The Treatment of Acute Asthma: Role of Short-Acting ß-Agonists in Acute and Emergency Department Treatment

At an industry-sponsored symposium held in conjunction with CHEST 2003, the annual meeting of the American College of Chest Physicians, three thought leaders discussed management of acute exacerbations of asthma in the emergency department and in the hospital. Topics included the role of ß-agonists in the emergency department, corticosteroids in treatment of acute asthma, and treatment of asthma in the hospital.

This program was supported in part by an educational grant from Sepracor.

Role of ß-Agonists in the ED

James F. Donohue, MD, FCCP, Professor, Chief of Pulmonary and Critical Care at the University of North Carolina at Chapel Hill, began by reviewing the central role of inflammation in the pathophysiology of asthma. Patients with the most severe disease are thought to be at the highest risk of an acute event leading to the emergency department (ED), hospitalization, or death. However, “even those with mild disease can have a very rapid and fatal kind of episode,” Dr. Donohue said.

It is crucial to recognize which patients are at risk of a fatal or near-fatal asthma attack. Patients who are sitting or standing bolt upright, diaphoretic, and using accessory muscles are more likely to have severe obstruction. Elevated respiratory rate (> 30 breaths per minute), tachycardia (>120 beats per minute), pulsus paradoxus (> 12 mm Hg) and wheezing with a silent chest also are associated with severe disease (British Thoracic Society. Thorax 2003;58[Suppl 1]).

Two types of patients have responses to dyspnea that place them at elevated risk for a severe or fatal episode. One group is unable to sense the presence of airway obstruction and therefore may not seek medical care promptly. The other type has blunted hypoxic ventilatory drive and does not hyperventilate in response to hypoxia. The latter is a “big risk factor for why people with acute asthma can get into trouble,” he said.

Lung function in the ED is measured using peak expiratory flow (PEF). If PEF is less than 40% of predicted value, patients should be admitted. Patients with PEF of 40% to 69% of predicted value should be monitored. The goal for discharge is PEF of 70% predicted value (National Asthma Education and Prevention Program Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma, 1997. NIH Publication No. 97-4051).

Although these are standard practices, physicians also must consider patient symptoms, history, and physical data in determining management. “Many exacerbations are characterized by an escalation of symptoms, far in advance of any change in peak flow,” he said. “You wouldn’t rely entirely on that one number.”

The goals of treating asthma exacerbations in the ED and hospital include correcting hypoxia, rapidly reversing airway obstruction, and decreasing the chance of recurrence. “The go-to drugs are ß-2-agonists in very high concentration,” he said. ß-agonists must be used continuously until clinical response occurs or toxicity develops.

Based on review of guidelines from several sources, the best choice for therapy is albuterol by nebulizer 2.5 to 5 mg/3 to 5 cc saline (National Asthma Education and Prevention Program Expert Panel Report. J Clin Allergy Immunol 2002;110[part 2]; British Thoracic Society. Thorax 2003;58[Suppl 1]). Following three such treatments 20 minutes apart, the physician should attempt to switch patients to the metered dose inhaler (MDI), at a dose of 4 to 10 puffs per hour as needed.

Patients with very low lung function (< 40% PEFR [peak expiratory flow rate]) may benefit from continuous nebulizer therapy at 10 to 20 mg/hour. “Only 5% of emergency doctors use continuous nebs when that was recently looked at,” he said. Another choice for such patients may be formoterol, a complete b-agonist with “very, very high intrinsic activity that works very, very rapidly.” Guidelines recommend against using intravenous (IV) or subcutaneous b-agonists instead of inhaled therapy. Minimal data indicate that adding IV or subcutaneous ß-agonists to inhaled therapy does not help and may cause harm.

High doses of b-agonist therapy are tolerated well in acute asthma. They lead to more rapid increase in lung function, earlier discharge from the ED, and fewer hospitalizations (McFadden ER Jr., et al. Am J Med 1998;105:12-17).

Use of long-acting ß2-agonists in maintenance therapy does not increase risk of status asthmaticus (Donohue JF. Chest 2000;119:283-285). “I know there’s been a lot of concern about that,” he said. Patients using long-acting ß2-agonists who are seen in the ED for status asthmaticus receive the same dose of emergency bronchodilator therapy as other asthma patients. Adding albuterol to the long-acting ß2-agonist salmeterol causes little change in heart rate or QTc interval.

