SUMMARY OF KEY POINTS

• Asthma is an inflammatory airways disease and all but the mildest attacks require treatment with corticosteroids; this is also true for asthmatic exacerbations of chronic obstructive pulmonary disease (COPD).

• For exacerbations of asthma or COPD, preferentially start an inhaled bronchodilator drug (beta-adrenergic or anti-cholinergic) along with the oral or intravenous corticosteroids. Theophylline is no longer a first-line drug in the treatment of asthma or exacerbations of COPD; it is a second or third-line drug for this indication.

• The role of anti-leukotriene drugs in chronic asthma management is not yet clearly defined. These drugs are not to be used for therapy of acute asthma exacerbations.

• When air flow improvement is expected with treatment, monitor some measurement of air flow: peak flow or spirometry. Arterial blood gases are not necessary to manage most asthmatics; they are most useful when peak flow is repeatedly less than 35% of predicted.

6 DRUG GROUPS FOR ASTHMA/COPD

Unlike other chronic conditions (hypertension, arthritis, peptic ulcer disease, psychiatric depression), asthma is an affliction for which there have been few new drugs. Only four types of drugs are currently available to treat an acute asthma attack, or the air flow obstruction of a COPD exacerbation (Table). Three drug types are bronchodilators and one is anti-inflammatory. The most recently introduced drug type for treatment of acute asthma, corticosteroids, came into clinical practice about 1950.

Mediator-release inhibitors (cromones), first introduced in the early 1970s, include cromolyn sodium (Intal) and nedocromil (Tilade); however, they are used only to prophylax against airway exacerbations, not to treat them.

A whole new class of anti-asthma drugs is now available -- the anti-leukotrienes. There are currently two types, based on mechanism of action: leukotriene-receptor antagonists and leukotriene synthesis inhibitors. While the anti-leukotrienes are not indicated for acute asthma exacerbations, they are useful in treating chronic asthma, and in lessening the need for other types of medication. The fact that they are in pill form promises much better compliance than with inhaled medication.

Leukotrienes are endogenous molecules formed by the breakdown of a membrane constituent, arachidonic acid, via the 5-lipoxygenase enzyme pathway. This pathway produces several different leukotrienes that result in both bronchoconstriction and the inflammatory response characteristic of asthma: increased vascular permeability, increased mucous production, decreased ciliary transport.

Leukotriene-receptor antagonists (LTRAs) block the broncho-constrictive effects of leukotriene D₄ (LTD₄), in both the early-phase and late-phase asthmatic response, and inflammation in the late phase response. Leukotriene synthesis inhibitors attenuate the asthma-causing effects of leukotrienes. In clinical trials both types of anti-leukotriene drugs have shown beneficial results in asthma.

The anti-leukotrienes currently on the market are:

• ZAFIRLUKAST, a leukotriene-receptor antagonist, brand name ACCOLATE; dose 20 mg bid
• ZILEUTON, a leukotriene-synthesis inhibitor, brand name ZYFLO; dose 600 mg qid.

• MONTELUKAST, a leukotriene-receptor antagonist, brand name SINGULAIR, dose 10 mg qd for adults, 5 mg qd for ages 6-14.

Zileuton, but not Zafirlukast or Montelukast, requires liver function monitoring for the first few months of therapy.

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The anti-leukotrienes are an evolving group of drugs and it remains unclear what their future role will be in treating the universe of asthma patients. Despite the paucity of new drugs for asthma, there have been some improvements in therapy over the last 20 years, discussed below and on the next few pages.

A shift in our understanding of the asthma attack, from a 'bronchospastic' disease to an 'inflammatory' disease. A generation ago the predominant pathophysiology of acute asthma was felt to be bronchospasm: smooth muscle contraction causing airway narrowing. Now the main pathophysiology of the attack is understood as an inflammatory response: an outpouring of eosinophils, mucosal edema, and mucous cell hypertrophy with production of thick mucous. All severe asthma attacks, including asthmatic exacerbations in patients with underlying COPD, are characterized by bronchial inflammation. "Inflammation drives the bronchospasm," not the other way around.

