Asthma Management: Guidelines for the Primary Care Physician

Author:

Miles Weinberger M.D.
Department of Pediatrics
University of Iowa College of Medicine

Peer Review Status: Externally Peer Reviewed
Creation Date: May 1995
Last Revision Date: May 2001

Table of Contents

• The Problem
• Guideline Goals
• Diagnosis of Asthma
• Classification by Clinical Pattern
• Therapeutic Strategies
• Follow-up Guidelines
• Guidelines for Urgent Physician Care of Acute Symptoms
• Formulary of Commonly Used Anti-asthmatic Medication
• Tables
• References
• Recommendations for Further Reading
• Other Educational Resources

The Problem
Asthma is the most common medical diagnosis among hospitalized children. In the United States, asthma has accounted for about 15% of non-surgical admissions to the hospital in the pediatric age group.^[1] Asthma is also one of the leading causes for emergency care requirements, one of the leading causes for missed school and a cause for considerable morbidity, disability, and occasional mortality at all ages. Despite these discouraging statistics, there is convincing data indicating that this failure of asthma management is not the result of inadequate therapeutic potential, but instead represents a failure of effective medical care delivery. Conflicting and/or complex regimens from multiple sources result in confusion and lack of clear guidelines realistically applicable in the primary care setting.

Guideline Goals
Guidelines realistically applicable in the primary care setting can be termed low intensity, and it is the goal of this guide to emphasize those low-intensity measures likely to have the greatest influence on outcome. These strategies can therefore be called low-intensity high-yield measures for managing asthma.

Low-intensity measures for assessment and therapy are necessary in the primary care setting because of the prevalence of asthma, the likelihood that most patients with asthma will continue to receive most of their care from primary care physicians, and the limited time available per patient in the primary care setting. Choosing those measures that provide high-yield are necessary to gain the greatest clinical benefit with the least clinician time and cost. These guidelines therefore are not an attempt to identify all possible measures that might be useful for asthma. Measures that are high intensity and/or low yield may be very important for selected patients but are probably most appropriate in a subspecialty setting. These guidelines are therefore designed to cut through the morass of potential diagnostic and therapeutic options in order to isolate the most efficient initial means of effectively managing asthma.

Diagnosis of Asthma
Establishing the diagnosis is critical, although historically asthma has been misdiagnosed. Particularly in the young child, the symptoms resulting from airway inflammation associated with asthma have been misdiagnosed as pneumonia and bronchitis, leading to ineffective and unnecessary use of antibiotics (Figure 1). If there is not a firmly established alternative diagnosis, asthma should be considered when patients present with the following symptoms:

• recurrent or chronic lower respiratory wheezing most prominent on expiration
• recurrent or chronic coughing
• repeated diagnoses of bronchitis
• repeated diagnoses of pneumonia not clinically consistent with pyogenic infection

The diagnosis of asthma is most efficiently confirmed by demonstrating the complete response of symptoms, or spirometric measurement of airway obstruction, to an inhaled b₂ agonist and/or a 5 to 10 day course of high dose oral corticosteroids. Patients not clearly made asymptomatic with these measures should be referred to an appropriate subspecialist for further investigation of other inflammatory or occasionally functional disorders that can cause similar symptoms. These can include such varied disorders as cystic fibrosis, cigarette smoking induced chronic obstructive pulmonary disease, primary ciliary dyskinesia, tracheal or bronchial malacia, foreign body aspiration, vocal cord dysfunction, or habit cough syndrome.

Classification by Clinical Pattern
Planning effective and efficient strategies for managing asthma requires identification of the clinical pattern of disease in the patient to be treated. These clinical patterns include:

Intermittent. Patients with episodic illness interspersed with extended symptom-free periods. Episodes are most commonly triggered by viral respiratory infections or transient exposure to an environmental allergen or irritant.

Chronic. Patients experience virtually daily symptoms and, in the absence of continuous therapy, do not have extended symptom-free periods.

