In an effort to keep the GINA Workshop report as up to date as possible, a GINA Science Committee has been established to review published research on asthma management and prevention, and to post yearly updates on the GINA Web site. See the GINA Web site for archived versions of the GINA guidelines.

Exercise-induced bronchoconstriction. Physical activity is an important cause of asthma symptoms for most asthma patients, and for some it is the only cause. However, exercise-induced bronchoconstriction often indicates that the patient's asthma is not well controlled, and stepping up controller therapy generally results in the reduction of exercise-related symptoms. For those patients who still experience exercise-induced bronchoconstriction despite otherwise well-controlled asthma, and for those in whom exercise-induced bronchoconstriction is the only manifestation of asthma, a rapid-acting inhaled beta₂-agonist (short- or long-acting), taken prior to exercise or to relieve symptoms that develop after exercise, is recommended. A leukotriene modifier or cromone are alternatives (Evidence A). Training and sufficient warm-up also reduce the incidence and severity of exercise-induced bronchoconstriction (Evidence B). Information on treatment of exercise-induced asthma in athletes can be found in a Joint Task Force Report prepared by the European Respiratory Society, the European Academy of Allergy and Clinical Immunology, and GA(2)LEN and the World Anti-Doping Agency website (http://www.wada-ama.org).

Step 2: Reliever Medication Plus a Single Controller

Treatment Steps 2 through 5, combine an as-needed reliever treatment with regular controller treatment. At Step 2, a low-dose inhaled glucocorticosteroid is recommended as the initial controller treatment for asthma patients of all ages (Evidence A). Equivalent doses of inhaled glucocorticosteroids, some of which may be given as a single daily dose, are provided in Figure 3-1 in the original guideline document for adults and in Figure 3-4 in the original guideline document for children 5 years and younger.

Alternative controller medications include leukotriene modifiers (Evidence A), appropriate particularly for patients who are unable or unwilling to use inhaled glucocorticosteroids, or who experience intolerable side effects such as persistent hoarseness from inhaled glucocorticosteroid treatment and those with concomitant allergic rhinitis (Evidence C).

Other options are available but not recommended for routine use as initial or first-line controllers in Step 2. Sustained-release theophylline has only weak anti-inflammatory and controller efficacy (Evidence B) and is commonly associated with side effects that range from trivial to intolerable. Cromones (nedocromil sodium and sodium cromoglycate) have comparatively low efficacy, though a favorable safety profile (Evidence A).

Step 3: Reliever Medication Plus One or Two Controllers

At Step 3, the recommended option for adolescents and adults is to combine a low-dose of inhaled glucocorticosteroid with an inhaled long-acting beta₂-agonist, either in a combination inhaler device or as separate components (Evidence A). Because of the additive effect of this combination, the low-dose of glucocorticosteroid is usually sufficient, and need only be increased if control is not achieved within 3 or 4 months with this regimen (Evidence A). The long-acting beta₂-agonist formoterol, which has a rapid onset of action whether given alone or in combination inhaler with budesonide, has been shown to be as effective as short-acting beta₂-agonist in acute asthma exacerbation. However its use as monotherapy as a reliever medication is strongly discouraged since it must always be used in association with an inhaled glucocorticosteroid.

For all children but particularly those 5 years and younger, combination therapy has been less well studied and the addition of a long-acting beta agonist may not be as effective as increasing the dose of inhaled glucocorticosteroids in reducing exacerbations.

If a combination inhaler containing formoterol and budesonide is selected, it may be used for both rescue and maintenance. This approach has been shown to result in reductions in exacerbations and improvements in asthma control in adults and adolescents at relatively low doses of treatment (Evidence A). Whether this approach can be employed with other combinations of controller and reliever requires further study.

Another option for both adults and children, but the one recommended for children, is to increase to a medium-dose of inhaled glucocorticosteroids (Evidence A). For patients of all ages on medium- or high-dose of inhaled glucocorticosteroid delivered by a pressurized metered-dose inhaler (MDI), use of a spacer device is recommended to improve delivery to the airways, reduce oropharyngeal side effects, and reduce systemic absorption (Evidence A).

Another option at Step 3 is to combine a low-dose inhaled glucocorticosteroid with leukotriene modifiers (Evidence A). Alternatively, the use of sustained-release theophylline given at low-dose may be considered (Evidence B). These options have not been fully studied in children 5 years and younger.

Step 4: Reliever Medication Plus Two or More Controllers

The selection of treatment at Step 4 depends on prior selections at Steps 2 and 3. However, the order in which additional medications should be added is based, as far as possible, upon evidence of their relative efficacy in clinical trials. Where possible, patients who are not controlled on Step 3 treatments should be referred to a health professional with expertise in the management of asthma for investigation of alternative diagnoses and/or causes of difficult-to-treat asthma.

The preferred treatment at Step 4 is to combine a medium- or high-dose of inhaled glucocorticosteroid with a long-acting inhaled beta₂-agonist. However, in most patients, the increase from a medium- to a high-dose of inhaled glucocorticosteroid provides relatively little additional benefit (Evidence A), and the high-dose is recommended only on a trial basis for 3 to 6 months when control cannot be achieved with medium-dose inhaled glucocorticosteroid combined with a long-acting beta₂-agonist and/or a third controller (e.g., leukotriene modifiers or sustained-release theophylline) (Evidence B). Prolonged use of high-dose inhaled glucocorticosteroids is also associated with increased potential for adverse effects. At medium- and high-doses, twice-daily dosing is necessary for most but not all inhaled glucocorticosteroids (Evidence A). With budesonide, efficacy may be improved with more frequent dosing (four times daily) (Evidence B). (Refer to Figure 3-1 in the original guideline document for adults and Figure 3-4 in the original guideline document for children 5 years and younger for recommendations on dosing and frequency for different inhaled glucocorticosteroids.)