Because eosinophils are so prominent during the asthmatic attack (present in both blood and sputum), asthma is often characterized as "eosinophilic bronchitis." The inflammation must be treated, which means using corticosteroids. To treat the bronchospasm without treating the inflammation has been likened to treating appendicitis with pain medication only. Although eosinophils are not a prominent feature in COPD exacerbations, inflammation is often present as well. Steroids are the only available anti-inflammatory drug effective in acute asthma and the airway obstruction of COPD exacerbations. Inhaled steroids are useful for prophylaxis of COPD and asthma, but not for relieving symptoms of an acute attack. For the acutely symptomatic patient with pure asthma or a COPD exacerbation, either oral or IV steroids must be used.

A shift to using inhaled beta-adrenergic or anticholinergic drug along with the steroids. We have achieved better understanding of inhaled beta-adrenergic drugs and how to use them. Metered-dose inhalers can be used with spacers to enhance drug delivery, and many patients are now using machine nebulizers at home, a method that is almost guaranteed to deliver an effective drug dose into the airways. Atrovent, the only available anticholinergic inhaled drug, is another type of bronchodilator to try in some patients. Patients who cannot use hand held inhalers can be given a spacer device, of which several are on the market. Alternatively, some patients may benefit from beta-adrenergic tablets, although these tend to have more side effects than inhalation therapy.

A Canadian study (Spitzer 1992) correlated asthma morbidity and mortality with use of inhaled albuterol and fenoterol (the latter drug is not available in the U.S.). The problem with this study is that there is no way to know if the patients died because they were sicker (and used more inhaled beta-adrenergic drug as a result), or if they died because they used too much of the drug. Most pulmonologists seem to feel the former explains the excess deaths, and that frequent use of beta-adrenergic inhalers is a marker for severe asthma, not the cause of morbidity or mortality.

Limiting the role of theophylline in the treatment of asthma and COPD. Theophylline and other methyl xanthines used to be first-line therapy for asthma and COPD. In the 1980s theophylline became even more popular with the advent of long acting oral preparations and rapid measurement of drug levels. In the last few years however, use of theophylline preparations has declined. Today theophylline is no longer considered first line therapy for COPD or asthma. There are several reasons for the fall in theophylline usage.

a) DOUBTS ABOUT THEOPHYLLINE'S EFFICACY. Theophylline is now perceived as a relatively weak bronchodilator, one that adds little to inhaled beta-adrenergic agents in the acute setting. On the other hand, a study by Wrenn et al (Ann Intern Med, 1991) found that IV aminophylline, used in the ER for acute bronchospasm, played a role in preventing hospitalization of patients. However, the aminophylline-treated group demonstrated no greater improvement in airflow than the placebo-treated group. As both the study authors and an accompanying editorial by McFadden point out, this unexpected finding (prevention of hospitalization) needs to be reconfirmed by others before IV aminophylline can again be routinely recommended for acute bronchospasm.

b) CONCERN ABOUT SIDE EFFECTS. Theophylline carries the potential for serious toxicity. Many patients who use the long-acting oral preparations report GI upset and palpitations. Theophylline commonly causes tachycardia and can lead to serious arrhythmias even at serum concentrations considered to be therapeutic (see Bittar 1991). In a patient taking theophylline, multi-focal atrial tachycardia (MAT) and other supraventricular arrhythmias should be considered as due to theophylline until proven otherwise. In addition to potential toxicity, intravenous aminophylline requires a bulky pump (with stand) for drug administration. Also, blood tests are necessary to monitor drug levels. The result is often much patient discomfort, with no proof of additional efficacy over corticosteroids and inhaled beta-adrenergic drugs.

c) PROBLEMS WITH DRUG LEVEL MONITORING. Theophylline has such a narrow therapeutic range that drug level monitoring is necessary to assure a beneficial effect and to avoid toxicity. However, drug levels are tricky to use, in part because of theophylline's variable pharmacokinetics. Many drugs and clinical conditions can affect theophylline metabolism, and the drug has peaks and troughs. Food in the stomach and smoking also affect theophylline clearance. The previous textbook "therapeutic level" of 10-20 mgm/L was based on young patients with mild asthma; elderly patients and those with liver disease or congestive heart failure invariably require less drug; the new therapeutic range is now considered to be 5-15 mgm/L. These points raise the question: If the patient can benefit from a drug for which levels are not necessary to measure, why bother with theophylline?

As theophylline's side effects became better appreciated, physicians also came to understand the inflammatory nature of asthma and the importance of anti-inflammatory (steroid) therapy. Theophylline is a weak bronchodilator with minimal anti-inflammatory activity. It is now considered a 2nd- or 3rd-line drug, and rarely (if ever) a first line drug for asthma or COPD exacerbations. A trial of theophylline is reasonable in patients who remain symptomatic despite a trial of steroids and inhaled bronchodilators. An excellent review article on the current position of theophylline is by Vassallo and Lipsky (1998).