Seasonal allergic. Patients experience virtually daily symptoms during an inhalant allergy season.^[2] In the North Central United States, this is most commonly from outdoor molds that grow on decaying vegetation from early Spring through late Fall, with peaks particularly in the Spring and Fall. Allergens and seasonal patterns will vary with the geographic region. In other parts of the world, seasonal symptoms may be in reaction to molds, pollens, or a combination of both.

There is potential overlap among these clinical patterns. For example, patients with chronic disease often have intermittent exacerbations from viral respiratory illness and may have seasonal allergic exacerbations. Nonetheless, identification of the clinical pattern contributes to the determination of a therapeutic strategy.

Severity, as assessed by degree of morbidity, is independent of the clinical pattern. Both intermittent and chronic disease may range from relatively benign to life-threatening. Severity should be judged by the frequency and intensity of urgent care requirements, missed school or work, and interference with activity or sleep.

Therapeutic Strategies
Therapeutic strategies fall into 2 categories: intervention, defined as measures to stop acute symptoms, and maintenance, defined as measures to prevent symptoms from occurring.

All patients require availability of efficient and effective intervention measures. Effective intervention requires anticipating symptom progression so that anti-inflammatory corticosteroids, which act slowly, may be started before urgent care is needed. Therefore, b₂ agonists and corticosteroids should be available at home, and patients and their families should be taught when and how to apply them, as outlined below.

Intervention alone is sufficient for treatment of those with intermittent asthma. However, patients with chronic disease need maintenance medication in addition, to prevent their daily symptoms. Patients with seasonal allergic disease may require maintenance medication, but only seasonally, and patients with chronic disease may require seasonal increases in their maintenance medication during seasonal allergic exacerbations. Adding or increasing maintenance medication at the times when increased symptoms are anticipated avoids morbidity and decreases the likelihood that urgent care will be needed.

Pharmacologic therapy must meet several criteria to be considered successful in controlling asthma (Table 1). First, the treatment plan should eliminate the need for hospitalization and unscheduled medical care due to asthma, and should prevent asthma from interfering with sleep or any activities, including competitive athletics. Maintenance therapy, when needed, should minimize the need for intervention with inhaled b₂ agonist to a maximum of twice daily, not counting pre exercise prophylaxis, and reduce the need for intervention with short courses of high dose daily oral corticosteroids ideally to no more than 4 times yearly. Long-term use of daily oral corticosteroids is not safe in any dose and is not indicated for acceptable control of asthma. Patients on maintenance therapy should be capable of normal post-bronchodilator pulmonary function by office spirometry. Finally, patients should suffer no adverse medication effects or adverse effects of treatment on their quality of life.

Low-intensity High-yield Early Intervention Measures
The first intervention should be a b₂ agonist delivered promptly by age-appropriate inhalational device (Figure 2). This should be applied repeatedly when needed. An inhaled b₂ agonist is also the most effective means of prophylaxis for exercise-induced bronchospasm. Careful instruction regarding appropriate use of the prescribed device is essential.

In the case of subresponsiveness to b₂ agonists, high dose oral corticosteroids should be initiated immediately and continued until the patient is symptom-free for 24 hours. This usually requires 5 to 10 days of therapy (Figure 3). Patients must be educated on the criteria for subresponsiveness to b₂ agonists, which include failure to experience complete relief of symptoms, failure of the b₂ agonist effect to last 4 hours, and repeated use (for example, symptoms requiring a third use within any 8 hour period). This algorithm should be clearly communicated to the patient. Patients who have had previous urgent care requirements or hospitalizations require a low threshold for progression to corticosteroid therapy (Table II).

Early and vigorous intervention with these measures efficiently and effectively prevents at least 90% of acute exacerbations of asthma from requiring emergency medical care or hospitalization.^[3-5] There are no absolute contraindications to either of these measures. It should be noted, however, that corticosteroids will increase hyperglycemia in diabetics. Also, the onset of chickenpox in children receiving corticosteroids during the incubation period justifies institution of acyclovir in full recommended doses. An oral b₂ agonist syrup may be appropriate for infants and toddlers with trivial symptoms who have never required emergency care, in order to avoid the expense and bother of a nebulizer.

Low-intensity High-yield Maintenance Measures
Low dose inhaled corticosteroids or reliably absorbed slow-release theophylline depending on preference for an inhaled or oral medication, should be administered twice a day as the first-line of treatment in preventing asthma exacerbations.

