BRONCHIAL
ASTHMA
ABSTRACT.-Asthma is one of the most common respiratory problems in modern industrialized countries, affecting over 5% of the population. It affects all age groups from infants to senior citizens, and mortality rates Rom asthma appear to be increasing during the past few years in the United States as well as in other industrialized countries. Asthma tends to occur in families, associated with other allergic disease, and may be induced by a wide variety of environmental antlgens, most commonly inhaled allergens such as pollen and dust. Bronchial challenge with a specific allergen results in an early bronchospastic response with a relatively brief duration, and in a significant number of patients there is a late response with onset after 3 to 4 hours, lasting hours to days. This late response is associated with a bronchial hypersensitivity reaction, which is demonstrable by nonspecific challenge testing in the laboratory. During the period of bronchial hyperresponsiveness patients are prone to develop attacks following exposure to a wide variety of “triggers,” including cold air, fmnes, or cigarette smoke. The current approach to management of patients with asthma emphasizes prevention, with avoidance of specific allergens when possible, and chronic use of anti-inflammatory agents including corticosteroids and cromolyn sodium. The goal is to decrease the bronchial hyperresponsiveness. Management of the acute asthma attack consists of bronchodilator therapy, primarily with inhaled beta-adrenergic agonists, and administration of oral or systemic corticosteroids if the attack is not rapidly relieved. Additional therapeutic agents inclutig theophylline and anticholinergics may be useful in some situations. Response to therapy during the first couple of hours in the emergency room is the most important predictor of the course of the acute attack, and patients who 142
LJM, March
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have not responded significantly after 2 hours of maximum therapy are candidates for hospital admission or prolonged emergency room observation. The goal of acute therapy is to wean the patient from intravenous drugs and place him or her on rapidly tapering doses of oral prednisone while hihiating a vigorous program of preventive therapy. Follow-up observation, both in the office and in the patient’s home, is vital and involves extensive patient education and objective testing of peak airflow. In general, the course of asthma is relatively benign compared with other obstructive ah-way diseases; however, significant mortality exists, especially in older patients and those with late-onset asthma. IN BRIEF Asthma affects over 5% of the total population of industrialized countries, involving all ages from infants to the elderly. It is best defined as a syndrome that includes a variety of clinical patterns from mild exercise-induced bronchospasm to severe chronic disability and bouts of acute respiratory failure. Mortality rates from asthma in several industrialized countries, including the United States and Canada, have increased over the past decade. The reasons for this are not clear and may involve a variety of factors, including improved reporting. However, one possibility is that the emphasis on bronchodilator therapy to the exclusion of avoidance techniques and anti-inflammatory agents may explain in part the increased mortality. While the increased mortality affects all age groups, it appears to be most marked in older patients. PATHOPHYSZOLOGY It has long been known that asthma, like other allergic diseases, has a familial predisposition. The mechanisms of inheritance have not been elucidated; however, there appear to be inherited variations in cells and cell mediators that cause them to behave differently in different populations. Recent evidence indicates that increased bronchial hyperreactivity may precede the onset of asthma by several years in patients from families with a high incidence of allergic diseases. There are a number of sensitizing agents, the most prominent of which are inhaled allergens, such as pollens, dust, and industrial agents. Other environmental agents that produce increased airway hyperresponsiveness include viral respiratory infections and toxic DM, March
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143
fumes. Once bronchial hyperreactivity is present, a variety of “trigger” agents may produce acute bronchospasm; these include cigarette smoke, exercise, and cold air. The acute response to an inhaled allergen occurs almost immediately and persists for perhaps an hour or so. In a significant number of patients with asthma, this acute response is followed by a delayed response with onset after approximately 3 to 4 hours and persistence for several hours or even days. This late asthmatic response has been related to the development of bronchial hyperresponsiveness and is a precursor of recurrent asthmatic attacks. The early bronchospastic response is a classic antigen-antibody reaction, wherein mast cells are initially sensitized by “reagin” or antigen-specific IgE antibody, which attaches to the cell wall. When this sensitized cell is re-exposed to the specific antigen, mediators are released, including histamine, leukotrienes, and pneumotaxic factors, that attract inflammatory cells to the area. It is the convergence of these inflammatory cells that appears to correlate with the late asthmatic reaction. Cells associated with the late asthmatic reaction include neurophils, lymphocytes, basophils, epithelial cells, and alveolar macrophages. Among the most important cells involved in the late asthmatic reaction is the eosinophil, which migrates to the bronchial wall in response to chemotactic substances released by macrophages and other cells, and is stimulated by mediators such as platelet activating factor to release a number of substances including major basic protein, which cause inflammation in the bronchial wall. Late effects of the asthmatic reaction include sloughing of mucosal cells, which in turn causes a loss of the protective effects of the epithelium and exposure of irritants to nerve fibers. During the acute asthmatic attack, there is edema of the bronchial wall and the mucus in the bronchial lumen becomes thick and tenacious. The major physiologic abnormality is airway obstruction with air-trapping and hyperinflation. This is manifested by a decrease in peak flow rates and vital capacity with an increase in residual lung volume and hyperinflation on the chest film. With the diffuse abnormality in distribution of ventilation there is progressive ventilationperfusion mismatching, with mild to moderate hypoxemia and secondary hyperventilation probably related to stimulation of neural receptors . CLINICAL
FINDINGS
Symptoms during the acute attack consist of dyspnea, wheezing, and cough in varying combinations. Physical findings include hyperinflation of the chest, tachypnea, tachycardia, sweating, wheezing, and decreased breath sounds. Other significant abnormalities dur144
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ing severe asthma attacks are sternomastoid muscle contractions, presence of a pulsus paradoxus, and changes in mental status indicating progressive fatigue. Symptoms and physical findings have been shown to correlate poorly with the severity of the airways obstruction and it is necessary to obtain objective tests of peak flow, either l-second forced expiratory volume (FEV,) or peak expiratory flow rate (PEFR), to assess the severity of the acute attack. Arterial blood gases show mild to moderate hypoxemia, which is correctable with increased FIO,, and hyperventilation with low PaCO,. The presence of a normal or increased PaCO, value during an acute asthma attack is an ominous finding portending exhaustion and impending respiratory failure. PvfANAGEMENT
Management of the patient with asthma involves two major goals; first, the prevention of the acute attacks and second, the treatment of acute attacks when they occur. Prevention of asthma attacks ideally is achieved by avoidance of the responsible antigens. This is rarely possible except in two situations, pet allergies and occupational asthma. A careful history and use of detailed questionnaires will help determine any avoidable responsible agents. Skin test reactions may help to confirm the presence of immediate sensitivity to an allergen. If symptoms such as seasonal allergy or wheezing on exposure to a specific agent are reported and if allergens identified by skin tests are compatible with the history, a trial on densensitization may be indicated, especially in young patients. However, success has been proved with only a few well-standardized antigens, including house dust mite and cat dander antigen. Desensitization is associated with inconvenience, cost, and sometimes serious reactions and should be employed only if demonstrated to be beneficial. Several drugs may cause bronchospasm and these include beta-adrenergic blockers and angiotensin-converting enzyme inhibitors. A history of concomitant drug therapy is an important aspect of the patient’s record. Pharmacotherapy consists of both bronchodilators and agents that decrease bronchial hypersensitivity. The principal bronchodilator compounds are the beta-adrenergic agonists, especially the beta,specific agents, including albuterol, metaproterenol, terbutaline, pirbuterol, and bitolterol. These compounds are relatively equivalent in relation to their effectiveness and duration of action. They are available in various preparations including metered dose inhaler (MDI), nebulizer solution, oral tablets, powders, and parenteral agents. The best method of administration of these agents is by inhalation, usually by MDI, in which case they are extremely effective with few or OM, March
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no side effects. Additional bronchodilator agents currently used in the treatment of asthma are the methylxanthine compounds (theophylline, aminophylline) and the anticholinergic agent, ipratropium bromide. These agents clearly have a lesser role in the management of asthma than the beta-adrenergics; however, they may be useful in some patients because of synergy and their longer duration of action. Sustained-released theophylline or a sustained-release oral beta-adrenergic agent may be useful at bedtime in patients with prominent nocturnal symptoms. The principal anti-inflammatory agents used for management of asthma are corticosteroids and cromolyn sodium. Corticosteroids are vital in the therapy of severe asthma attacks and should be initiated early and in adequate dosages; however, because of their severe side effects when given systemically for long periods, patients should be weaned from them as soon as possible. Inhaled corticosteroid preparations are increasingly accepted as first-line therapy in asthma, and are generally given via MD1 two to four times daily on a regular, long-term basis. Cromolyn. sodium is an alternative antiinflammatory agent for some patients with asthma, especially younger patients with extrinsic disease. Approximately half or more of patients will respond to cromolyn therapy and it should be attempted in patients with uncontrolled or recurrent symptoms. Its major benefit is that it has essentially no side effects; however, it must be given by inhalation several times a day and requires considerable patient cooperation. Additional anti-inflammatory drugs that are presently being investigated include antihistamines, methotrexate and other immunosuppressive agents, and gold salts. COURSE AND PROGNOSIS The course and response to therapy following an acute asthma attack are quite favorable, especially when compared with the other chronic obstructive lung diseases. With adequate therapy, response tends to be fairly complete, allowing for long-term follow-up on an outpatient basis. The key to follow-up care is supervision, and this should include objective tests of airflow in the office or clinic, and preferably in the patient’s home. This can be done by means of peak flow meters and daily records that patients can be taught to maintain on their own. Patients should be encouraged to seek help whenever they find it necessary and to report changes in their symptoms and flow rates to the physician as soon as possible. The need for emergency room care or hospitalization should be considered a failure of long-term care and should be followed by a complete revision of maintenance therapy. Mortality in asthma occurs in all ages, but peak mortality has been 146
DA4, March
19%
shown to occur in older patients, especially those cent onset of their disease. Thus, the most likely asthma would be a middle-aged or older person asthma for 10 years or less, especially if he or she attacks or has required steroid therapy during the
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who have had reperson to die of with a history of has had frequent previous year.
147
Ronald B. George, M.D. graduated from medical school at Tulane University School of Medicine in New Orleans, Louisiana, where he also served his medical residency and his Fellowship in Pulmonary Diseases. He continued on the faculty there until 1972, when he came to Shreveport, Louisiana to develop a new section of Pulmonary Diseases of the Department of Medicine at Louisiana State University Medical School. He is now Professor and Deputy Head of the Department of Medicine and Chief of the Section of Pulmonary and Critical Care Medicine.
Michael W. Owens, M.D. graduated from the Louisiana State University School of Medicine in Shreveport. He served a medical residency in Internal Medicine and a Pulmonary and Critical Care Fellowship at the same institution. He is currently an Assistant Professor of Medicine in the Section of Pulmonary and Critical Care Medicine, Department of Medicine, Louisiana State University School of Medicine. 148
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BRONCHIAL
ASTHMA
Asthma is one of the most common respiratory diseases, with an incidence of more than 5% of the total population in industrialized countries. Attempts to develop a definition for this common problem that would include all of its variations have persisted up until the present. Those who would define asthma as a disease are frustrated by its many variations, from occasional transient attacks of bronchospasm occurring after exercise or during the pollen season, to severe “intrinsic” or late-onset asthma, resulting in chronic disability. Furthermore, the factors that precipitate asthma attacks are diverse and involve a variety of mechanisms. There are a number of problems inherent in defining asthma as a distinct disease; alternatively, it might be better defined as a syndrome in which a number of mechanisms cause a common resp0nse.l An accepted definition of the asthma syndrome is included in an official statement of the American Thoracic Society, published in 1987.2 This statement defines asthma as a clinical syndrome characterized by increased responsiveness of the tracheobronchial tree to a variety of stimuli. The major symptoms are episodes of dyspnea, wheezing, and cough varying from mild and almost undetectable to severe and unremitting. The primary physiologic manifestation is variable airway obstruction, taking the form of spontaneous fluctuations in the severity of obstruction, substantial improvement following bronchodilators or corticosteroids, or increased obstruction caused by drugs or other stimuli. Histologically, patients with fatal asthma have evidence of edema of the bronchial mucosa; infiltration of the bronchial walls with inflammatory cells, especially eosinophils; and shedding of epithelium with obstruction of peripheral airclinical component of this ways with mucus.’ The most important definition is its emphasis on a change in airway resistance over time, the characteristic that separates asthma from the other chronic obstructive airway diseases. The syndrome of asthma is more than just reversible airflow obstruction; a working definition of asthma should include the underlying airway inflammation with its physiologic correlate, bronchial hyperresponsiveness. Reversible airway obstruction may be related not only to exposure to natural airborne allergies, but also to inhaled DA4, March
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occupational chemicals such as toluene diisocyanate and reactions following exposure to drugs such as aspirin.3 Infectious agents such as viruses and fungi may also produce bronchial hyperreactivity, through acute or chronic alteration of the bronchial wall and/or the immune system. There is evidence that the prevalence and severity of asthma and the number of deaths from asthma are increasing in several industrialized countries where accurate records are available.4-7 The gradual annual decline in deaths from asthma in the United States, as reported by the National Center for Health Statistics, ended in 1978.8 Since then there has been a progressive increase in the total number of deaths from asthma as well as in the number of deaths per 100,000 of population (Fig 1). As noted in Figure 2, while mortality has remained relatively stable in children, the increase has occurred primarily in patients older than 15 years. There was a revision in the international classification of diseases code that may have accounted for at least part of the increase in 1979; deaths from Total
Population
Line Chart for columns: X,Y,
1.8
1966
Deaths/Year-100,000
1968
1970
1972
1974
1976
1978
1980
1982
1984
1986
Year
FIG 1. Deaths from bronchial asthma per 100,000 population in the United States, 1968- 1984. (From Robin ED: Death from bronchial asthma. Chest 1988; 93:614. Used by permission.) 160
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Age-adjusted Oall
Death Rate for Asthma ~55-64 a >85
05-14
l 7.5-84
e 65-74
.; 1966
1968
1970
1972
1974
1976
1978
1980
1982
1984
1986
Year
FIG 2. death rates from bronchial asthma in the United States, 1968-1984. (From Robin ED: Death from bronchial asthma. Chest 1988; 93:614. Used by permission.)
Age-specific
asthmatic bronchitis, which were previously assigned to bronchitis, were reassigned to asthma. However, since this revision the increase has continued. The increase in mortality from asthma is especially disturbing because it has occurred despite significant improvements in therapeutic agents and an increase in the amount of prescribed asthma therapy.’ Indeed it may be that our reliance on the potent bronchodilator agents currently available has caused a change in the approach to asthma, which may be responsible for some increase in mortality. Prior to availability of these effective bronchodilator agents, physicians relied on such preventive measures as household cleansing, avoidance of irritants, and desensitization therapy. As the new agents became available, these measures may have been abandoned as physicians switched their patients to drugs that produce rapid symptomatic relief. Recently there has been a resurgence of interest in the late asthmatic response and persistence of symptoms for OA4, March 1991
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hours ago.”
to days after an acute attack, as noted
originally
100 years
CLASSIFICATION A proposed classification for the asthma syndrome is shown in Table 1. Allergen-induced or “extrinsic” asthma can occur at any age, but is more often seen in younger patients. It tends to be seasonal, with prolonged symptom-free periods. Extrinsic asthma may be induced not only by such inhaled allergens as house dust, pollens, and spores, but by occupational exposure or viral respiratory infections. Once the bronchial inflammation is present, subjects are prone to bronchospasm during exercise, inhalation of cold air, or hyperventilation. Irritants such as cigarette smoke and air pollution may also initiate an attack in susceptible patients. TABLE 1. Classification of the Asthma Svndmme
Allergic asthma
Asthmatic bronchitis
Occupational
asthma
Drug-induced
asthma
Allergic bronchopulmonaly aspergillosis
Synonyms
Clinical Characteristics
Extrinsic asthma Exercise-induced asthma Childhood asthma Seasonal asthma Late-onset asthma Intrinsic asthma Perennial asthma
Early onset Intermittent symptoms Rapid response to therapy May decrease with age Adult onset (older than age 301 Progressive decrease in FEV, Partial response to therapy Symptoms related to work May persist after changing jobs Partial response to therapy
Occupational airways disorders Industrial bronchitis Reactive airways dysfunction syndrome mADEi) Aspirin sensitivity “Cough syndrome” of ACE* inhibitors
Eosinophilic pneumonitis Pulmonary infiltrates with eosinophilia (PIE syndrome)
Causative agent usually apparent Partial or complete remission on removal of dw Proximal bronchiectasis Respiratory infiltrates Chronic symptoms Response to steroids Aspergillus precipitins and positive skin test usually present
'ACE = angiotensin-converting enzyme. 152
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Late-onset, or “intrinsic” asthma, is more commonly seen in older subjects, as the name implies. A popular term for this syndrome is asthmatic bronchitis, which indicates that airway inflammation is always present although it varies in intensity depending on various factors such as time of the year and climatic conditions. It is often impossible to define a causative allergic exposure in patients with intrinsic asthma. Although bronchodilator agents are effective in these patients, their response to bronchodilators is usually less dramatic than that of extrinsic asthma. The recognition that chronic bronchial inflammation is present in this population has led to the increased use of anti-inflammatory agents, including corticosteroids and disodium cromoglycate given over prolonged periods.ll’ l2 Occupational asthma, distinguished by its occurrence in workers exposed to industrial dust, vapors, fumes, or gases, may affect more than half a million people in the United States. A list of occupational agents associated with asthma, classified on the basis of molecular weight, is shown in Table 2.13 Occupational asthma may be defined as variable airway narrowing that develops after a period of symptomless exposure to a sensitizing agent at work. The latent period of months to years before symptoms occur suggests that immunologic mechanisms are involved in the pathogenesis of the disease. Whether a subject develops occupational asthma depends not only on the level and duration of exposure to an inciting agent, but also on certain host factors including atopy, cigarette smoking, and nonspecific bronchial hyperreactivity. Some agents associated with occupational asthma apparently do not depend on host atopy; these include the diisocyanates and Western cedar. Cigarette smoking may play a role through its interference with clearance mechanisms, which allows for prolonged contact of the inciting agents with the distal airways. Nonspecific bronchial hyperreactivity may be induced by the exposure rather than by acting as a predisposing host factor. Pm-employment challenge studies will clarify the presence or absence of nonspecific hyperreactivity prior to the development of occupational asthma. Several medications have been associated with increased bronchial hyperreactivity, and these agents may actually induce acute asthma attacks. Therapeutic agents associated with bronchial hyperreactivity include aspirin and the other nonsteroidal anti-inflammatory drugs. Angiotensin converting enzyme (ACE) inhibitor therapy has also been associated with bronchial hyperreactivity, possibly related to a decrease in the catabolism of kinins caused by the enzyme inhibitor.14’ I5 Allergic bronchopulmonary aspergillosis (ABPA) is a form of asthma that is characterized by recurrent radiographic infiltrates often seen in the upper lung fields, proximal bronchiectasis, and a clinical course that varies from remission to endstage fibrosis. First DM, March
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TABLE 2. Causes of Occuaational Asthma* Large molecular weight compounds/ chemicals Animal proteins Laboratory animals Domestic animals Birds Sea squirts Prawns Grain weevils and mites Enzyme lanimal~ Subtilisin Trypsin, pancreatin Plant Proteins Cereal grains Legumes (coffee, soy, castor bean Seeds (cotton, flex, linseed) Enzymes (plant) Papain, bmmelain, pectinase, diastase Vegetable gums Karaya, tragacanth, acacia (arabic), quillaja Small molecular weight compounds/ chemicals Anhydrides Phthalic, trimellitic, hexahydrophthalic, tetrachlomphthalic, hemic Platinum salts Dyes Azo, anthraquinone Diisocyanates Toluene diisocyanate Diphenylmethane diisocyanate Hexamethylene diisocyanate Antibiotics Metallic salts Nickel Chromium Aluminum Fluxes Colophony Aminoethylethanolamine Miscellaneous Formaldehyde Pyrethrum Extract of henna ‘From Care
Brooks
Update permission.
154
SM: ACCP Pulmonary and Critical 1986, volume 2, lesson 13. Used by
DM, March 1991
recognized in 1952,16 ABPA has many features that are also seen in patients with asthma but without ABPA. It is thought to result from an intense inflammatory response of the airways to the fungal hyphae that colonize the tenacious bronchial mucus of patients with asthma. Antigenic material released from the fungus into the bronchi reacts with mast cells, antibodies, and sensitized lymphocytes, often resulting in destruction of bronchial wall structures and bronchiectasis. Interstitial fibrosis is thought to result from recurrent inflammatory infiltrates in the lung parenchyma. PATHOPHYSIOLOGY It has long been recognized that asthma often affects multiple members of a single family. Asthma patients frequently have family members with other allergic symptoms such as eczema and allergic rhinitis. While the presence of a genetic tendency to develop exaggerated airway reactivity has long been accepted, at least for some asthmatics, a unifying theory has not been advanced to explain the inheritance of asthma.17 A recent report from a large study of the natural history of asthma indicates that bronchial hyperresponsiveness to a methacholine challenge may precede the onset of asthma by several years in subjects from asthmatic families, suggesting a genetic basis for enhanced airway reactivity.” The acute asthma attack may be precipitated by a variety of different “triggers,” both allergenic and nonallergenic.1s,20 The allergenic stimuli produce a biphasic response: an early response consisting primarily of bronchospasm, which may resolve in 30 to 60 minutes, followed by late response that becomes evident hours later and may be associated with hyperresponsive airways lasting for up to several weeks or months (Fig 3). The early and late asthmatic responses were first demonstrated in susceptible individuals by allergen inhalation challenge in the laboratory by Herxheimer in the early 1950s.Z1 He also noted that late asthmatic responses could occur without a preceding immediate reaction. Subsequently it was reported by Altounyan that hyperresponsiveness to nonspecific irritants such as methacholine was present in patients with allergic asthma.” Cockcroft and associates demonstrated the association between an increase in nonspecific hyperreactivity and the late asthmatic response.23 The characteristics of the early and late asthmatic responses after inhalation challenge are shown in Table 3.” Nonallergenic stimuli produce acute bronchospasm that usually lasts less than 1 hour and is not followed by the secondary or late response. This is characteristic of the response following challenge with nonspecific agents such as exercise, methacholine, or cold air inhalation. DM, March
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155
@ &
0--0w
-
D. PTERONVSSINUS
5.0 I-o----+ --so c P
4.0 -
3.0 -
FIG 3. The upper panel shows an isolated early bronchospastic response to inhalation of house dust mite extract (Dermatophagoides pteronyssinus). The lower pane/ shows an early followed by a late response after inhalation of the house dust mite extract. Open circles represent response to diluent alone, while closed circles represent response to antigen. The late response begins after 2 to 3 hours and persists for hours to days. (From O’Byrne PM: Late asthmatic responses. Am Rev Respir Dis 1967; 136:740. Used by permission.)
