Managing Severe Exacerbations of Asthma

Emerg Med 38(4):20-32, 2006

What are the critical differentials for a patient who appears to be having an asthmatic crisis? When is a chest X-ray justified? How do functional assessment results and arterial blood gas measurements correlate with severity? Exactly what are the options for pharmacotherapeutic rescue, and which nonstandard therapies are worth considering? What are the best ways to prevent short-term relapse? The authors address these and other issues.

By Joseph John, MD, PhD, and Steven Idell, MD, PhD, FCCP

The 1997 Expert Panel Report 2 from the National Asthma Education and Prevention Program details principles and goals for managing asthma exacerbations, based on the scientific literature and the opinions of the panelists. In this article, we will summarize the panel’s recommendations and present practical approaches to the evaluation and management of patients with asthma exacerbations. Methods for assessing and classifying the severity of asthma exacerbations, which will help define treatment objectives and facilitate patient disposition, will be discussed. Lastly, a review of pharmacologic agents used in the treatment of asthma exacerbations will be provided.

MAJOR HEALTH PROBLEM

Bronchial asthma remains a major health problem in the United States, and asthma exacerbations are a common cause of morbidity and mortality. From 1980 to 1996, the prevalence of asthma increased among all age, sex, and racial groups. Mortality due to asthma also increased throughout the Western hemisphere from 1940 to 1990 despite a better understanding of the pathophysiology of the illness.

Acute severe asthma accounts for two million emergency department visits, 500,000 hospital admissions, and 5,000 deaths annually in the United States. Data from the last decade, however, indicate that the mortality rate may have plateaued or even started to decline.

Bronchial asthma is characterized by the triad of airway hyperresponsiveness, reversible airflow limitation, and chronic inflammation in the submucosa of the airways. An acute exacerbation of asthma is associated with worsening shortness of breath and usually with signs of airway obstruction and deranged objective measures of pulmonary function. Depending on the severity of asthma symptoms, signs, and objective data, an asthma exacerbation can be classified as mild, moderate, or severe. During the course of the illness or treatment, the patient may move from one classification to another.

Airway inflammation is the cardinal pathologic feature of asthma. The airways are characteristically infiltrated with mast cells, eosinophils, T-lymphocytes, macrophages, and neutrophils. Activation of these cells and production of potent mediators of inflammation cause exudation of mucus that obstructs the airways. In susceptible subjects, these inflammatory events precipitate recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. Pulmonary function measurements reveal airflow obstruction that can vary in severity and is often reversible.

PATIENT PRESENTATION

The classic symptomatic triad of asthma is cough, dyspnea, and wheezing. The cough may be dry or productive of tenacious mucus. Patients may have a sensation of chest constriction. Mental acuity and the ability to talk should be assessed. If the patient can speak, a brief history should detail the onset and duration of symptoms, previous hospitalizations, and need for mechanical ventilation. Key points to be elicited from the history include aggravating factors, exacerbation profile, family and social history, risk factors for death (see box), and personal best spirometric variables if the patient is engaged in a self-monitoring plan.

Upper respiratory tract infections (usually viral) and exposure to allergens are thought to be the most common triggers of severe asthma exacerbations. Increased airway responsiveness secondary to infection may last from two to eight weeks. Exercise, stress, aspirin, indoor antigens, nonsteroidal anti-inflammatory drugs, sulfites, endocrine factors, multiple pharmaceutical and occupational agents, and other inhaled irritants can also lead to an exacerbation. The history can often reliably identify causative factors.

The physical examination should include the degree of respiratory distress, as reflected by respiratory rate, use of accessory muscles, vital signs, and pulsus paradoxus, which is defined as a difference between inspiratory and expiratory systolic blood pressure of more than 10 mm Hg. As dyspnea progresses, the patient will typically start to use accessory muscles and maintain an upright position, and expiration will become more prolonged. A silent chest and the absence of audible wheezing usually indicate severe airway obstruction. Conversely, the development of wheezing in a patient with a silent chest usually indicates improved airflow. Percussion may reveal hyperresonance.

Tachycardia may occur with the onset of respiratory failure. Development of bradycardia and bradypnea associated with hypoxemia during the course of management of acute severe asthma is an ominous sign. A pulsus paradoxus of more than 12 mm Hg is also commonly found in the late stages of an exacerbation.