If the inhaled corticosteroid was the first agent used for maintenance therapy and the asthma does not meet criteria for control (Table I), add theophylline or inhaled salmeterol to the inhaled corticosteroid. If theophylline was initiated first and was found to be inadequate, add an inhaled corticosteroid or alternate-morning oral prednisone (or equivalent corticosteroid) to theophylline. These combinations are the only ones with well-documented additive effect.^[6-9]. Cromolyn has been shown to have no additive effect with theophylline or inhaled corticosteroids, and nedocromil is no more effective than cromolyn, according to the package insert. Alternate-morning administration of shorter-acting oral corticosteroids such as prednisone, prednisolone, or methylprednisolone provide an acceptable and safe alternative to inhaled corticosteroids for most patients who cannot or will not comply with inhaled corticosteroids (Table III).

A maximum of 2 maintenance medications at a twice-daily schedule with judicious use of a pre-exercise b₂ agonist and appropriate measures of intervention, is generally sufficient for control of asthma. Patients requiring maintenance medication should, in general be evaluated to determine the role of environmental factors involved in their symptoms. This evaluation involves careful history and skin testing for specific IgE. This would be particularly relevant for patients requiring more than either theophylline or low-dose inhaled steroids for maintenance.

If asthma is resistant to control by the regimens listed above, the patient should be referred to subspecialty clinical care for more intensive evaluation and treatment.

Comments: (1) Theophylline is toxic at excessive serum concentrations; a high degree of effectiveness while still assuring safety with theophylline requires that doses be individualized with reliably absorbed preparations to maintain serum concentrations between 10 and 20 µ/mL;^[10] consequently, theophylline should only be prescribed by those responsible for the ongoing care of the patient and familiar with the guidelines for its usage, which go beyond the scope of this publication (see recommendations for further reading). (2) Montelukast is at least as effective than cromolyn or nedocromil, which makes these latter two agents of no further interest. While montelukast does not match the efficacy of a low dose inhaled corticosteroid and appears to be beneficial predominantly for very mild chronic asthma), it does offer simplicity and absence of adverse effects. The other leukotriene modifiers available are not justified as an alternative for initial therapy because of less convenience (zafirlukast) or potential toxicity (zyleutin). (3) Oral b₂ agonists are generally not good choices as maintenance therapy. Regularly scheduled use (as opposed to p.r.n. or pre-exercise prophylaxis) of shorter acting inhaled b2 agonists such as albuterol is not indicated for maintenance therapy. Salmeterol, an ultra-long acting inhaled ß₂ agonist, indicated for twice daily maintenance therapy (not for intervention), is not generally recommended as initial therapy; low dose inhaled corticosteroid is preferable although salmeterol appears to be useful when added to an inhaled corticosteroid.

Follow-up Guidelines
Patients whose disease meets criteria for control should receive routine follow-up at scheduled intervals to assess control and assure safety of treatment (Table IV). Measurement of pre- and post-bronchodilator pulmonary function with office spirometry should be performed at each visit. Growth and weight gain should be monitored, because both asthma and treatment with maintenance inhaled or alternate-morning oral corticosteroids have the potential to slow growth. Blood pressure measurement and eye exam for cataracts should be performed on all patients receiving maintenance corticosteroids. In susceptible patients, increased blood pressure may be a systemic effect of corticosteroids. Also, an increased risk of cataracts has been demonstrated even from inhaled corticosteroids.^[11]

Frequency of follow-up. Patients with an intermittent pattern of asthma can be followed with annual checkups if they meet criteria for control. However, more frequent visits may be required to reinforce instructions. Patients with a chronic pattern of asthma should be followed closely until criteria for control are met. Once disease control on stable doses of medication has been achieved, appropriate follow-up depends on the maintenance regimen. Patients requiring more than low doses of inhaled corticosteroids, alternate morning prednisone, or more than one maintenance medication should be seen every 3 months. Patients on low doses of inhaled corticosteroid or other single-maintenance medication may be followed once every 6 months.