Salmeterol can be used safely in the hospital. “You don’t use it up front, but as you want to cut down on respiratory therapy doses, you can add on this drug,” he explained. There is some increased risk of complications when using long-acting ß2-agonists in persons with active coronary artery disease (CAD) or other heart disease (Donohue JF. Chest 2000;119:283-285).

Levalbuterol is another ß2-agonist that “may have a role in the emergency room,” he said. The most commonly prescribed ß2-agonist, racemic albuterol, contains two mirror-image enantiomers termed (R)- and (S)-albuterol. Most of the bronchodilator effect comes from the (R)-albuterol, or levalbuterol. (S)-albuterol has no bronchodilating properties and “may exaggerate airway reactivity,” Dr. Donohue said. Preclinical data show “a lot of adverse effects of the S isomer,” on intracellular calcium, calcium fluxes, and proinflammatory activity.

Hospitals face the question of “(whether) there is added value by using this drug,” Dr. Donohue said. One of the first peer-reviewed papers focused on inpatient care showed that levalbuterol use was associated with significantly fewer nebulizer treatments, shorter length of stay, fewer readmissions within 30 days, and lower cost of nebulizer therapy compared to racemic albulterol in asthma and chronic obstructive pulmonary disease (Figure 1) (Truitt T, et al. Chest 2003;123-128-135). “(It) was quite impressive,” Dr. Donohue said.

Two studies in press at the time of the presentation also demonstrate positive results for levalbuterol in the ED, he said. One showed improved effect on FEV1 (forced expiratory volume in one second) compared to racemic albuterol in “critically ill, very, very sick asthmatics,” Dr. Donohue stated. Another, a large double-blind randomized trial, demonstrated a lower admission rate from the ED for patients treated with levalbulterol compared to racemic albuterol. “Levalbuterol may prove to be more efficacious and less toxic than racemic albuterol,” he said. Further studies of this agent are needed.

Steroids in the Treatment of Acute Asthma

Kenneth R. Chapman, MD, FCCP, Professor of Medicine and Director, Asthma & Airway Centre at Toronto Western Hospital, University of Toronto, Ontario, Canada, reviewed the use of inhaled, oral, and intravenous (IV) corticosteroids in acute asthma.

Corticosteroids in acute care are designed to produce medium- to long-term anti-inflammatory effects, “things that are going to be happening in hours to days,” noted Dr. Chapman. Even inhaled corticosteroids may be changing the inflammatory process “all the way back to the bone marrow,” he said (Wood LJ, et al. Am J Respir Crit Care Med 1999; 159[5 Pt 1]:1457-1463). Effects may not be limited to reducing inflammation; topical beclomethasone has been shown to increase the number of ß2-receptors in airway mucosa (Baraniuk JN, et al. Am J Respir Crit Care Med 1997; 155: 704-710).

Several studies in the 1980s through the mid-1990s demonstrated that IV hydrocortisone or methylprednisolone speed improvement in lung function during an acute exacerbation. Higher doses are no more effective than lower ones in improving FEV1 or decreasing rates of admission to the hospital. Another series of studies found that IV corticosteroids offered no advantage over oral formulations in acute asthma.

Investigators then asked whether inhaled corticosteroids could replace oral or parenteral formulations. One study documented an advantage for inhaled treatment (Devidayal, SS, et al. Acta Paediatr 1999;88:835-840). Another reported contradictory results (Schuh S, et al. N Engl J Med 2000;343:689-694). Based on these findings, Dr. Chapman said, “Inhaled steroids are not due to take over from oral or parenteral corticosteroids just yet.”

Another problem with inhaled steroids in the ED is that there is some question about whether the drug consistently reaches the lower airways. Dr. Chapman displayed a scintigram of radiolabeled drug deposition showing that nebulized medication did not reach the lung in a crying infant, but deposited throughout the lower airway in a sleeping child. This issue, he said, “certainly will be important if we’re going to rely on inhaled corticosteroids in the emergency room to ensure drug deposition in...severely obstructed children, the elderly, the uncooperative, and so on.”

Preventing relapse
At least 75% of patients treated for asthma in the ED are discharged home. About 25% to 35% relapse within the next 10 to 21 days (Ducharme FM, Kramer MS. J Clin Epidemiol 1993;46: 1395-1402; Emerman CL. J Asthma 2000;37:701-708). Oral prednisone given for 7 days after discharge reduces risk of relapse in the first and second 10-day period following release from the hospital (Chapman KR, et al. N Engl J Med 1991;324:788-794). Adding an inhaled corticosteroid (budesonide) to oral prednisone as part of the postdischarge regimen reduces relapse rates to roughly half those seen with oral prednisone alone (Rowe BH, et al. JAMA 1999;281:2119-2126).

