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Asthma

by Matthew C. Miles, MD, Stephen P. Peters, MD, PhD

Asthma is a disease of diffuse airway inflammation caused by a variety of triggering stimuli resulting in partially or completely reversible bronchoconstriction. Symptoms and signs include dyspnea, chest tightness, cough, and wheezing. The diagnosis is based on history, physical examination, and pulmonary function tests. Treatment involves controlling triggering factors and drug therapy, most commonly with inhaled β 2 -agonists and inhaled corticosteroids. Prognosis is good with treatment.

Epidemiology

The prevalence of asthma has increased continuously since the 1970s, and it now affects an estimated 235 million people worldwide. More than 25 million people in the US are affected. Asthma is one of the most common chronic diseases of childhood, affecting more than 6 million children in the US; it occurs more frequently in boys before puberty and in girls after puberty. It also occurs more frequently in non-Hispanic blacks and Puerto Ricans. Despite its increasing prevalence, however, there has been a recent decline in mortality. In the US, About 3400 deaths occur annually as a result of asthma. However, the death rate is 2 to 3 times higher for blacks than for whites. Asthma is the leading cause of hospitalization for children and is the number one chronic condition causing elementary school absenteeism. Asthma is estimated to cost the US $56 billion/yr in medical care and lost productivity.

Etiology

Development of asthma is multifactorial and depends on the interactions among multiple susceptibility genes and environmental factors.

Susceptibility genes are thought to include those for T-helper cells types 1 and 2 (T h 1 and T h 2), IgE, interleukins (IL-3, -4, -5, -9, -13), granulocyte-monocyte colony-stimulating factor (GM-CSF), tumor necrosis factor-α (TNF-α), and the ADAM33 gene, which may stimulate airway smooth muscle and fibroblast proliferation or regulate cytokine production.

Environmental factors may include the following:

  • Allergen exposure

  • Diet

  • Perinatal factors

Evidence clearly implicates household allergens (eg, dust mite, cockroach, pet) and other environmental allergens in disease development in older children and adults. Diets low in vitamins C and E and in ω–3 fatty acids have been linked to asthma, as has obesity. Asthma has also been linked to perinatal factors, such as young maternal age, poor maternal nutrition, prematurity, low birthweight, and lack of breastfeeding.

On the other hand, endotoxin exposure early in life can induce tolerance and may be protective. Air pollution is not definitively linked to disease development, although it may trigger exacerbations. The role of childhood exposure to cigarette smoke is controversial, with some studies finding a contributory and some a protective effect.

Genetic and environmental components may interact by determining the balance between T h 1 and T h 2 cell lineages. Infants may be born with a predisposition toward proallergic and proinflammatory T h 2 immune responses, characterized by growth and activation of eosinophils and IgE production. Early childhood exposure to bacterial and viral infections and endotoxins may shift the body to T h 1 responses, which suppresses T h 2 cells and induces tolerance. Trends in developed countries toward smaller families with fewer children, cleaner indoor environments, and early use of vaccinations and antibiotics may deprive children of these T h 2-suppressing, tolerance-inducing exposures and may partly explain the continuous increase in asthma prevalence in developed countries (the hygiene hypothesis).

Reactive airways dysfunction syndrome (RADS)

Indoor exposures to nitrogen oxide and volatile organic compounds (eg, from paints, solvents, adhesives) are implicated in the development of RADS, a persistent asthma-like syndrome in people with no history of asthma (see Occupational Asthma). RADS appears to be distinct from asthma and may be, on occasion, a form of environmental lung disease. However, RADS and asthma have many clinical similarities (eg, wheezing, dyspnea, cough), and both may respond to corticosteroids.


Pathophysiology

Asthma involves

  • Bronchoconstriction

  • Airway edema and inflammation

  • Airway hyperreactivity

  • Airway remodeling

In patients with asthma, T h 2 cells and other cell types—notably, eosinophils and mast cells, but also other CD4+ subtypes and neutrophils—form an extensive inflammatory infiltrate in the airway epithelium and smooth muscle, leading to airway remodeling (ie, desquamation, subepithelial fibrosis, angiogenesis, smooth muscle hypertrophy). Hypertrophy of smooth muscle narrows the airways and increases reactivity to allergens, infections, irritants, parasympathetic stimulation (which causes release of pro-inflammatory neuropeptides, such as substance P, neurokinin A, and calcitonin gene-related peptide), and other triggers of bronchoconstriction. Additional contributors to airway hyperreactivity include loss of inhibitors of bronchoconstriction (epithelium-derived relaxing factor, prostaglandin E 2 ) and loss of other substances called endopeptidases that metabolize endogenous bronchoconstrictors. Mucus plugging and peripheral blood eosinophilia are additional classic findings in asthma and may be epiphenomena of airway inflammation. However, not all patients with asthma have eosinophilia.

Triggers

Common triggers of an asthma exacerbation include

  • Environmental and occupational allergens (numerous)

  • Infections

  • Exercise

  • Inhaled irritants

  • Emotion

  • Aspirin

  • Gastroesophageal reflux disease (GERD)

Infectious triggers in young children include respiratory syncytial virus, rhinovirus, and parainfluenza virus infection. In older children and adults, URIs (particularly with rhinovirus) and pneumonia are common infectious triggers. Exercise can be a trigger, especially in cold or dry environments. Inhaled irritants, such as air pollution, cigarette smoke, perfumes, and cleaning products, are often involved. Emotions such as anxiety, anger, and excitement sometimes trigger exacerbations.

Aspirin is a trigger in up to 30% of patients with severe asthma and in < 10% of all patients with asthma. Aspirin -sensitive asthma is typically accompanied by nasal polyps with nasal and sinus congestion.

GERD is a common trigger among some patients with asthma, possibly via esophageal acid-induced reflex bronchoconstriction or by microaspiration of acid. However, treatment of asymptomatic GERD (eg, with proton pump inhibitors) does not seem to improve asthma control.

Allergic rhinitis often coexists with asthma; it is unclear whether the two are different manifestations of the same allergic process or whether rhinitis is a discrete asthma trigger.


Response

In the presence of triggers, there is reversible airway narrowing and uneven lung ventilation. Relative perfusion exceeds relative ventilation in lung regions distal to narrowed airways; thus, alveolar O 2 tensions fall and alveolar CO 2 tensions rise. Most patients can compensate by hyperventilating, but in severe exacerbations, diffuse bronchoconstriction causes severe gas trapping, and the respiratory muscles are put at a marked mechanical disadvantage so that the work of breathing increases. Under these conditions, hypoxemia worsens and Pa co 2 rises. Respiratory and metabolic acidosis may result and, if left untreated, cause respiratory and cardiac arrest.


Classification

Unlike hypertension (eg, in which one parameter (BP) defines the severity of the disorder and the efficacy of treatment), asthma causes a number of clinical and testing abnormalities. Also, unlike most types of hypertension, asthma manifestations typically wax and wane. Thus, monitoring (and studying) asthma requires a consistent terminology and defined benchmarks.

Severity is the intrinsic intensity of the disease process (ie, how bad it is). Severity can usually be assessed directly only before treatment is started, because patients who have responded well to treatment by definition have few symptoms. Asthma severity is categorized as

  • Intermittent

  • Mild persistent

  • Moderate persistent

  • Severe persistent

The term status asthmaticus describes severe, intense, prolonged bronchospasm that is resistant to treatment.

Control is the degree to which symptoms, impairments, and risks are minimized by treatment. Control is the parameter assessed in patients receiving treatment. The goal is for all patients to have well controlled asthma regardless of disease severity. Control is classified as

  • Well controlled

  • Not well controlled

  • Very poorly controlled

Severity and control are assessed in terms of patient impairment and risk (see Table: Classification of Asthma Control* , †).