Guidelines For Urgent Physician Care of Acute Symptoms
Patients should be treated immediately with oxygen if they are in respiratory distress (Figure 4). They should also be given a b₂ agonist immediately, by inhalation if they are capable of effective inhalation, and by injection if they are severely dyspneic. High dose systemic corticosteroids should be administered promptly by mouth if there is no concern regarding retention, and parenterally if the patient is obtunded or vomiting. The patient should be monitored with pulse oximetry. Blood gases should be drawn (venous or capillary gases are adequate when pulse oximeter is used) if O₂ saturation is less than 94% on room air and patient is dyspneic or retracting, or if O₂ saturation is less than 90% regardless of signs or symptoms (Table V).

Patients may be discharged if they are comfortable at rest without retractions or use of accessory muscles of respiration, and if O₂ saturation is greater than 90% on room air. Early follow-up is important. Patients should be admitted to the hospital if respirations continue to be labored or their O₂ saturation is less than or equal to 90%. They should also be admitted if they are sufficiently dehydrated to require IV hydration, or if they have a history of rapid deterioration and distant access to an appropriately staffed ICU (Table VI). Dehydration is particularly likely to occur in small children because of decreased intake during an extended period of respiratory distress, combined with increased insensible losses.

Once admitted, patients may be discharged when they are comfortable at rest without retractions or use of accessory muscles of respiration and their O₂ saturation greater than 90%. Discharge should be delayed if labored respirations continue or O₂ saturation remains below 90%, the patient is sufficiently dehydrated to require IV hydration, there is a history of rapid deterioration and distant access to an appropriately staffed ICU, or social concerns regarding home care.

The considerations for decision-making regarding admission or discharge for asthma are based on three related principles. First, there are no medications for asthma that are inherently more effective parenterally than orally or by inhalation. Second, there is therefore nothing that can routinely be done in the hospital that can not be done at home, except providing oxygen, close monitoring, and assisted ventilation, if needed. And third, admission and discharge decisions are based on the level of concern for the possibility of respiratory failure.

Formulary of Commonly Used Anti-asthmatic Medication
Inhaled b₂ agonists. Albuterol (Proventil, Ventolin), Pirbuterol (Maxair Autohaler). Two to six inhalations of the metered dose inhaler can be used p.r.n. for acute symptoms or pre-exercise to block exercise induced bronchospasm. Use an assist device such as the Maxair Autohaler (3M) or AeroChamber (Monoghan), or one that permits comfortable rebreathing into a holding chamber such as the InspirEase (Schering) for patients with difficulty coordinating inspiration with activation. Albuterol nebulizer solution, 2.5 mg can be used via a compressed air driven nebulizer but generally provides no more benefit than 6 inhalations from the MDI through an AeroChamber (with face mask if needed).

Systemic corticosteroids. (Deltasone or Orasone prednisone tablets, Orapred prednisolone syrup) For interventional therapy, a sufficiently high dose of prednisone or equivalent such that more is unlikely to be beneficial. For prednisone, use the following doses: less than 1 year old, 10 mg bid; 1 to 3 years old, 20 mg bid; 3 to 13 years old, 30 mg b.i.d.; >13 years old, 40 mg bid. Higher doses may be justified for impending or actual respiratory failure. For ambulatory use, patients should be instructed to discontinue the evening dose if any side effects develop during the course of therapy. These may include insomnia, mood or behavior changes, musculoskeletal pains, or bloating. Methylprednisolone may be used as a substitute for prednisone at 80% of the prednisone dose if side effects from short courses of prednisone remain troublesome. Dosage should be continued until the patient is free from symptoms and signs of asthma. The mean duration of therapy is 7 days, with a usual range of 5 to 10 days. Dosage should be discontinued without tapering. Oral corticosteroids are as effective as parenteral unless they are not retained.

When used as maintenance medication, dosages of 20 to 40 mg of prednisone or prednisolone on alternate mornings (16 to 32 mg methylprednisolone) are generally needed and tolerated. Dosing should begin high and then be reduced to the lowest dose consistent with control of asthma.