Because it would be preferable to avoid the side effects of systemic steroids, investigators then examined whether inhaled corticosteroids could reduce relapse as well as the oral formulation. Analysis of seven randomized controlled trials revealed no significant difference between relapse rates with oral or inhaled steroids. However, authors noted that severely ill patients were excluded and a Type II error was possible (Edmonds ML, et al. Chest 2002;121: 1798-1805).

Another approach to minimizing relapse rate after an acute exacerbation may be to add long-acting ß-agonist therapy to steroid treatment after discharge. There is “obvious interaction or…some would say, synergy, between long-acting ß-agonists such as formoterol and inhaled corticosteroids such as budesonide,” said Dr. Chapman. A study in stable outpatients reported that adding formoterol to inhaled budesonide therapy significantly reduced the annual exacerbation rate compared to the steroid alone (Pauwels CG, et al. N Engl J Med 1997; 337:1405-1411;erratum appears in N Engl J Med 1998;338:139).

“It’s a logical enough extrapolation to think that we might just give such a combination to patients upon their discharge from the emergency room” to prevent relapse and future events, Dr. Chapman said. A combination of budenoside/formoterol is unavailable in the US; the most comparable product available in the US is salmeterol/fluticasone. Several studies of salmeterol/fluticasone as maintenance therapy have shown that the combination leads to a lower exacerbation rate than treatment with either drug alone or with placebo (Shapiro G, et al. Am J Respir Crit Care Med 2000; 161[2 Pt 1]:527-534). Research is needed to determine if this finding could be applied usefully in the post-emergency room discharge setting, however.

In summary, Dr. Chapman said:

• Systemic and inhaled corticosteroids should be used together to resolve an acute asthma attack
• Oral and inhaled corticosteroids should be used together to prevent relapse following ED discharge.
• In exacerbation-prone asthma patients, inhaled corticosteroids and long-acting b-agonists should be used together to reduce risk of recurrence.

Treatment of Acute Asthma

Jay Peters, MD, FCCP, Professor of Medicine and Director of Critical Care at the University of Texas Health Science Center in San Antonio, reviewed inpatient management of acute asthma.

Risk assessment
Asthma exacerbations leading to hospitalization typically follow one of three profiles, he said (Arnold AG, et al. Br J Dis Chest 1982;76:157-163). One involves slow deterioration over days to weeks. The second features instability for days to weeks, followed by acute deterioration. Finally, patients with so-called hyper-acute asthma are stable and symptom-free until 1 to 2.5 hours prior to presenting at the ED. This group, somewhat surprisingly, accounts for 13% of all asthma exacerbations (Arnold AG, et al. Br J Dis Chest 1982;76:157-163). These are generally young, atopic patients, most of whom are aspirin-sensitive. Many display blunted hypoxic ventilatory drive or reduced perception of dyspnea.

The strongest predictor of respiratory arrest or death during hospitalization is a pattern characterized as “morning dipper” — ie, a 50% diurnal variation in pulmonary function, with a decrease early in the morning (Hetzel et al, Br Med J 1979;1:808-811). Identify-ing these patients is important, as aggressive therapy during the night for the first day or two of hospitalization can prevent admission to the intensive care unit (ICU) and other negative outcomes, he said.

Assessing pulmonary function by measuring PEFR or FEV1 is crucial (Rodrigo G, Rodrigo C. Chest 1993;104: 1325-1328). Without this data, physician assessment of patient severity is incorrect about 50% of the time. PEFR or FEV1 (>60% of predicted value) is the best predictor of readiness for discharge. PEFR or FEV1 also are a criterion for ICU admission. Values of less than 40% predicted after initial bronchodilator treatment in the ED are a common indication for ICU admission; the same is true for an increase of less than 10% in peak flow after ED treatment (Rodrigo G, Rodrigo C. Chest 1993;104:1325-1328).

Treatment with ß-agonists
Dr. Peters then reviewed use of ß-agonist therapy in the hospital. About two-thirds of patients respond well to bronchodi-lator therapy (Strauss L, et al. Am J Respir Crit Care Med 1997;155: 454-458). The remaining 30% appear to require relatively high doses of ß-agonist therapy (>3.6 mg via MDI with holding chamber) (Rodrigo C, Rodrigo G, et al. Chest 1998;113:593-598). Identifying this subgroup and treating them aggressively may reduce their duration of
hospitalization said Dr. Peters.

