The assessment and treatment of asthma: A conference report

Rostrum

The article published below is the result of the thoughtful workshop deliberations of many investigators interested in and very experienced in the assessment and treatment of asthma. As noted by them, the article is not intended to be a set of authoritative guidelines, but rather a presentation of the opinions of the interested individuals. Committees of the American Acad- emy of Allergy and immunology are also currently addressing some of the points discussed here. I believe that our readers will be very interested in reading these thoughts about areas in which we all still have much to learn-Button Zweiman, MD, Editor.

The assessment and treatment of asthma: A conference report*

Frederick E. Hargreave, Jerry Dolovich, Michael T. Newhouse--Editors

A meeting was held in Toronto, Ontario, Canada, in May 1989, to develop a standardized approach to the assessment and treatment of asthma. There have been a number of developments in recent years that motivated this project. First, there appears to be a worldwide increase in morbidity and mortality from asthma. Second, population studies have repeatedly demonstrated underdiagnosis and undertreatment of asthma. These findings are paradoxical considering our improved understanding of asthma and the improved quality and range of modalities of treatment that have become available in the past decade. It is reasonable to expect that a more efficient use of presently available treatment can reduce the morbidity and mortality from asthma.

This article is intended as a practical guide; it deals with assessment and treatment. The focus is on the achievement and maintenance of control or best result.

Sponsored by Medical Research Council of Canada and Glaxo Canada, Inc., Toronto, Ontario, Canada.

Based in part on proceedings of a meeting held in Toronto, Ontario, Canada, May 18-20, 1989.

Reprint requests: Frederick E. Hargreave, MD, Firestone Regional Chest and Allergy Unit, St. Joseph’s Hospital, 50 Charlton Ave., East Hamilton, Ontario, Canada L8N 4A6.

*List of patticipants and authors: Peter J. Barnes, Louis-Philippe Boulet, Andre Cattier, Timothy J. H. Clark, Donald W. Cock- croft, Jerry Dolovich (Coch . amum), Pierre-Paul Ernst (observer), Leonardo M. Fabbri, J. Mark Fitzgerald, Frederick E. Hargreave (Chairman), Karel F. Kerrebijn, Peter K&rig, Peter T. Ma&em, JeanLuc Malo, Jean Marsac, Michael T. New- house (Cochairman), Paul M. O’Byrne, Tom A. E. Platts-Mills, E. Helen Ramsdale, Charles Reed, Malcolm R. Sears, Michael Silverman, F. Estelle R. Simons, John H. Toogood, Paul A. Vermeire, Haydn Walters (observer), C. Peter W. Warren, Ann J. Woolcock, Moira M. Chan-Yeung, and Barry Zimmerman.

l/l/20416

I I Abbreviations used PEPR: Peak expiratory flow rate MDI: Metered-dose inhaler

ER: Emergency room VC: Vital capacity

ASA: Acetylsalicylic acid I I

Issues such as pathogenesis and mechanisms of action of drugs have been excluded, although they form the basis for the approach to treatment. Many aspects of assessment and treatment remain, at best, an educated guess and must await validation by controlled clinical trials. It is to be expected that about 30 participants with different areas of interest, from different countries, would not necessarily have a complete conver- gence of opinions. We believe that this article is a fair representation of the prevailing opinions expressed by these experts at the meeting and in the course of subsequent editing.

A second meeting to consider these guidelines took place in Quebec City, Canada, on October 27 and 28, 1989. It was attended by 180 specialists, including chest physicians, pediatricians, and allergists. Many suggestions made at this meeting have been incor- porated into this article.

This article is not presented as an absolute or definitive statement on assessment and treatment. The committee that developed these guidelines is not an official delegation empowered to provide such a statement. Moreover, there remains a lack of definitive information and a lack of agreement among experts on several questions. The assessment and treatment

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Assessment and treatment of asthma 1099

TABLE I. Definition of control of asthma

Minimal symptoms, ideally none Normal activities of daily living

(work, school, recreational exercise)

Inhaled P-agonist needed not more than twice daily, ideally none

Airflow rates normal or near normal at rest

Airflow rates normal after inhaled pz- agonist

Daily variation of PEPR* <20%, ideally < 10%

Minimal side effects from medications

*APPENDIX.

of the individual patient remain the responsibility of the individual physician.

OBJEmE§ Of TREATMENT

The primary objective of the treatment of asthma is to achieve and maintain control, as defined in Table I, and to prevent severe exacerbations. Control is achievable for most subjects with asthma although it may not be possible in subjects with severe asthma. In such subjects, vigorous initial treatment is needed to achieve and define the “best result,” meaning the fewest symptoms and the best airflow rates that can be achieved without unacceptable side effects. Then, ongoing treatment should maintain and attempt to improve gradually on this best result.

PrinciQles of treatment

1. These guidelines stress the need for treatment to be outcome oriented; the requirement is to achieve and maintain control or the best result.

2. The avoidance of harmful factors is generally preferable to the requirement for treatment with medications.

3. Control of disease (intlammation)‘-9 is superior to control of airway constriction. Control of disease is accomplished by avoidance of potentially harmful factors (Table II) and the use of inhaled steroid or cromogiycate or ingested steroid.

4. Neither &-agonist” nor theophylline” therapy appears to be effective in improving the severity of disease (inflammation).

5. Steps in the assessment and treatment (management plan) are to (1) make the diagnosis, (2) provide initial treatment to establish, quickly, control or the best result by avoidance of causal factors and use of medications, (3) determine the smallest amount of treatment with medications needed to maintain control or the best result, (4) provide and

TABLE II. Causes of airway disease or constriction

Potentially harmful Allergens Occupational chemical sensitizers Viral respiratory infections Additives to foods, beverages, and drugs Drugs (P-blockers, nonsteroid anti-inflammatory

dws) Cigarette smoke Aggravating conditions (e.g., gastroesophageal

reflux, sinusitis) Generally less harmful

Exercise Cold air Air pollution Emotional stress

explain a written “action plan’ for early treatment of exacerbations, individualized to the patient, (5) educate the patient, (6) review the patient regu- larly, and (7) consider when to refer.