Leukotriene modifiers as add-on treatment to medium-to high-dose inhaled glucocorticosteroids have been shown to provide benefit (Evidence A), but usually less than that achieved with the addition of a long-acting beta₂-agonist (Evidence A). The addition of a low-dose of sustained-release theophylline to medium- or high-dose inhaled glucocorticosteroid and long-acting beta₂-agonist may also provide benefit (Evidence B).

Step 5: Reliever Medication Plus Additional Controller Options

Addition of oral glucocorticosteroids to other controller medications may be effective (Evidence D) but is associated with severe side effects (Evidence A) and should only be considered if the patient's asthma remains severely uncontrolled on Step 4 medications with daily limitation of activities and frequent exacerbations. Patients should be counseled about potential side effects and all other alternative treatments must be considered.

Addition of anti-immunoglobulin E (anti-IgE) treatment to other controller medications has been shown to improve control of allergic asthma when control has not been achieved on combinations of other controllers including high-doses of inhaled or oral glucocorticosteroids (Evidence A).

Monitoring to Maintain Control

When asthma control has been achieved, ongoing monitoring is essential to maintain control and to establish the lowest step and dose of treatment necessary, which minimizes the cost and maximizes the safety of treatment. On the other hand, asthma is a variable disease, and treatment has to be adjusted periodically in response to loss of control as indicated by worsening symptoms or the development of an exacerbation.

Asthma control should be monitored by the health care professional and preferably also by the patient at regular intervals, using either a simplified scheme as presented in the Levels of Asthma Control table, above, or a validated composite measure of control. The frequency of health care visits and assessments depends upon the patient's initial clinical severity, and the patient's training and confidence in playing a role in the ongoing control of his or her asthma. Typically, patients are seen one to three months after the initial visit, and every three months thereafter. After an exacerbation, follow-up should be offered within two weeks to one month (Evidence D).

Duration and Adjustments to Treatment

For most classes of controller medications, improvement begins within days of initiating treatment, but the full benefit may only be evident after 3 or 4 months. In severe and chronically undertreated disease, this can take even longer.

The reduced need for medication once control is achieved is not fully understood, but may reflect the reversal of some of the consequences of long-term inflammation of the airways. Higher doses of anti-inflammatory medication may be required to achieve this benefit than to maintain it. Alternatively, the reduced need for medication might simply represent spontaneous improvement as part of the cyclical natural history of asthma. Rarely, asthma may go into remission particularly in children aged 5 years and younger and during puberty. Whatever the explanation, in all patients the minimum controlling dose of treatment must be sought through a process of regular follow-up and staged dose reductions.

At other times treatment may need to be increased either in response to loss of control or threat of loss of control (return of symptoms) or an acute exacerbation, which is defined as a more acute and severe loss of control that requires urgent treatment. (An approach to exacerbations is provided in Component 4 below.)

Stepping Down Treatment When Asthma Is Controlled

There is little experimental data on the optimal timing, sequence, and magnitude of treatment reductions in asthma, and the approach will differ from patient to patient depending on the combination of medications and the doses that were needed to achieve control. These changes should ideally be made by agreement between patient and health care professional, with full discussion of potential consequences including reappearance of symptoms and increased risk of exacerbations.

Although further research on stepping down asthma treatment is needed, some recommendations can be made based on the current evidence:

• When inhaled glucocorticosteroids alone in medium-to-high-doses are being used, a 50% reduction in dose should be attempted at 3 month intervals (Evidence B).
• Where control is achieved at a low-dose of inhaled glucocorticosteroids alone, in most patients treatment may be switched to once-daily dosing (Evidence A).
• When asthma is controlled with a combination of inhaled glucocorticosteroid and long-acting beta₂-agonist, the preferred approach is to begin by reducing the dose of inhaled glucocorticosteroid by approximately 50% while continuing the long-acting beta₂-agonist (Evidence B). If control is maintained, further reductions in the glucocorticosteroid should be attempted until a low-dose is reached, when the long-acting beta₂-agonist may be stopped (Evidence D). An alternative is to switch the combination treatment to once-daily dosing. A second alternative is to discontinue the long-acting beta₂-agonist at an earlier stage and substitute the combination treatment with inhaled glucocorticosteroid monotherapy at the same dose contained in the combination inhaler. However, for some patients these alternative approaches lead to loss of asthma control (Evidence B).
• When asthma is controlled with inhaled glucocorticosteroids in combination with controllers other than long-acting beta₂-agonists, the dose of inhaled glucocorticosteroid should be reduced by 50% until a low-dose of inhaled glucocorticosteroid is reached, then the combination treatment stopped as described above (Evidence D).
• Controller treatment may be stopped if the patient's asthma remains controlled on the lowest dose of controller and no recurrence of symptoms occurs for one year (Evidence D).