The persistence of increased hyperresponsiveness following an acute asthma attack has been the subject of intensive study in recent years. Cockcroft has proposed a hypothesis to explain the relationship of the acute allergic reaction to the late asthmatic response and to bronchial hyperreactivity. This theory is illustrated in Figure 4.24
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TABLE 3. Features of Early and Late Asthmatic Response After Inhaled Allergen*
Onset Peak Duration Prolonged increase in nonallergic responsiveness Treatment Beta,
Sodium cromoglycate Glucocorticoids
O’Bym~e
PM: A m
THE ACUTE
Rev
Late Asthmatic Response
Cl0 minutes 10 to 30 minutes 1.5 to 3 hours present
3 to 4 hours 8 to 12 hours >12 hours absent
Reverses Premedication inhibits
Partially reverses Premeditation has no effect Premeditation can inhibit Premeditation can inhibit
Pmmedication can inhibit Premeditation inhibits if administered long enough Premeditation has no effect
Indomethacin ‘From
Early Asthmatic Response
Respir Dis 1987: 136:740-751.
ASTHMATIC
Used
Premeditation
can inhibit
by permission.
RESPONSE
The acute allergic asthmatic response is the classic one, mediated by immunoglobulins (IgE) or “reagins.” Identifying the specific offending allergen requires an in-depth history with emphasis on timing of asthma attacks, frequency, duration, environmental exposure both at home and at work, drugs or food consumed, pets, and other contacts. The process of identifying one or more allergic “triggers” may be involved, and at times no definitive allergen is ever identified. Once the exposure has taken place, the sensitized individual develops an early response (within minutes) that is characterized by bronchospasm with acute airflow obstruction and increased mucous secretion that peaks within 10 to 15 minutes and resolves within 2 hours (see Table 3).25-28 The reaction is initiated by the combination of allergen with IgE bound to mast cells in the bronchial mucosa. The IgE-laden mast cells release histamine, products of arachidonic acid metabolism, vasodilators, and factors that increase vascular permeability.25 Degranulation of mast cells results in the release of a number of mediators that participate in the late phase response. These include not only mediators of the acute response such as histamine, prostaglandin D,, leukotrienes, heparin, and chymotrypsinltrypsin, but also additional mediators that may be involved in the initiation of the late phase response, including eosinophil chemotactic factor, neutrophil chemotactic factor, basophil chemotactic factor, and platelet activating factor (PAF). DM, March 1991
157
ALLERGEN + ‘gE
ALLERGIC REACTION
SYB%‘TOMS ON EXPOSURE TO NONALLERGIC STIMULI (IRRITANTS,EXERCISE.
etc)
FIG 4. Proposed relationship of the acute allergic reaction to the late asthmatic response and to bronchial hyperreactivity. (From Cockcroft DW: Airway hyperresponsiveness and late asthmatic response. Chest 1988; 94:178. Used by permission.)
THE LATE ASTHMATIC
RESPONSE
Approximately 50% of sensitized asthmatic subjects will develop a late asthmatic response following recovery from the acute response. ls This late response begins 3 to 4 hours following challenge and peaks at approximately 8 to 12 hours (see Table 3). Important features that distinguish the late asthmatic response include its persistence (it lasts sometimes for days), and its decreased responsiveness to bronchodilators when compared with acute bronchospasm. The onset of the late phase reaction is associated with the development of airway inflammation with cellular infiltration, predominantly eosinophils and lymphocytes, and persistent airway hyperreactivity. Thus, the late phase reaction is in several ways similar to 158
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1991
chronic or ‘intrinsic” asthma. Because airway inflammation is characteristic of the late asthmatic response, current interest is centered on the mechanisms that produce inflammation. The late asthmatic response begins with an influx of inflammatory cells including macrophages, eosinophils, neutmphils, and lymphocytes; within 2 hours, basophils also become plentiful. The macrophages may be activated by an allergen-IgE reaction on the cell membrane and thus may participate with the mast cells in the development of late responses. In contrast to mast cells, macmphages are inhibited by corticosteroids but not by the beta-adrenergic agonists, which rapidly reverse the acute allergic reaction. It appears that the IgE-allergen reaction induces mast cells and perhaps macrophages to release mediators that initiate the late asthmatic response (Table 4). These mediators have been shown to recruit eosinophils and other inflammatory cells to the bronchial mucosa and these cells in turn sustain the inflammatory response.2Y BRONCHLU
HWERRESPONSIVENESS
Many inflammatory asthma and probably
mediators have now been implicated in contribute to the various features of asthma,
TABLE 4. Mediators Associated With the Late Phase Asthmatic Response* Cell Source
Mediator
Mast cell
Histamine Platelet-activating factor Leukotrienes Eosinophil chemotactic factor Neutmphil chemotactic factor Basophil chemotactic factor Heparin Chymotrypsinitrypsin Major basic protein Eosinophilic cationic protein Platelet-activating factor Leukotriene C4 Unknown unknown
Eosinophil
Neutrophils Basophils
‘From Gullatt TJ, Gear@ RB: ACCP Pulmona~ Critical Care Update 1989, volume 4, lesson Used by permission.
DM, March 1991
and 30.
159
including bronchoconstriction, microvascular leakage, and mucus secretion.30 The products of arachidonic acid metabolism, including prostaglandin D, and leukotrienes, cause an increase in bronchial hyperresponsiveness. One mediator, PAF, causes a sustained increase in bronchial responsiveness that may persist up to 4 weeks even in normal subjects.31 Not only does PAF cause recruitment of eosinophils to the lungs but it also stimulates the release of basic proteins from the eosinophils. These basic proteins are toxic to epithelial cells in the airways and cause the bronchial mucosal cells to exfoliate into the bronchial lumen, with actual denuding of epithelial basement membranes?’ Epithelial shedding may in turn contribute to bronchial hyperresponsiveness through the loss of a proposed epithelial relaxant factor present in the cells or a decrease in degradation of inflammatory mediators by the cells. This loss of epithelial surface also results in impairment of mucus removal via the mucociliary escalator, and exposes sensory nerves, which are then triggered more readily.” NEURAL MEChXNlSMS Cholinergic reflex bronchoconstriction, mediated through afferent and efferent fibers in the vagus nerves, has long been implicated as a cause of nonallergic bronchospasm.33’ 34 In addition, there has been a recent interest in the role of nonadrenergic, noncholinergic nerves in asthma, which may be the source of inflammatory neuropepinclude substance P, an inducer of mitides.35 These neuropeptides crovascular permeability and mucous secretion; and neurokinin, a potent bronchoconstrictor. Another neuropeptide, vasointestinal peptide (VIP) relaxes airway smooth muscle, and current research focuses on abnormalities of VIP function in patients with asthma.36 Neurogenic inflammation may be a tar et for investigation into future therapeutic approaches to asthma. #S OBSTRUCTION
TO AIRFLOW
During acute asthma attacks, the inflammatory response in the airways causes contraction of smooth muscle layers in the walls of the bronchi. With repeated attacks, the muscle layers hypertrophy so that the normally thin muscular layers become thickened and prominent. The capillaries in the submucosa dilate and become hyperemic, and there is leakage through capillary walls resulting in edema of the bronchial walls. Mucous secretion is increased and the character of the mucus is altered so that it becomes thick and tenacious. In patients dying from asthma there is denudation of the bronchial mucosa with large chunks of mucosal lining cells adhering to the bronchial mucous plugs. These clumps of epithelial cells 160
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form the Creola bodies in the sputum that are typical of severe acute asthma attacks. Inflammatory cells are prominent in the walls of the bronchi, consisting primarily of eosinophils and, to a lesser extent, lymphocytes. Bronchospasm, mucosal edema, and mucous plugging all result in a common abnormality of lung function, that is, airflow obstruction. Of these, only smooth muscle spasm is responsive to bronchodilator therapy to any significant extent. The other abnormalities, mucosal edema and mucous plugging, are reversed by anti-inflammatory agents over a period of hours to days. Airway obstruction produces air-trapping, with marked hyperinflation of the lungs visible on chest films taken during acute attacks. The diaphragms are low and flat, thus interfering with normal diaphragm function. To compensate for reduced diaphragm activity, patients use the accessory muscles of respiration, the sternocleidomastoids and intercostals, which serve to enlarge the diameter of the thorax. While this is helpful, it is a relatively inefficient method of ventilating the lungs and results in increased work of breathing and muscle fatigue. With airway obstruction, both inspiration and expiration become active processes, and marked changes in pleural pressure from inspiration to expiration occur in the thorax. These dramatic changes, as much as 50 cm H,O or more during respiration, result in alteration of venous return to the heart and the clinical finding of pulsus paradoxus (a variation of 10 mm or more of systolic pressure from inspiration to expiration). This is a relatively reliable clinical finding in severe asthma, and the l-second forced expiratory volume (FEV,) is usually 40% or less of the predicted value when pulsus paradoxus is present.37 Severe airway obstruction may be present without pulsus paradoxus, however, especially with the onset of muscle fatigue and a resulting decrease in the pleural pressures generated. Since the degree of obstruction varies from one area of the lung to another, there are marked abnormalities of distribution of inhaled air into the lungs. There are also abnormalities in the distribution of perfusion, so that significant mismatching of ventilation to perfusion occurs. This results in mild to moderate arterial hypoxemia, which is relatively easily correctable by increasing inspired oxygen concentrations. The decrease in PaO, correlates roughly with the severity of airway obstruction, although there is a wide variation in PaO, values in different asthma patients with similar severity of disease.38 The ‘normal” respiratory response in acute asthma is hyperventilation, with a decrease in arterial carbon dioxide tension (PaCO,) and respiratory alkalosis. This decrease in PaCO, is not a response to arterial hypoxemia because it persists even when oxygen is administered and PaO, is normal or elevated. Hyperventilation is most likely related to neural reflexes in the lungs and chest wall associated with the obstruction to airflow and increased work of breathing. Most paDA4,March1991
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tients continue to hyperventilate until airway obstruction becomes severe, with FEV, in the range of 1 L or less. At this point, in some patients respiratory muscle fatigue progresses with normalization and increasing arterial PCO, levels. The normalization and later retention of CO,, leading to respiratory failure, may be hastened by the administration of sedatives.3g Metabolic acidosis may complicate the other acid-base changes in patients with severe asthma, perhaps because of increased oxygen consumption resulting from the work of breathing associated with a decrease in oxygen delivery. Carbon dioxide retention and metabolic acidosis are ominous signs in acute asthma attacks, associated with exhaustion, respiratory failure, and death.7’ 40,41 CLINICAL
FEATURES
SIGNS AND SYMpTolMS The literature is replete with descriptions of symptoms and physical findings during the acute asthma attack. The most common symptoms are cough, wheezing, and dyspnea, and the episodic appearance of these symptoms suggests a diagnosis of asthma. Dyspnea (difficulty of breathing, “shortness of breath”) is the most fiequent complaint of patients during an episode of asthma, and is usually associated with tightness in the chest and wheezing. A cough is usually present and may be the presenting symptom.42 A subset of patients with asthma is characterized by recurrent or chronic nonproductive cough without any overt wheezing.42 The history should include when the symptoms first started and how often and severe the attacks are (days per week); what activities/ agents provoke the attacks and whether they are seasonal; any patient history of atopy; prior therapy for asthma; presence of diurnal variation; impact of asthma on lifestyle and family; and family history (IgE-mediated allergy and asthma in relatives). Exercise-associated asthma usually results in cough, wheezing, and/or dyspnea toward the end of or following a period of exercise, rather than during the actual performance. These symptoms are usually short-lived and regress spontaneously or with treatment in most patients. A linear relationship exists between the degree of airflow obstruction and the magnitude of perceived dyspnea in a given patient,43 and patients may be better than their physicians at judging the severity of an asthma attack.44 In the asymptomatic patient, the chest examination may be unremarkable. However, examination of the eyes, ears, nose, and throat may reveal otitis media, conjunctivitis, rhinitis, nasal polyps, or sinusitis as evidence of an allergic diathesis. During mild exacerbations of asthma, wheezing may be heard only during forced expira162
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tion. With more severe disease, wheezing is heard during both inspiration and expiration and is associated with signs of hyperinflation. Physical examination during an acute exacerbation of asthma is usually associated with signs of hyperinflation and diffuse wheezing in all lung fields. However, during very severe attacks, as muscle fatigue decreases the ability to produce high expiratory pressures, there may be few or no audible wheezes. Thus, wheezing is of no help in establishing the severity of airway obstruction. Clinical evidence of hyperinflation is provided by an increase in the anteroposterior diameter of the chest, decreased cardiac dullness to percussion, and inferior descent of the zone of hepatic dullness. The use of accessory muscles of respiration (sternocleidomastoids) in an attempt to generate high negative intrapleural pressures is a particularly useful sign in evaluating the severity of airway obstruction. The two most reliable physical findings in judging the severity of the acute attack are sternocleidomastoid muscle contractions during inspiration and paradoxical pulse (Table 51. Accessory muscle contractions indicate the inability of the diaphragm to overcome the severe airway obstruction, and correlate with hyperinflation. While the presence of sternocleidomastoid contractions and paradoxical pulse is a significant finding, the absence of these is not very useful because this may occur with or without severe asthma attacks, and some patients with the most severe degrees of aitway obstruction may not manifest these findings. Another clinical finding that is extremely useful is a disturbance of consciousness. The severe asthma patient becomes exhausted and is frequently listless, somnolent, and somewhat confused. This is an ominous finding that correlates with CO, retention and indicates the possible need for mechanical ventilation. Note that all three significant findings-paradoxical pulse, sternocleidomastoid contractions, and disturbed conscious-
TABLE 5. Grading of Severity During an Acute Asthma Attack
Objective Findings FEV, or PEFR* PaO, PaCO, Clinical Findings Paradoxical pulse Sternocleidomastoid contractions Disturbed consciousness 'PEFR = Peak expiratcq flow Uhf, March 1991
Mild
Moderate
Severe
Over 60% predicted value 1 or+ i 4
40% to 60% predicted value
Less than 40% predicted value J J I,-+or t
Absent Absent
Absent Absent
May be present May be present
Absent rate.
Absent
May be present
i or--f
163
ness-are always important when present but their absence is not always relevant. Vital signs can be normal during a severe attack, but a heart rate above 110 beats/min and respiratory rate greater than 28/min are usual.45~ 46 Systolic blood pressure may increase, with a widened pulse pressure and an inspiratory decline in systolic blood pressure greater than 10 mm Hg (pulsus paradoxus). With response to therapy these signs will improve as hyperinflation decreases, while wheezing and rhonchi tend to linger without a reliable relationship to symptoms. The combination of an increased respiratory rate, use of accessory muscles, diaphoresis, and inability to complete sentences without interruption indicates the presence of a severe asthma attack.
DIFFERENT&IL
DlAGNOSIS
OF WHEEZING
Recurrent episodes of wheezing are almost always indicative of asthma; however, there are other causes of airway obstruction associated with wheezing. In children, foreign bodies in the trachea, bronchus, or esophagus, vascular rings, laryngotracheomalacia, enlarged lymph nodes or tumor, laryngeal webs, and tracheostenosis or bronchostenosis should be considered. Inspiratory/expiratory flow volume loops are helpful in eliminating large airway problems as a cause of episodic or sustained wheezing. Diseases that cause obstruction of both large and small airways, in addition to asthma, include viral bronchiolitis, cystic fibrosis, Chlamydia trachomatis infection, obliterative bronchiolitis, bronchopulmonary dysplasia, and aspiration secondary to swallowing mechanism dysfunction or gastroesophageal reflux. In adults, mechanical obstruction of the airways, exposure to toxic fumes, laryngeal dysfunction, chronic bronchitis and emphysema, left heart failure (cardiac asthma), pulmonary embolism, and allergic bronchopulmonary aspergillosis should be considered.
PULMONARY
FUNCTION
TESTS
Spirometric studies are helpful in the diagnosis and quantification of airflow obstruction and in measuring the response to therapy. Portable spirometers have been perfected to the point that they are sufficiently accurate for the clinical assessment of patients. Portable spirometers should provide a graphic record of the spirogram, and should be calibrated regularly.47 A forced expiratory curve is relatively simple to obtain even during a severe attack and can be interpreted immediately. If a patient cannot produce a 5-second forced 164
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expiration because of dyspnea, one can assume that the airway is severely obstructed. There are several methods of interpreting the forced expiratory curve in order to determine the severity of airway obstruction. The commonest measurements used are the FEV,, the forced vital capacity NC), the FEVJFVC ratio, and the maximum midexpiratory flow rate (FEF25.-75%). While all four of these measurements are useful, the FEV, is the easiest to measure and has the least intrinsic variation because it is not influenced by changes in the vital capacity, which itself changes significantly during attacks.48 Changes in the peak expiratory flow rate (PEFR) correlate well with changes in FEV, during asthma attacks. The PEFR is easier to perform and may be obtained when a spirogram is impossible. The disadvantage of the peak flow is that it is a single number and gives no estimate of error in performance, air trapping, or changes in lung volumes. Peak flow meters must be calibrated regularly, like portable spirometers. Whether the FEV, or PEFR is chosen as the primary measurement to quantitate the course and severity of an attack, it is of major importance to record baseline flows and maintain a flow sheet, with times, flow rates, and therapy. This flow sheet is of vital importance in continuing management of acute attacks and in decisions about follow-up care. Initially, the FEV,, FEVJFVC, and PEFR are significantly decreased, and their values assist in early assessment of severity (see Table 51. A decrease in FEVJFVC ratio to less than 60% indicates moderate severity, and a decrease below 40% indicates severe obstruction. There may be no increase in FEV, after bronchodilator administration at first, but responsiveness is an early sign of improvement. With a severe exacerbation of asthma the FVC is reduced with an increase in the residual volume (RV), functional residual capacity (FRC), and total lung capacity (TLC)?’ This loss of vital capacity with increase in RV and TLC is called air-trapping, and is a sign of significant airway obstruction. The FRC is increased in part because of continued contraction of the inspiratory muscles during expiration. The RV and FRC tend to be markedly increased (approximately 200% and 400% of predicted, respectively) in patients presenting to an emergency room with an acute attack. The diffusing capacity for carbon monoxide (DLCO) is usually preserved.50 Hypoxemia during the acute attack is the result of marked ventilation-perfusion mismatching, rather than a defect in gas exchange, and is corrected with increased FIO,. Peak flow measurements are especially useful when following asthmatics at home, because simple, inexpensive mini peak flow meters are available.51 The peak flow maneuver is very simple to perform and yields a single number that the patient may record on a flow chart at home. Diurnal variations in asthma and peak flow variDM, March
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ability indicate the degree of bronchial hyperresponsiveness. Because a patient’s symptoms are not reliable indicators of the severity of PEFR can help predict of airflow obstruction,52 the measurement abnormalities earlier and allow for more appropriate changes in medications. In the interval after an acute attack pulmonary function tests may be normal, or without continued treatment there may be some degree of airflow obstruction and hyperinflation.53-56 Even when the patient and the clinician believe the attack is over, there may still be significant abnormalities of pulmonary function, requiring continued active treatment.54 ARTERLAL
BLOOD
GASES
Arterial blood gas (ABG) analysis is helpful in determining the severity of an acute asthma attack and is indicated if flow rates are markedly decreased, if patient response is poor, or if there is evidence of associated disease-producing abnormalities in gas exchange that can lead to decreases such as chronic obstructive pulmonary disease.52’ 57S58 The PaO, falls in a fairly uniform manner as the FEV, decreases.5g With mild bronchospasm (FEV, > 2 L), ABG is a poor indicator of the severity of airflow obstruction, with a near normal PaO,, respiratory alkalosis, and a widened alveolar-arterial oxygen gradient .52 Patients who experience mild to moderate asthma attacks usually have some hypoxemia. Cyanosis is uncommon, but indicates an extreme degree of respiratory impairment if present. The PaCO, is mildly reduced (approximately 30 to 35 mm Hg) until the attack becomes severe (see Table 5). Approximately 75% of asthmatics seen in the emergency room have hypocarbia and respiratory alkalosis.52 As the FEV, decreases below 1 L, the PaCO, normalizes. If airflow worsens, hypercarbia and respiratory acidosis develop. The presence of hypercapnia and respiratory acidosis implies severe disease, with an FEV, of less than 15% of predicted.57 BADlOGBAPHIC
CHANGES
The chest radiograph is not helpful for diagnosing asthma or for determining the severity of an acute asthma attack,” but should be obtained when the patient is first seen to rule out other causes of airway obstruction or the presence of complicating illnesses such as cardiac disease or bronchiectasis. During acute attacks there is hyperinflation and a small elongated heart, such as that seen in patients with emphysema (Fig 5). A chest radiograph is helpful in patients with intractible episodes of asthma because it indicates complications of the acute attack, such as pneumonia, pneumothorax, 166
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FIG 5. Chest radiograph from a 2.5year-old man during an acute asthma attack. There is marked hyperinflation, with low, fiat diaphragm, and elongated heart. This film resembles that of a patient with advanced emphysema.
pneumomediastinum, or rib fractures. Sinus films are helpful in patients with symptoms of allergic rhinitis and sinusitis. Other radiographic studies such as computed tomography (CT) scans, arteriography, and chest fluoroscopy are rarely indicated unless additional diagnoses are suspected. OTHER
LABORATORY
TESTS
The sputum is usually white, thick, and mucoid, but can look purulent secondary to eosinophilia rather than polymorphonuclear cells. Microscopy may demonstrate eosinophilia, Charcot-Leyden DM, March
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crystals (degenerated eosinophils), Curschmann’s spirals, and Creola bodies. The presence of Creola bodies (clumps of epithelial cells) suggests a severe attack.61 The presence of brownish mucous plugs containing mycelia suggests Aspergillus colonization and ABPA. Nasal secretions can be stained for eosinophils; if they are present, one can establish an allergic etiology of associated rhinitis; the presence of a neurophilic nasal discharge suggests associated sinus infection. The complete blood count (CBC) may show an increase in white cells, frequently with increased eosinophils, and indicates a patient’s allergic predisposition. Eosinophils may not be present if the patient is taking steroids and can be used to judge the adequacy of the steroid dose.62 Marked eosinophilia (>3,000/mm3) raises the possibility of Loffler’s syndrome, ABPA, or Churg-Strauss syndrome. The electrocardiogram adds little to the diagnosis or routine management of asthma. It should be obtained in patients with a history of cardiovascular disease and those over the age of 50 years who present with an acute attack. The changes, usually seen with the more severe attacks, are nonspecific in nature. Sinus tachycardia is frequent, and right axis deviation, right ventricular hypertrophy, right bundle branch block, and premature ventricular contractions are sometimes present4’ and may be associated with right heart strain and/or heart failure. The more severe the asthma, the more likely one of these abnormalities is to be found. Other tests may be indicated in the presence of specific symptoms. For instance, in patients with recurrent nocturnal attacks associated with gastritis or heartburn, monitoring for gastroesophageal reflux with manometry or esophageal pH monitoring may be usefu1.63 Esophagrams and upper gastrointestinal series may help to exclude motility problems or hiatus hernia. Patients suspected of having deep vein thrombosis of. the legs may be candidates for ventilation/perfusion lung scans to rule out recurrent pulmonary emboli. Patients with copious sputum production and frequent infections should be screened for motility disorders including milder forms of cystic fibrosis, with sweat chloride levels or nasal ciliary biopsy. Patients with sensitivity to aspirin and nonsteroidal anti-inflammatory agents are usually aware of their problem, and will relate an association with these drugs. They often have chronic symptoms with sinusitis and nasal polyps, and will respond to a challenge with the offending agent.