Management plan

Diagnosis. The main symptoms of asthma are wheeze, breathlessness, tight chest, cough, and sputum. The diagnosis is suggest4 if these symptoms are variable, nocturnal, or early morning, elicited by stimuli, such as cold air or exercise, or are brought on by known allergens or sensitizers. Strong support for the diagnosis is provided by improvement in symptoms from the use of antiasthma medications.

Physical examination is important to exclude other conditions but is insensitive in the diagnosis of asthma. Wheeze is a clinical sign that is consistent with the diagnosis but is unreliable.

Measurement of airllow rates is necessary to establish the diagnosis, qua&ate the severity of the obstruction, and assess the response to therapy.‘* Mea- surement of PEW, and VC can assist in finishing between an obstructive and nonobstructive ventiIatory defect. If equipment for spirometry is not available, a peak flow meter can be used. The peak flow meter (APPENDIX) is inexpensive, easy to use+ and should be available in every physician’s office and ER in which a spirometer is not available. In patients with reduced airflow rates, an improvement of I5% or more after an inhaled &-agonist confirms the diagnosis, providing there is no chronic air&w limitation. If airllow limitation is not completely feversed, a carefully monitored trial of corticosteroid treatment per- mits the assessment of how much of the airflow limitation is reversible and how much is fixed.

If flow rates are normal, airway responsiveness can

1100 Hargreave et al. J. ALLERGY CLIN. IMMUNOL. JUNE 1990

be assessed by determination of the diurnal variation of PEPR (APPENDIX) at home or by the use of a histamine or methacholine inhalation test in the lab- oratory.13 An exercise test can also be used but is less sensitive to demonstrate increased airway responsiveness. l4 These provocation tests should be performed only in a well-standardized pulmonary function lab- oratory. The advantage of reliance on variability of PEPR rather than provocation tests is that it provides ongoing assessment. An increasingly prevalent approach is to measure the diurnal variation of PEPR for 2 weeks in patients with possible asthma to confirm the diagnosis and help assess the severity. One caution concerning this test is that it is highly effort dependent, and measurements are sometimes unreliable. Assessment of possible hyperresponsiveness is particularly useful if symptoms are atypical or if symptoms or signs fail to correspond to the response to treatment.

A chest radiograph should be taken at least once to rule out other conditions.

People with chronic cough may or may not have asthma. In asthma, cough can be the first expression of an exacerbation, and as such can be a useful signal for effective early treatment.15 Chronic cough in the presence of normal spirometry and normal methacholine airway responsiveness and in the absence of diurnal variation of PEPR does not fulfill the physiologic criteria of asthma and should not be diagnosed as asthma. Underlying diseases, which give rise to cough, should be considered. The differential diagnosis varies, depending on the age and clinical circumstances, including smoker or nonsmoker, produc- tive or nonproductive cough, and purulent or non- purulent sputum. If there is no evidence from history, physical examination, or chest radiographs of an underlying disease, then an early trial of treatment of the cough is indicated. In most cases this trial should be performed before consideration of bronchoscopy. There are few controlled clinical trials to provide guidance to the best choice of therapy. I6 At least some cases have an excellent clinical and sputum cytology response to inhaled steroid.”

Initial treatment to establish control or best result

Causal factors. Initial treatment involves the intro- duction of procedures to avoid potentially harmful factors. Recognition of these factors is from history and test procedures.

History. Questions in the history should identify any relationship between symptoms and exposure to (1) inhaled allergens or chemical sensitizers at home, at work, at school, in hobbies, or in seasons; (2) food and beverages with special reference to metabisulfitela

and monosodium glutamate,19 and specific foods, such as milk, egg, nuts, and fish; (3) drugs, particularly ASA and other nonsteroidal anti-inflammatory drugs,20 and P-blockers, including P-blocker eye- drop?; (4) tobacco smoke (active or passive) and other airborne pollutants; (5) exercise and cold air; and (6) emotional stress (Table II). The possible relationship of symptoms to sinus or more general upper respiratory tract infections** and gastroesophageal reflux23 should also be considered. Successful evaluation of the latter may require a rigorous trial of therapy.

Test procedures. After a careful history, allergy can generally be confirmed by allergy skin prick tests, which is the preferred skin test method.24 There may be a place for selective intradermal skin tests in some cases to increase the sensitivity of the tests.25 Allergy skin tests should be included in the evaluation of any subject with persisting asthma or with avoidable exposure to an allergen that could be responsible. An- tigens should include dust mite, dog, cat, pollens appropriate to the area, airborne molds appropriate to the area, Aspergillus, cockroach, or other insects when this is relevant, and other tests as indicated by the exposure history, such as to particular animals. Allergy skin tests and appropriate avoidance procedures should probably be applied to all patients with persisting symptoms or with attacks requiring acute treatment. Assays of serum IgE antibodies instead of skin tests may be indicated in young children, patients receiving antihistamines, patients with atopic der- matitis, or during pregnancy. Diagnostic inhalation or ingestion challenge tests should be limited to spe- cialized facilities. These tests are sometimes indicated for suspected intolerance to substances such as metabisulfite,‘* or sensitization to occupational chemicals, such as diisocyanates, 26 but are not appropriate for the diagnosis of sensitization to common inhalant allergens.

Avoidance procedures and prophylactic treatment. Avoidance of potentially harmful factors is required. These factors can (1) contribute to airway inflammation and hyperresponsiveness or (2) trigger sudden, severe, potentially fatal, airflow limitation (Table II). Detailed avoidance instructions are beyond the scope of this article. The successful use of avoidance procedures depends largely on the recognition of patients who may be affected by the different causal factors. Unnecessary restrictions should not become an adverse side effect of treatment. Handouts, which are useful when they are relevant for particular patients, include a feasible plan for avoidance of house dust mite” or mold, and a list of sources of potential exposure to ASA,” ASA-type medications, sulfite~,~~ or particular food allergens.