Classification of Asthma Control* , †

Component

Well-Controlled

Not Well-Controlled

Very Poorly Controlled

Symptoms

All ages except children 5–11 yr: 2 days/wk

Children 5–11 yr: 2 days/wk but not > once/day

All ages except children 5–11 yr: > 2 days/wk

Children 5–11 yr:> 2 days/wk or multiple times on ≤ 2 days/wk

For all ages: Throughout the day

Nighttime awakenings

Adults and children ≥ 12 yr: ≤ 2/mo

Children 5–11 yr: 1 /mo

Children 0–4 yr: 1 /mo

Adults and children ≥ 12 yr: 1–3/wk

Children 5–11 yr: ≥ 2/mo

Children 0–4 yr:> 1/mo

Adults and children ≥ 12 yr: ≥ 4/wk

Children 5–11 yr: 2/wk

Children 0–4 yr:> 1/wk

Interference with normal activity

None

Some limitation

Extreme limitation

Use of short-acting β 2 -agonist for symptom control (not prevention of exercise-induced asthma)

2 days/wk

> 2 days/wk

Several times/day

FEV 1 or peak flow

> 80% predicted/personal best

60–80% predicted/personal best

< 60% predicted/personal best

FEV 1 /FVC (children 5–11 yr)

> 80%

75–80%

< 75%

Exacerbations requiring oral systemic corticosteroids

0–1/yr

Adults and children ≥ 5 yr: ≥ 2/yr

Children 0–4 yr: 2–3/yr

Adults and children ≥ 5 yr: ≥ 2/yr

Children 0–4 yr:> 3/yr

Validated questionnaires:

  • ATAQ

0

1–2

3−4

  • ACQ

0.75

1.5

Ν/Α

  • ACT

20

16−19

15

Recommended action

Maintain current step

Follow up every 1–6 mo

Consider step down if well controlled for 3 mo

Step up 1 step

Reevaluate in 2–6 wk

For adverse effects, consider treatment options

Consider short course of systemic corticosteroids

Step up 1 or 2 steps

Reevaluate in 2 wk

For adverse effects, consider treatment options

*All ages unless specified differently.

Level of control is based on the most severe impairment or risk category. Additional factors to consider are progressive loss of lung function on pulmonary function tests, significant adverse effects, and severity and interval between exacerbations (ie, one exacerbation requiring intubation or 2 hospitalizations within 1 mo may be considered very poor control).

At present, there are inadequate data to correlate frequencies of exacerbations with different levels of asthma control. In general, more frequent and intense exacerbations (eg, requiring urgent, unscheduled care, hospitalization, or ICU admission) indicate poorer asthma control.

ACQ = asthma control questionnaire; ACT = asthma control test; ATAQ = asthma therapy assessment questionnaire; FEV 1 = forced expiratory volume in 1 sec; FVC = forced vital capacity.

Adapted from National Heart, Lung, and Blood Institute: Expert Panel Report 3: Guidelines for the diagnosis and management of asthma—full report 2007. August 28, 2007. Available at http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm .

Impairment refers to the frequency and intensity of patients' symptoms and functional limitations. Impairment is assessed by spirometry, mainly forced expiratory volume in 1 sec (FEV 1 ), and the ratio of FEV 1 to forced vital capacity (FVC), as well as clinical features such as

  • How often symptoms are experienced

  • How often the patient awakens at night

  • How often the patient uses a short-actingβ 2 -agonist for symptom relief

  • How often asthma interferes with normal activity

Risk refers to the likelihood of future exacerbations or decline in lung function and the risk of adverse drug effects. Risk is assessed by long-term trends in spirometry and clinical features such as

  • Frequency of need for oral corticosteroids

  • Need for hospitalization

  • Need for ICU admission

  • Need for intubation

It is important to remember that the severity category does not predict how serious an exacerbation a patient may have. For example, a patient who has mild asthma with long periods of no or mild symptoms and normal pulmonary function may have a severe, life-threatening exacerbation.

Symptoms and Signs

Patients with mild asthma are typically asymptomatic between exacerbations. Patients with more severe disease and those with exacerbations experience dyspnea, chest tightness, audible wheezing, and coughing. Coughing may be the only symptom in some patients (cough-variant asthma). Symptoms can follow a circadian rhythm and worsen during sleep, often around 4 am . Many patients with more severe disease waken during the night (nocturnal asthma).

Signs include wheezing, pulsus paradoxus (ie, a fall of systolic BP > 10 mm Hg during inspiration—see Pulsus paradoxus), tachypnea, tachycardia, and visible efforts to breathe (use of neck and suprasternal [accessory] muscles, upright posture, pursed lips, inability to speak). The expiratory phase of respiration is prolonged, with an inspiratory:expiratory ratio of at least 1:3. Wheezes can be present through both phases or just on expiration, but patients with severe bronchoconstriction may have no audible wheezing because of markedly limited airflow.

Patients with a severe exacerbation and impending respiratory failure typically have some combination of altered consciousness, cyanosis, pulsus paradoxus > 15 mm Hg, SaO 2 < 90%, Pa co 2 > 45 mm Hg, or hyperinflation. Rarely, pneumothorax or pneumomediastinum is seen on chest x-ray.

Symptoms and signs disappear between exacerbations, although soft wheezes may be audible during forced expiration at rest, or after exercise in some asymptomatic patients. Hyperinflation of the lungs may alter the chest wall in patients with long-standing uncontrolled asthma, causing a barrel-shaped thorax.

All symptoms and signs are nonspecific, are reversible with timely treatment, and typically are brought on by exposure to one or more triggers.

Diagnosis

  • Clinical evaluation

  • Pulmonary function testing

Diagnosis is based on history and physical examination and is confirmed with pulmonary function tests. Diagnosis of causes and the exclusion of other disorders that cause wheezing are also important. Asthma and COPD are sometimes easily confused; they cause similar symptoms and produce similar results on pulmonary function tests but differ in important biologic ways that are not always clinically apparent.

Pulmonary function tests

Patients suspected of having asthma should undergo pulmonary function testing to confirm and quantify the severity and reversibility of airway obstruction. Pulmonary function data quality is effort-dependent and requires patient education before the test. If it is safe to do so, bronchodilators should be stopped before the test: 6 h for short-acting β 2 -agonists, such as albuterol; 8 h for ipratropium; 12 to 36 h for theophylline; 24 h for long-acting β 2 -agonists, such as salmeterol and formoterol; and 48 h for tiotropium.

Spirometry (see Tests of Pulmonary Function (PFT)) should be done before and after inhalation of a short-acting bronchodilator. Signs of airflow limitation before bronchodilator inhalation include reduced FEV 1 and a reduced FEV 1 /FVC ratio. The FVC may also be decreased because of gas trapping, such that lung volume measurements may show an increase in the residual volume, the functional residual capacity, or both. An improvement in FEV 1 of > 12% or an increase 10% of predicted FEV 1 in response to bronchodilator treatment confirms reversible airway obstruction, although absence of this finding should not preclude a therapeutic trial of bronchodilators. Spirometry should be repeated at least every 1 to 2 yr in patients with asthma to monitor disease progression.

Flow-volume loops should also be reviewed to diagnose vocal cord dysfunction, a common cause of upper airway obstruction that mimics asthma.

Provocative testing, in which inhaled methacholine (or alternatives, such as inhaled histamine, adenosine, or bradykinin, or exercise testing) is used to provoke bronchoconstriction, is indicated for patients suspected of having asthma who have normal findings on spirometry and flow-volume testing and for patients suspected of having cough-variant asthma, provided there are no contraindications. Contraindications include FEV 1 < 1 L or < 50% predicted, recent MI or stroke, and severe hypertension (systolic BP > 200 mm Hg; diastolic BP > 100 mm Hg). A decline in FEV 1 of > 20% on a provocative testing protocol is relatively specific for the diagnosis of asthma. However, FEV 1 may decline in response to these drugs in other disorders, such as COPD. If FEV 1 decreases by < 20% by the end of the testing protocol, asthma is less likely to be present.