Stepping Up Treatment In Response To Loss Of Control

Treatment has to be adjusted periodically in response to worsening control, which may be recognized by the minor recurrence or worsening of symptoms. Treatment options are as follows:

• Rapid-onset, short-acting or long-acting beta₂-agonist bronchodilators. Repeated dosing with bronchodilators in this class provides temporary relief until the cause of the worsening symptoms passes. The need for repeated doses over more than one or two days signals the need for review and possible increase of controller therapy.
• Inhaled glucocorticosteroids. Temporarily doubling the dose of inhaled glucocorticosteroids has not been demonstrated to be effective, and is no longer recommended (Evidence A). A four-fold or greater increase has been demonstrated to be equivalent to a short course of oral glucocorticosteroids in adult patients with an acute deterioration (Evidence A). The higher dose should be maintained for seven to fourteen days but more research is needed in both adults and children to standardize the approach.
• Combination of inhaled glucocorticosteroids and rapid and long-acting beta₂-agonist bronchodilator (e.g., formoterol) for combined relief and control. The use of the combination of a rapid and long-acting beta₂-agonist and an inhaled glucocorticosteroid in a single inhaler both as a controller and reliever is effective in maintaining a high level of asthma control and reduces exacerbations requiring systemic glucocorticosteroids and hospitalization (Evidence A). The benefit in preventing exacerbations appears to be the consequence of early intervention at a very early stage of a threatened exacerbation since studies involving doubling or quadrupling doses of combination treatment once deterioration is established (for 2 or more days) show some benefit but results are inconsistent. Because there are no studies using this approach with other combinations of controller and relievers, other than budesonide/formoterol, the alternative approaches described in this section should be used for patients on other controller therapies. Combination therapy with budesonide and formoterol used both as maintenance and rescue has been shown to reduce asthma exacerbations in children ages 4 years and older with moderate to severe asthma.
• The usual treatment for an acute exacerbation is a high-dose of beta₂-agonist and a burst of systemic glucocorticosteroids administered orally or intravenously. (Refer to Component 4 below for more information.)

Following treatment for an exacerbation of asthma, maintenance treatment can generally be resumed at previous levels unless the exacerbation was associated with a gradual loss of control suggesting chronic undertreatment. In this case, provided inhaler technique has been checked, a step-wise increase in treatment (either in dose or number of controllers) is indicated.

Difficult-to-Treat Asthma

Although the majority of asthma patients can obtain the targeted level of control, some patients will not do so even with the best therapy. Patients who do not reach an acceptable level of control at Step 4 (reliever medication plus two or more controllers) can be considered to have difficult-to-treat asthma. These patients may have an element of poor glucocorticosteroid responsiveness, and require higher doses of inhaled glucocorticosteroids than are routinely used in patients whose asthma is easy to control. However, there is currently no evidence to support continuing these high doses of inhaled glucocorticosteroids beyond 6 months in the hope of achieving better control. Instead, dose optimization should be pursued by stepping down to a dose that maintains the maximal level of control achieved on the higher dose.

Because very few patients are completely resistant to glucocorticosteroids, these medications remain a mainstay of therapy for difficult-to-treat asthma, while additional diagnostic and generalized therapeutic options can and should also be considered:

• Confirm the diagnosis of asthma. In particular, the presence of chronic obstructive pulmonary disease (COPD) must be excluded. Vocal cord dysfunction must be considered.
• Investigate and confirm compliance with treatment. Incorrect or inadequate use of medications remains the most common reason for failure to achieve control.
• Consider smoking, current or past, and encourage complete cessation. A history of past tobacco smoking is associated with a reduced likelihood of complete asthma control, and this is only partly attributable to the presence of fixed airflow obstruction. In addition, current smoking reduces the effectiveness of inhaled and oral glucocorticosteroids. Counseling and smoking cessation programs should be offered to all asthma patients who smoke.
• Investigate the presence of comorbidities that may aggravate asthma. Chronic sinusitis, gastroesophageal reflux, and obesity/obstructive sleep apnea have been reported in higher percentages in patients with difficult-to-treat asthma. Psychological and psychiatric disorders should also be considered. If found, these comorbidities should be addressed and treated as appropriate, although the ability to improve asthma control by doing so remains unconfirmed.

When these reasons for lack of treatment response have been considered and addressed, a compromise level of control may need to be accepted and discussed with the patient to avoid futile over-treatment (with its attendant cost and potential for adverse effects). The objective is then to minimize exacerbations and need for emergency medical interventions while achieving as high a level of clinical control with as little disruption of activities and as few daily symptoms as possible. For these difficult-to-treat patients, frequent use of rescue medication is accepted, as is a degree of chronic lung function impairment.

Although lower levels of control are generally associated with an increased risk of exacerbations, not all patients with chronically impaired lung function, reduced activity levels, and daily symptoms have frequent exacerbations. In such patients, the lowest level of treatment that retains the benefits achieved at the higher doses of treatment should be employed. Reductions should be made cautiously and slowly at intervals not more frequent than 3 to 6 months, as carryover of the effects of the higher dose may last for several months and make it difficult to assess the impact of the dose reduction (Evidence D). Referral to a physician with an interest in and/or special focus on asthma may be helpful and patients may benefit from phenotyping into categories such as allergic, aspirin-sensitive, and/or eosinophilic asthma. Patients categorized as allergic might benefit from anti-IgE therapy, and leukotriene modifiers can be helpful for patients determined to be aspirin sensitive (who are often eosinophilic as well).