VOLUME 85 NUMBER 6


Allergen injection treatment can reduce sensitization, but the relative usefulness in the treatment of asthma appears to be limited.3o

A cause of airway constriction, which generally does not need to be avoided, is exercise. The usual key to the prevention of symptomatic airway narrow- ing from exercise is optimal day-to-day maintenance treatment. The additional use of inhaled P,-agonist, cromogiycate,3’ or both3’ just before exercise is usually effective.

Effects of intermittent exposure to allergen can be reduced or prevented by cromogiycate taken by MDI, 2 to 10 mg, or powder, 20 mg, just before the exposure and continued four times daily until any increase in symptoms has cieared.33 Inhaled corticosteroid, such as beclomethasone dipropionate, 200 to 500 p,g, or budesonide, 200 to 400 pg, two to four times daily, for a similar time can be effective.33g 34

Medications

General considerations. Since avoidance procedures may not yield immediate rewards35 and often are not sufficient by themselves, medications are generally required as well. Inhaled medications are preferred because of their effectiveness in small doses and their lower tendency to cause side effects. The level of initial treatment with medications is chosen on the basis of (1) an assessment of the severity of the asthma at that time and (2) the level of treatment with medication already being used. The objective of the initial treatment is to achieve control or identify the best result, preferably within 2 weeks.

Severity of asthma at a particular time. Severity is judged on the basis of symptoms, ahllow rates, and need for inhaled p,-agonist when this is taken as needed. Criteria of control are listed in Table I, and of levels of severity of asthma at a particular time, listed in Table III. The severity of symptoms does not always correlate with the magnitude of reduction of flow rates. In some patients the symptoms are the more sensitive indicator; in other patients, who appear to perceive or communicate airflow limitation poorly, the reduction in flow rates is more sensitive.36* 37 Mea- surements of PEFR or FEV, in the office during the day may underestimate the severity of an exacerbation because of the usual improvement in flow rates during the day. The daily variability of PEFR (APPENDIX) is closely related to the level of airway responsiveness, as reflected by histamine or methacholine sensitivity3*; in most patients, these measurements also correlate with other findings, including the frequency of symptoms and the dosage of &-agonist required to relieve the symptoms. 39

Treatment levels. In patients not receiving treatment

TABLE 111. Symptomsiventilatory function criteria* of the level of severityt of asthma at a particular time

Level

1 Asthma is controlled (Table I)

2 Symptoms slightly more than when asthma is controlled or elicited more readily in response

to mild provocation. Inhaled &- agonist needed slightly more often (from one to three or four times daily)

PEFR or FEV, about 85% of predicted or

known best result PEFR variability 20% to 30%

3 Symptoms of breathlessness or chest tightness occur repeatedly and disturb sleep or are pres-

ent on waking Inhaled B2-agonist required more often or more

than four times daily PEFR or FEV, 60% to 85% of predicted or

known best result PEFR variability >30%

4 Symptoms at rest, not completely reversed by inhaled P,-agonist PEFR or FEV, ~60% of predicted

*The allocation of particular symptom or flow-rate criteria to particular levels of severity is based on limited information. The levels should he taken only as a rough guide with the recognition that there may he discordance among criteria. In general, criteria indicating the highest level should he heeded.

Whe assessment of the severity of asthma, on the longex term, requires a consideration of symptoms and ventilatory function criteria in addition to the minimum level of treatment with medications required to maintain control or hesl result.

whose asthma is controlled (level 1 in severity, Tables I and III), inhaled P-agonist with or without cromogiycate taken as needed before stimuli, such as exercise or cold air, can be expected to prevent symptoms. If an episode of symptoms occurs, inhaled P-agonist can be expected to relieve it.

When symptoms are more severe, occur daily, in- terfere with activities, or lead to more frequent use of inhaled &-agonist, a higher level of treatment is required. To achieve control, it is often necessary to introduce treatment at a higher level than will likely be required to maintain control. Level 2 symptoms (Table III) imply the need for maintenance treatment (at least level 2, Table IV). For children with asthma, many pediatricians preferred cromogiycate in an initial trial of 3 to 6 weeks to low-dose inhaIed s&&d; cromoglycate is also occasionally used in adults. The dose of cromogiycate is 2 to 10 mg by MDI, or 20 mg of powder by Spinhaler (Fisons Corp., Rochester, N.Y.), four times daily. If this treatment fails to achieve con-


TABLE IV. Levels of treatment with medications

1 Inhaled &-agonist, as needed, plus/minus cromoglycate (before provocation only)

2 Level 1 plus trial of regular cromoglycate or low-dose inhaled steroid

3 Level 1 plus high-dose inhaled steroid plus/minus trial of additional sustained release theophylline or long-acting pz- agonist plus/minus inhaled ipratropium bromide

4 Level 3 treatment plus ingested prednisone

When the patient is observed, the level of treatment started will be determined by (1) the level of severity of asthma and (2) the medications and their doses already being used (see Table III and section on medications in text).

Once control or the best result is achieved, the medications should be reduced to the minimum that will maintain this result for months at a time.

Special considerations in young children and infants are discussed in the text.

All levels of treatment should be regarded as a trial of therapy. If the desired outcome is not achieved, the therapy should be changed or increased. In the case of level 2 treatment, if cromoglycate is tried and fails to achieve or maintain control, it is usual to switch to low-dose inhaled steroid.

trol or the best result, it is replaced by inhaled steroid. When inhaled steroid is used as initial maintenance therapy or as a replacement for cromoglycate, a usual starting dose would be beclomethasone dipropionate, 250 to 500 pg/day; budesonide, 200 to 400 pg/day; flunisolide, 500 to 1000 pg/day; or triamcinolone, 400 to 800 p.g / day in two divided doses.