Other tests

Other tests may be helpful in some circumstances:

  • Diffusing capacity for carbon monoxide (DL co )

  • Chest x-ray

  • Allergy testing

DL co testing can help distinguish asthma from COPD. Values are normal or elevated in asthma and usually reduced in COPD, particularly in patients with emphysema.

A chest x-ray may help exclude some causes of asthma or alternative diagnoses, such as heart failure or pneumonia. The chest x-ray in asthma is usually normal but may show hyperinflation or segmental atelectasis, a sign of mucous plugging. Infiltrates, especially those that come and go and that are associated with findings of central bronchiectasis, suggest allergic bronchopulmonary aspergillosis (see Allergic Bronchopulmonary Aspergillosis (ABPA)).

Allergy testing may be indicated for children whose history suggests allergic triggers (particularly for allergic rhinitis) because these children may benefit from immunotherapy. It should be considered for adults whose history indicates relief of symptoms with allergen avoidance and for those in whom a trial of therapeutic anti-IgE antibody therapy (see Asthma and Related Disorders:Drug therapy) is being considered. Skin testing and measurement of allergen-specific IgE via radioallergosorbent testing (RAST) can identify specific allergic triggers (see Specific tests).

Elevated blood eosinophils (> 400 cells/μL) and nonspecific IgE (>150 IU) are suggestive but not diagnostic of allergic asthma because they can be elevated in other conditions. However, eosinophilia is not sensitive.

Sputum evaluation for eosinophils is not commonly done; finding large numbers of eosinophils is suggestive of asthma but is neither sensitive nor specific.

Peak expiratory flow (PEF) measurements with inexpensive handheld flow meters are recommended for home monitoring of disease severity and for guiding therapy.


Evaluation of exacerbations

Patients with asthma with an acute exacerbation should have certain tests:

  • Pulse oximetry

  • PEF or FEV 1 measurement

All 3 measures help establish the severity of an exacerbation and document treatment response. PEF values are interpreted in light of the patient’s personal best, which may vary widely among patients who are equally well controlled. A 15 to 20% reduction from this baseline indicates a significant exacerbation. When baseline values are not known, the percent predicted FEV 1 value gives a general idea of airflow limitation but not the individual patient’s degree of worsening. When measuring FEV 1 is impractical (eg, in an emergency department) and baseline PEF is unknown, percent of predicted PEF based on age, height and sex may be used. Although percent predicted PEF is less accurate than comparison to a personal best, it may be helpful as a baseline to evaluate treatment response.

Chest x-ray is not necessary for most exacerbations but should be done in patients with symptoms or signs suggestive of pneumonia, pneumothorax, or pneumomediastinum.

ABG measurements should be done in patients with marked respiratory distress or symptoms and signs of impending respiratory failure.


Prognosis

Asthma resolves in many children, but for as many as 1 in 4, wheezing persists into adulthood or relapse occurs in later years. Female sex, smoking, earlier age of onset, sensitization to household dust mites, and airway hyperresponsiveness are risk factors for persistence and relapse.

Although a significant number of deaths each year are attributable to asthma, most of these are preventable with treatment. Thus, the prognosis is good with adequate access and adherence to treatment. Risk factors for death include increasing requirements for oral corticosteroids before hospitalization, previous hospitalization for acute exacerbations, and lower PEF values at presentation. Several studies show that use of inhaled corticosteroids decreases hospital admission and mortality rates.

Over time, the airways in some patients with asthma undergo permanent structural changes (remodeling) that prevent return to normal lung functioning. Early aggressive use of anti-inflammatory drugs may help prevent this remodeling.

Treatment

  • Control of triggers

  • Drug therapy

  • Monitoring

  • Patient education

  • Treatment of acute exacerbations

Treatment objectives are to minimize impairment and risk, including preventing exacerbations and minimizing chronic symptoms, including nocturnal awakenings; to minimize the need for emergency department visits or hospitalizations; to maintain baseline (normal) pulmonary function and activity levels; and to avoid adverse treatment effects.

Control of triggering factors

Triggering factors in some patients may be controlled with use of synthetic fiber pillows and impermeable mattress covers and frequent washing of bed sheets, pillowcases, and blankets in hot water. Upholstered furniture, soft toys, carpets, and pets should be removed to reduce dust mites and animal dander. Dehumidifiers should be used in basements and in other poorly aerated, damp rooms to reduce mold. Steam treatment of homes diminishes dust mite allergens. House cleaning and extermination to eliminate cockroach exposure is especially important. Although control of triggering factors is more difficult in urban environments, the importance of these measures is not diminished. High-efficiency particulate air (HEPA) vacuums and filters may relieve symptoms, but no beneficial effects on pulmonary function and on the need for drugs have been observed. Sulfite-sensitive patients should avoid red wine. Nonallergenic triggers, such as cigarette smoke, strong odors, irritant fumes, cold temperatures, high humidity, and exercise, should also be avoided or controlled when possible. Limiting exposure to people with viral URIs is also important.

Patients with aspirin -sensitive asthma can use acetaminophen, choline magnesium salicylate, or celecoxib in place of NSAIDs.

Asthma is a relative contraindication to the use of nonselective β-blockers, including topical formulations, but cardioselective drugs (eg, metoprolol, atenolol) probably have no adverse effects.


Drug therapy

Major drug classes commonly used in the treatment of chronic asthma and asthma exacerbations include

  • Bronchodilators (β 2 -agonists, anticholinergics)

  • Corticosteroids

  • Leukotriene modifiers

  • Mast cell stabilizers

  • Methylxanthines

Drugs in these classes (see Table: Drug Treatment of Chronic Asthma*) are inhaled or taken orally; inhaled drugs come in aerosolized and powdered forms. Use of aerosolized forms with a spacer or holding chamber facilitates deposition of the drug in the airways rather than the pharynx; patients are advised to wash and dry their spacers after each use to prevent bacterial contamination. In addition, use of aerosolized forms requires coordination between actuation of the inhaler (drug delivery) and inhalation; powdered forms reduce the need for coordination, because drug is delivered only when the patient inhales.

Drug Treatment of Chronic Asthma*

Drug

Form

Dosage

Comments

Children

Adults

Short-acting β-agonists

Albuterol

HFA: 90 mcg/puff

Same as adults

2 puffs q 4–6 h prn and 2 puffs 15 min before exercise

Albuterol is used mainly as a rescue drug.

It is not recommended for maintenance treatment.

Regular use indicates diminishing asthma control and need for additional drug.

MDI-DPI is as effective as nebulized therapy if patients can coordinate the inhalation maneuver using the spacer and holding chamber.

Nebulized albuterol can be mixed with other nebulizer solutions.

Nebulized solution: 5 mg/mL and 0.63, 1.25, and 2.5 mg/3 mL

< 5 yr: 0.63–2.5 mg in 3 mL of saline q 4–6 h prn

≥ 5 yr: 0.05 mg/kg in 3 mL saline q 4–6 h prn (minimum 1.25 mg, maximum 2.5 mg)

1.25–5 mg in 3 mL saline q 4–6 h prn

Levalbuterol

HFA: 45 mcg/puff

< 5 yr: Not established

≥ 5 yr: Same as adults

2 puffs q 4–6 hr prn

Levalbuterol is the R -isomer of albuterol. 0.63 mg is equivalent to 1.25 mg racemic albuterol.