ASSESSMENT
OF SEVERITY
Characterization of a patient’s asthma as mild, moderate, or severe enables the clinician to categorize the overall assessment of a pa168
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tient’s asthma and select appropriate therapy. The physician should consider all available data, including the frequency of symptoms, degree of exercise tolerance, presence of nocturnal asthma, chest radiographic findings, pulmonary function tests, and degree of methacholine sensitivity in determining the severity of disease. In general, the severity of asthma cannot be estimated from the history or physical examination, During the acute attack the symptoms and physical findings correlate rather poorly with the severity of obstruction.64 Symptoms should be relied upon to bring the patient to the hospital but after that, measurements should be objective because symptoms are frequently absent when obstruction is still marked. The most important variables in judging severity are the degree of airflow obstruction and the frequency and length of attacks. This information is best obtained from flow charts maintained by the physician in the office and by the patient or family at home. If the patient has rare (seasonal) attacks with few clinical symptoms of asthma between exacerbations, the diagnosis is mild asthma. Patients have moderate to severe asthma if their exercise tolerance is diminished, if persistent cough and wheezing are present, or if symptoms of nocturnal asthma occur at least two to three times per week with frequent interruption of sleep. If hyperinflation is evident on the chest radiograph when the patient is asymptomatic, this suggests moderate disease. If the chest radiograph reveals a chest deformity in children because of chronic hyperinflation, severe disease is likely. During asymptomatic periods in patients with mild asthma, pulmonary function tests reveal minimal or no evidence of airway obstruction, normal lung volumes, peak flow rates greater than 80% of predicted values, and a greater than 15% response to bronchodilator administration even though they are begun at near normal baseline levels. Between attacks in patients with moderate disease, there is evidence of airway obstruction on spirometry, with reduced expiratory flow at low lung volumes. Peak flow rates are 60% to 80% of predicted values, and RV is increased; however, there usually is still an increase of more than 15% after bronchodilator administration. With severe disease there is significant airway obstruction associated with marked increases in RV. Peak flow is less than 60% of predicted values, and limited reversibility may exist after bronchodilator administration. It is important to note that these objective measurements may be influenced by other underlying lung diseases. The FEV, and FVC may be affected by chronic bronchitis, emphysema, diseases of the chest wall or diaphragm, or neuromuscular disorders. Chronic bronchitis can cause hypoxemia and CO, retention, while hyperinflation and a decrease in DLCO are often seen with emphysema. DM, March
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NONSPECIFIC BRONCHW
PROVOCATION
Bronchial provocation testing is a simple and generally safe procedure that can be performed in the office setting in order to demonstrate bronchial hyperreactivity, especially in patients with episodic symptoms who present during an asymptomatic phase. An intrinsic feature of asthma, bronchial hyperreactivity is defined as a 20% or greater decrease in FEV, in response to a provoking factor that, at the same dose, causes less than a 5% change in a normal subject (Fig 6). Additionally, a patient has bronchial hyperreactivity if there is a 20% or greater increase in the FEV, in response to an inhaled bronchodilator. The degree of bronchial hyperreactivity to methacholine and histamine challenge correlates well with the severity of asthma symptoms, the diurnal variation in airway function, and the amount of therapy required to control symptoms.65 Methacholine is more widely used for bronchial challenge because it is more stable and is more readily available. Response to methacholine and histamine are similar, and correlate with other nonspecific challenges such as cold air inhalation or exercise. Patients should have near normal lung function and have had no bronchodilator drugs for 6 hours prior to performing a methacholine challenge test. The cumulative dose of methacholine causing a 20% of methacholine drop in FEV, (PD,, FEV,), or the concentration causing a similar drop (PC,,) are well standardized, widely accepted indices .66 The PD,, or PC,, FEV, following methacholine inhalation can be used to classify the patient into mild, moderate, and severe
I
I
PBS
I
1
1
1
O-03 O-08 O-125 O-25 O-5
Histamine (or methacholine)
1
I
I
I
1
2
4
8
concentration
(mglml)
FIG 6. Change in FEV, as a percent of the control value following the inhalation of increasing concentrations of aerosolized histamine or methacholine. The concentration of inhaled trritant which results in a 20% decrease in FEV, is the PC,, (Adapted from Cockcroft DW, et al: Allergen-induced increase in nonallergic bronchial reactivity. C/in Allergy 1977, 7:503-513.)
170
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bronchial reactivity (see Fig 6). The bronchial hyperreactivity level can also be used to follow the response to therapy, when preventive agents such as inhaled corticosteroids or cromolyn sodium are used. Exercise and cold air challenge are also commonly performed and well standardized, especially in patients with a history of exereiseinduced asthma.67 In general, they require more patient cooperation and a generally fit patient. Results are similar to methacholine challenge in those with exercise-induced asthma; however, methacholine appears to give a more reliable and more quantifiable result.
DETERMINATION
OF PROVOKING
AGENTS
It is important to determine, if possible, which agents are provoking asthma attacks so that they can be avoided or eliminated from the environment. A careful history will often reveal potential provoking agents. Questions concerning potential occupational exposures, pets, and food intolerance should be asked. Standard allergy history questionnaires are available from various volunteer organizations. The typical patient with work-related asthma develops wheezing, chest tightness, or cough with or without sputum production or rhinitis toward the end of a shift, which worsens during the night and improves toward morning. The patient often recognizes a relief of symptoms after a holiday or long weekend. The atopic status of a patient can be determined by simple skin prick tests using common airborne allergens. Immediate-type hypersensitivity skin testing detects IgE antibody against specific allergens. If positive, these tests suggest an allergic cause of the patient’s asthma. Skin test results should be considered clinically significant when they are associated with a positive history. The radioallergosorbent test (RAST) and enzyme-linked immunosorbent assay (ELISA) are in vitro tests for evaluation and quantification of antigen-specific IgE antibodies in serum.68 These tests correlate with results from skin tests and provocation testing. In vitro tests are advantageous because they avoid anaphylactic reactions, and can be done in the patient’s absence. Disadvantages include expense and decreased sensitivity compared with provocation testing. Patients whose skin tests correlate with history may be candidates for specific allergen inhalation challenge. Allergen challenge is a highly specialized procedure and should be performed only by Positive immediate bronchospastic reexperienced laboratories. sponses may be followed by late reactions in a significant number of patients.6” DM, March
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MANAGEMENT Asthma can be regarded as a heterogenous disease because of its presenting symptoms, severity, and response to therapy. Some basic concepts can facilitate the management of asthma. First, the patient must try to avoid known precipitating factors, such as known allergens, but also irritants such as smoke, strong perfumes, and aromatic room deodorizers. Second, the sooner an exacerbation is treated the easier it is to abate. Third, even patients with moderate asthma may have recurrent symptoms that may benefit from continuous rather than as-needed treatment. Fourth, patient compliance is an important part of the management program, and the more educated a patient is about asthma the more likely the patient is to comply with the treatment regimen. The aims of therapy include relief of bronchospasm, mobilization of secretions, maintenance of alveolar ventilation, a decrease in bronchial hyperresponsiveness, prevention of acute exacerbations of asthma, and avoidance of adverse effects from asthma treatment.
PHARMACOLOGIC
AGENTS
Drug therapy for asthma can be divided into bronchodilators and anti-inflammatory agents. Bronchodilators act to reduce bronchial smooth muscle contraction, clear mucous secretion, and dilate the airways. They are used mainly to treat symptoms when they occur (such as in exercise-induced asthma) and occasionally to prevent bronchospasm. Anti-inflammatory drugs reduce airway inflammation and reduce bronchial hyperresponsiveness. They are becoming first-line agents as the emphasis shifts from intervention during acute attacks to prevention of acute attacks by treating bronchial hyperresponsiveness. BRONCHODZLATORS Beta-adrenergic agonists (sympathomimetics) mimic the adrenal medullary hormones and neurotransmitters. They work by increasing cyclic adenosine monophosphate (CAMP) formation, with a resultant change in intracellular calcium concentrations7’ Beta receptor stimulation results in effects on the lungs, heart, and other organs. Beta, stimulation leads primarily to positive chronotrophy and inotrophy of the heart, while beta, stimulation results in various benefits to the respiratory system, such as relaxation of the smooth muscle of the bronchi, prevention of smooth muscle contraction by various stimuli in a dose-related response, increased clearance of mucus, decreased release of mediators from cells near the epithelial 172
DM. March
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surface (basophils and mast cells), and it may protect venular endothelial cells and partially prevent edema. Beta, receptors also cause vasodilation and skeletal muscle tremors, and probably have some direct stimulatory effects on the heart.‘l There are four classes of beta-adrenergic agonists: catecholamines, resorcinols, saligenins, and pro-drugs. Catecholamines have mixed alpha, beta,, and beta, effects. This group includes epinephrine, isoproterenol (a synthetic derivative of epinephrine) and isoetharine. Catecholamines are quickly methylated in the lung by catechol-omethyl-transferase with a resultant duration of action of only 1 to 2 hours7’ Their major disadvantages are their short half-life and lack of beta, specificity, and some patients develop tolerance to these agents.73 The resorcinols include metaproterenol, terbutaline, and fenoterol. They are more beta,-selective and have a longer half-life. The more selective beta, drugs are not methylated and their duration of action is much longer (about 4 to 6 hours).74, 75 Albuterol is from the saligenin group, which are relatively beta,-selective and have a longer half-life than isoproterenol. Pirbuterol differs from albuterol only by substitution of a nitrogen atom for a carbon atom in the benzene ring. Pro-drugs are inactive until they are metabolized. An example is bitolteml, which is cleaved in the lung by esterase to its active form, colterol. The level of esterase is higher in the lung than in the heart, resulting in fewer cardiac side effects. SigniRcant side effects of the sympathomimetic drugs involve several organ systems. Muscle tremor, a beta, effect, is present in varying amounts with all the beta,-specific agents. Catecholamines can cause hyperglycemia, hypokalemia, hypophosphatemia, hypocalcemia, hypomagnesemia, and increased levels of lactate, pyruvate, and ketones. A major advantage of beta-adrenergic agents is that they are quite effective when given by inhalation. This allows for control of symptoms with minimal side effects. Other advantages include ease of application, portability, and rapid onset of action. Aerosols may be produced by hand-held pressure nebulizers, by metered-dose inhalers (MD11 using freon or other compressed propellants, or in powder form using the pressure of rapid inhalation and a mixing chamber to suspend the powder in an aerosol (Spinhale@, Rotohaler@). Of these devices, the MD1 is by far the most commonly recommended because of its portability and effectiveness. The direct application of the adrenergic agent to the airway mucosa produces relief of bronchospasm in much smaller doses than those required for systemic therapy. Because only about 10% to 15% of the aerosol actually reaches the airway mucosa, side effects of the new beta,-adrenergic aerosols are minimal when given at recommended doses. Muscle tremor and tachycardia are the most common side effects, occurring in a minority of patients and gradually lessening as the aerosols are used. DIM, March
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There are two significant problems with the otherwise ideal inhaled beta,-adrenergic agents. One is their relatively short duration of action, 3 to 6 hours for the newer drugs, and the other is their requirement for adequate inhalation technique in order to reach their site of action. It has been shown that the majority of patients can use their inhalers properly’” with careful instruction, but repeated reinforcement is essential. A number of studies have attempted to define optimum MD1 use, but we recommend the technique outlined in Table 6, which is based on the report of Dolovich et al.77 Package inserts recommend keeping the mouth closed while using the mouthpiece, and many clinicians use this method; however, Dolovich et al. showed that this method increases deposition of aerosols in the mouth and throat rather than in the lung parenchyma.77 For patients who are unable to use their MD1 properly (children, the elderly, neurologic patients, etc.), alternate forms of delivering aerosols are available. Spacers and reservoir devices are useful for children, and especially for patients using inhaled corticosteroids, to decrease proximal deposition of large particles.78 Spacers allow for large particle deposition outside the mouth, while reservoirs avoid the need for coordination of activation with inspiration by providing an aerosol chamber.7g Other delivery devices include powder generators in which an aerosol powder is generated in a small chamber, so that whenever the patient inspires, powder is delivered. Hand-held nebulizers are bulky, expensive, and less portable, but are often used for aerosol delivery in hospitals and clinics, especially during acute asthma attacks. They require more medication (up to TABLE 6. Recommended Procedures for Optimum Use of Metered Dose Inhaler* 1. Shake the inhaler 2. Breathe out to end-expiration (the end of a normal breathl 3. Open the mouth wide and hold canister in the upright position 2 to 4 cm from mouth 4. While breathing in deeply and slowly (inspiration time approximately 5 seconds), depress the top of the canister 5. Hold breath as long as possible 6. Repeat as often as prescribed by physician, allowing at least I to 2 minutes between actuations ‘From
Guidry
GG, George
Critical Care Update, Used by permission. 174
RB: ACCP F’ulmonary and 1990, volume 6, lesson 1.
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1991
ten times the dose) for equivalent effect, primarily because the majority of the aerosol is lost in the equipment and surrounding atmosphere. Power nebulizers have been shown to provide no additional benefit over properly used MDIs in several studies.” Nevertheless, they are popular with patients, and allow busy hospital personnel to deliver adequate dose levels without constant coaching and supervision. Administration of beta-adrenergic agents by other methods (oral, parenterall is less satisfactory because of the larger dose requirements and the significant side effects.‘l Sustained-release preparations of beta, agents are available, and their principal advantage is their longer duration of action compared with the inhaled form. They may be indicated in patients with nocturnal symptoms, as an alternative to sustained-release theophylline. Parenteral beta-adrenergic agents are used primarily in younger patients, who appear to tolerate their side effects better.82 Subcutaneous terbutaline and epinephrine are commonly used during acute attacks, especially in children, to assure early and adequate drug effects. The only intravenous beta-adrenergic agents used in this country are isoprotereno1 and terbutaline. Several studies have documented the effectiveness of intravenous adrenergic drugs in severe, intractible asthma in children.82 In general, alternate urgent therapy including constant inspired aerosol and mechanical ventilation is preferred in older patients, but new information may change this approach. The older the patient, the more likely are significant complications, especially if there is evidence of associated cardiovascular disease.83 Methylxanthines such as caffeine, theophylline, and theobromine have been used in the treatment of asthma for many years. Theophylline, the most widely used of these agents, has been available for over 40 years, yet the mechanism of its bronchodilator action remains unclear. It relaxes the smooth muscle of bronchi, especially if it is constricted. The drug also increases diaphragm contractility and makes the diaphragm less susceptible to fatigue.84 Theophylline increases mucociliary clearance in some patients, antagonizes the effects of adenosine on mast cells, and reduces mediator re1eases8’ Theophylline inhibits phosphodiesterase, the enzyme that inactivates CAMP, resulting in increased levels of CAMP within the cells. However, this effect is minimal at serum concentrations that are achieved therapeutically.‘” Its benefit has been attributed to its effects on adenosine but again, this is unlikely its only mechanism of action.8” The bronchodilator response to theophylline is directly proportional to the log of the serum concentration in the range of 3 to 25 Pg/m1.87 Serum levels less than 10 p#ml minimally improve lung function and levels greater than 20 kg/ml are associated with significant side effects; therefore recommended therapeutic levels are 10 DM, March
1991
17.5
to 20 ~g/m1.87 We prefer lower serum levels in adults, in the range of 8 to 12 l.ig/ml. Plasma half-lives for theophylline vary considerably; patients who are supposedly “rapid-eliminators” require larger, more frequent dosing. Theophylline clearance is increased in children, smokers, marijuana users, those on high carbohydrate-low protein diets, and by drugs that induce formation of hepatic enzymes (phenobarbital, phenytoin). Theophylline clearance is decreased in neonates, elderly patients, and those with acute and chronic hepatic dysfunction, congestive heart failure, or a febrile illness, and by certain drugs (macrolide antibiotics, allopurinol, cimetidine, troleandomycin, and propranolol). Absorption may be slower at night in some patients, possibly because of the change in body position during sleep.” Intravenous theophylline or aminophylline (which is 85% theophylline) are often used together with beta-adrenergic agents and corticosteroids in the management of acute bronchospasm. A 6 to 8 mgkg loading dose of aminophylline may be given over 20 to 30 minutes if the patient has not been taking oral theophylline. The loading dose should be based on the lean body weight in order to avoid overdose in obese patients. If the patient has been taking theophylline the loading dose should be eliminated, and we advocate avoiding the loading dose in all patients unless a serum theophylline level is available. Adults are begun on a maintenance drip of 0.5 mg/kg per hour and the dose is adjusted later based on serum levels. A theophylline level should be obtained at 12 and 24 hours, and adjustment of the dose is based on results, assuming linear kinetics. For instance, if the level is 7 l.ig/rnl, then doubling the infusion rate will increase the level to 14 kg/ml after approximately four half-lives (24 to 30 hours). If toxic symptoms appear (tachycardia, ectopic beats, nausea, vomiting, anxiety, headache), stop the infusion and recheck the level in 6 to 8 hours, when it should decrease to half the original level. The side effects of theophylline are common, and in addition to those mentioned, include diarrhea, abdominal pain and anorexia, difficulty in urination in patients with prostate disorders, and relaxation of the lower esophageal sphincter leading to gastric reflux. A minority of patients cannot tolerate even minimal doses. The risk of seizures and cardiac arrhythmias increases when levels are greater than 30 Pg/ml. These serious complications are associated with a significant increase in mortality. The use of oral theophylline has decreased somewhat because of its requirement for systemic administration, the presence of significant associated side effects, and the availability of safer, more effective agents. Oral sustained-release theophylline may be a useful adjunct for patients with chronic, late-onset asthma or asthmatic bronchitis. Stable blood levels can be achieved over a 24-hour period us176
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ing current sustained-release agents, and may serve as a “cushion” between periods of beta-adrenergic or anticholinergic drug use. A common indication for oral sustained-release theophylline is bedtime use for patients with nocturnal symptoms.88 This avoids the vulnerable period after 3 to 4 hours when the inhaled agents are no longer effective, because sustained-release theophylline reaches peak serum levels after 4 to 8 hours in most patients. With the availability of the new sustained-release products, we know of no indication for oral short-acting theophylline in adults with asthma. Antichohergic drugs are among the oldest agents used for the treatment of asthma. They work by blocking postganglionic efferent vagal pathways with a subsequent reduction of the intrinsic vagal tone to the bronchial smooth muscle. They also block reflex bronchoconstriction caused by inhaled irritants, and decrease the release of mediators from mast cells after parasympathetic stimulation. Anticholinergic drugs have a slow onset of action, with a peak effect reached after 30 to 60 minutes. Inhaled atropine sulfate is rapidly absorbed from airway mucosa and is associated with significant anticholinergic side effects (tachycardia, blurred vision, urinary hesitancy). It should not be used in patients with narrow angle glaucoma or prostatic hypertrophy. Ipratropium bromide is a quaternary derivative of atropine sulfate that is poorly absorbed from the bronchial mucosa and consequently has fewer side effects. Ipratropium bromide is synergistic with sympathomimetics and methylxanthines in the treatment of asthma.“Y In nonurgent cases anticholinergic drugs may be useful in treating paroxysmal cough associated with irritated airways.” Other inhaled anticholinergic agents such as glycopyrrolate have been efagent for treatfective,“l but in general the preferred anticholinergic ment of asthma is inhaled ipratropium bromide. Oral and parenteral forms of atropine are available, but are rarely if ever indicated in the current management of asthma. Atropine tablets have been used for nocturnal relief because of the lack of central nervous system stimulation and gastric irritation.” They may be a useful adjunct in patients who cannot tolerate bedtime theophylline. Intravenous atropine is not recommended for the treatment of asthma.