If there is level 3 severity (Table III) at the time of evaluation and/ or the asthma has not improved during 1 week of level 2 treatment, high-dose inhaled steroid (level 3, Table IV) potentially with ingested bronchodilator and/or ingested prednisone (level 4, Table IV) is required. The level of treatment is guided by the severity of the asthma and the current level of treatment. High-dose inhaled budesonide or beclomethasone can be initiated in a dose of 800 to 1000 pg or more per day, preferably in three or four divided doses,40, 4’ and are best administered with an add-on device4’ to maximize the antiasthma effect and minimize upper airway side effects. High-dose inhaled steroid can be expected to reverse existing limitations more rapidly than low-dose treatment.43 A usual dose of prednisone is 25 to 50 mg daily, administered in a single dose after breakfast or in two divided doses, until control or best result is achieved; then, the dose can be reduced quickly during 1 or 2 weeks while inhalant treatment is continued. In the long term,

larger doses of inhaled steroid are preferable to ingested steroid and should be used with ingested steroid to minimize the dose of the latter.44

The addition of ingested sustained-action theophylline, ingested sustained-action &-agonist, or inhaled ipratropium bromide at treatment level 3 or 4 may help to reduce symptoms caused by variable airflow limitation. These medications can be used at an earlier level of treatment, although bronchodilation with an inhaled &agonist is usually preferable and is usually sufficient. Theophylline administration needs to be managed carefully according to standard regimens, which take into account blood levels and conditions, such as virus infection with fever or the use of erytbromycin that can change dosage require- merits . 45 The usual dose of inhaled ipratropium bromide is 40 to 80 p,g, four times daily. An unusual predisposition to side effects, such as tremor or tachycardia from the inhaled Pz-agonists in usual dosage is an indication for an early trial of inhaled ipratropium bromide as an alternative.

Careful monitoring is required to ascertain the level of treatment that is needed to achieve control or the best result. At all levels, the regimen should be considered a trial of therapy. If expected outcome is not achieved, the treatment should be changed or increased.

Antihistamines are not particularly useful for the management of asthma, but their administration to subjects with asthma for other indications is not con- traindicated.“‘j The place of ketotifen in treatment has not been established. Cromoglycate and nedocromil appear to have comparable indications. Low-dose methotrexate reveals early promise for its steroid- sparing effect to avoid large doses of ingested prednisone, but observations are as yet few in number.47 Troleandomycin should not be considered to have a steroid-sparing effect because the side effects of steroid in lower doses are enhanced.4B

Lowest level of treatment with medicetions required to maintain control or the best resutt

Once the minimal symptoms and the highest flow rates have been reached, then the level of treatment with medications (Table IV) can gradually be reduced to the lowest level that is required to maintain control or the best result for months at a time. If theophylline or ipratropium bromide have been used, they can be the first medications chosen for reduction; they can bc continued, especially in those patients still receiving high-dose inhaled steroid, if they are demonstrated to provide ongoing benefit. Regular treatment that maintains control or best result and prevents severe exacerbations may, over time, produce improve-

VOLUME 65 NUMBER 6

ment in best results,49 allow a reduction of regular medications, and prevent deterioration of the asthma.

Written “action plan” for early treatment of exacerbtions

Each patient and physician should discuss and agree on a written personal management plan. Components include (1) symptom plus/minus peak flow criteria to introduce or increase the dosage of inhaled steroid (dosage should be specified), (2) criteria to introduce or increase the dosage of prednisone (dosage should be specified), (3) criteria that indicate that the patient should immediately phone the physician treating the asthma or seek medical treatment at a specified emergency department.

Criteria of the severity of exacerbations include the frequency and intensity of increase in symptoms, the magnitude of the increase in the dose of inhaled &-agonist being taken to relieve symptoms, the extent of deterioration of PEFR (measured after inhaled P,-agonist), and the magnitude of the increase in variability of PEFR (Table III).

An example of an action plan based on symptoms and &-agonist requirement in a patient receiving regular inhaled corticosteroid, 200 or 250 pg twice daily, who usually needs a Pz-agonist twice daily, is as follows:

If cough, wheeze, or breathlessness begin to occur with milder provocation or if inhaled &-agonist is needed more often, increase the dose of inhaled steroid twofold or fourfold. If cough, wheeze, or breathlessness cause nocturnal or early morning symptoms two nights in a row or if there is a need for inhaled &agonist more than four times daily for more than 1 day, inhaled steroid, 1000 to 2000 kg per day for 1 to 2 days may be tried. Initially, or after a failure of high-dose inhaled steroid, begin prednisone, 25 to 50 mg daily, until control or the best result has been restored. If symptoms are persistent at rest or if the P,-agonist inhalations provide relief for less than 4 hours, seek medical treatment at a specified facility.

An example of an action plan follows, based on PEER that could be administered to an adult patient receiving inhaled corticosteroid with a “best PEFR” of 500 L/min.