Levalbuterol may have fewer adverse effects.

Nebulized solution: 0.31, 0.63, and 1.25 mg/3 mL and 1.25 mg/0.5 mL

< 5 yr: 0.31–1.25 mg in 3 mL q 4–6 h prn

5–11 yr: 0.31–0.63 mg q 8 h prn (maximum 0.63 mg q 8 h)

12 yr: Same as adults

0.63–1.25 mg q 6–8 h prn

Pirbuterol

MDI: 200 mcg/puff

< 12 yr: Not established

12 yr: Same as adults

1–2 puffs q 4–6 h (maximum 12 puffs/day)

Long-acting β 2 -agonists (not to be used as monotherapy)

Arformoterol

Nebulized solution: 15 mcg/2 mL

Not established

15–25 mcg inhalation q 12 h

Arformoterol is the R -isomer of formoterol and appears useful in COPD.

Formoterol

DPI: 12 mcg/capsule

≤ 5 yr: Not established

> 5 yr: Same as adults

12 mcg (1 capsule) q 12 h (maximum 24 mcg/day); when taken before exercise, should be taken at least 15 min before exercise

Capsules are for single use.

Patients should be taught to avoid swallowing capsules.

Salmeterol

HFA: 21 mcg/puff

12 yr: Same as adults

2 puffs q 12 h; when taken before exercise, should be taken 30–60 min before exercise

Duration of action is 12 h.

One dose nightly is helpful for nocturnal asthma.

Salmeterol is not to be used for acute symptom relief in an exacerbation.

DPI: 50 mcg/puff

< 4 yr: Not established

4 yr: Same as adults

1 puff q 12 h and 30 min before exercise

Anticholinergics

Ipratropium

MDI: 18 mcg/puff

< 12 yr: Not established

12 yr: Same as adults

2 puffs q 6 h prn (maximum 12 puffs/day)

Ipratropium may be mixed in the same nebulizer as albuterol.

It should not be used as first-line therapy.

It provides no clear benefit when added to β 2 -agonists in long-term maintenance therapy.

Nebulized solution: 500 mcg (0.02%)

< 12 yr: Not established

12 yr: Same as adults

500 mcg q 6–8 h prn

Tiotropium

DPI: 18 mcg/capsule

Not established

18 mcg (1 capsule) once/day

Tiotropium is longer acting than ipratropium.

Corticosteroids (inhaled)

Beclomethasone

MDI: 40–80 mcg/puff

< 5 yr: Not established

5–11 yr: 1 puff q 12 h (usual maximum 80 mcg bid)

12 yr: Same as adults

1–2 puffs q 12 h (usual maximum 320 mcg bid)

Doses depend on severity and range from 1–2 puffs to whatever dose is needed to control asthma.

All may have systemic effects when used long term.

Maximum threshold is that above which hypothalamic- pituitary-adrenal suppression is produced.

If higher doses are necessary for asthma control, specialist consultation should be considered.

Budesonide

DPI: 90 or 180 mcg/inhalation

< 6 yr: Not recommended

6 yr: Initial dose of 180 mcg bid (maximum 360 mcg bid)

Initial dose of 360 mcg bid (maximum 720 mcg bid)

Nebulized solution: 0.25, 0.5, or 1.0 mg

1–8 yr only: If previously taking bronchodilators alone, initial dose of 0.5 mg once/day or 0.25 mg bid (maximum 0.5 mg/day)

If previously taking inhaled corticosteroids, initial dose of 0.5 mg once/day or 0.25 mg bid

If previously taking oral corticosteroids, initial dose of 0.5 mg bid or 1 mg once/day (maximum 1 mg/day)

Not indicated for adults

Flunisolide

MDI-HFA: 80 mcg/inhalation

< 5 yr: Not established

5–11 yr: 1 inhalation bid (maximum 2 inhalations bid [320 mcg/day])

12 yr: Same as adults

2 inhalations bid (maximum 4 inhalations bid [640 mcg/day])

Fluticasone

MDI: 44, 110, or 220 mcg/inhalation

0–4 yr: Initially, 88--176 mcg bid (usual maximum 176 mcg bid)

5–11 yr: Initially, 88–176 mcg bid (usual maximum 176 mcg bid)

12 yr: Same as adults

If previously taking bronchodilators alone, initial dose of 88 mcg bid (maximum 440 mcg bid)

If previously taking inhaled corticosteroids, initial dose of 88–220 mcg bid (maximum 440 mcg bid)

If previously taking oral corticosteroids, initial dose of 440–880 mcg bid (maximum 880 mcg bid)

DPI: 50, 100, or 250 mcg/inhalation

0–4 yr: not established

5–11 yr: Initial dose of 50 mcg bid (maximum 100 mcg bid)

12 yr: Same as adults

If previously taking bronchodilators alone, initial dose of 100 mcg bid (maximum 500 mcg bid)

If previously taking inhaled corticosteroids, initial dose of 100–250 mcg bid (maximum 500 mcg bid)

If previously taking oral corticosteroids, initial dose of 500–1000 mcg bid (maximum 1000 mcg bid)

Mometasone

DPI: 110 or 220 mcg/inhalation

< 4 yr: Not established

4–11 yr: 110 mcg once/day in the evening

12 yr: Same as adults

If previously taking bronchodilators alone or inhaled corticosteroids, initial dose of 220 mcg once/day in the evening (maximum 220 mcg bid or 440 mcg once/day in the evening)

If previously taking oral corticosteroids, initial dose of 440 mcg bid (maximum 880 mcg bid)

Systemic corticosteroids (oral)

Methylprednisolone

Tablets: 2, 4, 8, 16, or 32 mg

0–11 yr: Short-course burst: 1–2 mg/kg once/day (maximum 60 mg) for 3–10 days

7.5–60 mg once/day in the morning or every other day in the morning

Short-course burst: 40–60 mg once/day (or 20–30 mg bid) for 3–10 days

Maintenance doses should be given in a single dose in the morning every day or every other day as needed for control.

Some evidence suggests clinical effectiveness increases with no increase in adrenal suppression when dose is given at 3 pm .

Short-course burst doses are effective for establishing control when initiating therapy or during a period of gradual deterioration.

The burst should be continued until PEF = 80% of personal best or symptoms resolve, possibly requiring > 3–10 days of therapy.

Prednisolone

Tablets: 5 mg

Solution: 5 mg/5 mL or 15 mg/5 mL

Prednisone

Tablets: 1, 2.5, 5, 10, 20, or 50 mg

Solution: 5 mg/mL or 5 mg/5 mL

Combination drugs

Ipratroprium and albuterol

MDI: 18 mcg/puff ipratropium and 90 mcg/puff albuterol

Not established

2 puffs qid (maximum 12 puffs/24 h)

Ipratroprium prolongs bronchodilator effect of albuterol.

Nebulized solution: 0.5 mg ipratropium and 2.5 mg albuterol in a 3-mL vial

3-mL vial via nebulization qid (maximum 6 doses/24 h)

Fluticasone and salmeterol

DPI: 100, 250, or 500 mcg fluticasone and 50 mcg salmeterol

< 4 yr: Not established

4–11 yr: 1 inhalation (100/50) bid

12 yr: Same as adults

1 inhalation bid

The 250/50 dose is indicated for asthma not controlled by low-to-medium doses of inhaled corticosteroids.

The 500/50 dose is indicated for asthma not controlled by medium-to-high doses of inhaled corticosteroids.

HFA: 45, 115, or 230 mcg fluticasone and 21 mcg salmeterol

< 12 yr: Not established

12 yr: Same as adults

2 inhalations bid

Budesonide and formoterol

HFA: 80 or 160 mcg budesonide and 4.5 mcg formoterol

< 12 yr: Not established

12 yr: Same as adults

2 inhalations bid (maximum 2 inhalations of 160/4.5 mcg bid)

The 80/4.5 dose is indicated for asthma not controlled by low-to-medium doses of inhaled corticosteroids.