Component 4: Manage Asthma Exacerbations

Introduction

Exacerbations of asthma (asthma attacks or acute asthma) are episodes of progressive increase in shortness of breath, cough, wheezing, or chest tightness, or some combination of these symptoms. Exacerbations usually have a progressive onset but a subset of patients (mostly adults) present more acutely. Respiratory distress is common. Exacerbations are characterized by decreases in expiratory airflow that can be quantified by measurement of lung function (PEF or FEV₁). These measurements are more reliable indicators of the severity of airflow limitation than is the degree of symptoms. The degree of symptoms may, however, be a more sensitive measure of the onset of an exacerbation because the increase in symptoms usually precedes the deterioration in peak flow rate. Still, a minority of patients perceive symptoms poorly, and may have a significant decline in lung function without a significant change in symptoms. This situation especially affects patients with a history of near-fatal asthma and also appears to be more likely in males. A clinically useful tool to assess the likelihood of asthma-related hospitalizations or emergency department visits in adults with severe or difficult to treat asthma has been described.

Strategies for treating exacerbations, though generalizable, are best adapted and implemented at a local level. Severe exacerbations are potentially life threatening, and their treatment requires close supervision. Patients with severe exacerbations should be encouraged to see their physician promptly or, depending on the organization of local health services, to proceed to the nearest clinic or hospital that provides emergency access for patients with acute asthma. Close objective monitoring (PEF) of the response to therapy is essential.

The primary therapies for exacerbations include—in the order in which they are introduced, depending on severity—repetitive administration of rapid-acting inhaled bronchodilators, early introduction of systemic glucocorticosteroids, and oxygen supplementation. The aims of treatment are to relieve airflow obstruction and hypoxemia as quickly as possible, and to plan the prevention of future relapses.

Patients at high risk of asthma-related death require closer attention and should be encouraged to seek urgent care early in the course of their exacerbations. These patients include those:

• With a history of near-fatal asthma requiring intubation and mechanical ventilation
• Who have had a hospitalization or emergency care visit for asthma in the past year
• Who are currently using or have recently stopped using oral glucocorticosteroids
• Who are not currently using inhaled glucocorticosteroids
• Who are overdependent on rapid-acting inhaled  beta₂-agonists, especially those who use more than one canister of salbutamol (or equivalent) monthly
• With a history of psychiatric disease or psychosocial problems, including the use of sedatives
• With a history of noncompliance with an asthma medication plan

Response to treatment may take time and patients should be closely monitored using clinical as well as objective measurements. The increased treatment should continue until measurements of lung function (PEF or FEV₁) return to their previous best (ideally) or plateau, at which time a decision to admit or discharge can be made based upon these values. Patients who can be safely discharged will have responded within the first two hours, at which time decisions regarding patient disposition can be made.

Assessment of Severity

The severity of the exacerbation (see Figure 4.4-1 in the original guideline document) determines the treatment administered. Indices of severity, particularly PEF (in patients older than 5 years), pulse rate, respiratory rate, and pulse oximetry, should be monitored during treatment.

Management—Community Settings

Most patients with severe asthma exacerbations should be treated in an acute care facility (such as a hospital emergency department) where monitoring, including objective measurement of airflow obstruction, oxygen saturation, and cardiac function, is possible. Milder exacerbations, defined by a reduction in peak flow of less than 20%, nocturnal awakening, and increased use of short acting beta₂-agonists can usually be treated in a community setting. If the patient responds to the increase in inhaled bronchodilator treatment after the first few doses, referral to an acute care facility is not required, but further management under the direction of a primary care physician may include the use of systemic glucocorticosteroids. Patient education and review of maintenance therapy should also be undertaken.

Treatment

Bronchodilators

For mild to moderate exacerbations, repeated administration of rapid-acting inhaled beta₂-agonists (2 to 4 puffs every 20 minutes for the first hour) is usually the best and most cost-effective method of achieving rapid reversal of airflow limitation. After the first hour, the dose of beta₂-agonist required will depend on the severity of the exacerbation. Mild exacerbations respond to 2 to 4 puffs every 3 to 4 hours; moderate exacerbations will require 6 to 10 puffs every 1 or 2 hours. Treatment should also be titrated depending upon the individual patient's response, and if there is a lack of response or other concern about how the patient is responding, the patient should be referred to an acute care facility.

Many patients will be able to monitor their PEF after the initiation of increased bronchodilator therapy. Bronchodilator therapy delivered via an MDI, ideally with a spacer, produces at least an equivalent improvement in lung function as the same dose delivered via nebulizer. At the clinic level, this route of delivery is the most cost effective, provided patients are able to use an MDI. No additional medication is necessary if the rapid-acting inhaled beta₂-agonist produces a complete response (PEF returns to greater than 80% of predicted or personal best) and the response lasts for 3 to 4 hours.

Glucocorticosteroids

Oral glucocorticosteroids (0.5 to 1 mg of prednisolone/kg or equivalent during a 24-hour period) should be used to treat exacerbations, especially if they develop after instituting the other short-term treatment options recommended for loss of control (see "Stepping up treatment in response to loss of control" in Component 3 above and in the original guideline document). If patients fail to respond to bronchodilator therapy, as indicated by persistent airflow obstruction, prompt transfer to an acute care setting is recommended, especially if they are in a high risk group.

Management—Acute Care Settings

Severe exacerbations of asthma are life-threatening medical emergencies, treatment of which is often most safely undertaken in an emergency department. The algorithm in Figure 4.4-2 in the original guideline document illustrates the approach to acute care-based management of exacerbations.