If, for 24 hours, PEFR after inhaled P-agonist is

1. <425 (85% of best result), increase the dose of inhaled corticosteroid twofold or fourfold until readings are within 10% of the best result

2. ~300 (60% of best result), take prednisone, 25 to

Assessment and treatment of w.:hma 1103

50 mg daily, until readings are again within 10% of the best result

3. <250 (50% of best result), take an additional 25 to 50 mg of prednisone and seek medical treatment at a specified medical facility

Provision at home for extra treatment can include (1) high-dose formulation of inhaled steroid, if this is available, (2) prednisone tablets for patients who might require prednisone for the treatment of exacerbations and fully understand the indications for its use, (3) epinepbrine” or a selective &-agonist in a form for subcutaneous injection for the very few patients who have a history of unusually severe sudden attacks of asthma with or without anaphylaxis, (4) a home nebulizer-compressor system, which may have been introduced as a consequence uf the inefficient use of the MD1 that often can be corrected by use of the MD1 with an add-on device, and (5) a home oxygen supply, particularly for patients who develop sudden severe attacks and do not have easy access to a medical facility for emergency treatment

Patient education

The properly educated patient is weEl situated to achieve and maintain control or the best result. Patient education should be ongoing and should include provision of an understanding of (I) causes of airway disease and of airway constriction and their avoidance, (2) the nature of the disease, (3) the severity, (4) the objectives of treatment (control or best result), (5) the place in treatment and side effects of individual medications, (6) proper technique of administration of medications, and (7) criteria for the recognition of deterioration as a basis for a self-administered increase in treatment and for seeking urgent medical attention.51. 52 The earIy recognition of exacerbations and the availability and use of self-administered increases in treatment are undoubtedly very important components of any program to reduce morbidity and mortality from asthma.

Regular follow-up

Regular follow-up visits are essential (Table V). When the treatment has achieved control or best result and the lowest level of treatment is established to maintain this result, follow-up at 6- to It-month intervals is appropriate.

Evidence of denial of asthma, noncompliance with management programs, poor perception of worsening of asthma, or serious psychologic problems indicate the need for more frequent visits and more explicit instructions.

If control or the best result has been maintained, a trial of reduction of medications can he undertaken.


TABLE V. For consideration at follow-up visits

1 Current level of Symptoms (on exertion, in the night, or on waking,

and how often do symptoms require treatment with an inhaled P,-agonist)

PEFR or FEV, and VC Treatment

Side effects from medications

Exacerbation(s) since last observed Number Probable causes(s)

4

5

6

7

8

9

10

Were they treated according to previous action plan Duration

Contributing (causal) factors Review possible changes

Demonstration by the patient of the use of inhaled medications and, if it is appropriate, of the techniques of PEFR measurement

Need for additional investigations, such as allergy skin tests, PEFR, and PC, measurements in relation to occupational exposure, or chest or sinus radiographs

Decide on the level of treatment

Review action plan

New prescriptions

Return appointment

Conversely, a lapse in control or best result is an indication to increase the level of treatment (Table Iv). When to refer

Referral to a suitable specialist is recommended in the following circumstances:

1. There is doubt about the diagnosis of asthma 2. Factors including allergens or occupational expo-

sures could be involved and have not been properly evaluated

3. There is a requirement for level 3 or level 4 treatment (Table IV)

4. There is an apparent discrepancy between the severity of the symptoms and the success of the treatment

5. There has been a need for emergency treatment or hospital admission

6. Any persistent respiratory symptoms in infants and young children

EMkRGENCY CARE A usually preventable situation

Severe life-threatening asthma can develop quickly as a result of ingestion of a food to which there is marked allergy, metabisulfite or a nonsteroid anti- inflammatory drug, ingestion or ocular use of a

P-blocker, exposure to a large dose of aeroallergen or chemical sensitizer, or unknown reasons. However, the usual situation is the exacerbation in which there is progressive deterioration for days or weeks, Early recognition by the patient or physician and early and adequate corticosteroid treatment can usually prevent the exacerbation from becoming severe. Thus, severe life-threatening asthma and asthma mortality should be regarded as almost always preventable.

Surveys of emergency care of acute exacerbations of asthma53-5s have highlighted deficiencies in both assessment and treatment including (1) failure to measure the severity of airflow limitation by spirometry or PEFR and to determine the amount of improvement after treatment, (2) failure to treat with adequate doses of corticosteroid, and (3) failure to arrange adequate follow-up for long-term treatment to achieve control and prevent subsequent severe exacerbations.

Assessment

The history should document the severity of symptoms, the duration of lack of control, the amount of inhaled P-agonist and theophylline used in the past 24 hours, the quantity of other treatment and its duration, and any causes of the exacerbation. Symptoms that occur at rest or have disturbed sleep, and/or excessive use of inhaled &-agonist suggest severe

VOLUME 85 NUMBER 6

Assessment and treatment of &hma 1105

asthma. The level of previous maintenance treatment and medication requirements during previous exacerbations serve as a guide to the additional treatment required.

A general examination should document the state of exhaustion, the level of consciousness, any cya- nosis, the use of accessory muscles, the pulse and respiratory rates, and the magnitude of pulsus para- doxus. Complications of severe asthma, such as at- electasis, pneumothorax, and pneumonia should be excluded.

FFV, and VC or PEFR must be measured early, if this is feasible, before adequate dose of inhaled S-agonist treatment and certainly after this treatment. It cannot be overemphasized that attempting to manage acute asthma without objective measurement of airflow is like attempting to manage chest pain without an electrocardiograph or a hypertensive crisis without a sphygmomanometer. The assessment of the severity of airflow limitation from symptoms and signs alone is inaccurate.37. 46 Measurement of arterial blood gases is especially indicated if FEV, or PEFR remain <40% of predicted after initial treatment5’ or if the patient appears fatigued and is not responding to therapy. A chest radiograph is not routinely required5* but should be performed for suspected pneumothorax, atelecta- sis, or pneumonia, and in all patients who fail to respond to initial therapy in the ER.Z9

Treatment in the ER

The objectives of treatment are to (1) relieve hypoxemia, (2) relieve airflow limitation to the degree that is possible, (3) reverse airway inflammation, and (4) avoid toxicity from overdose with &agonists, theophylline, or ipratropium. Treatment must begin at once and takes precedence over investigations (i.e., PEFR or arterial blood gases) unless these can be done within minutes of arrival and the patient does not appear to be in a life-threatening phase. The priorities of treatment are as follows:

1. Oxygen should be administered by mask in con- centrations high enough to relieve the expected hypoxemia. In patients with asthma, the oxygen concentration is not limited by the potential for inducing CO, retention, since hypercapnia in asthma reflects the severity of airhow limitation and muscle fatigue rather than decreased COZ drive, as may be the case in patients with chronic airflow limitation. In contrast, if there is the possibility of chronic airflow limitation in elderly patients, the oxygen concentration should initially be limited to 24% or 28%, and the effect of this on Paco2 and SaO, should be monitored. An SaO, of 390% (PaoZ >60 mm Hg) should be achieved.