Inhaled corticosteroids. Beclomethasone dipropionate is available at 40 and 80 micrograms per metered inhalation (QVAR 40 or 80) with 100 metered inhalations per canister and 84 mcg per metered inhalation; this HFA formulation provides considerably improved delivery over older formulations of this drug. Fluticasone is available at 3 concentrations, each with 120 metered inhalations per canister - 44, 110, and 220 mcg per metered inhalation (Flovent 44, Flovent 110, Flovent 120); budesonide (Pulmicort Turbuhaler) is available as a 200 dose dry powder inhaler at 200 mcg per inhalation and as nebules for delivery by compressed air driven nebulizer with face mask (250 mcg or 500 mcg/dose). However, metered dose inhalers, propellent driven or dry powder, are much more convenient and cost effective than the nebulizer preparation. Even for infants and toddlers, an assist device, such as the AeroChamber with soft flexible face mask (Monoghan) permits effective delivery from an MDI. For all inhaled corticosteroids, the lower end of the dose recommendations (e.g., 1 inhalation b.i.d. (For the lowest concentration of preparations with multiple formulations) is generally adequate since inhaled corticosteroids have a shallow dose-response. Adding salmeterol or theophylline is more effective than increasing the dose of inhaled corticosteroid.

Salmeterol (Serevent MDI and Diskus; salmeterol with fluticasone (Advair Diskus)). Available as a 25 mcg per metered dose inhaler, with 120 metered doses per canister or a 50 mcg per inhalation dry powdered inhaler containing 60 doses. Dosage is limited to 50 mcg q 12 h. Also available in combination with fluticasone containing 100, 250, and 500 µg/inhalation of the fluticasone with 50 µg/inhalation of salmeterol. This should not be used p.r.n. Patients need to be carefully instructed so that salmeterol is not confused with an interventional b₂ agonist.

Theophylline. Therapy should begin with no more than the lesser of 10 mg/kg/day or 300 mg/day using Theo-Dur or Unidur Tablets or Slo-bid Gyrocaps in 2 divided doses at 12 hour intervals. Slo-bid Gyrocaps can be opened and sprinkled on a spoonful of soft food for children who cannot swallow solid dosage forms. The dose may be increased no more frequently than at 3 day intervals in 2 increments to no more than the lesser of 16 mg/kg/day or 600 mg/day. These values for maximum dosage approximate current observations of the mean dosage necessary to attain serum concentrations of 10 to 20 mcg/mL. It must be noted that the weight adjusted dosage for infants 1 to 6 months old is much lower. Metabolic enzymes for theophylline mature rapidly during the first year of life. This makes theophylline somewhat difficult to use at this age. Initial dosage is described by the regression equation {[(0.2 multiplied by the age in weeks) + 5] mg/kg/day}. Guide final dosage by measurement of serum concentration. Target the lower half of the therapeutic range of serum concentrations, especially for patients with above-average dose requirements. Be aware of the potential for drug interactions with theophylline (see package insert). Do not increase the dose if it is already at the lower end of the therapeutic range in an attempt to reach levels at the upper end of the range. Allow for a degree of biologic flux. Do not maintain any dose that is not tolerated. Do not permit generic substitution.

Montelukast (Singulaire). Montelukast is marketed as a once daily evening dosage preparation, 10 mg plain tablets with 5 and 4 mg chewable tablets for younger children. It's efficacy is modest but often adequate for those with mild chronic disease. There is at least some additive effect with inhaled corticosteroids. No toxicity or drug interactions has been described.

• Absence of hospitalization
• Absence of unscheduled medical care
• Absence of interference with sleep or activities (including competitive athletics)
• Intervention with inhaled b₂ agonist (not counting pre-exercise prophylaxis) < twice-daily
• Intervention with short courses of high dose daily oral corticosteroids < 4 times yearly^*
• Normal post-bronchodilator pulmonary function by office spirometry
• Absence of adverse medication effects and adverse effects of treatment on quality of life

^*Long-term use of daily oral corticosteroids is not safe in any dose and is inconsistent with acceptable control of asthma.