ANTI-INFLAMM4TORY
AGENTS
Cromolp sodium was first used in 1967 as a mast cell membranestabilizing agent in the management of asthma.Y” It blocks calcium transport across the mast cell membrane, and prevents the release of mediators of immediate hypersensitivity from the mast cell granules. Cromoltivn sodium also decreases type C fiber stimulation and DM, March
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chemotaxis on the part of eosinophils and neutrophils. It is available as a powder, nebulizer solution, or MDI. Cromolyn sodium is most effective in young patients with mild to moderate extrinsic asthma, but may be effective in older patients with chronic asthma.” Cromolyn sodium decreases nonspecific bronchial hyperreactivity in both allergic and nonallergic asthma. It takes 4 to 6 weeks to achieve benefit from inhibition of mediator release, and is successful in 60% to 90% of patients.s4 It suppresses both immediate and late onset reactions secondary to a variety of aeroallergens, as well as reactions to exercise, cold air, sulfur dioxide, ultrasonic aerosols, toluene, and propranolol.” A single dose prior to unavoidable exposure to known allergens can prevent development of immediate and late-phase responses. Side effects include irritation of the throat, cough, occasional minor bronchospasm, and transient skin rashes. Bronchospasm is prevented by combining the inhaled cromolyn sodium with a beta-adrenergic agent. New cromolyn-like agents are currently under active investigation. These drugs, some of which have antihistamine-type properties, may be effective when given orally, thus avoiding the inconvenience and throat irritation associated with the inhaled drug. Recent reviews’” give more information regarding these new investigational agents. Ghcocorticoids were first used in the treatment of asthma in the 1950s. Their mechanism of action is unknown, but is thought to involve a decrease in the number and activity of inflammatory cells,g7 a decrease in the release of arachidonic metabolites,” increase in beta,-adrenergic responsiveness,” prevention of increased vascular permeability,100 a decrease in airway hyperreactivity,10”‘02 and prevention of the directed migration of inflammatory cells. These effects are not immediate and take at least 6 to 12 hours to occur.1o3 Steroids can be given orally, parenterally, or by inhalation. Oral and parenteral corticosteroids are extremely effective in the management of the acute asthma attack. Their use over prolonged periods should be reserved for patients with severe asthma, because chronic systemic steroid administration is associated with significant side effects including adrenal suppression, hypertension, diabetes, Cushing’s syndrome, and impaired host immune defense mechanisms. If systemic therapy is necessary, it should be given on an every-other-day regimen with the lowest possible dose of a medium-duration preparation such as prednisone. Because prednisone must be metabolized to prednisolone in the liver, patients with liver disease may respond more rapidly to methylprednisolone, which does not have to undergo hepatic conversionlo Inhaled steroids are being used more frequently as primary preventive therapy for moderate and severe asthma. Inhaled steroids have minimal systemic absorption and are free of systemic side effects; in adults they are not associated with signs of hyperadreno178
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corticism, and daily doses of up to 800 l.~g (16 puffs of beclomethasane) have been shown to cause minimal pituitary-adrenal suppression.lo4 Because of local deposition in the mouth and pharynx, about 10% of patients will develop candidiasis and/or dysphonia associated with the local effects. Rinsing and gargling with water after use of inhaled steroids will usually prevent oral side effects, and if oropharyngeal candidiasis occurs it is readily treated with local therapy. The usual daily dose of inhaled steroids is approximately equivalent to 10 to 15 mg/day of prednisone. Beclomethasone is marketed in the United States at a concentration of 50 pg/puff. There is a dose-related response with doses up to 1,600 pg/day (32 puffs of currently available beclomethasone preparations). Flunisolide is currently available in the United States at 250 cLg/puff, and more potent aerosols of other inhaled steroids should be available soon. Inhaled steroids may irritate the airways, and it may be beneficial to give a beta,-adrenergic agonist prior to the steroid. The use of inhaled steroids may allow a decrease of the dose of chronic oral steroids and should be attempted in all patients requiring long-term systemic corticosteroid therapy. Antihistamines are being reevaluated for their use in the treatment of asthma, and early reports of a drying effect of antihistamines on bronchial mucosa have not been substantiated.l” In addition to blocking the acute bronchoconstrictor effects of histamine some of these agents have mild bronchodilating properties. Oral antihistamines have been shown to be better than placebo in reducing symptoms in some patients who have exercise-induced asthma.lo6 Troleandromycin, a macrolide antibiotic, has a steroid-sparing capacity with long-term use.*07 It appears to work by decreasing hepatic metabolism, resulting in higher blood levels. The addition of this drug allows the dose of methylprednisolone to be decreased over the course of weeks to months. It is rarely indicated, and should be used only by physicians experienced in its use. A chemical hepatitis develops in some patients, but is reversible when the drug is stopped. Methotrexate has been used in the treatment of severe asthma, allowing for a reduction in the dose of steroids required?” Again, the side effects of methotrexate, while different from those of the corticosteroids, are significant, and include hepatic fibrosis, bone marrow depression, and teratogenicity in unborn children. Gold compounds have been used recently in the management of steroid-dependent asthma.“’ They were first used in Japan, and were selected on the basis of their effectiveness in rheumatoid arthritis, another disease of immunologic basis. Disadvantages of gold include its expense and its significant side effects, including interstitial lung disease and bone marrow abnormalities. Trials are currently underway using oral preparations of gold salts on a longterm basis. DM, March
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PREVENTION AVOIDANCE
OF THE ACUTE ASTHMA OF PRECIPITATING
AlTACK
FACTORS
While avoidance of factors that cause asthma attacks is an extremely effective means of preventing the attack, it is not practical in many cases. Young, active individuals with exercise-induced asthma may find that a sedentary lifestyle is unsatisfactory, and patients allergic to common pollens, dust, and air pollutants may be forced to exist in environments that exacerbate asthma attacks. There are two areas where avoidance appears to be especially useful. The first is in patients allergic to household pets. While it may be painful to get rid of the pets, this is a reasonable alternative to long-term steroid therapy. A second potential usefulness of avoidance is in occupational asthma, where a patient’s occupation or location of work may be changed to place him in a more suitable environment. Pet allergies and occupational allergies should be documented as well as possible prior to removal of the pet or a move to another workplace because this represents a significant change in lifestyle. In many cases patients prefer continued exposure with alternate means of prevention. For example, patients with exercise-induced asthma need not avoid exercise entirely but can prevent acute attacks by inhaling a beta-adrenergic aerosol prior to exercising. Patients with skin test sensitivity to house dust mites may benefit from frequent careful house cleaning with a mop or wet rag, especially in the bedroom. The bedroom should be closed off from the rest of the house and a room air conditioner should be installed if possible with changing of filters at least weekly. Roaches have been shown to be a source of allergenic extracts, and roaches should be prevented from entering the house if possible by outdoor measures, so that potentially irritating insecticides need not be used inside the house. In some young asthma patients, unrecognized substances in the diet can exacerbate asthma. One study demonstrated that 10% of children with asthma responded to treatment with an elimination Beverages with sulfur dioxide, aspirin, and preservatives diet.“’ such as sulfites can worsen asthma in some patients.ll’
IMMUNOTHElW’Y
FOR ASTHMA
While nearly all asthma has some IgE-related component, correlation between asthma and immediate hypersensitivity skin test reactions is not complete and tends to decrease with advancing age.l” Many allergic individuals demonstrate bronchial hyperreactivity to a number of antigens such as pollens, house dust mites, molds, and various animals. Furthermore, unrelated factors such as viral infec180
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tions, irritant exposures or drug therapy can alter the severity of the disease in the absence of allergen exposure. Thus, it has been difficult to evaluate the effectiveness of immunotherapy in the prevention of asthma. In general, a majority of acceptable studies show some clinical benefit of this treatment provided the antigen is carefully identified and the purity and dose of allergen administered is adequate to produce antigen-specific IgG.l13 Immunotherapy is based upon the presumption that, beginning with a very dilute antigen extract, tolerance or hyposensitization may be produced by gradual increase in the amount of antigen injected subcutaneously. Hyposensitization is thought to be produced by the development of “blocking antibodies,” believed to be antigenspecific IgG, which interfere with the antigen-IgE allergic reaction. However, other immunologic alterations are also likely to be involved. Among the specific desensitization antigens that have been most carefully studied are cat allergen-I extract and house dust mite antigen. Both these preparations have been shown to decrease allergen-related bronchospasm in caref~~lly studied subjects.l14 Ragweed antigen-E has also been carefully standardized and shown to result in a good clinical response. Therapy with grass pollen and birch pollen has been shown to blunt a seasonal increase in symptoms associated with a decrease in immunologic mediators. Other commonly used immunotherapeutic agents such as house dust and molds are poorly standardized and have not been convincingly shown to produce beneficial effects. Given the limited information available and a lack of proven benefit in many studies, pharmacotherapy has in general been the preferred course. When pharmacologic treatment has been optimized and still does not avoid symptoms or causes serious side effects, immunotherapy may be a reasonable consideration in carefully selected patients. For immunotherapy to be effective, there must be a positive correlation between symptoms and immediate hypersensitivity skin test reactions. It should be discontinued after a trial period if no objective benefits are noted. Side effects of immunotherapy are significant and in addition to the inconvenience of twice-weekly injections, often for years, there are a number of reported fatalities from skin testing or immunotherapy given for various reasons.115 Patients who have an FEV, of less than 80% of predicted value at the time of injection have a high probability of developing a serious reaction and should avoid immunotherapy on that day.‘16 PREVENTIVE DRUG THERAPY The current approach to the management of asthma is in a state of evolution from a posture of reaction (treating the attack once iniDM, March
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tiated) to a more aggressive approach, taking measures to avoid attacks by controlling bronchial hypersensitivity and the late inflammatory reaction.117-11g The drugs used for preventive therapy have been previously discussed on an individual basis. This discussion will concentrate on their application to the prevention of acute asthma attacks. While beta agonists are useful in treating acute bronchospasm they are ineffective in preventing the late-phase response.120 Preventive therapy is based on prevention of the latephase response with corticosteroids or cromolyn sodium. Inhaled corticosteroio!s are effective through a variety of mechanisms. The preferred route of administration, in the absence of acute bronchospasm, is by inhalation. A number of inhaled corticosteroid preparations are available at the present time. Beclomethasone has been available for the longest period and is the most extensively studied. Its major drawback is that it is only available in the United States in 50 pg/puff dosage and a large number of puffs per day are frequently required. Triamcinolone is said to induce less coughing than the other inhaled steroids and is packaged with a built-in spacer. It is given in an initial dose of eight puffs a day.lzl Flunisolide is available in higher concentrations (250 l.~g/puff) and is given in doses of four or more puffs per day. Once symptoms have been controlled, the dosage of all these agents may be reduced to maintenance levels required to prevent symptoms. Inhaled corticosteroids cannot be used during the acute asthma attack because they are bronchial irritants and induce coughing. They should be begun after the acute attack is controlled, during the period that oral or parenteral corticosteroid doses are being tapered. Patients must be instructed and encouraged to comply with dosing regimens because benefits are not readily appreciated as are those with beta agonists. Furthermore, they are relatively expensive and are required for long periods. Cromolyn sodium is useful in preventing exercise-induced asthma, has some effect on the early phase response, and is extremely useful in preventing the late-phase asthmatic response.12’ Cromolyn is safe, easy to use, has few side effects, and is available by MDI, nebulizer solution, or powder. Cromolyn has achieved a prominent role in managing patients with asthma, and has proven useful in preventing asthma attacks initiated by antigen contact, exercise, cold air, or hyperventilation. Cromolyn therapy is effective in almost half of all patients, and thus deserves a trial even in adults with chronic asthma.‘lg While the majority of benefit is usually apparent within 2 weeks of initiating therapy, a significant number of individuals may not see complete benefit for 6 to 8 weeks.lz2 A major benefit of inhaled cromolyn is its lack of significant side effects. Comprehensive preventive care of the asthma patient involves regular clinic follow-up with office visits and determination of flow 182
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rates both in the office and in the home. Home peak flow measurements should be reviewed with the patient with each office visit and any new complaint or change in severity of the disease should be noted. For patients who report weekly or more frequent attacks, maintenance therapy should include prolonged inhalation therapy with either corticosteroids or cromolyn, and an inhaled beta-adrenergic agent should be kept available should mild bouts of bronchospasm occur. Failure of this regimen with the need for emergency care, and a full-blown asthma attack represents a failure of preventive care and should result in a complete review of the therapeutic regimen and changes as needed. TREATMENT
OF THE ACUTE ASTHMA
ATTACK
Patients are frequently seen for the first time while having an acute asthma attack. The initial approach to management of acute asthma attacks is through the use of inhaled beta-adrenergic agonists. These agents have become the mainstay of acute therapy and are also useful in the preventive maintenance program as previously noted. Their major limitation is their relatively short duration of action (no more than about 6 hours in most patients). Beta agonists, while effective in the acute phase, have little or no effect on the late inflammatory response.1z0 When the acute asthma patient is first seen in the emergency room he is often too ill to provide an adequate history, and a thorough physical should be delayed until an initial estimate of severity is made and therapy, including nasal ozygen, is initiated. Laboratory tests should consist primarily of a spirogram or peak flow measurement, and ABGs are indicated only if the FEV, is below 2 L or the patient has other associated disease. Chest films and other laboratory tests are indicated if evidence of complications or other disease is present. Patients should be initially started on inhaled oxygen supplementation and a slow intravenous infusion should be begun for administration of drugs. Fluids may be administered if the patient is dehydrated, but are not routinely necessary. Once oxygen is started and an intravenous line is established, therapy with inhaled bronchodilators should be begun. Characteristics of currently available beta-adrenergic agents are shown in Table 7. The newer agents are similar in duration of action and clinical effectiveness and many are available in multiple forms including syrup, tablets, MDI, nebulizer solution, powder, or subcutaneous injection preparations. The majority of patients are treated with beta agonists administered via MDIs, which are convenient and relatively easy to use. Patients who cannot use MDIs effectively may require spacers or hand-held nebulizers. Hand-held nebulizers are DM, March
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TABLE 7. Commercially Available Beta,-Adrenergic Agents in the United States* Agent Isoetharine Metapmterenol Terbutaline Albuterol Bitolteml Pirbuteml
Dosage Formst
Duration of Action (hours)
N,M NJ%0
2-3 3-4 4-6 4-6 4-6 4-fi
M,O,S
N,M,O,P M M
‘From Gullatt I’J, George RB: ACCPPulmonary and Critical Care lipdate 1989, volume 4, lesson 30. Used by permission. tN = nebulizer solution; M = meterx&dose inhaler; 0 = oral preparation; S = subcutaneous injection; P = powder for inhalation.
often used in emergency room settings to assure adequate dose delivery, although their effects are similar to MDIs.lz3 Subcutaneous epinephrine or terbutaline may be used if aerosol administration is not possible, especially in infants and younger children. Doses given should be carefully monitored and patients observed for tachycardia or other signs of toxicity. The second pharmacologic agent that is invaluable in treatment of the acute asthma attack is corticosteroids. Corticosteroids should not be given by inhalation during the acute attack because they cause bronchial irritation; they may be given orally, by injection, or intravenously. We prefer to administer corticosteroids intravenously during the emergency treatment of asthma because this eliminates vomiting and poor intestinal absorption and assures prompt achievement of adequate blood levels. While some have advocated very high doses of steroids in the management of acute asthma, others have shown that moderate doses achieve equivalent effects. Britton et al. compared high-dose intravenous corticosteroid therapy with medium- and low-dose treatment during acute episodes.lz4 They found that medium and low doses (200 to 400 mg hydrocortisane/day) achieved the same benefit in terms of improvement in airflow over the first week of therapy as did the higher dose. Based on these and other reports we recommend moderate dosages of intravenous corticosteroids, approximately 200 mg of hydrocortisone every 6 to 8 hours or an equivalent dose of methylprednisolone. It is important to recognize that corticosteroids do not have significant effects on airflow for approximately 6 hours or more, even when given in high doses intravenously.‘z5 Therefore, it is important to initiate corticosteroid therapy as soon as failure to respond to beta-adl&l
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renergic agents to an adequate degree is noted, or if patients have required steroids for therapy during the previous 6 months. The place for intravenous theophylline during the acute management of asthma is changing somewhat in recent years. In general, the emphasis has been away from theophylline; however, it would be a mistake to ignore theophylline therapy in a review such as this because it is still commonly used in many hospitals. Siegel et al. showed that the addition of intravenous theophylline to beta-adrenergic aerosols had no additional effect over a S-hour period in patients with acute asthma.lzfi Moreover in the same study they showed that patients who were given intravenous theophylline had twice as many side effects as those treated with beta-adrenergics alone. Principal side effects in patients with acute asthma include gastrointestinal upset, tachycardia, and ectopic cardiac beats. The gastrointestinal side effects are especially bothersome and may limit the amount of theophylline tolerated. Anticholinergics have been recommended in the acute setting. Rebuck et al. showed that the addition of ipratropium bromide to a therapeutic dose of fenoterol (a beta agonist) produced added bronchodilation in a group of patients with acute asthma.” Other studies have suggested that while ipratropium may yield some benefit, atropine sulfate, when given with beta-adrenergic agents in the emergency setting, provides no additional benefit.lz7’ lz8 Patients should be observed closely in the emergency room during the management of their acute asthma attack, and serial objective tests of airflow should be performed whenever possible (about every 30 minutes to 1 hour). The determination for long-term care is dependent primarily on the response of the patient to optimum bronchodilator therapy during the initial 2 hours or so of treatment. A review of studies of emergency room management indicates that during early posttreatment, FEV, is a reliable indicator of the ultimate course of the acute attack, and will help determine whether the patient can be successfully discharged, will relapse after returning home, or will require immediate hospital admission. If the patient is responding well after a couple of hours and has not had recent life-threatening episodes, he should be discharged on tapering oral corticosteroid therapy with adequate bronchodilator medications and should be told how to get help in an emergency if necessary. He should be seen within the next week and objective tests repeated to determine if his condition continues to be satisfactory. Patients who are not successfully treated in the emergency room (i.e., do not have a satisfactory response to initial therapy) should be considered candidates for hospitalization. They should be admitted to the intensive care unit if possible, where they can be closely observed. They should be treated there until their condition has stabilized and they can be transferred to a general medicine ward. When DM, March
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oral and inhaled medications can be administered and flow rates are stable or improving, the patient can be transferred to the general ward, but should not be sent home directly from the intensive care unit. A period of 12 to 24 hours’ observation in the ward setting is necessary because death from acute asthma is common during the initial postrecovery period, when attention is directed to other patients and observation is lax. Once symptoms are controlled, flow rates are stable, and steroids are being tapered, an active regimen of preventive therapy including inhaled corticosteroids and other agents should be initiated. Occasionally patients do not respond to maximum therapy with oxygen supplementation, inhaled bronchodilator agents, and corticosteroids. The failure of maximum therapy is indicated by the physical finding of progressive exhaustion. Chest excursions, sweating, and tremor decrease, and breathing becomes shallow and rapid. Patients become confused and lethargic and may seem disoriented. This is usually associated with persistent FEV, of 1 L or less and with normalization or progressive increase in PaCO,. Other physical signs at this point include marked intercostal space retractions, decrease in accessory muscle strength, and sometimes a decrease in wheezing. These signs indicate that medical therapy has failed and that mechanical ventilation is needed. Mechanical ventilation is rarely indicated in the management of severe asthma and is associated with a high incidence of complications, especially barotrauma.12’ Because the chest is already hyperinflated and air trapping is marked, the addition of positive airway pressure tends to exacerbate the problems of barotrauma and decreased cardiac output. Mechanical ventilation may require the addition of intravascular fluid volume because of its effect on systemic venous return. Patients generally require mechanical ventilation for brief periods of a day or less, and weaning should begin as soon as possible. MANAGEMENT
FOLLOWING
THE ACUTE ATTACK
Prior to discharge from the hospital, a patient should have been switched from intravenous to oral and inhaled therapeutic agents. The efficacy of oral preparations of theophylline and steroids is similar to intravenous preparations; therefore, the timing of the switch probably makes little difference. However, a good time is when the patient has demonstrated a significant clinical response to therapy, and the PEFR or FEV, is greater than 60% to 70% of predicted values. The physician should demonstrate that the improvement in airflow can be continued on the new regimen for at least 24 to 48 hours. If after that time the patient has minimal wheezing, good exercise capacity, and is able to sleep at night, then the patient is ready to be 186
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discharged. All other problems identified (pneumothorax, pneumonia) must have stabilized or improved. After being discharged, the patient must be closely monitored, and instructed in the proper use of a peak flow meter and told to record the results at least twice a day. It is important to remember that an asthma exacerbation is usually not resolved completely at the time of discharge, and there are persistent airflow abnormalities compared with baseline function. The patient should have a follow-up medical appointment scheduled at the time of discharge, preferably within a week of discharge. In addition to being educated about how to use a peak flow meter and the MDI, the potential side effects of the prescribed medications should be explained. The patient should have a good understanding of when to call a physician and/or go to the emergency room. Once the patient is at home, the dose of oral steroids can be tapered, with the rate of decrease depending on the patient’s past frequency and severity of asthma attacks and the results of this peak flow measurement. It is at this point that inhaled steroids can be added safely to the patient’s therapeutic regimen. SPECIAL
SITUATIONS
NOCTURNAL
ASTHhIA
Nocturnal asthma attacks occur most often between 2 and 8 A.M. and interfere with normal sleep patterns, leading to daytime somnolence and interference with normal daytime activities. While beta,-adrenergic agents remain the cornerstone of asthma therapy, they have the drawback of a relatively short duration of action. A dose taken at bedtime begins to lose effect within about 4 hours. Sustained-release oral beta-adrenergic agents are now available, but their use is associated with systemic side effects, including nervousness and insomnia. A single bedtime dose of oral sustained-release theophylline may prevent nocturnal asthma attacks with minimal side effects. An alternative is inhaled ipratropium bromide at bedtime along with an inhaled beta,-adrenergic, because ipratropium has been shown to prolong the bronchodilation effects of beta-adrenergic agonists.‘30 PREGNANCY
The treatment of asthma in the pregnant patient is similar to that of other asthmatics, with a few exceptions. Pregnancy affects asthma in an unpredictable fashion with approximately one third of patients becoming worse, one third improving, and one third remaining the same. In those who become worse, peak severity is usually during DM, March
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the third trimester. After delivery, the asthma severity usually returns to baseline within 3 months.131 Uncontrolled asthma has significant harmful effects on the fetus, with increased prematurity and perinatal mortality.132 The drugs commonly used in the treatment of asthma have no demonstrated harmful effects on the fetus. Therefore, it is important to aggressively control the mother’s asthma in order to prevent placental hypoxemia. In general, as few medications as possible, preferably delivered by the inhaled route, should be used. If a pregnant asthma patient presents with an exacerbation of asthma, she should be treated aggressively with bronchodilators, corticosteroids, and supplemental oxygen. It must be kept in mind that if the patient has taken steroids during the year preceding delivery she may need steroid supplementation at the time of delivery. ELDERLY ASTHMA PATIENTS ASSOCZATED DISEASES
AND
THOSE
WlTH
Treatment of elderly asthma patients is similar to treatment of other asthma patients, with the following exceptions and precautions. These patients are likely to be on medications for other diseases that may affect their asthma, such as aspirin for arthritis, or beta blockers for heart disease or glaucoma. For this reason it is important to closely monitor the patient’s complete drug regimen. Despite the fact that patients with coexistent heart and lung disease rarely have an increase in cardiac arrhythmias and angina secondary to drug therapy, theophylline and the adrenergic medications must be watched closely for a worsening of heart disease.83 When treating patients over the age of 50 it is especially important to monitor for hypoxemia during acute attacks, which could exacerbate an underlying cardiac abnormality. Additionally, if oxygen supplementation is indicated it should be done carefully with ABG determination to note CO, retention, because some patients will have a combination of chronic obstructive pulmonary disease and asthma. The physician should be aware that the patient may have impaired hearing and eyesight, which could affect patient-physician communication, recording of information, performance of peak flow measurements, and proper use of MDIs. COURSE AND PROGNOSIS The course of acute asthma attacks varies markedly with or without medical intervention. Mild attacks, as in exercise-induced asthma, may respond to a single administration of an inhaled bronchodilator medication or may resolve spontaneously within a few minutes. Severe attacks persist over hours to days, and fatal asthma 188