The 160/4.5 dose is indicated for asthma not controlled by medium-to-high doses of inhaled corticosteroids.

Mometasone and formoterol

HFA: 100 mcg or 200 mcg mometasone and 5 mcg formoterol

< 5 yr: Not established

≥ 5 yr: Same as adults

2 inhalations bid

The 100/5 dose is recommended for asthma not controlled by low-to-medium–dose inhaled corticosteroids.

The 200/5 dose is recommended for asthma not controlled by high-dose inhaled corticosteroids.

Mast cell stabilizers

Cromolyn

Nebulized solution: 20 mg/ampule

< 2 yr: Not established

2 yr: Same as adults

1 ampule tid–qid

Cromolyn should be taken before exercise or allergen exposure.

One dose provides effective prophylaxis for 1–2 h.

Leukotriene modifiers

Montelukast

Tablets, chewable tablets, and granules: 4, 5, or 10 mg

12 mo–5 yr: 4 mg po once/day in the evening

6–14 yr: 5 mg po once/day in the evening

15 yr: Same as adults

10 mg po once/day in the evening

Exercise-induced asthma: 10 mg po 2 h before exercise

Montelukast is a leukotriene receptor antagonist that is a competitive inhibitor of leukotrienes D4 and E4.

Zafirlukast

Tablet: 10 or 20 mg

< 5 yr: Not established

5–11 yr: 10 mg po bid

12 yr: Same as adults

20 mg po in the evening

Zafirlukast is a leukotriene receptor antagonist that is a competitive inhibitor of leukotrienes D4 and E4.

It must be taken 1 h before or 2 h after meals.

Zileuton

Tablet, immediate-release: 600 mg

<12 yr: Not established

12 yr: Same as adults

600 mg po qid

Zileuton inhibits 5-lipoxygenase.

Dosing may limit adherence.

Zileuton may cause liver enzyme elevations and inhibit metabolism of drugs processed by CYP3A4, including theophylline.

Extended-release: 1200 mg

< 12 yr: Not established

≥ 12 yr: Same as adults

1200 mg po bid within 1 h after morning and evening meals

Methylxanthines

Theophylline

Capsule, extended-release: 100, 200, 300, and 400 mg

Elixir: 80 mg/15 mL

Tablet, extended-release: 100, 200, 400, 450, or 600 mg

Initial dose of 10 mg/kg/day up to 600 mg/day, then adjusted to achieve a serum concentration of 5–15 mcg/mL at steady state

Initial dose of 10 mg/kg/day up to 600 mg/day, then adjusted to achieve a serum concentration of 5–15 mcg/mL at steady state

The wide variability in metabolic clearance, drug interactions, and potential for adverse effects mandate routine serum level monitoring.

Availability of safer alternatives has led to declining use of this drug.

Safety may be better with a target level <10 mcg/mL.

Immunomodulator

Omalizumab

Injection sc: 150 mg/1.2 mL

< 12 yr: Not recommended

≥ 12 yr: Same as adults

150–375 mg sc q 2–4 wk, depending on body weight and pretreatment serum IgE level

Maximum dose per injection site is 150 mg.

*All ages unless specified differently.

DPI = dry-powder inhaler; HFA = hydrofluoroalkane; MDI = metered-dose inhaler; PEF = peak expiratory flow.

Adapted from the National Heart, Lung, and Blood Institute: Expert Panel Report 3, Guidelines for the diagnosis and management of asthma—full report 2007. August 28, 2007. Available at www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf .

β 2 -Agonists relax bronchial smooth muscle, decrease mast cell degranulation and histamine release, inhibit microvascular leakage into the airways, and increase mucociliary clearance. β 2 -Agonists come in short- and long-acting preparations (see Table: Drug Treatment of Chronic Asthma*). Short-acting β 2 -agonists (eg, albuterol) 2 puffs q 4 h inhaled prn are the drug of choice for relieving acute bronchoconstriction and preventing exercise-induced asthma. They should not be used alone for long-term maintenance of persistent asthma. They take effect within minutes and are active for up to 6 to 8 h, depending on the drug. Tachycardia and tremor are the most common acute adverse effects of inhaled β 2 -agonists and are dose-related. Mild hypokalemia occurs uncommonly. Use of levalbuterol (a solution containing the R -isomer of albuterol) theoretically minimizes adverse effects, but its long-term efficacy and safety are unproved. Oral β 2 -agonists have more systemic effects and generally should be avoided.

Long-acting β 2 -agonists (eg, salmeterol) are active for up to 12 h and are used for moderate and severe asthma but should never be used as monotherapy. They interact synergistically with inhaled corticosteroids and permit lower dosing of corticosteroids. The safety of regular long-term use of β 2 -agonists is controversial. Long-acting β 2 -agonists may increase the risk of asthma-related death when used as monotherapy. Therefore, when treating patients with asthma, these drugs (salmeterol and formoterol) should be used only in combination with an inhaled corticosteroid for patients whose condition is not adequately controlled with other asthma controllers (eg, low- to medium-dose inhaled corticosteroids) or whose disease severity clearly warrants additional maintenance therapies. Daily use or diminishing effects of short-acting β 2 -agonists or use of ≥ 1 canister per month suggests inadequate control and the need to begin or intensify other therapies.

Anticholinergics relax bronchial smooth muscle through competitive inhibition of muscarinic (M 3 ) cholinergic receptors. Ipratropium may have an additive effect when combined with short-acting β 2 -agonists. Adverse effects include pupillary dilation, blurred vision, and dry mouth. Tiotropium is a 24-h inhaled anticholinergic that can be used for patients with COPD. In patients with asthma, recent clinical trials of tiotropium added to either inhaled corticosteroids or to a combination of an inhaled long-acting β 2 -agonist plus a corticosteroid have shown improved pulmonary function and decreased asthma exacerbations. Data concerning the long-term safety of tiotropium in patients with asthma are incomplete.

Corticosteroids inhibit airway inflammation, reverse β-receptor down-regulation, and inhibit cytokine production and adhesion protein activation. They block the late response (but not the early response) to inhaled allergens. Routes of administration include oral, IV, and inhaled. In acute asthma exacerbations, early use of systemic corticosteroids often aborts the exacerbation, decreases the need for hospitalization, prevents relapse, and speeds recovery. Oral and IV routes are equally effective. Inhaled corticosteroids have no role in acute exacerbations but are indicated for long-term suppression, control, and reversal of inflammation and symptoms. They substantially reduce the need for maintenance oral corticosteroid therapy. Adverse local effects of inhaled corticosteroids include dysphonia and oral candidiasis, which can be prevented or minimized by having the patient use a spacer, gargle with water after corticosteroid inhalation, or both. Systemic effects are all dose related, can occur with oral or inhaled forms, and occur mainly with inhaled doses > 800 mcg/day. They include suppression of the adrenal-pituitary axis, osteoporosis, cataracts, skin atrophy, hyperphagia, and easy bruisability. Whether inhaled corticosteroids suppress growth in children is controversial. Most children treated with inhaled corticosteroids eventually reach their predicted adult height. Latent TB may be reactivated by systemic corticosteroid use.

Mast cell stabilizers inhibit histamine release from mast cells, reduce airway hyperresponsiveness, and block the early and late responses to allergens. They are given by inhalation prophylactically to patients with exercise-induced or allergen-induced asthma. They are ineffective once symptoms have occurred. They are the safest of all antiasthmatic drugs but the least effective.