RESOLUTION OF EXACERBATIONS

Most acute asthma exacerbations resolve spontaneously or within minutes to hours of the initiation of appropriate treatment. However, the mortality rates for acute severe asthma differ markedly by ethnicity and race, with the highest case fatality rates reported among black men who live in the inner cities. Asthma symptoms and signs that have a rapid onset and progress quickly are more serious and generally require closer attention and more acute intervention than symptoms with a more gradual onset and progression. Unfortunately, risk factors for death are present in less than half of the patients who die from acute severe asthma. Most asthma deaths occur at home or en route to the hospital, highlighting the fact that the primary reason for death from asthma is the delay in seeking medical attention.

In evaluating patients with acute shortness of breath and putative asthma, it is important to remember that certain findings in bronchial asthma are common to other conditions. Absence of breath sounds may indicate the presence of pneumothorax, aspiration of a foreign body, atelectasis, or hypoventilation. Localized wheezing may be associated with foreign body aspiration, bronchial tumors, mucus plugging, endobronchial obstruction or, rarely, pulmonary embolism. Wheezing may be more generalized in congestive heart failure or vocal cord dysfunction. Crackles may indicate mucus plugging, pneumonia, or atelectasis. A complete evaluation of a patient with an asthma exacerbation includes the identification of other diseases that may affect asthma (such as rhinitis, allergic rhinitis, and sinusitis) and evaluation for complications of asthma (such as pneumonia, pneumothorax, and pneumomediastinum).

FUNCTIONAL ASSESSMENT

Lung function assessments may be done to document a decrease in expiratory airflow. They are most commonly accomplished using a peak flow meter, which provides a rapid, objective evaluation of lung function and sequential measurements that help to determine response to treatment. Patient cooperation is essential for these tests to be reliable.

Functional assessments that are helpful include peak expiratory flow rate (PEFR), forced expiratory volume in one second (FEV₁), room air arterial blood oxygen saturation (SaO₂), and room air partial pressure of arterial oxygen and carbon dioxide (PaO₂ and PaCO₂). The PEFR and FEV₁ are the best tests to determine the severity of an asthma attack, assess response to treatment, and determine the need for admission. These tests should be done on all patients who have had an acute asthma attack and are able to perform the required maneuvers.

The PEFR is defined as the maximum flow rate that can be sustained during a forced expiration starting from total lung capacity. The FEV₁ is defined as the volume of air forcibly exhaled in one second starting from total lung capacity. When classifying asthma severity using PEFR or FEV₁ values expressed as a percentage of personal best, it is important to consider the effect of irreversible airflow obstruction. For example, for a patient whose best PEFR is 160 L/min, a fall of 40% represents severe, potentially life-threatening airflow obstruction. An FEV₁ or peak flow of less than 50% of predicted or personal best has been defined as a severe exacerbation of asthma, according to NIH guidelines for the diagnosis and management of asthma.

Predicted norms for PEFR and FEV₁ are based on age, sex, and weight and are available in tabular form. These measurements are not applicable to moribund patients or those who are cyanotic or exhausted or who otherwise appear to be confused.

Pulse oximetry is a useful and convenient technique for assessing oxygen saturation during treatment, but it should be used in conjunction with other tools. The main reason to determine arterial blood gas (ABG) levels during an asthma exacerbation is to assess for the presence of hypoventilation with carbon dioxide retention and respiratory acidosis. It is important to note that because respiratory drive typically increases during asthma exacerbations, a “normal” PaCO₂ value of 40 mm Hg or a “normal” pH indicate severe airflow obstruction and a heightened risk of respiratory failure. Hypercapnia generally develops only when the FEV₁ is less than 25% of predicted.

Infants require special attention due to the relatively limited assessment options and their greater risk for respiratory failure during severe asthma exacerbations. Assessment of infants should focus on the physical examination. A respiratory rate above 60 breaths/min, use of accessory respiratory muscles, the presence of thoracic indrawing or thoracoabdominal asynchrony and cyanosis are key signs of serious distress in infants. It is particularly important to monitor SaO₂ by pulse oximetry in infants because their ventilation-perfusion characteristics cause them to become hypoxemic more readily than adults.