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attacks are characterized by a lack of response to the usual therapy. The term “status asthmaticus” literally means prolonged or persistent asthma, i.e., not relieved by the usual therapeutic interventions. Several prognostic signs indicate a favorable outcome of the acute attack. These are all based on serial objective measurements, and depend on adequate baseline data obtained prior to therapy if possible, allowing for quantitation of changes during treatment. Some of these favorable early signs are shown in Table 8. Change in the extent of wheezing is not a valid prognostic sign, because the wheezes are produced by rapid airflow across small bronchial orifices. Large pressures are required to produce this rapid airflow, and with muscle fatigue flow rates may fall and wheezing may actually decrease or disappear. Some unfavorable prognostic signs during the acute attack are shown in Table 8. Just as good response to initial treatment has a good prognostic implication, poor response is an important negative prognostic finding, and is the basis of many indices of severity that are used to determine the need for hospitalization.38’ 40,133 The patient’s recent history is a clue to the prognosis for the present attack, and the presence of frequent attacks or prolonged attacks over the past few months suggests a poor response. Patients who have required corticosteroid therapy within the past 6 months tend to respond relatively poorly. While physical findings are poor quantitative indices, serial changes in physical findings over time may be helpful. The disapTABLE 8. Early Prognostic Signs in Acute Asthma Attacks* Favorable Signs Increase in peak flow or FEV, Increase in FVC Stable or improving PaO, and PaCO, Decrease in use of accessory respiratory muscles Decreased pulsus paradoxus Unfavorable Signs Severe attack (FEV,
ASTHMA
ABSTRACT.-Asthma is one of the most common respiratory problems in modern industrialized countries, affecting over 5% of the population. It affects all age groups from infants to senior citizens, and mortality rates Rom asthma appear to be increasing during the past few years in the United States as well as in other industrialized countries. Asthma tends to occur in families, associated with other allergic disease, and may be induced by a wide variety of environmental antlgens, most commonly inhaled allergens such as pollen and dust. Bronchial challenge with a specific allergen results in an early bronchospastic response with a relatively brief duration, and in a significant number of patients there is a late response with onset after 3 to 4 hours, lasting hours to days. This late response is associated with a bronchial hypersensitivity reaction, which is demonstrable by nonspecific challenge testing in the laboratory. During the period of bronchial hyperresponsiveness patients are prone to develop attacks following exposure to a wide variety of “triggers,” including cold air, fmnes, or cigarette smoke. The current approach to management of patients with asthma emphasizes prevention, with avoidance of specific allergens when possible, and chronic use of anti-inflammatory agents including corticosteroids and cromolyn sodium. The goal is to decrease the bronchial hyperresponsiveness. Management of the acute asthma attack consists of bronchodilator therapy, primarily with inhaled beta-adrenergic agonists, and administration of oral or systemic corticosteroids if the attack is not rapidly relieved. Additional therapeutic agents inclutig theophylline and anticholinergics may be useful in some situations. Response to therapy during the first couple of hours in the emergency room is the most important predictor of the course of the acute attack, and patients who 142
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1993
have not responded significantly after 2 hours of maximum therapy are candidates for hospital admission or prolonged emergency room observation. The goal of acute therapy is to wean the patient from intravenous drugs and place him or her on rapidly tapering doses of oral prednisone while hihiating a vigorous program of preventive therapy. Follow-up observation, both in the office and in the patient’s home, is vital and involves extensive patient education and objective testing of peak airflow. In general, the course of asthma is relatively benign compared with other obstructive ah-way diseases; however, significant mortality exists, especially in older patients and those with late-onset asthma. IN BRIEF Asthma affects over 5% of the total population of industrialized countries, involving all ages from infants to the elderly. It is best defined as a syndrome that includes a variety of clinical patterns from mild exercise-induced bronchospasm to severe chronic disability and bouts of acute respiratory failure. Mortality rates from asthma in several industrialized countries, including the United States and Canada, have increased over the past decade. The reasons for this are not clear and may involve a variety of factors, including improved reporting. However, one possibility is that the emphasis on bronchodilator therapy to the exclusion of avoidance techniques and anti-inflammatory agents may explain in part the increased mortality. While the increased mortality affects all age groups, it appears to be most marked in older patients. PATHOPHYSZOLOGY It has long been known that asthma, like other allergic diseases, has a familial predisposition. The mechanisms of inheritance have not been elucidated; however, there appear to be inherited variations in cells and cell mediators that cause them to behave differently in different populations. Recent evidence indicates that increased bronchial hyperreactivity may precede the onset of asthma by several years in patients from families with a high incidence of allergic diseases. There are a number of sensitizing agents, the most prominent of which are inhaled allergens, such as pollens, dust, and industrial agents. Other environmental agents that produce increased airway hyperresponsiveness include viral respiratory infections and toxic DM, March
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143
fumes. Once bronchial hyperreactivity is present, a variety of “trigger” agents may produce acute bronchospasm; these include cigarette smoke, exercise, and cold air. The acute response to an inhaled allergen occurs almost immediately and persists for perhaps an hour or so. In a significant number of patients with asthma, this acute response is followed by a delayed response with onset after approximately 3 to 4 hours and persistence for several hours or even days. This late asthmatic response has been related to the development of bronchial hyperresponsiveness and is a precursor of recurrent asthmatic attacks. The early bronchospastic response is a classic antigen-antibody reaction, wherein mast cells are initially sensitized by “reagin” or antigen-specific IgE antibody, which attaches to the cell wall. When this sensitized cell is re-exposed to the specific antigen, mediators are released, including histamine, leukotrienes, and pneumotaxic factors, that attract inflammatory cells to the area. It is the convergence of these inflammatory cells that appears to correlate with the late asthmatic reaction. Cells associated with the late asthmatic reaction include neurophils, lymphocytes, basophils, epithelial cells, and alveolar macrophages. Among the most important cells involved in the late asthmatic reaction is the eosinophil, which migrates to the bronchial wall in response to chemotactic substances released by macrophages and other cells, and is stimulated by mediators such as platelet activating factor to release a number of substances including major basic protein, which cause inflammation in the bronchial wall. Late effects of the asthmatic reaction include sloughing of mucosal cells, which in turn causes a loss of the protective effects of the epithelium and exposure of irritants to nerve fibers. During the acute asthmatic attack, there is edema of the bronchial wall and the mucus in the bronchial lumen becomes thick and tenacious. The major physiologic abnormality is airway obstruction with air-trapping and hyperinflation. This is manifested by a decrease in peak flow rates and vital capacity with an increase in residual lung volume and hyperinflation on the chest film. With the diffuse abnormality in distribution of ventilation there is progressive ventilationperfusion mismatching, with mild to moderate hypoxemia and secondary hyperventilation probably related to stimulation of neural receptors . CLINICAL
FINDINGS
Symptoms during the acute attack consist of dyspnea, wheezing, and cough in varying combinations. Physical findings include hyperinflation of the chest, tachypnea, tachycardia, sweating, wheezing, and decreased breath sounds. Other significant abnormalities dur144
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ing severe asthma attacks are sternomastoid muscle contractions, presence of a pulsus paradoxus, and changes in mental status indicating progressive fatigue. Symptoms and physical findings have been shown to correlate poorly with the severity of the airways obstruction and it is necessary to obtain objective tests of peak flow, either l-second forced expiratory volume (FEV,) or peak expiratory flow rate (PEFR), to assess the severity of the acute attack. Arterial blood gases show mild to moderate hypoxemia, which is correctable with increased FIO,, and hyperventilation with low PaCO,. The presence of a normal or increased PaCO, value during an acute asthma attack is an ominous finding portending exhaustion and impending respiratory failure. PvfANAGEMENT
Management of the patient with asthma involves two major goals; first, the prevention of the acute attacks and second, the treatment of acute attacks when they occur. Prevention of asthma attacks ideally is achieved by avoidance of the responsible antigens. This is rarely possible except in two situations, pet allergies and occupational asthma. A careful history and use of detailed questionnaires will help determine any avoidable responsible agents. Skin test reactions may help to confirm the presence of immediate sensitivity to an allergen. If symptoms such as seasonal allergy or wheezing on exposure to a specific agent are reported and if allergens identified by skin tests are compatible with the history, a trial on densensitization may be indicated, especially in young patients. However, success has been proved with only a few well-standardized antigens, including house dust mite and cat dander antigen. Desensitization is associated with inconvenience, cost, and sometimes serious reactions and should be employed only if demonstrated to be beneficial. Several drugs may cause bronchospasm and these include beta-adrenergic blockers and angiotensin-converting enzyme inhibitors. A history of concomitant drug therapy is an important aspect of the patient’s record. Pharmacotherapy consists of both bronchodilators and agents that decrease bronchial hypersensitivity. The principal bronchodilator compounds are the beta-adrenergic agonists, especially the beta,specific agents, including albuterol, metaproterenol, terbutaline, pirbuterol, and bitolterol. These compounds are relatively equivalent in relation to their effectiveness and duration of action. They are available in various preparations including metered dose inhaler (MDI), nebulizer solution, oral tablets, powders, and parenteral agents. The best method of administration of these agents is by inhalation, usually by MDI, in which case they are extremely effective with few or OM, March
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no side effects. Additional bronchodilator agents currently used in the treatment of asthma are the methylxanthine compounds (theophylline, aminophylline) and the anticholinergic agent, ipratropium bromide. These agents clearly have a lesser role in the management of asthma than the beta-adrenergics; however, they may be useful in some patients because of synergy and their longer duration of action. Sustained-released theophylline or a sustained-release oral beta-adrenergic agent may be useful at bedtime in patients with prominent nocturnal symptoms. The principal anti-inflammatory agents used for management of asthma are corticosteroids and cromolyn sodium. Corticosteroids are vital in the therapy of severe asthma attacks and should be initiated early and in adequate dosages; however, because of their severe side effects when given systemically for long periods, patients should be weaned from them as soon as possible. Inhaled corticosteroid preparations are increasingly accepted as first-line therapy in asthma, and are generally given via MD1 two to four times daily on a regular, long-term basis. Cromolyn. sodium is an alternative antiinflammatory agent for some patients with asthma, especially younger patients with extrinsic disease. Approximately half or more of patients will respond to cromolyn therapy and it should be attempted in patients with uncontrolled or recurrent symptoms. Its major benefit is that it has essentially no side effects; however, it must be given by inhalation several times a day and requires considerable patient cooperation. Additional anti-inflammatory drugs that are presently being investigated include antihistamines, methotrexate and other immunosuppressive agents, and gold salts. COURSE AND PROGNOSIS The course and response to therapy following an acute asthma attack are quite favorable, especially when compared with the other chronic obstructive lung diseases. With adequate therapy, response tends to be fairly complete, allowing for long-term follow-up on an outpatient basis. The key to follow-up care is supervision, and this should include objective tests of airflow in the office or clinic, and preferably in the patient’s home. This can be done by means of peak flow meters and daily records that patients can be taught to maintain on their own. Patients should be encouraged to seek help whenever they find it necessary and to report changes in their symptoms and flow rates to the physician as soon as possible. The need for emergency room care or hospitalization should be considered a failure of long-term care and should be followed by a complete revision of maintenance therapy. Mortality in asthma occurs in all ages, but peak mortality has been 146
DA4, March
19%
shown to occur in older patients, especially those cent onset of their disease. Thus, the most likely asthma would be a middle-aged or older person asthma for 10 years or less, especially if he or she attacks or has required steroid therapy during the
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who have had reperson to die of with a history of has had frequent previous year.
147
Ronald B. George, M.D. graduated from medical school at Tulane University School of Medicine in New Orleans, Louisiana, where he also served his medical residency and his Fellowship in Pulmonary Diseases. He continued on the faculty there until 1972, when he came to Shreveport, Louisiana to develop a new section of Pulmonary Diseases of the Department of Medicine at Louisiana State University Medical School. He is now Professor and Deputy Head of the Department of Medicine and Chief of the Section of Pulmonary and Critical Care Medicine.
Michael W. Owens, M.D. graduated from the Louisiana State University School of Medicine in Shreveport. He served a medical residency in Internal Medicine and a Pulmonary and Critical Care Fellowship at the same institution. He is currently an Assistant Professor of Medicine in the Section of Pulmonary and Critical Care Medicine, Department of Medicine, Louisiana State University School of Medicine. 148
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BRONCHIAL
ASTHMA
Asthma is one of the most common respiratory diseases, with an incidence of more than 5% of the total population in industrialized countries. Attempts to develop a definition for this common problem that would include all of its variations have persisted up until the present. Those who would define asthma as a disease are frustrated by its many variations, from occasional transient attacks of bronchospasm occurring after exercise or during the pollen season, to severe “intrinsic” or late-onset asthma, resulting in chronic disability. Furthermore, the factors that precipitate asthma attacks are diverse and involve a variety of mechanisms. There are a number of problems inherent in defining asthma as a distinct disease; alternatively, it might be better defined as a syndrome in which a number of mechanisms cause a common resp0nse.l An accepted definition of the asthma syndrome is included in an official statement of the American Thoracic Society, published in 1987.2 This statement defines asthma as a clinical syndrome characterized by increased responsiveness of the tracheobronchial tree to a variety of stimuli. The major symptoms are episodes of dyspnea, wheezing, and cough varying from mild and almost undetectable to severe and unremitting. The primary physiologic manifestation is variable airway obstruction, taking the form of spontaneous fluctuations in the severity of obstruction, substantial improvement following bronchodilators or corticosteroids, or increased obstruction caused by drugs or other stimuli. Histologically, patients with fatal asthma have evidence of edema of the bronchial mucosa; infiltration of the bronchial walls with inflammatory cells, especially eosinophils; and shedding of epithelium with obstruction of peripheral airclinical component of this ways with mucus.’ The most important definition is its emphasis on a change in airway resistance over time, the characteristic that separates asthma from the other chronic obstructive airway diseases. The syndrome of asthma is more than just reversible airflow obstruction; a working definition of asthma should include the underlying airway inflammation with its physiologic correlate, bronchial hyperresponsiveness. Reversible airway obstruction may be related not only to exposure to natural airborne allergies, but also to inhaled DA4, March
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occupational chemicals such as toluene diisocyanate and reactions following exposure to drugs such as aspirin.3 Infectious agents such as viruses and fungi may also produce bronchial hyperreactivity, through acute or chronic alteration of the bronchial wall and/or the immune system. There is evidence that the prevalence and severity of asthma and the number of deaths from asthma are increasing in several industrialized countries where accurate records are available.4-7 The gradual annual decline in deaths from asthma in the United States, as reported by the National Center for Health Statistics, ended in 1978.8 Since then there has been a progressive increase in the total number of deaths from asthma as well as in the number of deaths per 100,000 of population (Fig 1). As noted in Figure 2, while mortality has remained relatively stable in children, the increase has occurred primarily in patients older than 15 years. There was a revision in the international classification of diseases code that may have accounted for at least part of the increase in 1979; deaths from Total
Population
Line Chart for columns: X,Y,
1.8
1966
Deaths/Year-100,000
1968
1970
1972
1974
1976
1978
1980
1982
1984
1986
Year
FIG 1. Deaths from bronchial asthma per 100,000 population in the United States, 1968- 1984. (From Robin ED: Death from bronchial asthma. Chest 1988; 93:614. Used by permission.) 160
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Age-adjusted Oall
Death Rate for Asthma ~55-64 a >85
05-14
l 7.5-84
e 65-74
.; 1966
1968
1970
1972
1974
1976
1978
1980
1982
1984
1986
Year
FIG 2. death rates from bronchial asthma in the United States, 1968-1984. (From Robin ED: Death from bronchial asthma. Chest 1988; 93:614. Used by permission.)
Age-specific
asthmatic bronchitis, which were previously assigned to bronchitis, were reassigned to asthma. However, since this revision the increase has continued. The increase in mortality from asthma is especially disturbing because it has occurred despite significant improvements in therapeutic agents and an increase in the amount of prescribed asthma therapy.’ Indeed it may be that our reliance on the potent bronchodilator agents currently available has caused a change in the approach to asthma, which may be responsible for some increase in mortality. Prior to availability of these effective bronchodilator agents, physicians relied on such preventive measures as household cleansing, avoidance of irritants, and desensitization therapy. As the new agents became available, these measures may have been abandoned as physicians switched their patients to drugs that produce rapid symptomatic relief. Recently there has been a resurgence of interest in the late asthmatic response and persistence of symptoms for OA4, March 1991
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hours ago.”
to days after an acute attack, as noted
originally
100 years
CLASSIFICATION A proposed classification for the asthma syndrome is shown in Table 1. Allergen-induced or “extrinsic” asthma can occur at any age, but is more often seen in younger patients. It tends to be seasonal, with prolonged symptom-free periods. Extrinsic asthma may be induced not only by such inhaled allergens as house dust, pollens, and spores, but by occupational exposure or viral respiratory infections. Once the bronchial inflammation is present, subjects are prone to bronchospasm during exercise, inhalation of cold air, or hyperventilation. Irritants such as cigarette smoke and air pollution may also initiate an attack in susceptible patients. TABLE 1. Classification of the Asthma Svndmme
Allergic asthma
Asthmatic bronchitis
Occupational
asthma
Drug-induced
asthma
Allergic bronchopulmonaly aspergillosis
Synonyms
Clinical Characteristics
Extrinsic asthma Exercise-induced asthma Childhood asthma Seasonal asthma Late-onset asthma Intrinsic asthma Perennial asthma
Early onset Intermittent symptoms Rapid response to therapy May decrease with age Adult onset (older than age 301 Progressive decrease in FEV, Partial response to therapy Symptoms related to work May persist after changing jobs Partial response to therapy
Occupational airways disorders Industrial bronchitis Reactive airways dysfunction syndrome mADEi) Aspirin sensitivity “Cough syndrome” of ACE* inhibitors
Eosinophilic pneumonitis Pulmonary infiltrates with eosinophilia (PIE syndrome)
Causative agent usually apparent Partial or complete remission on removal of dw Proximal bronchiectasis Respiratory infiltrates Chronic symptoms Response to steroids Aspergillus precipitins and positive skin test usually present
'ACE = angiotensin-converting enzyme. 152
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Late-onset, or “intrinsic” asthma, is more commonly seen in older subjects, as the name implies. A popular term for this syndrome is asthmatic bronchitis, which indicates that airway inflammation is always present although it varies in intensity depending on various factors such as time of the year and climatic conditions. It is often impossible to define a causative allergic exposure in patients with intrinsic asthma. Although bronchodilator agents are effective in these patients, their response to bronchodilators is usually less dramatic than that of extrinsic asthma. The recognition that chronic bronchial inflammation is present in this population has led to the increased use of anti-inflammatory agents, including corticosteroids and disodium cromoglycate given over prolonged periods.ll’ l2 Occupational asthma, distinguished by its occurrence in workers exposed to industrial dust, vapors, fumes, or gases, may affect more than half a million people in the United States. A list of occupational agents associated with asthma, classified on the basis of molecular weight, is shown in Table 2.13 Occupational asthma may be defined as variable airway narrowing that develops after a period of symptomless exposure to a sensitizing agent at work. The latent period of months to years before symptoms occur suggests that immunologic mechanisms are involved in the pathogenesis of the disease. Whether a subject develops occupational asthma depends not only on the level and duration of exposure to an inciting agent, but also on certain host factors including atopy, cigarette smoking, and nonspecific bronchial hyperreactivity. Some agents associated with occupational asthma apparently do not depend on host atopy; these include the diisocyanates and Western cedar. Cigarette smoking may play a role through its interference with clearance mechanisms, which allows for prolonged contact of the inciting agents with the distal airways. Nonspecific bronchial hyperreactivity may be induced by the exposure rather than by acting as a predisposing host factor. Pm-employment challenge studies will clarify the presence or absence of nonspecific hyperreactivity prior to the development of occupational asthma. Several medications have been associated with increased bronchial hyperreactivity, and these agents may actually induce acute asthma attacks. Therapeutic agents associated with bronchial hyperreactivity include aspirin and the other nonsteroidal anti-inflammatory drugs. Angiotensin converting enzyme (ACE) inhibitor therapy has also been associated with bronchial hyperreactivity, possibly related to a decrease in the catabolism of kinins caused by the enzyme inhibitor.14’ I5 Allergic bronchopulmonary aspergillosis (ABPA) is a form of asthma that is characterized by recurrent radiographic infiltrates often seen in the upper lung fields, proximal bronchiectasis, and a clinical course that varies from remission to endstage fibrosis. First DM, March
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TABLE 2. Causes of Occuaational Asthma* Large molecular weight compounds/ chemicals Animal proteins Laboratory animals Domestic animals Birds Sea squirts Prawns Grain weevils and mites Enzyme lanimal~ Subtilisin Trypsin, pancreatin Plant Proteins Cereal grains Legumes (coffee, soy, castor bean Seeds (cotton, flex, linseed) Enzymes (plant) Papain, bmmelain, pectinase, diastase Vegetable gums Karaya, tragacanth, acacia (arabic), quillaja Small molecular weight compounds/ chemicals Anhydrides Phthalic, trimellitic, hexahydrophthalic, tetrachlomphthalic, hemic Platinum salts Dyes Azo, anthraquinone Diisocyanates Toluene diisocyanate Diphenylmethane diisocyanate Hexamethylene diisocyanate Antibiotics Metallic salts Nickel Chromium Aluminum Fluxes Colophony Aminoethylethanolamine Miscellaneous Formaldehyde Pyrethrum Extract of henna ‘From Care
Brooks
Update permission.
154
SM: ACCP Pulmonary and Critical 1986, volume 2, lesson 13. Used by
DM, March 1991
recognized in 1952,16 ABPA has many features that are also seen in patients with asthma but without ABPA. It is thought to result from an intense inflammatory response of the airways to the fungal hyphae that colonize the tenacious bronchial mucus of patients with asthma. Antigenic material released from the fungus into the bronchi reacts with mast cells, antibodies, and sensitized lymphocytes, often resulting in destruction of bronchial wall structures and bronchiectasis. Interstitial fibrosis is thought to result from recurrent inflammatory infiltrates in the lung parenchyma. PATHOPHYSIOLOGY It has long been recognized that asthma often affects multiple members of a single family. Asthma patients frequently have family members with other allergic symptoms such as eczema and allergic rhinitis. While the presence of a genetic tendency to develop exaggerated airway reactivity has long been accepted, at least for some asthmatics, a unifying theory has not been advanced to explain the inheritance of asthma.17 A recent report from a large study of the natural history of asthma indicates that bronchial hyperresponsiveness to a methacholine challenge may precede the onset of asthma by several years in subjects from asthmatic families, suggesting a genetic basis for enhanced airway reactivity.” The acute asthma attack may be precipitated by a variety of different “triggers,” both allergenic and nonallergenic.1s,20 The allergenic stimuli produce a biphasic response: an early response consisting primarily of bronchospasm, which may resolve in 30 to 60 minutes, followed by late response that becomes evident hours later and may be associated with hyperresponsive airways lasting for up to several weeks or months (Fig 3). The early and late asthmatic responses were first demonstrated in susceptible individuals by allergen inhalation challenge in the laboratory by Herxheimer in the early 1950s.Z1 He also noted that late asthmatic responses could occur without a preceding immediate reaction. Subsequently it was reported by Altounyan that hyperresponsiveness to nonspecific irritants such as methacholine was present in patients with allergic asthma.” Cockcroft and associates demonstrated the association between an increase in nonspecific hyperreactivity and the late asthmatic response.23 The characteristics of the early and late asthmatic responses after inhalation challenge are shown in Table 3.” Nonallergenic stimuli produce acute bronchospasm that usually lasts less than 1 hour and is not followed by the secondary or late response. This is characteristic of the response following challenge with nonspecific agents such as exercise, methacholine, or cold air inhalation. DM, March
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155
@ &
0--0w
-
D. PTERONVSSINUS
5.0 I-o----+ --so c P
4.0 -
3.0 -
FIG 3. The upper panel shows an isolated early bronchospastic response to inhalation of house dust mite extract (Dermatophagoides pteronyssinus). The lower pane/ shows an early followed by a late response after inhalation of the house dust mite extract. Open circles represent response to diluent alone, while closed circles represent response to antigen. The late response begins after 2 to 3 hours and persists for hours to days. (From O’Byrne PM: Late asthmatic responses. Am Rev Respir Dis 1967; 136:740. Used by permission.)