Leukotriene modifiers are taken orally and can be used for long-term control and prevention of symptoms in patients with mild persistent to severe persistent asthma. The main adverse effect is liver enzyme elevation (which occurs with zileuton). Although rare, patients have developed a clinical syndrome resembling eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome).

Methylxanthines relax bronchial smooth muscle (probably by inhibiting phosphodiesterase) and may improve myocardial and diaphragmatic contractility through unknown mechanisms. Methylxanthines appear to inhibit intracellular release of Ca, decrease microvascular leakage into the airway mucosa, and inhibit the late response to allergens. They decrease the infiltration of eosinophils into bronchial mucosa and of T cells into epithelium. The methylxanthine theophylline is used for long-term control as an adjunct to β 2 -agonists. Extended-release theophylline helps manage nocturnal asthma. Theophylline has fallen into disuse because of its many adverse effects and interactions compared with other drugs. Adverse effects include headache, vomiting, cardiac arrhythmias, and seizures. Methylxanthines have a narrow therapeutic index; multiple drugs (any metabolized by the cytochrome P-450 pathway, eg, macrolide antibiotics) and conditions (eg, fever, liver disease, heart failure) alter methylxanthine metabolism and elimination. Serum theophylline levels should be monitored periodically and maintained between 5 and 15 μg/mL (28 and 83 μmol/L).

Immunomodulators include omalizumab, an anti-IgE antibody developed for use in severely allergic patients with asthma who have elevated IgE levels. Omalizumab may decrease asthma exacerbations, decreases corticosteroid requirements, and relieves symptoms. Dosing is determined by a dosing chart based on the patient’s weight and IgE levels. The drug is administered sc q 2 to 4 wk. Clinicians who administer omalizumab should be prepared to identify and treat anaphylaxis, which may occur after any dose of omalizumab, even if previous doses have been well tolerated.

Pearls & Pitfalls

  • Prepare for possible anaphylactic reactions in patients being treated with omalizumab, regardless of how such treatments have been tolerated previously.

Other drugs are used uncommonly in specific circumstances. Magnesium is often used in the emergency department, but it is not recommended in the management of chronic asthma. Immunotherapy may be indicated when symptoms are triggered by allergy, as suggested by history and confirmed by allergy testing. Immunotherapy is generally more effective in children than adults. If symptoms are not significantly relieved after 24 mo, then therapy is stopped. If symptoms are relieved, therapy should continue for 3 yr, although the optimum duration is unknown. Other drugs that suppress the immune system are occasionally given to reduce dependence on high-dose oral corticosteroids, but these drugs have a significant risk of toxicity. Low-dose methotrexate (5 to 15 mg po or IM once/wk) can lead to modest improvements in FEV 1 and modest decreases in daily oral corticosteroid use. Gold and cyclosporine are also modestly effective, but toxicity and need for monitoring limit their use. Other therapies for management of chronic asthma include nebulized lidocaine, nebulized heparin, colchicine, and high-dose IV immune globulin. Limited evidence supports the use of any of these therapies, and their benefits are unproved, so none are currently recommended for routine clinical use.


Monitoring response to treatment

Guidelines recommend office use of spirometry (FEV 1 , FEV 1 /FVC, FVC) to measure airflow limitation and assess impairment and risk. Outside the office, home PEF monitoring, in conjunction with patient symptom diaries and the use of an asthma action plan, is especially useful for charting disease progression and response to treatment in patients with moderate to severe persistent asthma. When asthma is quiescent, one PEF measurement in the morning suffices. Should PEF measurements fall to <80% of the patient’s personal best, then twice/day monitoring to assess circadian variation is useful. Circadian variation of > 20% indicates airway instability and the need to re-evaluate the therapeutic regimen.


Patient education

The importance of patient education cannot be overemphasized. Patients do better when they know more about asthma—what triggers an exacerbation, what drug to use when, proper inhaler technique, how to use a spacer with a metered-dose inhaler (MDI), and the importance of early use of corticosteroids in exacerbations. Every patient should have a written action plan for day-to-day management, especially for management of acute exacerbations, that is based on the patient’s best personal peak flow rather than on a predicted normal value. Such a plan leads to much better asthma control, largely attributable to improved adherence to therapies.


Treatment of acute exacerbation

The goal of asthma exacerbation treatment is to relieve symptoms and return patients to their best lung function. Treatment includes

  • Inhaled bronchodilators (β 2 -agonists and anticholinergics)

  • Usually systemic corticosteroids

Patients having an exacerbation are instructed to self-administer 2 to 4 puffs of inhaled albuterol or a similar short-acting β 2 -agonist up to 3 times spaced 20 min apart for an acute exacerbation and to measure PEF if possible. When these short-acting rescue drugs are effective (symptoms are relieved and PEF returns to > 80% of baseline), the acute exacerbation may be managed in the outpatient setting. Patients who do not respond, have severe symptoms, or have a PEF persistently <80% should follow a treatment management program outlined by the physician or should go to the emergency department (see Table: Drug Treatment of Asthma Exacerbations* for specific dosing information).

Drug Treatment of Asthma Exacerbations*

Drug

Form

Dosage

Comments

Child

Adult

Systemic β 2 -agonists

Epinephrine

Injectable solution: 1 mg/mL (1:1000)

0.01 mL/kg /dose sc (maximum 0.4–0.5 mL q 20 min for 3 doses or q 4 h prn)

0.2–0.5 mg sc q 20 min (for maximum of 3 doses) or q 2 h prn

Subcutaneous administration is no more effective than inhalation and may have more adverse effects.

Use in adults is controversial and may be contraindicated if significant cardiovascular disease is present.

Terbutaline

Injectable solution: 1 mg/mL

< 12 yr: 0.005–0.01 mg/kg q 20 min up to 3 doses; may repeat q 2–6 h prn

12 yr: Same as adults

0.25 mg sc once

May repeat in 15–30 min (maximum 0.5 mg over 4 h)

Short-acting β 2 -agonists

Albuterol

HFA: 90 mcg/puff

Same as adults

4–8 puffs q 20 min for 3 doses, then q 1–4 h prn

MDI is as effective as nebulized solution if patients can coordinate inhalation maneuver using spacer and holding chamber.

Nebulized solution: 5 mg/mL and 0.63, 1.25, and 2.5 mg/3 mL

0.15 mg/kg (minimum 2.5 mg) q 20 min for 3 doses, then 0.15–0.3 mg/kg up to 10 mg q 1–4 h prn

Alternatively, 0.5 mg/kg/h continuous nebulization

2.5–5 mg q 20 min for 3 doses, then 2.5–10 mg q 1–4 h prn

(Alternatively, 10–15 mg/h continuous nebulization is similarly effective but increases frequency of adverse effects.)

Levalbuterol

HFA: 90 mcg/puff

Same as adults

4–8 puffs q 20 min for 3 doses, then q 1–4 h prn

Levalbuterol is the R -isomer of albuterol.

0.63 mg is equivalent to 1.25 mg racemic albuterol.

Levalbuterol may have fewer adverse effects than albuterol.

Nebulized solution: 0.63 and 1.25 mg/3 mL

0.075 mg/kg (minimum 1.25 mg) q 20 min for 3 doses, then 0.075–0.15 mg/kg up to 5 mg q 1–4 h prn

Alternatively, 0.25 mg/kg/h continuous nebulization

1.25–2 mg q 20 min for 3 doses, then 1.25–5 mg q 1–4 h prn

Alternatively, 5–7.5 mg/h continuous nebulization

Pirbuterol

MDI: 200 mcg/puff

Same as adults

Same as albuterol

Anticholinergics

Ipratroprium

Nebulized solution: 500 mcg/2.5 mL (0.02%)

0.25–0.5 mg q 20 min for 3 doses, then q 2–4 h prn

0.5 mg q 20 min for 3 doses, then q 2–4 h prn

Ipratropium should be added to β 2 -agonists and not used as first-line therapy.