Understanding the importance of objective air flow measurements. All acute asthmatics, especially those who present to an emergency room or for hospitalization, should have some measurement of air flow. Clinical assessment of severity is unreliable except for asthmatics in obvious acute distress. A brief trial of bronchodilator therapy can make the asthmatic feel much better, but the proof is in some objective measurement of air flow. Patients can have severe limitation without seeming very short of breath. Measurement of air flow can be peak flow or full spirometry. The peak flow is easily done with a hand-held device and requires that the patient blow out with maximal effort for less than one second. Normal range for peak flow in average-sized adults ranges between 400 and 600 L/min.

Without objective measurement, there is no way to know just how severe the problem is. Generally, patients with peak flow less than about 35% of predicted (e.g., less than 150 L/min in average-sized adult) are at risk for CO₂ retention, and should have a blood gas measurement. Patients with peak flow greater than 50% predicted (e.g., > 200 L/min) are not at risk for CO₂ retention, and do not need a blood gas for assessment of severity.

NOTE: Patients with fixed air flow obstruction may not improve their peak flow (or other measurements of airflow) with treatment. However, the only way to know is to measure airflow, or to have past experience with the same patient in the same clinical situation. In fact, the distinction between "true asthma" and "COPD with an asthma exacerbation" is that in the former air flow obstruction improves toward normal, whereas the latter does not. If you know a patient has fixed air flow obstruction and will not show significant improvement in air flow measurements (despite symptomatic improvement), there is no reason to push for repeated measurements of peak flow. However, if you don't know this information in a given patient, it is important to monitor some measurement of air flow.

After the asthma attack has subsided, an objective test of air flow should be obtained before therapy is lessened or discontinued, to make sure the air flow has improved to normal or near normal. In the true asthmatic, dose and duration of steroids should be guided not just by symptoms but by objective air flow measurement. Again, the difference between COPD and asthma is largely defined by the degree of reversibility. If the asthmatic does not reverse fully his or her airway obstruction, the condition is no longer asthma it is COPD.

Under-treated asthma is one cause of COPD. The only way to know if you are dealing with asthma or COPD is to check pulmonary function when the patient has been clinically optimized on therapy.

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Despite our better understanding of asthma and its treatment, the number of asthma deaths has increased yearly over the past decade. Asthma affects over 100 million people worldwide, with widely varying prevalences, from high in the U.S. and United Kingdom, to low in Scandinavia, Japan and India. The increase in the number of asthma deaths in the U.S. (approximately 4000/year) and other western countries is somewhat of a paradox, since we are more aware of the role of inflammation and how to treat it. The cause(s) for the increased mortality is a mystery. Some implicated causes include: over-reliance on beta-adrenergic inhalers to the exclusion of anti-inflammatory drugs (by both patient and doctor); patient non-compliance; concomitant substance abuse; and a statistical reflection of increased asthma incidence due to environmental factors. Regardless of the cause(s), it is important to realize that asthma can be fatal, but with proper diagnosis and therapy the risk of death can be greatly minimized.

BIBLIOGRAPHY (listed in chronologic order)

Lam A, Newhouse MT. Management of asthma and chronic airflow limitation. Are methylxanthines obsolete? Chest 1990;98:44-52.

Newhouse MT. Is theophylline obsolete? Chest 1990;98:1-3.

Sessler CN. Theophylline toxicity: Clinical features of 116 consecutive cases. Amer J Med 1990;88:567-76.

Wrenn K, Slovis C, Murphy F, Greenberg RS. Aminophylline therapy for acute bronchospastic disease in the emergency room. Ann Intern Med 1991;115:241-47. (See also editorial, pages 323-24 same issue.)

Bittar G, Friedman HS. The arrhythmogenicity of theophylline. Chest 1991;6:1415-20.

Molfino NA, Nannini LJ, Martelli AN, Slutsky AS. Respiratory arrest in near-fatal asthma. N Engl J Med 1991;324:285-8.

Spitzer WO, Suissa S, Ernest P, et al. The use of B-agonists and the risk of death and near death from asthma. New Engl J Med 1992;326;501-6.