Assessment

A brief history and physical examination pertinent to the exacerbation should be conducted concurrently with the prompt initiation of therapy. The history should include severity and duration of symptoms, including exercise limitation and sleep disturbance; all current medications, including dose (and device) prescribed, dose usually taken, dose taken in response to the deterioration, and the patient's response (or lack thereof) to this therapy; time of onset and cause of the present exacerbation; and risk factors for asthma-related death.

The physical examination should assess exacerbation severity by evaluating the patient's ability to complete a sentence, pulse rate, respiratory rate, use of accessory muscles, and other signs detailed in Figure 4.4-2 in the original guideline document. Any complicating factors should be identified (e.g., pneumonia, atelectasis, pneumothorax, or pneumomediastinum).

Functional assessments such as PEF or FEV₁ and arterial oxygen saturation measurements are strongly recommended as physical examination alone may not fully indicate the severity of the exacerbation, particularly the degree of hypoxemia. Without unduly delaying treatment, a baseline PEF or FEV₁ measurement should be made before treatment is initiated. Subsequent measurements should be made at intervals until a clear response to treatment has occurred.

Oxygen saturation should be closely monitored, preferably by pulse oximetry. This is especially useful in children because objective measurements of lung function may be difficult. Oxygen saturation in children should normally be greater than 95%, and oxygen saturation less than 92% is a good predictor of the need for hospitalization (Evidence C).

In adults a chest x-ray is not routinely required, but should be carried out if a complicating cardiopulmonary process is suspected, in patients requiring hospitalization, and in those not responding to treatment where a pneumothorax may be difficult to diagnose clinically. Similarly, in children routine chest x-rays are not recommended unless there are physical signs suggestive of parenchymal disease.

Although arterial blood gas measurements are not routinely required, they should be completed in patients with a PEF of 30 to 50% predicted, those who do not respond to initial treatment, or when there is concern regarding deterioration. The patient should continue on supplemental oxygen while the measurement is made. A partial pressure of oxygen in arterial blood (PaO₂) <60 mm Hg (8 kPa) and a normal or increased partial pressure of carbon dioxide in the arterial blood (PaCO₂) (especially >45 mm Hg, 6 kPa) indicates the presence of respiratory failure.

Treatment

The following treatments are usually administered concurrently to achieve the most rapid resolution of the exacerbation:

Oxygen

To achieve arterial oxygen saturation of >90% (>95% in children), oxygen should be administered by nasal cannulae, by mask, or rarely by head box in some infants. PaCO₂ may worsen in some patients on 100 percent oxygen, especially those with more severe airflow obstruction. Oxygen therapy should be titrated against pulse oximetry to maintain a satisfactory oxygen saturation.

Rapid-Acting Inhaled Beta₂–Agonists

Rapid-acting inhaled beta₂-agonists should be administered at regular intervals (Evidence A). Although most rapid-acting beta₂-agonists have a short duration of effect, the long-acting bronchodilator formoterol, which has both a rapid onset of action and a long duration of effect, has been shown to be equally effective without increasing side effects, though it is considerably more expensive. The importance of this feature of formoterol is that it provides support and reassurance regarding the use of a combination of formoterol and budesonide early in asthma exacerbations.

A modestly greater bronchodilator effect has been shown with levalbuterol compared to racemic albuterol in both adults and children with an asthma exacerbation. In a large study of acute asthma in children, and in adults not previously treated with glucocorticosteroids, levalbuterol treatment resulted in lower hospitalization rates compared to racemic albuterol treatment, but in children the length of hospital stay was no different.

A reasonable approach to inhaled therapy in exacerbations would be the initial use of continuous therapy, followed by intermittent on-demand therapy for hospitalized patients. There is no evidence to support the routine use of intravenous beta₂-agonists in patients with severe asthma exacerbations.

Epinephrine

A subcutaneous or intramuscular injection of epinephrine (adrenaline) may be indicated for acute treatment of anaphylaxis and angioedema, but is not routinely indicated during asthma exacerbations.

Additional Bronchodilators

Ipratropium bromide. A combination of nebulized beta₂- agonist with an anticholinergic (ipratropium bromide) may produce better bronchodilation than either drug alone (Evidence B) and should be administered before methylxanthines are considered. Combination beta₂-agonist/anticholinergic therapy is associated with lower hospitalization rates (Evidence A) and greater improvement in PEF and FEV₁ (Evidence B). Similar data have been reported in the pediatric literature (Evidence A). However, once children with asthma are hospitalized following intensive emergency department treatment, the addition of nebulized ipratropium bromide to nebulized beta₂-agonist and systemic glucocorticosteroids appears to confer no extra benefit.

Theophylline. In view of the effectiveness and relative safety of rapid-acting beta₂-agonists, theophylline has a minimal role in the management of acute asthma. Its use is associated with severe and potentially fatal side effects, particularly in those on long-term therapy with sustained-release theophylline, and their bronchodilator effect is less than that of beta₂-agonists. The benefit as add-on treatment in adults with severe asthma exacerbations has not been demonstrated. However, in one study of children with near-fatal asthma, intravenous theophylline provided additional benefit to patients also receiving an aggressive regimen of inhaled and intravenous beta₂-agonists, inhaled ipratropium bromide, and intravenous systemic glucocorticosteroids.