2. Inhaled P-agonist with or without ipratropium bromide must be administered immediately by a nebulizer or by an MD1 with a valved add-on spacer device, in larger than maintenance doses.6’1”’ In severe asthma, the dose of aerosol generated bears little relationship to the dose deposited in the airways; most of the dose may be wasted, whether it is produced by nebulizer or MIX Presently, it is more common to administer &-agonist by nebulizer with oxygen. The recommended dose of salbutamol is 2.5 to 5 mg; terbutaline, 2 to 5 mg; metaproterenol, 10 to 15 mg; and fenoterol, 0.5 to 2.5 mg. Ipratropium bromide, 0.25 to 0.5 mg, may also be added to the &-agonist but should not be administered alone, since the magnitude of bronchodilation may be small and since it may cause a paradoxical airway constriction. The drugs may be administered with a mouthpiece or mask and may be repeated every 20 minutes if this is necessary. If acute treatment with an MD1 and add- on-device is used as an alternative, an appropriate dose of &agonist is four puffs (fenoterol, 800 pg; salbutamol, 400 p,g; metaproterenol or terbutaline, 1000 p.g) during 2 minutes, and then one puff each minute until there are side effects. such as tremor or until the breathlessness and flow rates improve. The dose of four puffs can be repeated. if this is necessary, at intervals of 20 to 30 minutes until additional systemic corticosteroid treatment, administered at the same time, takes effect; then, the amount and frequency can be gradually reduced to maintenance levels.

3. The use of corticosteroid by ingestion (prednisone / prednisolone) or by intravenous injection (hydrocortisone or methylprednisolone)w-h8 is im- perative and should not be delayed or deferred in severe asthma, even if a positive response to bronchodilator is initially achieved, since this is often temporary. Generally, corticosteroid begins to act in less than 4 hours, but it may take days to reverse the exacerbation. Appropriate doses of prednisone are 30 or 40 mg immediately, then twice or three times in the first 24 hours (up to 2 mgi kg/24 hr) according to the response, and then daily until control is achieved. At alternative, particularly for patients with a very severe exacerbanon. is intravenous methylprednisolone,69 125 mg (or 500 mg of hydrocortisone) in a single dose, followed by ingested predisonelprednisolone as above. From past experience, high corticosteroid maintenance levels or a poor response in some parients can be indications for altering these doses of ingested or injected corticosteroid.

4. Spirometry or PEFR is required to measure the response to treatment. Measurement of blood gases


may need to be repeated if the initial Pace, is raised, the SaO, is <90%, or if there is subsequent deterioration.

5. Other medications that need to be considered are epinephrine, aminophylline, and intravenous B-agonists. For asthma, epinephrine by subcutaneous or intramuscular injection has been largely replaced by inhaled I&agonists.“. ‘I However, for the acute treatment of anaphylaxis, for angio- edema, or, rarely, for asthma with sudden severe attacks unrelieved by inhaled B-agonist, epinephrine is required. Such patients with asthma should carry self-injectable epinephrine for future sudden severe attacks to tide them over until reaching medical help. The use of intravenous aminophylline for severe asthma is presently controversial.‘*-” It may be tried if there is a failure to respond to inhaled bronchodilators; if theophylline was not previously used, the loading dose is 5 mg/kg during 20 minutes, and the usual maintenance dose is about 0.6 mg / kg / hr in the adult. ‘K 76 The required dose may be larger, up to 1 mg/kg/hr in children or adult smokers, and it may be lower in patients who are elderly, have heart failure or liver disease, or are receiving drugs, such as cimetidine or eryth- romycin. During use, careful observation is needed for evidence of toxicity, including nausea, vomiting, tachycardia, arrhythmias, or seizures. Blood levels must be monitored; otherwise, severe toxicity may occur without warning. Intravenous Bz-agonist may be tried, if this is available, in a loading dose of 5 to 10 kg/ kg during 5 to 10 minutes, followed by a maintenance dose of 0.1 to 0.2 pg/kg/min. Failure to relieve obstruction by adequate bronchodilation is likely due to nar- rowing of the airways from inflammatory exudate rather than unrelieved bronchoconstriction.

6. Mechanical ventilation is required when the patient is obtunded at first observation or has progressive respiratory failure in spite of the above treatment. The patient should be paralyzed, and controlled hypoventilation is preferred to reduce the impact of barotrauma.“* 78

Criteria for discharge home and follow-up

There are no absolute criteria that assure safe discharge. Discharge should be considered if (1) the FEV, or PEFR has improved to >50% of predicted79-81 or >50% of the known previous best values, (2) the physician is confident that improvement is likely to be sustained, (3) the patient under- stands the need to continue with regular high-dose corticosteroid treatment until the exacerbation has resolved*’ or has received injected long-acting corticosteroid, if compliance is questionable,83z 84 and (4)

arrangements have been made for follow-up by the family physician or specialist within a few days of discharge. Patients who have required emergency treatment should be referred to a specialist and should have a plan of direct access to acute care for possible subsequent exacerbations.“’ 52

Criteria for admission to hospital

Admission to hospital is mandatory if there is any concern about an inadequate response to emergency treatment or if there is persisting severe airflow limitation. Generally, if the patient feels the need for admission for safety, admission should be arranged.