It may be mixed in same nebulizer as albuterol.

Dose delivered from MDI is low and has not been studied in exacerbations.

Combination drugs

Ipratroprium and albuterol

MDI:

20 mcg ipratroprium and 100 mcg albuterol per inhalation

Same as adults

One inhalation q 30 min for 3 doses, then q 2–4 h prn

Ipratropium prolongs bronchodilator effect of albuterol.

Nebulized solution: 0.5 mg ipratropium and 2.5 mg albuterol in a 3-mL vial

1.5 mL q 20 min for 3 doses, then q 2–4 h prn

3 mL q 30 m for 3 doses, then q 2–4 h prn

Systemic corticosteroids

Methylprednisolone

Tablets: 2, 4, 8, 16, and 32 mg

Inpatient:1 mg/kg q 6 h for 48 h, then 0.5–1.0 mg/kg bid (maximum, 60 mg/day) until PEF = 70% of predicted or personal best

Outpatient burst: 0.5–1.0 mg/kg bid (maximum 60 mg/day for 3–10 days)

Inpatient: 40–60 mg q 6 h or q 8 h for 48 h, then 60–80 mg/day until PEF = 70% of predicted or personal best

Outpatient burst: 40–60 mg in single or 2 divided doses for 3–10 days

IV has no advantage over oral administration if GI function is normal.

Higher doses provide no advantage in severe exacerbations.

Usual regimen is to continue frequent multiple daily doses until FEV 1 or PEF = 50% of predicted or personal best and then lower the dose to bid, usually within 48 h.

Therapy after a hospitalization or ED visit may last 3–10 days.

Tapering the dose is not needed if patients are also given inhaled corticosteroids.

Prednisolone

Tablets: 5 mg

Orally disintegrating tablets: 10, 15, and 30 mg

Solution: 5, 10, 15, 20 and 25 mg/5 mL

Prednisone

Tablets: 1, 2.5, 5, 10, 20, and 50 mg

Solution: 5 mg/mL and 5 mg/5 mL

*All ages unless specified differently.

ED = emergency department; FEV 1 = forced expiratory volume in 1 sec; HFA = hydrofluoroalkane; MDI = metered-dose inhaler; PEF = peak expiratory flow.

Adapted from National Heart, Lung, and Blood Institute: Expert Panel Report 3: Guidelines for the diagnosis and management of asthma—full report 2007. August 28, 2007. Available at www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf .

Inhaled bronchodilators (β 2 -agonists and anticholinergics) are the mainstay of asthma treatment in the emergency department. In adults and older children, albuterol given by an MDI and spacer is as effective as that given by nebulizer. Nebulized treatment is preferred for younger children because of difficulties coordinating MDIs and spacers; evidence suggests that bronchodilator response improves when the nebulizer is powered with helium-O 2 (heliox) rather than with O 2 . Subcutaneous epinephrine 1:1000 solution or terbutaline is an alternative for children. Terbutaline may be preferable to epinephrine because of its lesser cardiovascular effects and longer duration of action, but it is no longer produced in large quantities and is expensive. Subcutaneous administration of β 2 -agonists in adults raises concerns of adverse cardiostimulatory effects. However, clinically important adverse effects are few, and subcutaneous administration may benefit patients unresponsive to maximal inhaled therapy or patients unable to receive effective nebulized treatment (eg, those who cough excessively, have poor ventilation, or are uncooperative). Nebulized ipratropium can be co-administered with nebulized albuterol for patients who do not respond optimally to albuterol alone; some evidence favors simultaneous high-dose β 2 -agonist and ipratropium as first-line treatment, but no data favor continuous β 2 -agonist nebulization over intermittent administration. Theophylline has very little role in treatment.

Systemic corticosteroids (prednisone, prednisolone, methylprednisolone) should be given for all but the mildest acute exacerbation; they are unnecessary for patients whose PEF normalizes after 1 or 2 bronchodilator doses. IV and oral routes of administration are probably equally effective. IV methylprednisolone can be given if an IV line is already in place and can be switched to oral dosing whenever necessary or convenient. Tapering usually starts after 7 to 10 days and should last 2 to 3 wk.

Antibiotics are indicated only when history, examination, or chest x-ray suggests underlying bacterial infection; most infections underlying asthma exacerbations are probably viral in origin.

Supplemental O 2 is indicated for hypoxemia and should be given by nasal cannula or face mask at a flow rate or concentration sufficient to maintain SaO 2 > 90%.

Reassurance is the best approach when anxiety is the cause of asthma exacerbation. Anxiolytics and morphine are relatively contraindicated because they are associated with increased mortality and the need for mechanical ventilation.

Hospitalization generally is required if patients have not returned to their baseline within 4 h of aggressive emergency department treatment. Criteria for hospitalization vary, but definite indications are failure to improve, worsening fatigue, relapse after repeated β 2 -agonist therapy, and significant decrease in Pa o 2 (< 50 mm Hg) or increase in Pa co 2 (> 40 mm Hg), indicating progression to respiratory failure.

Patients who continue to deteriorate despite aggressive treatment are candidates for noninvasive positive pressure ventilation or endotracheal intubation and invasive mechanical ventilation (see Respiratory Failure and Mechanical Ventilation). Patients requiring intubation may benefit from sedation, but routine use of neuromuscular blocking agents should be avoided because of possible interactions with corticosteroids that can cause prolonged neuromuscular weakness.

Generally, volume-cycled ventilation in assist-control mode is used because it provides constant alveolar ventilation when airway resistance is high and changing. The ventilator should be set to a relatively low frequency with a relatively high inspiratory flow rate (>80 L/min) to prolong exhalation time, minimizing auto positive end-expiratory pressure (PEEP). Initial tidal volumes can be set to 6 to 8 mL/kg of ideal body weight. High peak airway pressures will generally be present because they result from high airway resistance and inspiratory flow rates. In these patients, peak airway pressure does not reflect the degree of lung distention caused by alveolar pressure. However, if plateau pressures exceed 30 to 35 cm H 2 O, then tidal volume should be reduced to limit the risk of pneumothorax. When reduced tidal volumes are necessary, a moderate degree of hypercapnia is acceptable, but if arterial pH falls below 7.10, a slow NaHCO 3 infusion is indicated to maintain pH between 7.20 and 7.25. Once airflow obstruction is relieved and Pa co 2 and arterial pH normalize, patients can usually be quickly weaned from the ventilator.

Pearls & Pitfalls

  • In asthma patients on a ventilator, plateau pressure is a better reflection of risk of pneumothorax than peak airway pressure; if plateau pressures exceed 30 to 35 cm H 2 O, reduce tidal volume.

Other therapies are reportedly effective for asthma exacerbation, but none have been thoroughly studied. Heliox is used to decrease the work of breathing and improve ventilation through a decrease in turbulent flow attributable to helium, a gas less dense than O 2 . Despite the theoretical benefits of heliox, studies have reported conflicting results concerning its efficacy; lack of ready availability and inability to concurrently provide high concentrations of O 2 (due to the fact that 70 to 80% of the inhaled gas is helium) may also limit its use. Magnesium sulfate relaxes smooth muscle, but efficacy in management of asthma exacerbation in the emergency department is debated. General anesthesia in patients with status asthmaticus causes bronchodilation by an unclear mechanism, perhaps by a direct relaxant effect on airway smooth muscle or attenuation of cholinergic tone.