Systemic Glucocorticosteroids

Systemic glucocorticosteroids speed resolution of exacerbations and should be utilized in the all but the mildest exacerbations (Evidence A), especially if:

• The initial rapid-acting inhaled beta₂-agonist therapy fails to achieve lasting improvement
• The exacerbation develops even though the patient was already taking oral glucocorticosteroids
• Previous exacerbations required oral glucocorticosteroids

Oral glucocorticosteroids are usually as effective as those administered intravenously and are preferred because this route of delivery is less invasive and less expensive. If vomiting has occurred shortly after administration of oral glucocorticosteroids, then an equivalent dose should be re-administered intravenously. In patients discharged from the emergency department, intramuscular administration may be helpful, especially if there are concerns about compliance with oral therapy. Oral glucocorticosteroids require at least 4 hours to produce clinical improvement. Daily doses of systemic glucocorticosteroids equivalent to 60-80 mg methylprednisolone as a single dose, or 300-400 mg hydrocortisone in divided doses, are adequate for hospitalized patients, and 40 mg methylprednisolone or 200 mg hydrocortisone is probably adequate in most cases (Evidence B). An oral glucocorticosteroid dose of 1 mg/kg daily is adequate for treatment of exacerbations in children with mild persistent asthma. A 7-day course in adults has been found to be as effective as a 14-day course, and a 3- to 5-day course in children is usually considered appropriate (Evidence B). Current evidence suggests that there is no benefit to tapering the dose of oral glucocorticosteroids, either in the short-term or over several weeks (Evidence B).

Inhaled Glucocorticosteroids

Inhaled glucocorticosteroids are effective as part of therapy for asthma exacerbations. In one study, the combination of high-dose inhaled glucocorticosteroids and salbutamol in acute asthma provided greater bronchodilation than salbutamol alone (Evidence B), and conferred greater benefit than the addition of systemic glucocorticosteroids across all parameters, including hospitalizations, especially for patients with more severe attacks.

Inhaled glucocorticosteroids can be as effective as oral glucocorticosteroids at preventing relapses. Patients discharged from the emergency department on prednisone and inhaled budesonide have a lower rate of relapse than those on prednisone alone (Evidence B). A high dose of inhaled glucocorticosteroid (2.4 mg budesonide daily in four divided doses) achieves a relapse rate similar to 40 mg oral prednisone daily (Evidence A). Cost is a significant factor in the use of such high-doses of inhaled glucocorticosteroids, and further studies are required to document their potential benefits, especially cost effectiveness, in acute asthma.

Magnesium

Intravenous magnesium sulphate (usually given as a single 2 g infusion over 20 minutes) is not recommended for routine use in asthma exacerbations, but can help reduce hospital admission rates in certain patients, including adults with FEV₁ 25-30% predicted at presentation, adults and children who fail to respond to initial treatment, and children whose FEV₁ fails to improve above 60% predicted after 1 hour of care (Evidence A). Nebulized salbutamol administered in isotonic magnesium sulfate provides greater benefit than if it is delivered in normal saline (Evidence A). Intravenous magnesium sulphate has not been studied in young children.

Helium Oxygen Therapy

A systematic survey of studies that have evaluated the effect of a combination of helium and oxygen, compared to helium alone, suggests there is no routine role for this intervention. It might be considered for patients who do not respond to standard therapy.

Leukotriene Modifiers

There is little data to suggest a role for leukotriene modifiers in acute asthma.

Sedatives

Sedation should be strictly avoided during exacerbations of asthma because of the respiratory depressant effect of anxiolytic and hypnotic drugs. An association between the use of these drugs and avoidable asthma deaths has been demonstrated.

Criteria for Discharge from the Emergency Department vs. Hospitalization

Patients with a pre-treatment FEV₁ or PEF <25% predicted or personal best, or those with a post-treatment FEV₁ or PEF <40% predicted or personal best, usually require hospitalization. Patients with post-treatment lung function of 40 to 60% predicted may be discharged, provided that adequate follow-up is available in the community and compliance is assured. Patients with post-treatment lung function >60% predicted can be discharged.

Management of acute asthma in the intensive care unit is beyond the scope of this document and readers are referred to recent comprehensive reviews.

For patients discharged from the emergency department:

• At a minimum, a 7-day course of oral glucocorticosteroids for adults and a shorter course (3 to 5 days) for children should be prescribed, along with continuation of bronchodilator therapy.
• The bronchodilator can be used on an as-needed basis, based on both symptomatic and objective improvement, until the patient returns to his or her pre-exacerbation use of rapid-acting inhaled beta₂-agonists.
• Ipratropium bromide is unlikely to provide additional benefit beyond the acute phase and may be quickly discontinued.
• Patients should initiate or continue inhaled glucocorticosteroids.
• The patient's inhaler technique and use of peak flow meter to monitor therapy at home should be reviewed. Patients discharged from the emergency department with a peak flow meter and action plan have a better response than patients discharged without these resources.
• The factors that precipitated the exacerbation should be identified and strategies for their future avoidance implemented.
• The patient's response to the exacerbation should be evaluated. The action plan should be reviewed and written guidance provided.
• Use of controller therapy during the exacerbation should be reviewed: whether this therapy was increased promptly, by how much, and, if appropriate, why oral glucocorticosteroids were not added. Consider providing a short course of oral glucocorticosteroids to be on hand for subsequent exacerbations.
• The patient or family should be instructed to contact the primary health care professional or asthma specialist within 24 hours of discharge. A follow-up appointment with the patient's usual primary care professional or asthma specialist should be made within a few days of discharge to assure that treatment is continued until baseline control parameters, including personal best lung function, are reached. Prospective data indicate that patients discharged from the emergency department for follow-up with specialist care do better that patients returned to routine care.