YOUNG CHILDREN AND INFANTS: SPECIAL ISSUES IN THE YOUNG

1. Methods of measurement of ventilatory function are not generally available. Accordingly, the results of a trial of therapy of asthma, recorded on a diary card and a scoring system for acute asthma, have greater relevance than in older children and adults.85

2. Some alternative conditions that require consideration at this age include cystic fibrosis, congen- ital heart disease with left to right shunt, unsus- pected aspirated foreign body, gastroesophageal reflux, and airway obstruction by vascular ring or cyst. These might be suggested by history or physical examination or poor response to treatment.

3. Underdiagnosis of asthma is a frequent problem. It is still not generally recognized that 50% of children with asthma develop their initial symptoms before their first birthday.*‘j There is still com- monly a mislabeling of young children with asthma who wheeze with respiratory infections as wheezy bronchitis, asthmatic bronchitis, or bronchitis de- spite ample evidence that there is variable airflow limitation and the proper diagnosis is asthma.*‘. ** Another cause of underdiagnosis is the failure to recognize that asthma may accompany other chronic respiratory disease, such as bronchopulmonary dysplasia,89 cystic fibrosis,gO or recurrent croup,9’ which can dominate the clinical picture.

4. Devices for successful inhalation treatment often need to be adapted to the child’s age.

5. Truly episodic disease with acute attacks at the time of viral infections and apparent complete re- mission between episodes is probably more common in children than in adults.

6. Harmful factors in children that can be of major importance and can often be avoided include household allergens, secondhand smoke, and other indoor pollutants, such as fumes from gas stoves and open fires.

VOLUME 85 NUMBER 6


7. Parents, teachers, and school nurses need to be educated to participate in the management plan.

Most principles of treatment are similar to treatment in the adult

The objectives of treatment are the same (Table I), and (1) avoidance of harmful factors is preferable to treatment with medications, (2) inhalation is the preferred route of delivery of antiasthmatic medications, (3) antibiotic is not a treatment of asthmatic attacks, including acute attacks associated with upper respiratory tract infections. Antibiotic use should be based on separate indications of infection, such as unusually high or persisting fever or the presence of purulent sputum. and (4) there is a major requirement for a continuity of care.

Treatment with medications in children

Inhalant treatment in children generally requires an add-on device with an MD1 or the use of a powder device. Powder devices require a greater inspiratory flow rate to generate effectively an inhalable aerosol; they may therefore not always provide adequate therapy during more severe episodes. If there is a risk of overuse of inhaled bronchodilator, powder devices permit better monitoring of dosage. An MD1 and an add-on device with mouthpiece has been demonstrated to be effective from the age of 2 to 3 years.92 Children aged 3 years or younger may require a device with a face mask. Presently, a compressor/nebulizer system with mask or mouth tube is usually used. An add-on device with mask for use with an MD1 is available as a convenient alternative to a compressor nebulizer system” in young children and infants, but additional proof of its efficacy is required.

There are some children who are extremely well for long periods of time but have breathlessness and/or excessive cough for days or weeks, presum- ably in association with viral upper respiratory tract infections. There are few studies that provide guidance in treatment, although antibiotics have been demonstrated not to be helpful for the airway problem, and ingested prednisone, in one study, was effective. Treatment based on symptom information with the level of treatment (Table IV), determined by the level of severity. would appear to be reasonable, although regimens based on past experience introduced at the first sign of a respiratory infection may provide best results.

For level 1 treatment (Table IV) of mild episodic asthma, inhaled &-agonist plus/minus cromoglycate is generally sufficient. Episodic use of cromoglycate is appropriate only before an event, such as exercise, that can provoke symptoms; it does not relieve symptoms that have developed. Ingested sustained-relief

theophylline or ingested I&-agonist may be altema- tives in a small number of patients who arc unwilling or unable to inhale medications, but they are generally less effective and associated with more side effects. The use of ingested bronchodilators IS declining.

More severe asthma generally requires continuous treatment in addition to inhaled P,-agonist on an as- needed basis. For level 2 treatment, an initial trial of inhaled cromoglycate, such as 2 to 10 mg by MDI, or 20 mg of powder four times daily for 3 to 6 weeks, was favored for children by many of thct therapists (Table IV). When cromoglycate does not achieve and maintain control or best result, low-dose inhaled steroid should be substituted. Higher levels of treatment (Table IV) may be required according to the level of severity, as in the adult.

Emergency treatment in children

Principles and modalities of emergency treatment are the same as in adults. Differences pertain mainly to dosage of medications.

Inhaled oxygen is an important part of emergency treatment. On an urgent basis, on the way to and during initial ER treatment, as in the adult, inhaled P,-agonist is required in much larger than usual maintenance doses. Regimens that have been reported in refractory asthma include salbutamol, nebulized with oxygen, in doses up to 0.15 mg/kg to a maximum of 5 .O mg, followed by as much as 0.05 rngi kg every 20 minutes for 2 hours,94 and continuous nebulization of terbutaline, 4 mg/ hr.‘”

Acute treatment with a &-agonist from an MDI with an add-on device has been demonstrated to produce equivalent or superior bronchodilation to the compressor/nebulizer system in adults,‘” but acute treatment with the MD1 in children has not been cval- uated

Increased inhaled steroid or ingested steroid are required for exacerbations. A usual dose of prednisone is 1 to 2 mglkgiday (up to 50 me/day) until control or best result has been achieved. The dosage is then tapered during about I to 2 weeks.

It may be useful to add inhaled ipratropium bromide to inhaled &agonist to treat acute episodes. although this treatment remains controversial.“-‘R’ Aminoph- ylline, 6 mg/ kg, can be administered intravenously during 20 minutes, if theophylline was not being used

at the time the patient was first observed.‘“, 76 Indi- cations include children who fail to demonstrate either symptomatic improvement or a satisfactory increase in oxygen saturation by oximeter within 30 minutes of starting emergency treatment with inhaled bronchodilator in adequate doses or who have life- threatening airflow limitation. The maintenance dose of aminophylline needs to be individuaiized and ad-


justed on the basis of factors that can affect clearance. The use of aminophylline in acute treatment of asthma is controversial and is decreasing because of lower efficacy and higher toxicity than with inhaled BZ- agonist.