McFadden, ER Jr. Dosages of corticosteroids in asthma. Am Rev Resp. Dis 1993;147:1306-1310.

McFadden ER, Gilbert IA. Asthma. New Engl J Med 1992:327:1928-1937.

Management of Asthma During Pregnancy. National Institutes of Health, U.S. Department of Health and Human Services, NIH Publication No. 93-3279, 1993.

Goldstein RA, Paul WE, Metcalfe DD, Busse WW, Reece ER. NIH Conference: Asthma. Annals Int Med 1994;121:698-708.

Emerman CL, Cydulka R. A randomized comparison of 100-mg vs. 500-mg dose of methylprednisolone in the treatment of acute asthma. Chest 1995:107:1559-1563.

Pauwels RA, Joos GF, Kips JC. Leukotrienes as therapeutic target in asthma. Allergy 1995;50:615-622.

Woolcock AJ. Corticosteroid resistant asthma: definitions. Resp and Crit Care Medicine 1996 (Supplement); 154:S45-S48.

Busse WW, McGill K, Jarjour NN. Current management of asthma patients with corticosteroid resistance. Resp and Crit Care Medicine 1996 (Supplement);154:S70-S74.

Levenson T, Greenberger PA, Donghue ER, Lifschultz BD. Asthma deaths confounded by substance abuse. An assessment of fatal asthma. Chest 1996;110:604-610.

Drazen JM, Israel E, Boushey HA, et. al. Comparison of regularly scheduled with as-needed use of albuterol in mild asthma. New Engl J Med 1996;335:841-847.

Smith, Lewis J. Leukotrienes in asthma (Review). The potential therapeutic role of antileukotriene agents. Arch Intern Med 1996;156:2181-2189.

Suissa S, Dennis R, Ernst P, et. al. Effectiveness of the leukotriene receptor antagonist Zafirlukast for mild-to-moderate asthma. A randomized, double-blind, placebo-controlled trial. Annals Int Med 1997;126:177-183.

Rebuck A, O'Byrne PM. Asthma management: Perspectives and paradigms in a changing environment. Chest Supplement, Volume 111, No. 2, February 1997.

McFadden ER, Warren EL. Observations on asthma mortality. Annals Int Med 1997;127:142-147, July, 1997.

Guidelines for the Diagnosis and Management of Asthma. National Heart, Lung, and Blood Institute, National Institutes of Health, 1997; Bethesda, Maryland 20892; 1997.

Vassallo R, Lipsky J. Theophylline: Recent advances in the understanding of its mode of action and uses in clinical practice. May Clin Proc 1998;73:346-354.

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QUIZ - Dx & Rx of SEVERE ASTHMA/COPD EXACERBATIONS

Lawrence Martin, M.D. Either complete the sentence as indicated or choose the single best answer.

1)The % of the U.S. population with asthma is approximately ______________%.

2)Eosinophilia in the wheezy patient most likely indicates asthma

a) of any origin

b) of allergic origin

c) of infectious origin

d) complicated by parasite infection

3) True or False: Asthma may lead to COPD (fixed airway obstruction) and COPD may lead to asthma (a reversible component of airflow obstruction).

4) The most significant difference between the management of asthma and COPD is (choose one:)

a) type of drugs used for treatment

b) dose of drugs used for treatment

c) degree of expected improvement in air flow

d) expectation of improvement in patient symptoms.

e) length of hospital stay

5) How many distinct drug groups are available to treat asthma? _______ How many to treat an acute asthma exacerbation? _______ (A drug group is one whose members all have the same or similar pharmacologic action, e.g., calcium channel blockers, beta blockers, serotonin antagonists, etc.)

6) The last new drug group introduced to treat asthma was __________________ in the year ____________.

7) The number of different brand names of bronchodilator drugs in the PDR is about ________________.

8) The best single test to follow in managing most cases of severe asthma in the emergency room or hospital wards is _________________.

9) The role of tranquilizers in managing the patient with a severe asthma attack is ______________________.

10) In managing acute asthma attacks, theophylline is considered:

a) a first line drug

b) a second line drug

c) not at all.

11) PaCO₂ starts to go up in acute asthma exacerbation when the peak flow is approximately __________% of predicted.

12) A patient with acute asthma should be intubated when

a) the PaCO2 goes above 50 mm Hg.

b) the PaCO2 goes above 60 mm Hg.

c) the pH is less than 7.25.

d) there is worsening respiratory failure and increasing fatigue.