An exacerbation severe enough to require hospitalization may reflect a failure of the patient's self-management plan. Hospitalized patients may be particularly receptive to information and advice about their illness. Health care providers should take the opportunity to review patient understanding of the causes of asthma exacerbations, avoidance of factors that may cause exacerbations (including, where relevant smoking cessation), the purposes and correct uses of treatment, and the actions to be taken to respond to worsening symptoms or peak flow values (Evidence A).

Referral to an asthma specialist should be considered for hospitalized patients. Following discharge from continuous supervision, the patient should be reviewed by the family health care professional or asthma specialist regularly over the subsequent weeks until personal best lung function is reached. Use of incentives improves primary care follow up but has shown no effect on long term outcomes. Patients who come to the emergency department with an acute exacerbation should be especially targeted for an asthma education program, if one is available.

Component 5: Special Considerations

Pregnancy

Inhaled glucocorticosteroids have been shown to prevent exacerbations of asthma during pregnancy (Evidence B). As in other situations, the focus of asthma treatment must remain on control of symptoms and maintenance of normal lung function. Acute exacerbations should be treated aggressively in order to avoid fetal hypoxia. Treatment should include nebulized rapid-acting beta₂-agonists and oxygen and systemic glucocorticosteroids should be instituted when necessary.

While all patients should have adequate opportunity to discuss the safety of their medications, pregnant patients with asthma should be advised that the greater risk to their baby lies with poorly controlled asthma, and the safety of most modern asthma treatments should be stressed. Even with a good patient/health care professional relationship, independent printed material, such as a statement from the US National Asthma Education and Prevention Program on the treatment of asthma during pregnancy, will provide important additional reassurance.

Surgery

Airway hyperresponsiveness, airflow limitation, and mucus hypersecretion predispose patients with asthma to intraoperative and postoperative respiratory complications. The likelihood of these complications depends on the severity of asthma at the time of surgery, the type of surgery (thoracic and upper abdominal surgeries pose the greatest risks), and type of anesthesia (general anesthesia with endotracheal intubation carries the greatest risk). These variables need to be assessed prior to surgery and pulmonary function should be measured. If possible, this evaluation should be undertaken several days before surgery to allow time for additional treatment. In particular, if the patient's FEV₁ is less than 80% of personal best, a brief course of oral glucocorticosteroids should be considered to reduce airflow limitation (Evidence C). Furthermore, patients who have received systemic glucocorticosteroids within the past 6 months should have systemic coverage during the surgical period (100 mg hydrocortisone every 8 hours intravenously). This should be rapidly reduced 24 hours following surgery, as prolonged systemic glucocorticosteroid therapy may inhibit wound healing (Evidence C).

Rhinitis

Treatment of rhinitis may improve asthma symptoms (Evidence A). Anti-inflammatory agents including glucocorticosteroids and cromones as well as leukotriene modifiers and anticholinergics can be effective in both conditions. However, some medications are selectively effective against rhinitis (e.g., H₁-antagonists) and others against asthma (e.g., beta₂-agonists) (Evidence A). Use of intra-nasal glucocorticosteroids for concurrent rhinitis has been found to have a limited benefit in improving asthma and reducing asthma morbidity in some but not all studies. Leukotriene modifiers, allergen-specific immunotherapy, and anti-IgE therapy are effective in both conditions (Evidence A).

Sinusitis

Sinusitis is a complication of upper respiratory infections, allergic rhinitis, nasal polyps, and other forms of nasal obstruction. Both acute and chronic sinusitis can worsen asthma. Clinical features of sinusitis lack diagnostic precision, and computed tomography (CT) scan confirmation is recommended when available. In children with suspected rhinosinusitis, antibiotic therapy for 10 days is recommended (Evidence B). Treatment should also include medications to reduce nasal congestion, such as topical nasal decongestants or topical nasal or even systemic glucocorticosteroids. These agents remain secondary to primary asthma therapies.

Occupational Asthma

Pharmacologic therapy for occupational asthma is identical to therapy for other forms of asthma, but it is not a substitute for adequate avoidance. Consultation with a specialist in asthma management or occupational medicine is advisable.

Respiratory Infections

Treatment of an infectious exacerbation follows the same principles as treatment of other asthma exacerbations—that is, rapid-acting inhaled beta₂-agonists and early introduction of oral glucocorticosteroids or increases in inhaled glucocorticosteroids by at least four-fold are recommended. Because increased asthma symptoms can often persist for weeks after the infection is cleared, anti-inflammatory treatment should be continued for this full period to ensure adequate control.

Aspirin-Induced Asthma (AIA)

A characteristic history of reaction is considered adequate for initiating avoidance strategies. However, the diagnosis can only be confirmed by aspirin challenge, as there are no suitable in vitro tests for diagnosis. The aspirin challenge test is not recommended for routine practice as it is associated with a high risk of potentially fatal consequences and must only be conducted in a facility with cardiopulmonary resuscitation capabilities. Further safeguards are that patients should only be challenged when their asthma is in remission and their FEV₁ is greater than 70% of predicted or personal best. Bronchial (inhalational) and nasal challenges with lysine aspirin are safer than oral challenges and may be performed in specialized centers. Once aspirin or NSAID hypersensitivity develops, it is present for life. Patients with AIA should avoid aspirin, products containing it, other analgesics that inhibit COX-1, and often also hydrocortisone hemisuccinate. Avoidance does not prevent progression of the inflammatory disease of the respiratory tract. Where a nonsteroidal anti-inflammatory drug (NSAID) is indicated, a cyclooxygenase-2 (COX-2) inhibitor may be considered with appropriate physician supervision and observation for at least one hour after administration (Evidence B). Glucocorticosteroids continue to be the mainstay of asthma therapy, but leukotriene modifiers may also be useful for additional control of the underlying disease (Evidence B). For NSAID-sensitive patients with asthma who require NSAIDs for other medical conditions, desensitization may be conducted in the hospital under the care of a specialist.