Treatment of chronic asthma

Current asthma guidelines initiate treatment based on the severity classification. Continuing therapy is based on assessment of control (see Table: Classification of Asthma Control* , †). Therapy is increased in a stepwise fashion (see Table: Steps of Asthma Management*) until the best control of impairment and risk is achieved (step-up). Before therapy is stepped up, adherence, exposure to environmental factors (eg, trigger exposure), and presence of comorbid conditions (eg, obesity, allergic rhinitis, GERD, COPD, obstructive sleep apnea, vocal cord dysfunction) are reviewed. These factors should be addressed before increasing drug therapy. Once asthma has been well controlled for at least 3 mo, drug therapy is reduced if possible to the minimum that maintains good control (step-down). For specific drugs and doses, see Table: Drug Treatment of Chronic Asthma*.

Steps of Asthma Management*

Step

Preferred Treatment

Alternate Treatment

1 (starting point for intermittent asthma)

Short-acting β 2 -agonist prn

2 (starting point for mild persistent asthma)

Low-dose inhaled corticosteroid

Mast cell stabilizer, leukotriene receptor antagonist, or theophylline

3 (starting point for moderate persistent asthma)

Medium-dose inhaled corticosteroid

or

Low-dose inhaled corticosteroid plus long-acting β 2 -agonist

Low-dose inhaled corticosteroid plus one of the following: a leukotriene receptor antagonist, theophylline, or zileuton

4

Medium-dose inhaled corticosteroid plus long-acting β 2 -agonist

Medium-dose inhaled corticosteroid plus one of the following: leukotriene receptor antagonist, theophylline, or zileuton

5 (starting point for severe persistent asthma)

High-dose inhaled corticosteroid plus long-acting β 2 -agonist and

possibly omalizumab for patients with allergies

6

High-dose inhaled corticosteroid plus long-acting β 2 -agonist plus oral corticosteroid and

possibly omalizumab for patients with allergies

*Before stepping up, adherence, environmental factors (eg, trigger exposure), and comorbid conditions should be reviewed and managed if needed.

A short-acting ß 2 -agonist is indicated to provide quick relief at all steps and to prevent exercise-induced asthma.


Exercise-induced asthma

Exercise-induced asthma can generally be prevented by inhalation of a short-acting β 2 -agonist or mast cell stabilizer before starting the exercise. If β 2 -agonists are not effective or if exercise-induced asthma is associated with severe symptoms, the patient likely has more severe asthma than was initially recognized and requires controller therapy.


Aspirin-sensitive asthma

The primary treatment for aspirin -sensitive asthma is avoidance of NSAIDs. Celecoxib does not appear to be a trigger. Leukotriene modifiers can blunt the response to NSAIDs. Alternatively, inpatient desensitization has been successful in a few patients.


Future therapies

Multiple therapies are being developed to target specific components of the inflammatory cascade. Therapies directed at IL-4, IL-13, tumor necrosis factor-α, other chemokines, and cytokines or their receptors are all under investigation or consideration as therapeutic targets.


Special Populations

Infants, children, and adolescents

Asthma is difficult to diagnose in infants; thus, under-recognition and undertreatment are common (see also Wheezing and Asthma in Infants and Young Children). Empiric trials of inhaled bronchodilators and anti-inflammatory drugs may be helpful for both. Drugs may be given by nebulizer or MDI with a holding chamber with or without a face mask. Infants and children <5 yr requiring treatment > 2 times/wk should be given daily anti-inflammatory therapy with inhaled corticosteroids (preferred), leukotriene receptor antagonists, or cromolyn.

Children > 5 yr and adolescents with asthma can be treated similarly to adults. They should be encouraged to maintain physical activities, exercise, and sports participation. Predicted norms for pulmonary function tests in adolescents are closer to childhood (not adult) standards. Adolescents and mature younger children should participate in developing their own asthma management plans and establishing their own goals for therapy to improve adherence. The action plan should be understood by teachers and school nurses to ensure reliable and prompt access to rescue drugs. Cromolyn and nedocromil are often tried in this group but are not as beneficial as inhaled corticosteroids. Long-acting drugs prevent the problems (eg, inconvenience, embarrassment) of having to take drugs at school.


Pregnant women

About one third of women with asthma who become pregnant notice relief of symptoms, one third notice worsening (at times to a severe degree), and one third notice no change. GERD may be an important contributor to symptomatic disease in pregnancy. Asthma control during pregnancy is crucial (see Asthma in Pregnancy), because poorly controlled maternal disease can result in increased prenatal mortality, premature delivery, and low birth weight. Asthma drugs have not been shown to have adverse fetal effects, but safety data are lacking. (See also guidelines from the National Asthma Education and Prevention Program, Managing Asthma During Pregnancy: Recommendations for Pharmacologic Treatment–Update 2004 .) In general, uncontrolled asthma is more of a risk to mother and fetus than adverse effects due to asthma drugs. During pregnancy, normal blood P CO 2 level is about 32 mm Hg. Therefore, CO 2 retention is probably occurring if P CO 2 approaches 40 mm Hg.

Pearls & Pitfalls

  • Suspect CO 2 retention and respiratory failure in pregnant women with status asthmaticus and PCO 2 levels near 40 mm Hg.


Elderly patients

The elderly have a high prevalence of other obstructive lung disease (eg, COPD—see Chronic Obstructive Pulmonary Disease (COPD)), so it is important to determine the magnitude of the reversible component of airflow obstruction (eg, by a 2- to 3-wk trial of inhaled corticosteroids or pulmonary function testing with bronchodilator challenge). The elderly may be more sensitive to adverse effects of β 2 -agonists and inhaled corticosteroids. Patients requiring inhaled corticosteroids, particularly those with risk factors for osteoporosis, may benefit from measures to preserve bone density (eg, Ca and vitamin D supplements, bisphosphonates).


Key Points

  • Asthma triggers range from environmental allergens and respiratory irritants to infections, aspirin, exercise, emotion, and GERD.

  • Consider asthma in patients who have unexplained persistent coughing, particularly at night.

  • If asthma is suspected, arrange pulmonary function testing, with methacholine provocation if necessary.

  • Educate patients on how to avoid triggers.

  • Control chronic asthma with drugs that modulate the allergic and immune response—usually inhaled steroids—with other drugs (eg, long-acting bronchodilators, mast cell stabilizers, leukotriene inhibitors) added based on asthma severity.

  • Treat acute exacerbations with inhaled β 2 -agonists and anticholinergic drugs, systemic corticosteroids, and sometimes injected epinephrine.

  • If mechanical ventilation is necessary, consider using high inspiratory flow rates (to prolong expiration) with low tidal volumes, even at the cost of a slight increase in P CO 2 (permissive hypercapnia).

  • Treat asthma aggressively during pregnancy.

More Information

Resources In This Article

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • MIACALCIN
  • No US brand name
  • SEREVENT
  • ADENOCARD
  • FORADIL AEROLIZER, PERFOROMIST
  • ATROVENT
  • SPIRIVA
  • PROVENTIL-HFA, VENTOLIN-HFA
  • ELIXOPHYLLIN
  • LOPRESSOR, TOPROL-XL
  • TENORMIN
  • TYLENOL
  • CELEBREX
  • CUTIVATE, FLONASE
  • BROVANA
  • ZYFLO
  • MEDROL
  • ACCOLATE
  • MAXAIR
  • SINGULAIR
  • AEROSPAN HFA
  • XOPENEX
  • CROLOM
  • NEORAL, SANDIMMUNE
  • XOLAIR
  • XYLOCAINE
  • PANHEPRIN
  • COLCRYS
  • BECONASE
  • ELOCON, NASONEX
  • PULMICORT, RHINOCORT
  • OTREXUP
  • ORAPRED, PRELONE
  • RAYOS
  • ADRENALIN
  • DURAMORPH PF, MS CONTIN
  • ALOCRIL

* This is a professional Version *