• Intermittent - Reassess at 6 to 12 month intervals once controlled, however:
  • Reinforce intervention measures with telephone contact during acute exacerbations
  • Monitor frequency of intervention
  • Reassess if b₂ used multiple times weekly
• Chronic
  • Reassess at least monthly until controlled
  • Once controlled, reassess at 6 to 12 month intervals for patients on stable low-dose inhaled corticosteroids or theophylline
  • Reassess others at no greater than 3 month intervals

• Immediate oxygen for patients in respiratory distress
• Immediate b₂ agonist by inhalation if patient can inhale effectively
• Initial dose by injection if patient is severely dyspneic
• Prompt administration of high dose systemic corticosteroid
• Monitor with pulse oximeter
• Blood gases if O₂ saturation <94% at room air and patient is dyspneic or retracting, or if O₂ saturation <90% regardless of signs or symptoms

• Admission not generally needed if:
  • Comfortable at rest without retractions or use of accessory muscles of respiration
  • O₂ saturation >90% at room air^*
• Admit to hospital if:
  • Labored respirations continue
  • O₂ saturation less than or equal to 90%
  • Dehydrated sufficient to require IV hydration
  • History of rapid deterioration and distant access to appropriately staffed ICU

^*Early follow-up is important.

References

1. Perrin JM, Homer CJ, Berwick DM, et al.: Variations in rates of hospitalization of children in three urban communities. N Eng J Med 320: 1183-1187, 1989.
2. Reid MJ, Moss RB, Hsu YP, et al.: Seasonal asthma in northern California: Allergic causes and efficacy of immunotherapy. J Allergy Clin Immunol 78: 590-600, 1986.
3. Brunette MG, Lands L, Thibodeau LP: Childhood asthma: Prevention of attacks with short-term corticosteroid treatment of upper respiratory tract infection. Pediatrics 81: 624-629, 1988.
4. Harris JB, Weinberger M, Nassif E, et al.: Early intervention with short courses of prednisone to prevent progression of asthma in ambulatory patients incompletely responsive to bronchodilators. J Pediatr 110: 627-644, 1987.
5. Weinberger M: Corticosteroids for exacerbations of asthma: Current status of the controversy. Pediatrics 81: 726-729, 1990.
6. Toogood JH, Jennings B, Lefcoe NM: A clinical trial of combined cromolyn/beclomethasone treatment for chronic asthma. J Allergy Clin Immunol 67: 317-324, 1981.
7. Hiller EF, Milner AD: Betamethasone 17 valerate aerosol and disodium chromoglycate in severe childhood asthma. Br J Dis Chest 69: 103-106, 1975.
8. Dawood AG, Hendry AT, Walker SR: The combined use of betamethasone valerate and sodium chromoglycate in the treatment of asthma. Clin Allergy 7: 161-165, 1977.
9. Patel KR, Wall RT: Dose-duration effect of sodium chromoglycate aerosol in exercise-induced asthma. Eur J Respir Dis 69: 256-260, 1986.
10. Weinberger M, Hendeles L: Drug therapy: Theophylline in asthma. N Eng J Med 334: 1380-1388, 1996.
11. Cummings RG, Mitchell P, Leeder SR: Use of inhaled corticosteroids and the risk of cataracts. N Eng J Med 337: 8-14, 1997.

Recommendations for Further Reading
Weiss EB, Stein M, (eds): Bronchial Asthma: Mechanisms and Therapeutics (3rd ed). Boston, Little, Brown and Co., 1993. This book is an extensively referenced multi-authored encyclopedic text on asthma, covering virtually all aspects of this disease. It is an excellent major reference source.

Barnes PJ, Grunstein MM, Leff AR, Woolcock AJ. Asthma. Lippincott-Raven, 1997. Very extensive multi-authored coverage of basic science and clinical aspects of asthma.

Weinberger M, Hendeles L. Theophylline in Asthma. N Engl J Med 1996;334:1380-88. Provides well referenced basic background for the rationale supporting the use of theophylline and essential knowledge for using theophylline with optimal safety and efficacy.

Other Educational Resources
http://www.uihealthcare.com/depts/med/pediatrics/divisions/allergy.html

Asthma Management: Guidelines for the Primary Care Physician
Copyright 1995
Revised 1998