Special considerations are required in managing asthma in relation to pregnancy; surgery; rhinitis, sinusitis, and nasal polyps; occupational asthma; respiratory infections; gastroesophageal reflux; aspirin-induced asthma; and anaphylaxis. See the original guideline document for a detailed discussion of these special considerations.

Definitions:

Public health strategies involving a broad coalition of stakeholders in asthma care, including medical societies, health care professionals, patient support groups, government, and the private sector, have been implemented in Australia (Australian National Asthma Campaign, http://www.nationalasthma.org.au), and the United States (National Asthma Education and Prevention Program, http://www.nhlbi.nih.gov).

An important part of the implementation process is to establish a system to evaluate the effectiveness and quality of care. Evaluation involves surveillance of traditional epidemiological parameters, such as morbidity and mortality, as well as the specific audit of both process and outcome within different sectors of the health care system. Each country should determine its own minimum sets of data to audit health outcomes. There are a variety of assessment tools which provide a consistent and objective assessment of asthma morbidity or control (e.g., Asthma Control Test, Asthma Control Questionnaire, Asthma Therapy Assessment Questionnaire). Results of these assessments should be recorded at each visit, providing a record of the long-term clinical response of the patient to treatment. Direct feedback provides several benefits—a means for the patient/caregiver to become familiar with, and sensitized to, satisfactory versus poor control of asthma; a reference point from which to evaluate deteriorating asthma; and an indicator of changes in asthma control in response to changes in treatment. The strategy of culturally appropriate direct feedback of clinical outcomes to physicians about specific health care results of their patients may be important for general practitioners who treat many diseases in addition to asthma and thus could not be expected to know guidelines in detail and handle patients accordingly.

See Chapter 5, "Implementation of Asthma Guideline in Health Systems," in the original guideline document for a discussion of the economic value of interventions and guideline implementation in asthma and dissemination and implementation resources.

For information about availability, see the "Availability of Companion Documents" and "Patient Resources" fields below.

Disclosures for members of Global Initiative for Asthma (GINA) Executive and Science Committees can be found at: http://www.ginasthma.com/Committees.asp?l1=7&l2=2.

In an effort to keep the GINA Workshop report as up to date as possible, a GINA Science Committee has been established to review published research on asthma management and prevention, and to post yearly updates on the GINA Web site. See the GINA Web site for archived versions of the GINA guidelines.

Electronic copies: Available in Portable Document Format (PDF) from the Global Initiative for Asthma (GINA) Web site.

Print copies: Available from the National Heart, Lung, and Blood Institute (NHLBI), Information Center, P.O. Box 30105, Bethesda, MD 20824-0105 and the Global Initiative for Asthma Secretariat, Professor Jean Bousquet, Service des Maladies Respiratoires, Hopital Arnaud de Villeneuve, 34295, Montpellier, Cedex 5, France

• Pocket guide for asthma management and prevention. Bethesda (MD): Global Initiative for Asthma, National Heart, Lung, and Blood Institute, 2007. Electronic copies: Available from the Global Initiative for Asthma (GINA) Web site.
• Pocket guide for asthma management and prevention in children. Bethesda (MD): Global Initiative for Asthma, National Heart, Lung, and Blood Institute, 2006. Electronic copies: Available from the Global Initiative for Asthma (GINA) Web site.
• GINA teaching slide set. Bethesda (MD): Global Initiative for Asthma, National Heart, Lung, and Blood Institute, 2006. Electronic copies: Available from the Global Initiative for Asthma (GINA) Web site.
• GINA guidelines at-a-glance desk reference. Global Initiative for Asthma, National Heart, Lung, and Blood Institute, 2006. Electronic copies: Available from the Global Initiative for Asthma (GINA) Web site.
• Guideline available in various translations: Electronic copies: Available from the Global Initiative for Asthma (GINA) Web site.
• Other resources. Electronic copies: Available from the Global Initiative for Asthma (GINA) Web site.
• A new table showing current combination therapies will be prepared, posted on the Global Initiative for Asthma (GINA) Web site, and updated as new formulations become available.

Print copies: Available from the National Heart, Lung, and Blood Institute (NHLBI), Information Center, P.O. Box 30105, Bethesda, MD 20824-0105 and the Global Initiative for Asthma Secretariat, Professor Jean Bousquet, Service des Maladies Respiratoires, Hopital Arnaud de Villeneuve, 34295, Montpellier, Cedex 5, France

• You can control your asthma. GINA patient guide. Bethesda (MD): Global Initiative for Asthma, National Heart, Lung, and Blood Institute, 2007 Jun. Electronic copies: Available from the Global Initiative for Asthma (GINA) Web site.

Print copies: Available from the National Heart, Lung, and Blood Institute (NHLBI), Information Center, P.O. Box 30105, Bethesda, MD 20824-0105 and the Global Initiative for Asthma Secretariat, Professor Jean Bousquet, Service des Maladies Respiratoires, Hopital Arnaud de Villeneuve, 34295, Montpellier, Cedex 5, France

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