The persistence of increased hyperresponsiveness following an acute asthma attack has been the subject of intensive study in recent years. Cockcroft has proposed a hypothesis to explain the relationship of the acute allergic reaction to the late asthmatic response and to bronchial hyperreactivity. This theory is illustrated in Figure 4.24
156
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TABLE 3. Features of Early and Late Asthmatic Response After Inhaled Allergen*
Onset Peak Duration Prolonged increase in nonallergic responsiveness Treatment Beta,
Sodium cromoglycate Glucocorticoids
O’Bym~e
PM: A m
THE ACUTE
Rev
Late Asthmatic Response
Cl0 minutes 10 to 30 minutes 1.5 to 3 hours present
3 to 4 hours 8 to 12 hours >12 hours absent
Reverses Premedication inhibits
Partially reverses Premeditation has no effect Premeditation can inhibit Premeditation can inhibit
Pmmedication can inhibit Premeditation inhibits if administered long enough Premeditation has no effect
Indomethacin ‘From
Early Asthmatic Response
Respir Dis 1987: 136:740-751.
ASTHMATIC
Used
Premeditation
can inhibit
by permission.
RESPONSE
The acute allergic asthmatic response is the classic one, mediated by immunoglobulins (IgE) or “reagins.” Identifying the specific offending allergen requires an in-depth history with emphasis on timing of asthma attacks, frequency, duration, environmental exposure both at home and at work, drugs or food consumed, pets, and other contacts. The process of identifying one or more allergic “triggers” may be involved, and at times no definitive allergen is ever identified. Once the exposure has taken place, the sensitized individual develops an early response (within minutes) that is characterized by bronchospasm with acute airflow obstruction and increased mucous secretion that peaks within 10 to 15 minutes and resolves within 2 hours (see Table 3).25-28 The reaction is initiated by the combination of allergen with IgE bound to mast cells in the bronchial mucosa. The IgE-laden mast cells release histamine, products of arachidonic acid metabolism, vasodilators, and factors that increase vascular permeability.25 Degranulation of mast cells results in the release of a number of mediators that participate in the late phase response. These include not only mediators of the acute response such as histamine, prostaglandin D,, leukotrienes, heparin, and chymotrypsinltrypsin, but also additional mediators that may be involved in the initiation of the late phase response, including eosinophil chemotactic factor, neutrophil chemotactic factor, basophil chemotactic factor, and platelet activating factor (PAF). DM, March 1991
157
ALLERGEN + ‘gE
ALLERGIC REACTION
SYB%‘TOMS ON EXPOSURE TO NONALLERGIC STIMULI (IRRITANTS,EXERCISE.
etc)
FIG 4. Proposed relationship of the acute allergic reaction to the late asthmatic response and to bronchial hyperreactivity. (From Cockcroft DW: Airway hyperresponsiveness and late asthmatic response. Chest 1988; 94:178. Used by permission.)
THE LATE ASTHMATIC
RESPONSE
Approximately 50% of sensitized asthmatic subjects will develop a late asthmatic response following recovery from the acute response. ls This late response begins 3 to 4 hours following challenge and peaks at approximately 8 to 12 hours (see Table 3). Important features that distinguish the late asthmatic response include its persistence (it lasts sometimes for days), and its decreased responsiveness to bronchodilators when compared with acute bronchospasm. The onset of the late phase reaction is associated with the development of airway inflammation with cellular infiltration, predominantly eosinophils and lymphocytes, and persistent airway hyperreactivity. Thus, the late phase reaction is in several ways similar to 158
DA4, March
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chronic or ‘intrinsic” asthma. Because airway inflammation is characteristic of the late asthmatic response, current interest is centered on the mechanisms that produce inflammation. The late asthmatic response begins with an influx of inflammatory cells including macrophages, eosinophils, neutmphils, and lymphocytes; within 2 hours, basophils also become plentiful. The macrophages may be activated by an allergen-IgE reaction on the cell membrane and thus may participate with the mast cells in the development of late responses. In contrast to mast cells, macmphages are inhibited by corticosteroids but not by the beta-adrenergic agonists, which rapidly reverse the acute allergic reaction. It appears that the IgE-allergen reaction induces mast cells and perhaps macrophages to release mediators that initiate the late asthmatic response (Table 4). These mediators have been shown to recruit eosinophils and other inflammatory cells to the bronchial mucosa and these cells in turn sustain the inflammatory response.2Y BRONCHLU
HWERRESPONSIVENESS
Many inflammatory asthma and probably
mediators have now been implicated in contribute to the various features of asthma,
TABLE 4. Mediators Associated With the Late Phase Asthmatic Response* Cell Source
Mediator
Mast cell
Histamine Platelet-activating factor Leukotrienes Eosinophil chemotactic factor Neutmphil chemotactic factor Basophil chemotactic factor Heparin Chymotrypsinitrypsin Major basic protein Eosinophilic cationic protein Platelet-activating factor Leukotriene C4 Unknown unknown
Eosinophil
Neutrophils Basophils
‘From Gullatt TJ, Gear@ RB: ACCP Pulmona~ Critical Care Update 1989, volume 4, lesson Used by permission.
DM, March 1991
and 30.
159
including bronchoconstriction, microvascular leakage, and mucus secretion.30 The products of arachidonic acid metabolism, including prostaglandin D, and leukotrienes, cause an increase in bronchial hyperresponsiveness. One mediator, PAF, causes a sustained increase in bronchial responsiveness that may persist up to 4 weeks even in normal subjects.31 Not only does PAF cause recruitment of eosinophils to the lungs but it also stimulates the release of basic proteins from the eosinophils. These basic proteins are toxic to epithelial cells in the airways and cause the bronchial mucosal cells to exfoliate into the bronchial lumen, with actual denuding of epithelial basement membranes?’ Epithelial shedding may in turn contribute to bronchial hyperresponsiveness through the loss of a proposed epithelial relaxant factor present in the cells or a decrease in degradation of inflammatory mediators by the cells. This loss of epithelial surface also results in impairment of mucus removal via the mucociliary escalator, and exposes sensory nerves, which are then triggered more readily.” NEURAL MEChXNlSMS Cholinergic reflex bronchoconstriction, mediated through afferent and efferent fibers in the vagus nerves, has long been implicated as a cause of nonallergic bronchospasm.33’ 34 In addition, there has been a recent interest in the role of nonadrenergic, noncholinergic nerves in asthma, which may be the source of inflammatory neuropepinclude substance P, an inducer of mitides.35 These neuropeptides crovascular permeability and mucous secretion; and neurokinin, a potent bronchoconstrictor. Another neuropeptide, vasointestinal peptide (VIP) relaxes airway smooth muscle, and current research focuses on abnormalities of VIP function in patients with asthma.36 Neurogenic inflammation may be a tar et for investigation into future therapeutic approaches to asthma. #S OBSTRUCTION
TO AIRFLOW
During acute asthma attacks, the inflammatory response in the airways causes contraction of smooth muscle layers in the walls of the bronchi. With repeated attacks, the muscle layers hypertrophy so that the normally thin muscular layers become thickened and prominent. The capillaries in the submucosa dilate and become hyperemic, and there is leakage through capillary walls resulting in edema of the bronchial walls. Mucous secretion is increased and the character of the mucus is altered so that it becomes thick and tenacious. In patients dying from asthma there is denudation of the bronchial mucosa with large chunks of mucosal lining cells adhering to the bronchial mucous plugs. These clumps of epithelial cells 160
DM, March
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form the Creola bodies in the sputum that are typical of severe acute asthma attacks. Inflammatory cells are prominent in the walls of the bronchi, consisting primarily of eosinophils and, to a lesser extent, lymphocytes. Bronchospasm, mucosal edema, and mucous plugging all result in a common abnormality of lung function, that is, airflow obstruction. Of these, only smooth muscle spasm is responsive to bronchodilator therapy to any significant extent. The other abnormalities, mucosal edema and mucous plugging, are reversed by anti-inflammatory agents over a period of hours to days. Airway obstruction produces air-trapping, with marked hyperinflation of the lungs visible on chest films taken during acute attacks. The diaphragms are low and flat, thus interfering with normal diaphragm function. To compensate for reduced diaphragm activity, patients use the accessory muscles of respiration, the sternocleidomastoids and intercostals, which serve to enlarge the diameter of the thorax. While this is helpful, it is a relatively inefficient method of ventilating the lungs and results in increased work of breathing and muscle fatigue. With airway obstruction, both inspiration and expiration become active processes, and marked changes in pleural pressure from inspiration to expiration occur in the thorax. These dramatic changes, as much as 50 cm H,O or more during respiration, result in alteration of venous return to the heart and the clinical finding of pulsus paradoxus (a variation of 10 mm or more of systolic pressure from inspiration to expiration). This is a relatively reliable clinical finding in severe asthma, and the l-second forced expiratory volume (FEV,) is usually 40% or less of the predicted value when pulsus paradoxus is present.37 Severe airway obstruction may be present without pulsus paradoxus, however, especially with the onset of muscle fatigue and a resulting decrease in the pleural pressures generated. Since the degree of obstruction varies from one area of the lung to another, there are marked abnormalities of distribution of inhaled air into the lungs. There are also abnormalities in the distribution of perfusion, so that significant mismatching of ventilation to perfusion occurs. This results in mild to moderate arterial hypoxemia, which is relatively easily correctable by increasing inspired oxygen concentrations. The decrease in PaO, correlates roughly with the severity of airway obstruction, although there is a wide variation in PaO, values in different asthma patients with similar severity of disease.38 The ‘normal” respiratory response in acute asthma is hyperventilation, with a decrease in arterial carbon dioxide tension (PaCO,) and respiratory alkalosis. This decrease in PaCO, is not a response to arterial hypoxemia because it persists even when oxygen is administered and PaO, is normal or elevated. Hyperventilation is most likely related to neural reflexes in the lungs and chest wall associated with the obstruction to airflow and increased work of breathing. Most paDA4,March1991
161
tients continue to hyperventilate until airway obstruction becomes severe, with FEV, in the range of 1 L or less. At this point, in some patients respiratory muscle fatigue progresses with normalization and increasing arterial PCO, levels. The normalization and later retention of CO,, leading to respiratory failure, may be hastened by the administration of sedatives.3g Metabolic acidosis may complicate the other acid-base changes in patients with severe asthma, perhaps because of increased oxygen consumption resulting from the work of breathing associated with a decrease in oxygen delivery. Carbon dioxide retention and metabolic acidosis are ominous signs in acute asthma attacks, associated with exhaustion, respiratory failure, and death.7’ 40,41 CLINICAL
FEATURES
SIGNS AND SYMpTolMS The literature is replete with descriptions of symptoms and physical findings during the acute asthma attack. The most common symptoms are cough, wheezing, and dyspnea, and the episodic appearance of these symptoms suggests a diagnosis of asthma. Dyspnea (difficulty of breathing, “shortness of breath”) is the most fiequent complaint of patients during an episode of asthma, and is usually associated with tightness in the chest and wheezing. A cough is usually present and may be the presenting symptom.42 A subset of patients with asthma is characterized by recurrent or chronic nonproductive cough without any overt wheezing.42 The history should include when the symptoms first started and how often and severe the attacks are (days per week); what activities/ agents provoke the attacks and whether they are seasonal; any patient history of atopy; prior therapy for asthma; presence of diurnal variation; impact of asthma on lifestyle and family; and family history (IgE-mediated allergy and asthma in relatives). Exercise-associated asthma usually results in cough, wheezing, and/or dyspnea toward the end of or following a period of exercise, rather than during the actual performance. These symptoms are usually short-lived and regress spontaneously or with treatment in most patients. A linear relationship exists between the degree of airflow obstruction and the magnitude of perceived dyspnea in a given patient,43 and patients may be better than their physicians at judging the severity of an asthma attack.44 In the asymptomatic patient, the chest examination may be unremarkable. However, examination of the eyes, ears, nose, and throat may reveal otitis media, conjunctivitis, rhinitis, nasal polyps, or sinusitis as evidence of an allergic diathesis. During mild exacerbations of asthma, wheezing may be heard only during forced expira162
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tion. With more severe disease, wheezing is heard during both inspiration and expiration and is associated with signs of hyperinflation. Physical examination during an acute exacerbation of asthma is usually associated with signs of hyperinflation and diffuse wheezing in all lung fields. However, during very severe attacks, as muscle fatigue decreases the ability to produce high expiratory pressures, there may be few or no audible wheezes. Thus, wheezing is of no help in establishing the severity of airway obstruction. Clinical evidence of hyperinflation is provided by an increase in the anteroposterior diameter of the chest, decreased cardiac dullness to percussion, and inferior descent of the zone of hepatic dullness. The use of accessory muscles of respiration (sternocleidomastoids) in an attempt to generate high negative intrapleural pressures is a particularly useful sign in evaluating the severity of airway obstruction. The two most reliable physical findings in judging the severity of the acute attack are sternocleidomastoid muscle contractions during inspiration and paradoxical pulse (Table 51. Accessory muscle contractions indicate the inability of the diaphragm to overcome the severe airway obstruction, and correlate with hyperinflation. While the presence of sternocleidomastoid contractions and paradoxical pulse is a significant finding, the absence of these is not very useful because this may occur with or without severe asthma attacks, and some patients with the most severe degrees of aitway obstruction may not manifest these findings. Another clinical finding that is extremely useful is a disturbance of consciousness. The severe asthma patient becomes exhausted and is frequently listless, somnolent, and somewhat confused. This is an ominous finding that correlates with CO, retention and indicates the possible need for mechanical ventilation. Note that all three significant findings-paradoxical pulse, sternocleidomastoid contractions, and disturbed conscious-
TABLE 5. Grading of Severity During an Acute Asthma Attack
Objective Findings FEV, or PEFR* PaO, PaCO, Clinical Findings Paradoxical pulse Sternocleidomastoid contractions Disturbed consciousness 'PEFR = Peak expiratcq flow Uhf, March 1991
Mild
Moderate
Severe
Over 60% predicted value 1 or+ i 4
40% to 60% predicted value
Less than 40% predicted value J J I,-+or t
Absent Absent
Absent Absent
May be present May be present
Absent rate.
Absent
May be present
i or--f
163
ness-are always important when present but their absence is not always relevant. Vital signs can be normal during a severe attack, but a heart rate above 110 beats/min and respiratory rate greater than 28/min are usual.45~ 46 Systolic blood pressure may increase, with a widened pulse pressure and an inspiratory decline in systolic blood pressure greater than 10 mm Hg (pulsus paradoxus). With response to therapy these signs will improve as hyperinflation decreases, while wheezing and rhonchi tend to linger without a reliable relationship to symptoms. The combination of an increased respiratory rate, use of accessory muscles, diaphoresis, and inability to complete sentences without interruption indicates the presence of a severe asthma attack.
DIFFERENT&IL
DlAGNOSIS
OF WHEEZING
Recurrent episodes of wheezing are almost always indicative of asthma; however, there are other causes of airway obstruction associated with wheezing. In children, foreign bodies in the trachea, bronchus, or esophagus, vascular rings, laryngotracheomalacia, enlarged lymph nodes or tumor, laryngeal webs, and tracheostenosis or bronchostenosis should be considered. Inspiratory/expiratory flow volume loops are helpful in eliminating large airway problems as a cause of episodic or sustained wheezing. Diseases that cause obstruction of both large and small airways, in addition to asthma, include viral bronchiolitis, cystic fibrosis, Chlamydia trachomatis infection, obliterative bronchiolitis, bronchopulmonary dysplasia, and aspiration secondary to swallowing mechanism dysfunction or gastroesophageal reflux. In adults, mechanical obstruction of the airways, exposure to toxic fumes, laryngeal dysfunction, chronic bronchitis and emphysema, left heart failure (cardiac asthma), pulmonary embolism, and allergic bronchopulmonary aspergillosis should be considered.
PULMONARY
FUNCTION
TESTS
Spirometric studies are helpful in the diagnosis and quantification of airflow obstruction and in measuring the response to therapy. Portable spirometers have been perfected to the point that they are sufficiently accurate for the clinical assessment of patients. Portable spirometers should provide a graphic record of the spirogram, and should be calibrated regularly.47 A forced expiratory curve is relatively simple to obtain even during a severe attack and can be interpreted immediately. If a patient cannot produce a 5-second forced 164
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expiration because of dyspnea, one can assume that the airway is severely obstructed. There are several methods of interpreting the forced expiratory curve in order to determine the severity of airway obstruction. The commonest measurements used are the FEV,, the forced vital capacity NC), the FEVJFVC ratio, and the maximum midexpiratory flow rate (FEF25.-75%). While all four of these measurements are useful, the FEV, is the easiest to measure and has the least intrinsic variation because it is not influenced by changes in the vital capacity, which itself changes significantly during attacks.48 Changes in the peak expiratory flow rate (PEFR) correlate well with changes in FEV, during asthma attacks. The PEFR is easier to perform and may be obtained when a spirogram is impossible. The disadvantage of the peak flow is that it is a single number and gives no estimate of error in performance, air trapping, or changes in lung volumes. Peak flow meters must be calibrated regularly, like portable spirometers. Whether the FEV, or PEFR is chosen as the primary measurement to quantitate the course and severity of an attack, it is of major importance to record baseline flows and maintain a flow sheet, with times, flow rates, and therapy. This flow sheet is of vital importance in continuing management of acute attacks and in decisions about follow-up care. Initially, the FEV,, FEVJFVC, and PEFR are significantly decreased, and their values assist in early assessment of severity (see Table 51. A decrease in FEVJFVC ratio to less than 60% indicates moderate severity, and a decrease below 40% indicates severe obstruction. There may be no increase in FEV, after bronchodilator administration at first, but responsiveness is an early sign of improvement. With a severe exacerbation of asthma the FVC is reduced with an increase in the residual volume (RV), functional residual capacity (FRC), and total lung capacity (TLC)?’ This loss of vital capacity with increase in RV and TLC is called air-trapping, and is a sign of significant airway obstruction. The FRC is increased in part because of continued contraction of the inspiratory muscles during expiration. The RV and FRC tend to be markedly increased (approximately 200% and 400% of predicted, respectively) in patients presenting to an emergency room with an acute attack. The diffusing capacity for carbon monoxide (DLCO) is usually preserved.50 Hypoxemia during the acute attack is the result of marked ventilation-perfusion mismatching, rather than a defect in gas exchange, and is corrected with increased FIO,. Peak flow measurements are especially useful when following asthmatics at home, because simple, inexpensive mini peak flow meters are available.51 The peak flow maneuver is very simple to perform and yields a single number that the patient may record on a flow chart at home. Diurnal variations in asthma and peak flow variDM, March
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ability indicate the degree of bronchial hyperresponsiveness. Because a patient’s symptoms are not reliable indicators of the severity of PEFR can help predict of airflow obstruction,52 the measurement abnormalities earlier and allow for more appropriate changes in medications. In the interval after an acute attack pulmonary function tests may be normal, or without continued treatment there may be some degree of airflow obstruction and hyperinflation.53-56 Even when the patient and the clinician believe the attack is over, there may still be significant abnormalities of pulmonary function, requiring continued active treatment.54 ARTERLAL
BLOOD
GASES
Arterial blood gas (ABG) analysis is helpful in determining the severity of an acute asthma attack and is indicated if flow rates are markedly decreased, if patient response is poor, or if there is evidence of associated disease-producing abnormalities in gas exchange that can lead to decreases such as chronic obstructive pulmonary disease.52’ 57S58 The PaO, falls in a fairly uniform manner as the FEV, decreases.5g With mild bronchospasm (FEV, > 2 L), ABG is a poor indicator of the severity of airflow obstruction, with a near normal PaO,, respiratory alkalosis, and a widened alveolar-arterial oxygen gradient .52 Patients who experience mild to moderate asthma attacks usually have some hypoxemia. Cyanosis is uncommon, but indicates an extreme degree of respiratory impairment if present. The PaCO, is mildly reduced (approximately 30 to 35 mm Hg) until the attack becomes severe (see Table 5). Approximately 75% of asthmatics seen in the emergency room have hypocarbia and respiratory alkalosis.52 As the FEV, decreases below 1 L, the PaCO, normalizes. If airflow worsens, hypercarbia and respiratory acidosis develop. The presence of hypercapnia and respiratory acidosis implies severe disease, with an FEV, of less than 15% of predicted.57 BADlOGBAPHIC
CHANGES
The chest radiograph is not helpful for diagnosing asthma or for determining the severity of an acute asthma attack,” but should be obtained when the patient is first seen to rule out other causes of airway obstruction or the presence of complicating illnesses such as cardiac disease or bronchiectasis. During acute attacks there is hyperinflation and a small elongated heart, such as that seen in patients with emphysema (Fig 5). A chest radiograph is helpful in patients with intractible episodes of asthma because it indicates complications of the acute attack, such as pneumonia, pneumothorax, 166
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FIG 5. Chest radiograph from a 2.5year-old man during an acute asthma attack. There is marked hyperinflation, with low, fiat diaphragm, and elongated heart. This film resembles that of a patient with advanced emphysema.
pneumomediastinum, or rib fractures. Sinus films are helpful in patients with symptoms of allergic rhinitis and sinusitis. Other radiographic studies such as computed tomography (CT) scans, arteriography, and chest fluoroscopy are rarely indicated unless additional diagnoses are suspected. OTHER
LABORATORY
TESTS
The sputum is usually white, thick, and mucoid, but can look purulent secondary to eosinophilia rather than polymorphonuclear cells. Microscopy may demonstrate eosinophilia, Charcot-Leyden DM, March
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crystals (degenerated eosinophils), Curschmann’s spirals, and Creola bodies. The presence of Creola bodies (clumps of epithelial cells) suggests a severe attack.61 The presence of brownish mucous plugs containing mycelia suggests Aspergillus colonization and ABPA. Nasal secretions can be stained for eosinophils; if they are present, one can establish an allergic etiology of associated rhinitis; the presence of a neurophilic nasal discharge suggests associated sinus infection. The complete blood count (CBC) may show an increase in white cells, frequently with increased eosinophils, and indicates a patient’s allergic predisposition. Eosinophils may not be present if the patient is taking steroids and can be used to judge the adequacy of the steroid dose.62 Marked eosinophilia (>3,000/mm3) raises the possibility of Loffler’s syndrome, ABPA, or Churg-Strauss syndrome. The electrocardiogram adds little to the diagnosis or routine management of asthma. It should be obtained in patients with a history of cardiovascular disease and those over the age of 50 years who present with an acute attack. The changes, usually seen with the more severe attacks, are nonspecific in nature. Sinus tachycardia is frequent, and right axis deviation, right ventricular hypertrophy, right bundle branch block, and premature ventricular contractions are sometimes present4’ and may be associated with right heart strain and/or heart failure. The more severe the asthma, the more likely one of these abnormalities is to be found. Other tests may be indicated in the presence of specific symptoms. For instance, in patients with recurrent nocturnal attacks associated with gastritis or heartburn, monitoring for gastroesophageal reflux with manometry or esophageal pH monitoring may be usefu1.63 Esophagrams and upper gastrointestinal series may help to exclude motility problems or hiatus hernia. Patients suspected of having deep vein thrombosis of. the legs may be candidates for ventilation/perfusion lung scans to rule out recurrent pulmonary emboli. Patients with copious sputum production and frequent infections should be screened for motility disorders including milder forms of cystic fibrosis, with sweat chloride levels or nasal ciliary biopsy. Patients with sensitivity to aspirin and nonsteroidal anti-inflammatory agents are usually aware of their problem, and will relate an association with these drugs. They often have chronic symptoms with sinusitis and nasal polyps, and will respond to a challenge with the offending agent.