Delivering ß-agonist therapy in patients receiving mechanical ventilation is complex. The procedures and devices used can greatly affect the amount of drug that reaches patient airways. “Be sure that the specific device (you wish to use) has been tested clinically and shown to be effective,” said Dr. Peters. Attaching an actuator to the end of an endotracheal tube, for example, was demonstrated to be ineffective (Manthous CA, et al. Am Rev Respir Dis 1993;148:1567-1570).

Placing the nebulizer as close as possible to the ventilator and stopping humidification during nebulizer treatment each increased the percentage of albuterol delivered to the patient by 25% (Manthous CA, et al. Am Rev Respir Dis 1993; 148:1567-1570). Two other measures shown to optimize delivery of ß-agonist therapy — lowering peak flow to 40 L/min and raising inspiratory time (TI/TTotal) — are “very difficult to do when people are intubated for status asthmaticus,” Dr. Peters said.

A protocol for ß-agonist therapy in mechanical ventilation recommends the following (Corbridge TC, Hall JB. Am J Respir Crit Care Med 1995;151:1296-1316):

• Initiate therapy at 2 to 3 times the usual dose of albuterol used in a small-volume nebulizer. “This may be a unique place where levalbuterol has specific utility” because tachycardia is so common in intubated patients with status asthmaticus, said Dr. Peters.

• Follow the peak-to-pause or peak-to-plateau pressure gradient. “This peak-to-plateau pause actually represents airway resistance,” he said. A fall in the gradient of more than 15% suggests that the dose of ß-agonist therapy is adequate. A reduction of 15% or less dictates a dose increase in 1.25- or 2.5-mg increments until airway resistance falls or toxicity (tachycardia or intolerable tremor) develops.

• Continue drug therapy hourly until the obstruction resolves and mechanical ventilation can be discontinued.

“There is very, very little role for systemic b-agonist therapy,” he said. One paper reported that 60% of patients who failed to respond to 2 hours of inhaled medication showed an increase of 20% in FEV1 after receiving subcutaneous epinephrine (Appel D, et al. J Allergy Clin Immun 1989; 84:90-98). These patients generally had exacerbations for 1 week before hospitalization. Theoretically, severe mucus plugging could prevent nebulized medications from reaching the lower airways in these persons, said Dr. Peters.

Other therapies during hospitalization
Postdischarge systemic steroids should continue for 5 to 10 days, or until the patient reaches 70% of baseline FEV1 or PEFR values (Rowe BH, et al. Am J Emerg Med 1992;10:301-310).

Anticholinergic therapy should be initiated in the ED and continued until the patient is stable, or for at least 36 hours, Dr. Peters said. A study showed that giving ipratropium for at least 36 hours after admission significantly reduced length of hospital stay. All patients also received high-dose ß-agonist therapy (Brophy C, et al. Thorax 1998;53: 363-367).

In another trial, adding ipratropium to albuterol in moderately severe to severe asthma patients resulted in 20% greater improvement in PEFR, and 48% greater improvement in FEV1, than did albuterol alone. Combination therapy also reduced risk of hospitalization by 49% compared to albuterol monotherapy (Rodrigo GJ, Rodrigo C. Am J Respir Crit Care Med 2000;161;1862-1868).

Ipratropium combined with albuterol has an additive benefit within 1 minute; its effect appears to peak with in 19 to 20 minutes (Bryant DH, Rodgers P. Chest 1992;102:742-747). It therefore should be given every 20 to 30 minutes initially, then every 1 to 4 hours once the patient is stabilized. There is little or no role for ipratropium in chronic asthma therapy, he said.

Secondary therapeutic options include magnesium sulfate, theophylline, helium-oxygen therapy, and noninvasive positive pressure ventilation. Available data do not support routine use of magnesium (Ho, AM-H, et al. Chest 2003; 123:882-890). In isolated cases, when patients do not respond to initial therapy, magnesium could be considered.

Similarly, there is no benefit to theophylline in early treatment of severe asthma (Gluckman TJ, Corbridge T. Current Opin Pulm Med 2000;6:79-85). Most studies using this agent involve initiation of therapy in the ED, with little data in hospitalized and ICU patients. Dr. Peters said that his institution recommends considering theophylline if a patient fails to respond to triple therapy (ß-agonist, steroid, anticholinergic) within the first 24 hours in the ICU, or within the first 48 hours as an inpatient.

A review of data does not support routine use of helium-oxygen mixtures, said Dr. Peters (Rodrigo GJ, et al. Chest 2003;123:891-896). A study reporting significant improvement in spirometric measures with a “unique system” of running 80% helium/20% oxygen for 30 minutes during albuterol nebulization (Kress JP, et al. Am J Respir Crit Care Med 2002;165:1317-1321).