Asthma in infancy

Because of the greater difficulty in administering treatment and achieving control, asthma in infancy should be managed by a specialist with experience of managing asthma in children. In acute attacks, patients should be brought to hospital without delay.

Infants appear to respond less readily than older children or adults to medications for asthma. A trial of bronchodilators is indicated. There is now increas- ing evidence that airflow obstruction in many infants can be improved in response to adrenergic or anti- cholinergic agentsg3. ‘01-‘03 The small minute volume in infants (3 to 3.5 L) compared to that of the nebulizer output (6 L) limits the amount of drug that can be inhaled. As a result, the amount of medication nebulized needs to be relatively high; for example, 0.5 to 1 mg of &-agonist four times per day and ipratropium bromide, lo3 0.2 mg up to four times per day, can be tried.

OCCUPATIONAL ASTHMA

Occupational asthma is defined as asthma caused by exposure to a sensitizing substance at work.26, ‘04 Persisting asthma may also follow an overexposure to noxious fumes, such as a leak of chlorine gas. Airway constriction triggered at work by nonsensitizers (e.g., irritant dust, fumes, or exercise) in the subject who otherwise has asthma is not considered to be occupational asthma. The possibility that the asthma is not controlled because of undertreatment should be considered.

The suspicion of occupational asthma depends on continuing alertness to the possibility and a systematic inclusion of questions about occupation in the history. A knowledge of the occupational sensitizers recognized as known to cause asthma is required. Agencies responsible for the health and safety of workers should make lists of these sensitizers available to physicians and management-worker safety committees. How- ever, the fact that a worker with asthma is exposed to an agent found on these lists is not adequate to establish the diagnosis of occupational asthma. Fur- thermore, occupational asthma can occur from previously unrecognized causes. When the history sug- gests a relationship between occupational exposure and symptoms of asthma, then the patient should be referred to a specialist or facility with an accepted standardized approach to the investigation of occu-

pational asthma. Prompt access to the specialist is essential.

The diagnosis of occupational asthma must be confirmed through objective means with daily measurements of PEFR and/or histamine or methacholine tests at work, compared with tests away from work, skin or serologic tests for antibodies, and the judicious use of occupational challenge tests with the suspected substance(s).26. ‘04* lo5

The patient should not resign from work until a firm diagnosis of occupational asthma has been made, the treatment has been considered by the specialist, and, in countries in which the condition is a compensatable disease, a compensation claim has been decided. If the asthma is disabling during a more severe exacerbation, then the worker should be away from work, as would any subject with asthma from any job.

The medical treatment of occupational asthma ideally requires the avoidance of the causative agent. This is best accomplished by a change of location in the organization but may require a change of job; if this change is necessary, efforts should be made to find resources to compensate for financial loss and dis- ability from the asthma and to help in the search for a new job. The specialist should be able to advise the worker on these issues.

The prognosis of occupational asthma is influenced by the speed of diagnosis and the success of avoidance of exposure. Early diagnosis and avoidance can be followed by a cure of the asthma. However, occupational asthma can continue after cessation of exposure to the causative agent,‘w1o8 although the severity of disease decreases.

Screening of workers to identify those at risk of developing occupational asthma has limited value. Atopic subjects, that is, subjects with IgE antibodies to common inhalant allergens, are somewhat more likely to become sensitized to small animals’Og or bi- ologic detergents. ‘lo However, screening workers for atopy before these exposures should not be used to exclude individuals from employment, because the specificity and sensitivity of this procedure is low. Screening for atopy can be used to counsel prospective workers about the slightly increased risk. No other tests identify workers at risk; specifically, previous asthma does not identify workers at risk for occupational asthma. Prior atopy is not a risk factor for sensitization to simple chemicals.

We thank Mr. Scott McConnell for organizing the workshop and for assistance in arrangements to prepare this article, and we acknowledge the secretarial contributions of ME.. Laurie Whitely and Mrs. Judy Walters. We derived great benefit from the opportunity to make liberal use of “The Australian Asthma Management Plan” provided by Dr. AM Woolcock.‘**

VOLUME 86 NUMBER 6


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APPENDIX PEFR measurements at home Method of use qf a peak Jlow meter

1. A full inspiration is followed by a maximal expiratory effort with the lips tightly around the mouthpiece.

2. The best of three readings on each occasion is recorded.

3. The times of measurement will depend on the objectives. Best postinhaled P-agonist values and daily variation can be obtained from twice-daily measurements, on waking and before bed, and before and after inhaled &agonist. Variability can be calculated from the mean highest and mean lowest values recorded for 1 or 2 weeks; variability (%) -=- (highest- lowest/highest) x 100.

Why home monitoring is important

1. To find the “best” airway function during intensive treatment

2. To measure the daily variability of PEFR readings as an indicator of the degree of airway responsiveness

3. To educate the patient about managing his/her asthma 4. To keep airway function close to “best” at all times 5. To determine the severity of an exacerbation and to

detect this early when the patient perceives symptoms poorly

6. To allow the patient to adjust doses of drugs to maintain normal function with minimal doses of drugs

7. To identify unknown or suspected trigger factors

Who should keep a peak Jlow meter at home

1. Patients who experience severe attacks with little warning

2. Patients who require level 2 treatment with special circumstances, such as a long distance from medical attention

3. Patients who require level 3 or 4 maintenance treatment

4. Patients with known marked diurnal variation of PEFR (>20%)

107. Mapp CE, Corona PC, DeMarzo N, Fabbri L. Persistent 5. Patients in whom the history appears to provide an asthma due to isocyanates. A follow-up study of subjects with unsatisfactory guide to treatment

Assessment and treatment of aqthma 1111

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The assessment and treatment of asthma: A conference report