ASSESSMENT
OF SEVERITY
Characterization of a patient’s asthma as mild, moderate, or severe enables the clinician to categorize the overall assessment of a pa168
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tient’s asthma and select appropriate therapy. The physician should consider all available data, including the frequency of symptoms, degree of exercise tolerance, presence of nocturnal asthma, chest radiographic findings, pulmonary function tests, and degree of methacholine sensitivity in determining the severity of disease. In general, the severity of asthma cannot be estimated from the history or physical examination, During the acute attack the symptoms and physical findings correlate rather poorly with the severity of obstruction.64 Symptoms should be relied upon to bring the patient to the hospital but after that, measurements should be objective because symptoms are frequently absent when obstruction is still marked. The most important variables in judging severity are the degree of airflow obstruction and the frequency and length of attacks. This information is best obtained from flow charts maintained by the physician in the office and by the patient or family at home. If the patient has rare (seasonal) attacks with few clinical symptoms of asthma between exacerbations, the diagnosis is mild asthma. Patients have moderate to severe asthma if their exercise tolerance is diminished, if persistent cough and wheezing are present, or if symptoms of nocturnal asthma occur at least two to three times per week with frequent interruption of sleep. If hyperinflation is evident on the chest radiograph when the patient is asymptomatic, this suggests moderate disease. If the chest radiograph reveals a chest deformity in children because of chronic hyperinflation, severe disease is likely. During asymptomatic periods in patients with mild asthma, pulmonary function tests reveal minimal or no evidence of airway obstruction, normal lung volumes, peak flow rates greater than 80% of predicted values, and a greater than 15% response to bronchodilator administration even though they are begun at near normal baseline levels. Between attacks in patients with moderate disease, there is evidence of airway obstruction on spirometry, with reduced expiratory flow at low lung volumes. Peak flow rates are 60% to 80% of predicted values, and RV is increased; however, there usually is still an increase of more than 15% after bronchodilator administration. With severe disease there is significant airway obstruction associated with marked increases in RV. Peak flow is less than 60% of predicted values, and limited reversibility may exist after bronchodilator administration. It is important to note that these objective measurements may be influenced by other underlying lung diseases. The FEV, and FVC may be affected by chronic bronchitis, emphysema, diseases of the chest wall or diaphragm, or neuromuscular disorders. Chronic bronchitis can cause hypoxemia and CO, retention, while hyperinflation and a decrease in DLCO are often seen with emphysema. DM, March
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NONSPECIFIC BRONCHW
PROVOCATION
Bronchial provocation testing is a simple and generally safe procedure that can be performed in the office setting in order to demonstrate bronchial hyperreactivity, especially in patients with episodic symptoms who present during an asymptomatic phase. An intrinsic feature of asthma, bronchial hyperreactivity is defined as a 20% or greater decrease in FEV, in response to a provoking factor that, at the same dose, causes less than a 5% change in a normal subject (Fig 6). Additionally, a patient has bronchial hyperreactivity if there is a 20% or greater increase in the FEV, in response to an inhaled bronchodilator. The degree of bronchial hyperreactivity to methacholine and histamine challenge correlates well with the severity of asthma symptoms, the diurnal variation in airway function, and the amount of therapy required to control symptoms.65 Methacholine is more widely used for bronchial challenge because it is more stable and is more readily available. Response to methacholine and histamine are similar, and correlate with other nonspecific challenges such as cold air inhalation or exercise. Patients should have near normal lung function and have had no bronchodilator drugs for 6 hours prior to performing a methacholine challenge test. The cumulative dose of methacholine causing a 20% of methacholine drop in FEV, (PD,, FEV,), or the concentration causing a similar drop (PC,,) are well standardized, widely accepted indices .66 The PD,, or PC,, FEV, following methacholine inhalation can be used to classify the patient into mild, moderate, and severe
I
I
PBS
I
1
1
1
O-03 O-08 O-125 O-25 O-5
Histamine (or methacholine)
1
I
I
I
1
2
4
8
concentration
(mglml)
FIG 6. Change in FEV, as a percent of the control value following the inhalation of increasing concentrations of aerosolized histamine or methacholine. The concentration of inhaled trritant which results in a 20% decrease in FEV, is the PC,, (Adapted from Cockcroft DW, et al: Allergen-induced increase in nonallergic bronchial reactivity. C/in Allergy 1977, 7:503-513.)
170
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bronchial reactivity (see Fig 6). The bronchial hyperreactivity level can also be used to follow the response to therapy, when preventive agents such as inhaled corticosteroids or cromolyn sodium are used. Exercise and cold air challenge are also commonly performed and well standardized, especially in patients with a history of exereiseinduced asthma.67 In general, they require more patient cooperation and a generally fit patient. Results are similar to methacholine challenge in those with exercise-induced asthma; however, methacholine appears to give a more reliable and more quantifiable result.
DETERMINATION
OF PROVOKING
AGENTS
It is important to determine, if possible, which agents are provoking asthma attacks so that they can be avoided or eliminated from the environment. A careful history will often reveal potential provoking agents. Questions concerning potential occupational exposures, pets, and food intolerance should be asked. Standard allergy history questionnaires are available from various volunteer organizations. The typical patient with work-related asthma develops wheezing, chest tightness, or cough with or without sputum production or rhinitis toward the end of a shift, which worsens during the night and improves toward morning. The patient often recognizes a relief of symptoms after a holiday or long weekend. The atopic status of a patient can be determined by simple skin prick tests using common airborne allergens. Immediate-type hypersensitivity skin testing detects IgE antibody against specific allergens. If positive, these tests suggest an allergic cause of the patient’s asthma. Skin test results should be considered clinically significant when they are associated with a positive history. The radioallergosorbent test (RAST) and enzyme-linked immunosorbent assay (ELISA) are in vitro tests for evaluation and quantification of antigen-specific IgE antibodies in serum.68 These tests correlate with results from skin tests and provocation testing. In vitro tests are advantageous because they avoid anaphylactic reactions, and can be done in the patient’s absence. Disadvantages include expense and decreased sensitivity compared with provocation testing. Patients whose skin tests correlate with history may be candidates for specific allergen inhalation challenge. Allergen challenge is a highly specialized procedure and should be performed only by Positive immediate bronchospastic reexperienced laboratories. sponses may be followed by late reactions in a significant number of patients.6” DM, March
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MANAGEMENT Asthma can be regarded as a heterogenous disease because of its presenting symptoms, severity, and response to therapy. Some basic concepts can facilitate the management of asthma. First, the patient must try to avoid known precipitating factors, such as known allergens, but also irritants such as smoke, strong perfumes, and aromatic room deodorizers. Second, the sooner an exacerbation is treated the easier it is to abate. Third, even patients with moderate asthma may have recurrent symptoms that may benefit from continuous rather than as-needed treatment. Fourth, patient compliance is an important part of the management program, and the more educated a patient is about asthma the more likely the patient is to comply with the treatment regimen. The aims of therapy include relief of bronchospasm, mobilization of secretions, maintenance of alveolar ventilation, a decrease in bronchial hyperresponsiveness, prevention of acute exacerbations of asthma, and avoidance of adverse effects from asthma treatment.
PHARMACOLOGIC
AGENTS
Drug therapy for asthma can be divided into bronchodilators and anti-inflammatory agents. Bronchodilators act to reduce bronchial smooth muscle contraction, clear mucous secretion, and dilate the airways. They are used mainly to treat symptoms when they occur (such as in exercise-induced asthma) and occasionally to prevent bronchospasm. Anti-inflammatory drugs reduce airway inflammation and reduce bronchial hyperresponsiveness. They are becoming first-line agents as the emphasis shifts from intervention during acute attacks to prevention of acute attacks by treating bronchial hyperresponsiveness. BRONCHODZLATORS Beta-adrenergic agonists (sympathomimetics) mimic the adrenal medullary hormones and neurotransmitters. They work by increasing cyclic adenosine monophosphate (CAMP) formation, with a resultant change in intracellular calcium concentrations7’ Beta receptor stimulation results in effects on the lungs, heart, and other organs. Beta, stimulation leads primarily to positive chronotrophy and inotrophy of the heart, while beta, stimulation results in various benefits to the respiratory system, such as relaxation of the smooth muscle of the bronchi, prevention of smooth muscle contraction by various stimuli in a dose-related response, increased clearance of mucus, decreased release of mediators from cells near the epithelial 172
DM. March
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surface (basophils and mast cells), and it may protect venular endothelial cells and partially prevent edema. Beta, receptors also cause vasodilation and skeletal muscle tremors, and probably have some direct stimulatory effects on the heart.‘l There are four classes of beta-adrenergic agonists: catecholamines, resorcinols, saligenins, and pro-drugs. Catecholamines have mixed alpha, beta,, and beta, effects. This group includes epinephrine, isoproterenol (a synthetic derivative of epinephrine) and isoetharine. Catecholamines are quickly methylated in the lung by catechol-omethyl-transferase with a resultant duration of action of only 1 to 2 hours7’ Their major disadvantages are their short half-life and lack of beta, specificity, and some patients develop tolerance to these agents.73 The resorcinols include metaproterenol, terbutaline, and fenoterol. They are more beta,-selective and have a longer half-life. The more selective beta, drugs are not methylated and their duration of action is much longer (about 4 to 6 hours).74, 75 Albuterol is from the saligenin group, which are relatively beta,-selective and have a longer half-life than isoproterenol. Pirbuterol differs from albuterol only by substitution of a nitrogen atom for a carbon atom in the benzene ring. Pro-drugs are inactive until they are metabolized. An example is bitolteml, which is cleaved in the lung by esterase to its active form, colterol. The level of esterase is higher in the lung than in the heart, resulting in fewer cardiac side effects. SigniRcant side effects of the sympathomimetic drugs involve several organ systems. Muscle tremor, a beta, effect, is present in varying amounts with all the beta,-specific agents. Catecholamines can cause hyperglycemia, hypokalemia, hypophosphatemia, hypocalcemia, hypomagnesemia, and increased levels of lactate, pyruvate, and ketones. A major advantage of beta-adrenergic agents is that they are quite effective when given by inhalation. This allows for control of symptoms with minimal side effects. Other advantages include ease of application, portability, and rapid onset of action. Aerosols may be produced by hand-held pressure nebulizers, by metered-dose inhalers (MD11 using freon or other compressed propellants, or in powder form using the pressure of rapid inhalation and a mixing chamber to suspend the powder in an aerosol (Spinhale@, Rotohaler@). Of these devices, the MD1 is by far the most commonly recommended because of its portability and effectiveness. The direct application of the adrenergic agent to the airway mucosa produces relief of bronchospasm in much smaller doses than those required for systemic therapy. Because only about 10% to 15% of the aerosol actually reaches the airway mucosa, side effects of the new beta,-adrenergic aerosols are minimal when given at recommended doses. Muscle tremor and tachycardia are the most common side effects, occurring in a minority of patients and gradually lessening as the aerosols are used. DIM, March
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There are two significant problems with the otherwise ideal inhaled beta,-adrenergic agents. One is their relatively short duration of action, 3 to 6 hours for the newer drugs, and the other is their requirement for adequate inhalation technique in order to reach their site of action. It has been shown that the majority of patients can use their inhalers properly’” with careful instruction, but repeated reinforcement is essential. A number of studies have attempted to define optimum MD1 use, but we recommend the technique outlined in Table 6, which is based on the report of Dolovich et al.77 Package inserts recommend keeping the mouth closed while using the mouthpiece, and many clinicians use this method; however, Dolovich et al. showed that this method increases deposition of aerosols in the mouth and throat rather than in the lung parenchyma.77 For patients who are unable to use their MD1 properly (children, the elderly, neurologic patients, etc.), alternate forms of delivering aerosols are available. Spacers and reservoir devices are useful for children, and especially for patients using inhaled corticosteroids, to decrease proximal deposition of large particles.78 Spacers allow for large particle deposition outside the mouth, while reservoirs avoid the need for coordination of activation with inspiration by providing an aerosol chamber.7g Other delivery devices include powder generators in which an aerosol powder is generated in a small chamber, so that whenever the patient inspires, powder is delivered. Hand-held nebulizers are bulky, expensive, and less portable, but are often used for aerosol delivery in hospitals and clinics, especially during acute asthma attacks. They require more medication (up to TABLE 6. Recommended Procedures for Optimum Use of Metered Dose Inhaler* 1. Shake the inhaler 2. Breathe out to end-expiration (the end of a normal breathl 3. Open the mouth wide and hold canister in the upright position 2 to 4 cm from mouth 4. While breathing in deeply and slowly (inspiration time approximately 5 seconds), depress the top of the canister 5. Hold breath as long as possible 6. Repeat as often as prescribed by physician, allowing at least I to 2 minutes between actuations ‘From
Guidry
GG, George
Critical Care Update, Used by permission. 174
RB: ACCP F’ulmonary and 1990, volume 6, lesson 1.
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ten times the dose) for equivalent effect, primarily because the majority of the aerosol is lost in the equipment and surrounding atmosphere. Power nebulizers have been shown to provide no additional benefit over properly used MDIs in several studies.” Nevertheless, they are popular with patients, and allow busy hospital personnel to deliver adequate dose levels without constant coaching and supervision. Administration of beta-adrenergic agents by other methods (oral, parenterall is less satisfactory because of the larger dose requirements and the significant side effects.‘l Sustained-release preparations of beta, agents are available, and their principal advantage is their longer duration of action compared with the inhaled form. They may be indicated in patients with nocturnal symptoms, as an alternative to sustained-release theophylline. Parenteral beta-adrenergic agents are used primarily in younger patients, who appear to tolerate their side effects better.82 Subcutaneous terbutaline and epinephrine are commonly used during acute attacks, especially in children, to assure early and adequate drug effects. The only intravenous beta-adrenergic agents used in this country are isoprotereno1 and terbutaline. Several studies have documented the effectiveness of intravenous adrenergic drugs in severe, intractible asthma in children.82 In general, alternate urgent therapy including constant inspired aerosol and mechanical ventilation is preferred in older patients, but new information may change this approach. The older the patient, the more likely are significant complications, especially if there is evidence of associated cardiovascular disease.83 Methylxanthines such as caffeine, theophylline, and theobromine have been used in the treatment of asthma for many years. Theophylline, the most widely used of these agents, has been available for over 40 years, yet the mechanism of its bronchodilator action remains unclear. It relaxes the smooth muscle of bronchi, especially if it is constricted. The drug also increases diaphragm contractility and makes the diaphragm less susceptible to fatigue.84 Theophylline increases mucociliary clearance in some patients, antagonizes the effects of adenosine on mast cells, and reduces mediator re1eases8’ Theophylline inhibits phosphodiesterase, the enzyme that inactivates CAMP, resulting in increased levels of CAMP within the cells. However, this effect is minimal at serum concentrations that are achieved therapeutically.‘” Its benefit has been attributed to its effects on adenosine but again, this is unlikely its only mechanism of action.8” The bronchodilator response to theophylline is directly proportional to the log of the serum concentration in the range of 3 to 25 Pg/m1.87 Serum levels less than 10 p#ml minimally improve lung function and levels greater than 20 kg/ml are associated with significant side effects; therefore recommended therapeutic levels are 10 DM, March
1991
17.5
to 20 ~g/m1.87 We prefer lower serum levels in adults, in the range of 8 to 12 l.ig/ml. Plasma half-lives for theophylline vary considerably; patients who are supposedly “rapid-eliminators” require larger, more frequent dosing. Theophylline clearance is increased in children, smokers, marijuana users, those on high carbohydrate-low protein diets, and by drugs that induce formation of hepatic enzymes (phenobarbital, phenytoin). Theophylline clearance is decreased in neonates, elderly patients, and those with acute and chronic hepatic dysfunction, congestive heart failure, or a febrile illness, and by certain drugs (macrolide antibiotics, allopurinol, cimetidine, troleandomycin, and propranolol). Absorption may be slower at night in some patients, possibly because of the change in body position during sleep.” Intravenous theophylline or aminophylline (which is 85% theophylline) are often used together with beta-adrenergic agents and corticosteroids in the management of acute bronchospasm. A 6 to 8 mgkg loading dose of aminophylline may be given over 20 to 30 minutes if the patient has not been taking oral theophylline. The loading dose should be based on the lean body weight in order to avoid overdose in obese patients. If the patient has been taking theophylline the loading dose should be eliminated, and we advocate avoiding the loading dose in all patients unless a serum theophylline level is available. Adults are begun on a maintenance drip of 0.5 mg/kg per hour and the dose is adjusted later based on serum levels. A theophylline level should be obtained at 12 and 24 hours, and adjustment of the dose is based on results, assuming linear kinetics. For instance, if the level is 7 l.ig/rnl, then doubling the infusion rate will increase the level to 14 kg/ml after approximately four half-lives (24 to 30 hours). If toxic symptoms appear (tachycardia, ectopic beats, nausea, vomiting, anxiety, headache), stop the infusion and recheck the level in 6 to 8 hours, when it should decrease to half the original level. The side effects of theophylline are common, and in addition to those mentioned, include diarrhea, abdominal pain and anorexia, difficulty in urination in patients with prostate disorders, and relaxation of the lower esophageal sphincter leading to gastric reflux. A minority of patients cannot tolerate even minimal doses. The risk of seizures and cardiac arrhythmias increases when levels are greater than 30 Pg/ml. These serious complications are associated with a significant increase in mortality. The use of oral theophylline has decreased somewhat because of its requirement for systemic administration, the presence of significant associated side effects, and the availability of safer, more effective agents. Oral sustained-release theophylline may be a useful adjunct for patients with chronic, late-onset asthma or asthmatic bronchitis. Stable blood levels can be achieved over a 24-hour period us176
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ing current sustained-release agents, and may serve as a “cushion” between periods of beta-adrenergic or anticholinergic drug use. A common indication for oral sustained-release theophylline is bedtime use for patients with nocturnal symptoms.88 This avoids the vulnerable period after 3 to 4 hours when the inhaled agents are no longer effective, because sustained-release theophylline reaches peak serum levels after 4 to 8 hours in most patients. With the availability of the new sustained-release products, we know of no indication for oral short-acting theophylline in adults with asthma. Antichohergic drugs are among the oldest agents used for the treatment of asthma. They work by blocking postganglionic efferent vagal pathways with a subsequent reduction of the intrinsic vagal tone to the bronchial smooth muscle. They also block reflex bronchoconstriction caused by inhaled irritants, and decrease the release of mediators from mast cells after parasympathetic stimulation. Anticholinergic drugs have a slow onset of action, with a peak effect reached after 30 to 60 minutes. Inhaled atropine sulfate is rapidly absorbed from airway mucosa and is associated with significant anticholinergic side effects (tachycardia, blurred vision, urinary hesitancy). It should not be used in patients with narrow angle glaucoma or prostatic hypertrophy. Ipratropium bromide is a quaternary derivative of atropine sulfate that is poorly absorbed from the bronchial mucosa and consequently has fewer side effects. Ipratropium bromide is synergistic with sympathomimetics and methylxanthines in the treatment of asthma.“Y In nonurgent cases anticholinergic drugs may be useful in treating paroxysmal cough associated with irritated airways.” Other inhaled anticholinergic agents such as glycopyrrolate have been efagent for treatfective,“l but in general the preferred anticholinergic ment of asthma is inhaled ipratropium bromide. Oral and parenteral forms of atropine are available, but are rarely if ever indicated in the current management of asthma. Atropine tablets have been used for nocturnal relief because of the lack of central nervous system stimulation and gastric irritation.” They may be a useful adjunct in patients who cannot tolerate bedtime theophylline. Intravenous atropine is not recommended for the treatment of asthma.
