, lessened dyspnea, and decreased inspiratory pressure. Despite those reports and the theoretical benefits, a recent meta-analysis²² found that the addition of helium-oxygen to standard asthma care was not more effective than treatment with oxygen alone, regardless of patient age or the helium-oxygen mixture used. The authors concluded that it was not an effective treatment.

One potential benefit of helium, however, persists. Nebulization using helium-oxygen mixtures, as opposed to oxygen alone, changes the size of the nebulized particles. In spite of some concerns about adverse effects because of that change, studies^22,23 using helium-oxygen to drive nebulizer therapy showed trends toward improved pulmonary function, suggesting that the use of helium-oxygen to power nebulization may improve drug delivery to distal airways.

The foundations of care for patients with acute asthma exacerbations are well established: b2-agonists and systemic corticosteroids. This is an area of medicine where research continues and new developments are being made. It is up to practitioners to keep abreast as therapies are shown to be successful or unsuccessful and to base their practices on scientific evidence.

Michael A. Frakes, RN, BSN, CFRN, CCRN, EMTP, is a senior flight nurse and the practice & research coordinator for LIFE STAR/Hartford Hospital, Hartford, Conn.

Tracy Evans, RN, MPH, ACNP, CEN, CCRN, EMTP, is trauma program manager and director of emergency medical services, Norwalk Hospital, Norwalk, Conn.

References
1. Frakes MA. Asthma in the emergency department. J Emerg Nurs. 1997;23:429-435.
2. National Asthma Education and Prevention Program. Expert panel report: guidelines for the diagnosis and management of asthma. Bethesda, Md: National Institutes of Health; 1991.
3. Stoodley RG. The role of ipratropium bromide in the emergency management of acute asthma exacerbation: a meta-analysis of randomized controlled trials. Ann Emerg Med. 1999;34:8-18.
4. Zorc JJ. Ipratropium bromide added to asthma treatment in the pediatric emergency department. Pediatrics. 1999;105:748-752.
5. Nelson HS, Bensch G, Pleskow WW, et al. Improved bronchodilation with levalbuterol compared with racemic albuterol in patients with asthma. J Allergy Clin Immunol. 1998;102:943-952.
6. Carl JC. Comparison of racemic albuterol and levalbuterol for treatment of acute asthma. J Pediatr. 2003;143:731-736.
7. Truitt T. Lev-abuterol compared to racemic albuterol: efficacy and outcomes in patients hospitalized with COPD or asthma. Chest. 2003;123:128-135.
8. Thompson M, Wise B, Hodenberg H. A preliminary comparison of levalbuterol and albuterol in prehospital care. J Emerg Med. 2004;26:271-277.
9. Kattan M. Mirror images: is lev-albuterol the fairest of them all? J Pediatr. 2003;143:702-704.
10. Dershewitz RA. Which form of albuterol for acute asthma in children? Journal Watch. 2004;24(2):1.
11. Callahan CW. Wet nebulization in acute asthma: the last refrain?. Chest. 2000;117:1226-8.
12. Numata Y. Teaching time for metered-dose inhalers in the emergency setting. Chest. 2002;122:498-504.
13. Leversha AM. Cost and effectiveness of spacer versus nebulizer in young children with moderate and severe acute asthma. J Pediatr. 2000;136;497-502.
14. Schuh S. Comparison of albuterol delivered by a metered dose inhaler with spacer versus a nebulizer in children with mild acute asthma. J Pediatr. 1999;135:22-27.
15. Silverman RA. IV magnesium sulfate in the treatment of acute severe asthma. Chest. 2002;122;488-497.
16. Rowe BH. Intravenous magnesium sulfate for treatment for acute asthma in the emergency department: a systematic review of the literature. Ann Emerg Med. 2000;36;181-190.
17. Frakes MA, Richardson LE. Magnesium sulfate therapy in certain emergency conditions. Am J Emerg Med. 1997;15:182-187.
18. Noppen M. Magnesium treatment for asthma: where do we stand? Chest. 2002;122:396-8.
19. Hughes R. Use of isotonic nebulised magnesium sulfate as an adjuvant to salbutamol in treatment of severe asthma in adults. Lancet. 2003;361;2114-2117.
20. Abd-Allah SA, Rogers MS, Terry M, et al. Helium-oxygen therapy for pediatric acute severe asthma requiring mechanical ventilation. Pediatr Crit Care Med. 2003;4:353-357.
21. Kudukis TM. Inhaled helium-oxygen revisited. J Pediatr. 1997;131:333-334.
22. Rodrigo G, Pollack C, Rodrigo C, Rowe BH. Use of helium-oxygen mixtures in the treatment of acute asthma. Chest. 2003;123:891-896.
23. Bag R, Bandi V, Fromm RE, Guntupalli K. The effect of heliox-driven bronchodilator aerosol therapy on pulmonary function tests in patients with asthma. J Asthma. 2002;39:659-665