A nonpharmacologic alternative is noninvasive positive pressure ventilation. The first controlled study of this option found that nasal BiPAP led to a greater rise in FEV1 (53% vs 28%) and reduced admission rate (17.6% vs 62.5%). Patients (N = 30) from the ED with FEV1 < 60% after one albuterol treatment were randomized to either nasal BiPAP or sham BiPAP (Soroksky A, et al. Chest 2003;123:1018-1025). “It’s an intriguing study,” Dr. Peters said. “We find that many asthmatics don’t tolerate the feeling of claustrophobia, of putting a BiPAP device on their nose.”

Current guidelines urge intubation of patients when clinically indicated. Failure to intubate is associated with anoxic injury, said Dr. Peters. “Cardio-pulmonary arrest is a far greater risk than early intubation,” he added.

Health Economics of AECOPD

“The global impact of COPD is pretty straightforward: it’s the second most common chronic, non-communicable disease in the world with some 600 million cases worldwide and associated with about 3 million deaths per year,” said Dr. Grossman, who returned to the podium for the final presentation. In 1990, COPD was the 12th largest burden of disability globally and the 6th leading cause of death, globally. With the increased population of aging smokers, it is now projected that by the year 2020, COPD will be the 5th leading reason for disability and the 3rd leading cause of death (Science. 1996;174:740; Lancet .1997;349:1498). In the United States, 117,522 deaths were attributed to COPD in 2000, equally among men and women. Previously this was thought to be a ‘man’s disease”, but we are starting to learn that women are more susceptible to tobacco smoke and Dr. Grossman said that over the next few years we will see more women than men actually dying from COPD.

Cost of COPD
Estimates of direct and indirect costs of lung diseases in the United States are shown in Table 1.

As shown, the total cost of COPD in 2000 was $30.4 billion and highest among the common lung diseases (asthma, pneumonia, tuberculosis). The high direct costs ($14.7 billion) of COPD are mostly due to the hospitalization and management of patients who have exacerbations. “The major driver of costs in this disease is that of treatment failure, leading to hospitalizations where the costs are 10- to 100-fold higher than the treatment in the outpatient setting,” stated Dr. Grossman. In a study by Hillman et al. examining the annual cost of COPD treatment in mild, moderate, and severe COPD, the costs were found to be $1681, $5037, and $10,812, respectively, with the majority of the costs in moderate and severe cases due to hospital costs (Chest. 2000;118:1278).

Interventions that can prevent exacerbations or stretch out the time between exacerbations can improve the patient’s health and lower medical costs. Miravitlles and colleagues looked at the distribution of COPD costs and attributed 63% of costs to treatment failure (Chest. 2002;121:1449). “When you look at the piece that drives the costs, it’s the cost of hospitalization and any intervention, including antibiotics, that will prevent hospitalization, will save the system money,” said Dr. Grossman. To illustrate this point, Dr. Grossman mentioned a study by Destache et al. (J Antimicrob Chemother. 1999;43{suppl A}:107). In patients who received first- line antibiotic therapy (amoxicillin or tetracycline) the average cost of treatment was $10.30 and 18% of the patients required hospitalization due to AECOPD relapse at an average cost of $942 per hospitalization. In contrast, patients who received 3rd line treatment (co-amoxiclav, azithromycin, or ciprofloxacin) at an average cost of $45 had a failure rate of only about 6% with each hospitalization averaging only $542. In patients receiving 2nd line treatment (cephradine, cefuroxime, cefaclor, or cefprozil), the average drug cost was $24 and 16% of the patients required hospitalization at an average cost of $563.

The net result is that choosing the right antibiotic can reduce exacerbations, relapse rates, and costs. “In outpatient studies, the treatment failure rate is up to one in three if the wrong antibiotic is chosen for the wrong patient,” stated Dr. Grossman (JAMA. 1995;274: 1852; Ann Emerg Med.1991;20:125; Chest. 2000;117:1345).

Concluding remarks
COPD continues to be a major cause of mortality and morbidity and the main precipitating factor is acute exacerbations. Frequent exacerbations are associated with a worsening quality of life and more rapid loss of lung function. “Finally, patient’s therapy needs to be tailored to their disease severity, previous antibiotic history, the risk of treatment failure and their ability to tolerate treatment failure,” concluded Dr. Grossman, adding, “choose an appropriate therapy for that individual patient.”