ANTI-INFLAMM4TORY
AGENTS
Cromolp sodium was first used in 1967 as a mast cell membranestabilizing agent in the management of asthma.Y” It blocks calcium transport across the mast cell membrane, and prevents the release of mediators of immediate hypersensitivity from the mast cell granules. Cromoltivn sodium also decreases type C fiber stimulation and DM, March
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chemotaxis on the part of eosinophils and neutrophils. It is available as a powder, nebulizer solution, or MDI. Cromolyn sodium is most effective in young patients with mild to moderate extrinsic asthma, but may be effective in older patients with chronic asthma.” Cromolyn sodium decreases nonspecific bronchial hyperreactivity in both allergic and nonallergic asthma. It takes 4 to 6 weeks to achieve benefit from inhibition of mediator release, and is successful in 60% to 90% of patients.s4 It suppresses both immediate and late onset reactions secondary to a variety of aeroallergens, as well as reactions to exercise, cold air, sulfur dioxide, ultrasonic aerosols, toluene, and propranolol.” A single dose prior to unavoidable exposure to known allergens can prevent development of immediate and late-phase responses. Side effects include irritation of the throat, cough, occasional minor bronchospasm, and transient skin rashes. Bronchospasm is prevented by combining the inhaled cromolyn sodium with a beta-adrenergic agent. New cromolyn-like agents are currently under active investigation. These drugs, some of which have antihistamine-type properties, may be effective when given orally, thus avoiding the inconvenience and throat irritation associated with the inhaled drug. Recent reviews’” give more information regarding these new investigational agents. Ghcocorticoids were first used in the treatment of asthma in the 1950s. Their mechanism of action is unknown, but is thought to involve a decrease in the number and activity of inflammatory cells,g7 a decrease in the release of arachidonic metabolites,” increase in beta,-adrenergic responsiveness,” prevention of increased vascular permeability,100 a decrease in airway hyperreactivity,10”‘02 and prevention of the directed migration of inflammatory cells. These effects are not immediate and take at least 6 to 12 hours to occur.1o3 Steroids can be given orally, parenterally, or by inhalation. Oral and parenteral corticosteroids are extremely effective in the management of the acute asthma attack. Their use over prolonged periods should be reserved for patients with severe asthma, because chronic systemic steroid administration is associated with significant side effects including adrenal suppression, hypertension, diabetes, Cushing’s syndrome, and impaired host immune defense mechanisms. If systemic therapy is necessary, it should be given on an every-other-day regimen with the lowest possible dose of a medium-duration preparation such as prednisone. Because prednisone must be metabolized to prednisolone in the liver, patients with liver disease may respond more rapidly to methylprednisolone, which does not have to undergo hepatic conversionlo Inhaled steroids are being used more frequently as primary preventive therapy for moderate and severe asthma. Inhaled steroids have minimal systemic absorption and are free of systemic side effects; in adults they are not associated with signs of hyperadreno178
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corticism, and daily doses of up to 800 l.~g (16 puffs of beclomethasane) have been shown to cause minimal pituitary-adrenal suppression.lo4 Because of local deposition in the mouth and pharynx, about 10% of patients will develop candidiasis and/or dysphonia associated with the local effects. Rinsing and gargling with water after use of inhaled steroids will usually prevent oral side effects, and if oropharyngeal candidiasis occurs it is readily treated with local therapy. The usual daily dose of inhaled steroids is approximately equivalent to 10 to 15 mg/day of prednisone. Beclomethasone is marketed in the United States at a concentration of 50 pg/puff. There is a dose-related response with doses up to 1,600 pg/day (32 puffs of currently available beclomethasone preparations). Flunisolide is currently available in the United States at 250 cLg/puff, and more potent aerosols of other inhaled steroids should be available soon. Inhaled steroids may irritate the airways, and it may be beneficial to give a beta,-adrenergic agonist prior to the steroid. The use of inhaled steroids may allow a decrease of the dose of chronic oral steroids and should be attempted in all patients requiring long-term systemic corticosteroid therapy. Antihistamines are being reevaluated for their use in the treatment of asthma, and early reports of a drying effect of antihistamines on bronchial mucosa have not been substantiated.l” In addition to blocking the acute bronchoconstrictor effects of histamine some of these agents have mild bronchodilating properties. Oral antihistamines have been shown to be better than placebo in reducing symptoms in some patients who have exercise-induced asthma.lo6 Troleandromycin, a macrolide antibiotic, has a steroid-sparing capacity with long-term use.*07 It appears to work by decreasing hepatic metabolism, resulting in higher blood levels. The addition of this drug allows the dose of methylprednisolone to be decreased over the course of weeks to months. It is rarely indicated, and should be used only by physicians experienced in its use. A chemical hepatitis develops in some patients, but is reversible when the drug is stopped. Methotrexate has been used in the treatment of severe asthma, allowing for a reduction in the dose of steroids required?” Again, the side effects of methotrexate, while different from those of the corticosteroids, are significant, and include hepatic fibrosis, bone marrow depression, and teratogenicity in unborn children. Gold compounds have been used recently in the management of steroid-dependent asthma.“’ They were first used in Japan, and were selected on the basis of their effectiveness in rheumatoid arthritis, another disease of immunologic basis. Disadvantages of gold include its expense and its significant side effects, including interstitial lung disease and bone marrow abnormalities. Trials are currently underway using oral preparations of gold salts on a longterm basis. DM, March
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PREVENTION AVOIDANCE
OF THE ACUTE ASTHMA OF PRECIPITATING
AlTACK
FACTORS
While avoidance of factors that cause asthma attacks is an extremely effective means of preventing the attack, it is not practical in many cases. Young, active individuals with exercise-induced asthma may find that a sedentary lifestyle is unsatisfactory, and patients allergic to common pollens, dust, and air pollutants may be forced to exist in environments that exacerbate asthma attacks. There are two areas where avoidance appears to be especially useful. The first is in patients allergic to household pets. While it may be painful to get rid of the pets, this is a reasonable alternative to long-term steroid therapy. A second potential usefulness of avoidance is in occupational asthma, where a patient’s occupation or location of work may be changed to place him in a more suitable environment. Pet allergies and occupational allergies should be documented as well as possible prior to removal of the pet or a move to another workplace because this represents a significant change in lifestyle. In many cases patients prefer continued exposure with alternate means of prevention. For example, patients with exercise-induced asthma need not avoid exercise entirely but can prevent acute attacks by inhaling a beta-adrenergic aerosol prior to exercising. Patients with skin test sensitivity to house dust mites may benefit from frequent careful house cleaning with a mop or wet rag, especially in the bedroom. The bedroom should be closed off from the rest of the house and a room air conditioner should be installed if possible with changing of filters at least weekly. Roaches have been shown to be a source of allergenic extracts, and roaches should be prevented from entering the house if possible by outdoor measures, so that potentially irritating insecticides need not be used inside the house. In some young asthma patients, unrecognized substances in the diet can exacerbate asthma. One study demonstrated that 10% of children with asthma responded to treatment with an elimination Beverages with sulfur dioxide, aspirin, and preservatives diet.“’ such as sulfites can worsen asthma in some patients.ll’
IMMUNOTHElW’Y
FOR ASTHMA
While nearly all asthma has some IgE-related component, correlation between asthma and immediate hypersensitivity skin test reactions is not complete and tends to decrease with advancing age.l” Many allergic individuals demonstrate bronchial hyperreactivity to a number of antigens such as pollens, house dust mites, molds, and various animals. Furthermore, unrelated factors such as viral infec180
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tions, irritant exposures or drug therapy can alter the severity of the disease in the absence of allergen exposure. Thus, it has been difficult to evaluate the effectiveness of immunotherapy in the prevention of asthma. In general, a majority of acceptable studies show some clinical benefit of this treatment provided the antigen is carefully identified and the purity and dose of allergen administered is adequate to produce antigen-specific IgG.l13 Immunotherapy is based upon the presumption that, beginning with a very dilute antigen extract, tolerance or hyposensitization may be produced by gradual increase in the amount of antigen injected subcutaneously. Hyposensitization is thought to be produced by the development of “blocking antibodies,” believed to be antigenspecific IgG, which interfere with the antigen-IgE allergic reaction. However, other immunologic alterations are also likely to be involved. Among the specific desensitization antigens that have been most carefully studied are cat allergen-I extract and house dust mite antigen. Both these preparations have been shown to decrease allergen-related bronchospasm in caref~~lly studied subjects.l14 Ragweed antigen-E has also been carefully standardized and shown to result in a good clinical response. Therapy with grass pollen and birch pollen has been shown to blunt a seasonal increase in symptoms associated with a decrease in immunologic mediators. Other commonly used immunotherapeutic agents such as house dust and molds are poorly standardized and have not been convincingly shown to produce beneficial effects. Given the limited information available and a lack of proven benefit in many studies, pharmacotherapy has in general been the preferred course. When pharmacologic treatment has been optimized and still does not avoid symptoms or causes serious side effects, immunotherapy may be a reasonable consideration in carefully selected patients. For immunotherapy to be effective, there must be a positive correlation between symptoms and immediate hypersensitivity skin test reactions. It should be discontinued after a trial period if no objective benefits are noted. Side effects of immunotherapy are significant and in addition to the inconvenience of twice-weekly injections, often for years, there are a number of reported fatalities from skin testing or immunotherapy given for various reasons.115 Patients who have an FEV, of less than 80% of predicted value at the time of injection have a high probability of developing a serious reaction and should avoid immunotherapy on that day.‘16 PREVENTIVE DRUG THERAPY The current approach to the management of asthma is in a state of evolution from a posture of reaction (treating the attack once iniDM, March
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tiated) to a more aggressive approach, taking measures to avoid attacks by controlling bronchial hypersensitivity and the late inflammatory reaction.117-11g The drugs used for preventive therapy have been previously discussed on an individual basis. This discussion will concentrate on their application to the prevention of acute asthma attacks. While beta agonists are useful in treating acute bronchospasm they are ineffective in preventing the late-phase response.120 Preventive therapy is based on prevention of the latephase response with corticosteroids or cromolyn sodium. Inhaled corticosteroio!s are effective through a variety of mechanisms. The preferred route of administration, in the absence of acute bronchospasm, is by inhalation. A number of inhaled corticosteroid preparations are available at the present time. Beclomethasone has been available for the longest period and is the most extensively studied. Its major drawback is that it is only available in the United States in 50 pg/puff dosage and a large number of puffs per day are frequently required. Triamcinolone is said to induce less coughing than the other inhaled steroids and is packaged with a built-in spacer. It is given in an initial dose of eight puffs a day.lzl Flunisolide is available in higher concentrations (250 l.~g/puff) and is given in doses of four or more puffs per day. Once symptoms have been controlled, the dosage of all these agents may be reduced to maintenance levels required to prevent symptoms. Inhaled corticosteroids cannot be used during the acute asthma attack because they are bronchial irritants and induce coughing. They should be begun after the acute attack is controlled, during the period that oral or parenteral corticosteroid doses are being tapered. Patients must be instructed and encouraged to comply with dosing regimens because benefits are not readily appreciated as are those with beta agonists. Furthermore, they are relatively expensive and are required for long periods. Cromolyn sodium is useful in preventing exercise-induced asthma, has some effect on the early phase response, and is extremely useful in preventing the late-phase asthmatic response.12’ Cromolyn is safe, easy to use, has few side effects, and is available by MDI, nebulizer solution, or powder. Cromolyn has achieved a prominent role in managing patients with asthma, and has proven useful in preventing asthma attacks initiated by antigen contact, exercise, cold air, or hyperventilation. Cromolyn therapy is effective in almost half of all patients, and thus deserves a trial even in adults with chronic asthma.‘lg While the majority of benefit is usually apparent within 2 weeks of initiating therapy, a significant number of individuals may not see complete benefit for 6 to 8 weeks.lz2 A major benefit of inhaled cromolyn is its lack of significant side effects. Comprehensive preventive care of the asthma patient involves regular clinic follow-up with office visits and determination of flow 182
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rates both in the office and in the home. Home peak flow measurements should be reviewed with the patient with each office visit and any new complaint or change in severity of the disease should be noted. For patients who report weekly or more frequent attacks, maintenance therapy should include prolonged inhalation therapy with either corticosteroids or cromolyn, and an inhaled beta-adrenergic agent should be kept available should mild bouts of bronchospasm occur. Failure of this regimen with the need for emergency care, and a full-blown asthma attack represents a failure of preventive care and should result in a complete review of the therapeutic regimen and changes as needed. TREATMENT
OF THE ACUTE ASTHMA
ATTACK
Patients are frequently seen for the first time while having an acute asthma attack. The initial approach to management of acute asthma attacks is through the use of inhaled beta-adrenergic agonists. These agents have become the mainstay of acute therapy and are also useful in the preventive maintenance program as previously noted. Their major limitation is their relatively short duration of action (no more than about 6 hours in most patients). Beta agonists, while effective in the acute phase, have little or no effect on the late inflammatory response.1z0 When the acute asthma patient is first seen in the emergency room he is often too ill to provide an adequate history, and a thorough physical should be delayed until an initial estimate of severity is made and therapy, including nasal ozygen, is initiated. Laboratory tests should consist primarily of a spirogram or peak flow measurement, and ABGs are indicated only if the FEV, is below 2 L or the patient has other associated disease. Chest films and other laboratory tests are indicated if evidence of complications or other disease is present. Patients should be initially started on inhaled oxygen supplementation and a slow intravenous infusion should be begun for administration of drugs. Fluids may be administered if the patient is dehydrated, but are not routinely necessary. Once oxygen is started and an intravenous line is established, therapy with inhaled bronchodilators should be begun. Characteristics of currently available beta-adrenergic agents are shown in Table 7. The newer agents are similar in duration of action and clinical effectiveness and many are available in multiple forms including syrup, tablets, MDI, nebulizer solution, powder, or subcutaneous injection preparations. The majority of patients are treated with beta agonists administered via MDIs, which are convenient and relatively easy to use. Patients who cannot use MDIs effectively may require spacers or hand-held nebulizers. Hand-held nebulizers are DM, March
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TABLE 7. Commercially Available Beta,-Adrenergic Agents in the United States* Agent Isoetharine Metapmterenol Terbutaline Albuterol Bitolteml Pirbuteml
Dosage Formst
Duration of Action (hours)
N,M NJ%0
2-3 3-4 4-6 4-6 4-6 4-fi
M,O,S
N,M,O,P M M
‘From Gullatt I’J, George RB: ACCPPulmonary and Critical Care lipdate 1989, volume 4, lesson 30. Used by permission. tN = nebulizer solution; M = meterx&dose inhaler; 0 = oral preparation; S = subcutaneous injection; P = powder for inhalation.
often used in emergency room settings to assure adequate dose delivery, although their effects are similar to MDIs.lz3 Subcutaneous epinephrine or terbutaline may be used if aerosol administration is not possible, especially in infants and younger children. Doses given should be carefully monitored and patients observed for tachycardia or other signs of toxicity. The second pharmacologic agent that is invaluable in treatment of the acute asthma attack is corticosteroids. Corticosteroids should not be given by inhalation during the acute attack because they cause bronchial irritation; they may be given orally, by injection, or intravenously. We prefer to administer corticosteroids intravenously during the emergency treatment of asthma because this eliminates vomiting and poor intestinal absorption and assures prompt achievement of adequate blood levels. While some have advocated very high doses of steroids in the management of acute asthma, others have shown that moderate doses achieve equivalent effects. Britton et al. compared high-dose intravenous corticosteroid therapy with medium- and low-dose treatment during acute episodes.lz4 They found that medium and low doses (200 to 400 mg hydrocortisane/day) achieved the same benefit in terms of improvement in airflow over the first week of therapy as did the higher dose. Based on these and other reports we recommend moderate dosages of intravenous corticosteroids, approximately 200 mg of hydrocortisone every 6 to 8 hours or an equivalent dose of methylprednisolone. It is important to recognize that corticosteroids do not have significant effects on airflow for approximately 6 hours or more, even when given in high doses intravenously.‘z5 Therefore, it is important to initiate corticosteroid therapy as soon as failure to respond to beta-adl&l
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renergic agents to an adequate degree is noted, or if patients have required steroids for therapy during the previous 6 months. The place for intravenous theophylline during the acute management of asthma is changing somewhat in recent years. In general, the emphasis has been away from theophylline; however, it would be a mistake to ignore theophylline therapy in a review such as this because it is still commonly used in many hospitals. Siegel et al. showed that the addition of intravenous theophylline to beta-adrenergic aerosols had no additional effect over a S-hour period in patients with acute asthma.lzfi Moreover in the same study they showed that patients who were given intravenous theophylline had twice as many side effects as those treated with beta-adrenergics alone. Principal side effects in patients with acute asthma include gastrointestinal upset, tachycardia, and ectopic cardiac beats. The gastrointestinal side effects are especially bothersome and may limit the amount of theophylline tolerated. Anticholinergics have been recommended in the acute setting. Rebuck et al. showed that the addition of ipratropium bromide to a therapeutic dose of fenoterol (a beta agonist) produced added bronchodilation in a group of patients with acute asthma.” Other studies have suggested that while ipratropium may yield some benefit, atropine sulfate, when given with beta-adrenergic agents in the emergency setting, provides no additional benefit.lz7’ lz8 Patients should be observed closely in the emergency room during the management of their acute asthma attack, and serial objective tests of airflow should be performed whenever possible (about every 30 minutes to 1 hour). The determination for long-term care is dependent primarily on the response of the patient to optimum bronchodilator therapy during the initial 2 hours or so of treatment. A review of studies of emergency room management indicates that during early posttreatment, FEV, is a reliable indicator of the ultimate course of the acute attack, and will help determine whether the patient can be successfully discharged, will relapse after returning home, or will require immediate hospital admission. If the patient is responding well after a couple of hours and has not had recent life-threatening episodes, he should be discharged on tapering oral corticosteroid therapy with adequate bronchodilator medications and should be told how to get help in an emergency if necessary. He should be seen within the next week and objective tests repeated to determine if his condition continues to be satisfactory. Patients who are not successfully treated in the emergency room (i.e., do not have a satisfactory response to initial therapy) should be considered candidates for hospitalization. They should be admitted to the intensive care unit if possible, where they can be closely observed. They should be treated there until their condition has stabilized and they can be transferred to a general medicine ward. When DM, March
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oral and inhaled medications can be administered and flow rates are stable or improving, the patient can be transferred to the general ward, but should not be sent home directly from the intensive care unit. A period of 12 to 24 hours’ observation in the ward setting is necessary because death from acute asthma is common during the initial postrecovery period, when attention is directed to other patients and observation is lax. Once symptoms are controlled, flow rates are stable, and steroids are being tapered, an active regimen of preventive therapy including inhaled corticosteroids and other agents should be initiated. Occasionally patients do not respond to maximum therapy with oxygen supplementation, inhaled bronchodilator agents, and corticosteroids. The failure of maximum therapy is indicated by the physical finding of progressive exhaustion. Chest excursions, sweating, and tremor decrease, and breathing becomes shallow and rapid. Patients become confused and lethargic and may seem disoriented. This is usually associated with persistent FEV, of 1 L or less and with normalization or progressive increase in PaCO,. Other physical signs at this point include marked intercostal space retractions, decrease in accessory muscle strength, and sometimes a decrease in wheezing. These signs indicate that medical therapy has failed and that mechanical ventilation is needed. Mechanical ventilation is rarely indicated in the management of severe asthma and is associated with a high incidence of complications, especially barotrauma.12’ Because the chest is already hyperinflated and air trapping is marked, the addition of positive airway pressure tends to exacerbate the problems of barotrauma and decreased cardiac output. Mechanical ventilation may require the addition of intravascular fluid volume because of its effect on systemic venous return. Patients generally require mechanical ventilation for brief periods of a day or less, and weaning should begin as soon as possible. MANAGEMENT
FOLLOWING
THE ACUTE ATTACK
Prior to discharge from the hospital, a patient should have been switched from intravenous to oral and inhaled therapeutic agents. The efficacy of oral preparations of theophylline and steroids is similar to intravenous preparations; therefore, the timing of the switch probably makes little difference. However, a good time is when the patient has demonstrated a significant clinical response to therapy, and the PEFR or FEV, is greater than 60% to 70% of predicted values. The physician should demonstrate that the improvement in airflow can be continued on the new regimen for at least 24 to 48 hours. If after that time the patient has minimal wheezing, good exercise capacity, and is able to sleep at night, then the patient is ready to be 186
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discharged. All other problems identified (pneumothorax, pneumonia) must have stabilized or improved. After being discharged, the patient must be closely monitored, and instructed in the proper use of a peak flow meter and told to record the results at least twice a day. It is important to remember that an asthma exacerbation is usually not resolved completely at the time of discharge, and there are persistent airflow abnormalities compared with baseline function. The patient should have a follow-up medical appointment scheduled at the time of discharge, preferably within a week of discharge. In addition to being educated about how to use a peak flow meter and the MDI, the potential side effects of the prescribed medications should be explained. The patient should have a good understanding of when to call a physician and/or go to the emergency room. Once the patient is at home, the dose of oral steroids can be tapered, with the rate of decrease depending on the patient’s past frequency and severity of asthma attacks and the results of this peak flow measurement. It is at this point that inhaled steroids can be added safely to the patient’s therapeutic regimen. SPECIAL
SITUATIONS
NOCTURNAL
ASTHhIA
Nocturnal asthma attacks occur most often between 2 and 8 A.M. and interfere with normal sleep patterns, leading to daytime somnolence and interference with normal daytime activities. While beta,-adrenergic agents remain the cornerstone of asthma therapy, they have the drawback of a relatively short duration of action. A dose taken at bedtime begins to lose effect within about 4 hours. Sustained-release oral beta-adrenergic agents are now available, but their use is associated with systemic side effects, including nervousness and insomnia. A single bedtime dose of oral sustained-release theophylline may prevent nocturnal asthma attacks with minimal side effects. An alternative is inhaled ipratropium bromide at bedtime along with an inhaled beta,-adrenergic, because ipratropium has been shown to prolong the bronchodilation effects of beta-adrenergic agonists.‘30 PREGNANCY
The treatment of asthma in the pregnant patient is similar to that of other asthmatics, with a few exceptions. Pregnancy affects asthma in an unpredictable fashion with approximately one third of patients becoming worse, one third improving, and one third remaining the same. In those who become worse, peak severity is usually during DM, March
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the third trimester. After delivery, the asthma severity usually returns to baseline within 3 months.131 Uncontrolled asthma has significant harmful effects on the fetus, with increased prematurity and perinatal mortality.132 The drugs commonly used in the treatment of asthma have no demonstrated harmful effects on the fetus. Therefore, it is important to aggressively control the mother’s asthma in order to prevent placental hypoxemia. In general, as few medications as possible, preferably delivered by the inhaled route, should be used. If a pregnant asthma patient presents with an exacerbation of asthma, she should be treated aggressively with bronchodilators, corticosteroids, and supplemental oxygen. It must be kept in mind that if the patient has taken steroids during the year preceding delivery she may need steroid supplementation at the time of delivery. ELDERLY ASTHMA PATIENTS ASSOCZATED DISEASES
AND
THOSE
WlTH
Treatment of elderly asthma patients is similar to treatment of other asthma patients, with the following exceptions and precautions. These patients are likely to be on medications for other diseases that may affect their asthma, such as aspirin for arthritis, or beta blockers for heart disease or glaucoma. For this reason it is important to closely monitor the patient’s complete drug regimen. Despite the fact that patients with coexistent heart and lung disease rarely have an increase in cardiac arrhythmias and angina secondary to drug therapy, theophylline and the adrenergic medications must be watched closely for a worsening of heart disease.83 When treating patients over the age of 50 it is especially important to monitor for hypoxemia during acute attacks, which could exacerbate an underlying cardiac abnormality. Additionally, if oxygen supplementation is indicated it should be done carefully with ABG determination to note CO, retention, because some patients will have a combination of chronic obstructive pulmonary disease and asthma. The physician should be aware that the patient may have impaired hearing and eyesight, which could affect patient-physician communication, recording of information, performance of peak flow measurements, and proper use of MDIs. COURSE AND PROGNOSIS The course of acute asthma attacks varies markedly with or without medical intervention. Mild attacks, as in exercise-induced asthma, may respond to a single administration of an inhaled bronchodilator medication or may resolve spontaneously within a few minutes. Severe attacks persist over hours to days, and fatal asthma 188
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attacks are characterized by a lack of response to the usual therapy. The term “status asthmaticus” literally means prolonged or persistent asthma, i.e., not relieved by the usual therapeutic interventions. Several prognostic signs indicate a favorable outcome of the acute attack. These are all based on serial objective measurements, and depend on adequate baseline data obtained prior to therapy if possible, allowing for quantitation of changes during treatment. Some of these favorable early signs are shown in Table 8. Change in the extent of wheezing is not a valid prognostic sign, because the wheezes are produced by rapid airflow across small bronchial orifices. Large pressures are required to produce this rapid airflow, and with muscle fatigue flow rates may fall and wheezing may actually decrease or disappear. Some unfavorable prognostic signs during the acute attack are shown in Table 8. Just as good response to initial treatment has a good prognostic implication, poor response is an important negative prognostic finding, and is the basis of many indices of severity that are used to determine the need for hospitalization.38’ 40,133 The patient’s recent history is a clue to the prognosis for the present attack, and the presence of frequent attacks or prolonged attacks over the past few months suggests a poor response. Patients who have required corticosteroid therapy within the past 6 months tend to respond relatively poorly. While physical findings are poor quantitative indices, serial changes in physical findings over time may be helpful. The disapTABLE 8. Early Prognostic Signs in Acute Asthma Attacks* Favorable Signs Increase in peak flow or FEV, Increase in FVC Stable or improving PaO, and PaCO, Decrease in use of accessory respiratory muscles Decreased pulsus paradoxus Unfavorable Signs Severe attack (FEV,