Decreased oxygen saturation is often an early sign of severe airway obstruction, and an SaO₂ below 91% is a good predictor of the need for hospitalization of small asthmatic infants. Capillary or ABG measurements should be performed in infants suspected of having respiratory failure. As with adults, an infant or child with a severe asthma exacerbation who has a normal PaCO₂ value is at high risk for respiratory failure.

SERIAL ASSESSMENTS

Serial assessments of a patient’s symptoms and airflow over time and after treatment are important. Measurements of PEFR (or FEV₁) should be made before bronchodilator therapy and again 15 to 20 minutes afterward during an acute exacerbation, and then at least daily until improvement occurs. Airflow values below 30% of predicted (or less than 100 L/min in an adult) that improve by less than 10% after bronchodilator therapy or that fluctuate widely over a 24-hour period indicate an increased risk of life-threatening deterioration and call for aggressive management. Dysphonia, inspiratory stridor, central wheezing, normal ABG values, and complete resolution of airflow obstruction with intubation may be present in patients with central airflow obstruction. These patients should be further evaluated by flow-volume curves and laryngoscopy.

A chest x-ray is only a complement to clinical assessment and should be obtained to rule out pneumonia or a suspected complicating cardiopulmonary process such as pneumothorax, pneumomediastinum, lobar atelectasis, or congestive heart failure. Hyperinflation on one side may suggest foreign body obstruction. While central airway obstruction is often difficult to document, frontal and lateral chest x-rays may suggest its presence.

Additional laboratory testing can be helpful in management or can suggest the presence of alternative diagnoses. Patients on theophylline should have their serum theophylline level measured. A complete blood cell count will likely show modest leukocytosis secondary to administration of a beta-2 agonist or corticosteroid or due to an underlying infection. An elevated D-dimer level in plasma may suggest pulmonary embolism. A combination of radiographic findings, elevated beta-type natriuretic peptide level, and the history may aid in the diagnosis of congestive heart failure. A routine ECG is generally not necessary but may reveal right ventricular strain or abnormal P waves or ST-T changes that resolve with treatment. Interestingly, asthma index scores have failed to predict outcome better than clinical judgment.

An important step in the development of a treatment plan is the classification of the severity of an asthma exacerbation. A combination of patient symptoms and signs and functional assessments can be used to classify asthma exacerbations into the general categories of mild, moderate, severe, and impending respiratory failure (see table). These classifications should be used only as general guidelines; more study is needed to determine how accurately the parameters can be used to predict asthma exacerbations. Not all criteria for a given severity level may be present in a patient at a given time.

 

Classification of Severity of Asthma Exacerbations   Mild Moderate Severe Impending respiratory failure breathlessness with activity with talking at rest at rest speech sentences phrases words mute body position able to recline prefers sitting unable to recline unable to recline respiratory rate increased increased often >30/min often >30/min use of accessory respiratory muscles inactive active active paradoxical thoracoabdominal movement wheezing at mid- to end expiration throughout expiration during inspiration and expiration little air movement, no wheezing heart rate <100/min 100-120/min >120/min relative bradycardia pulsus paradoxus (mm Hg) <10 10-25 often >25 in adults; 20-40 in children often absent mental status may be agitated usually agitated usually agitated confused or drowsy PEF (% predicted or personal best) >80 50-80 <50 (or response to therapy lasts <2 hrs) <50 SaO2 (%, room air) >95 91-95 <91 <91 PaO2 (mm Hg, room air) normal >60 <60 <60 PaCO2 (mm Hg) <42 <42 ≥42  ≥42 Source: The National Asthma Education and Prevention Program. Expert Panel Report 2. Guidelines for the Diagnosis and Management of Asthma. 1997; NIH publication 97-4051.

TREATMENT OF ACUTE SEVERE ASTHMA

Severe exacerbations of asthma can be life-threatening. Treatment should be started as soon as a severe exacerbation is recognized and an assessment of lung function is made. Early intervention may lessen the severity and duration of an exacerbation. Clinicians treating patients with asthma exacerbations should be familiar with the characteristics of patients at risk for life-threatening deterioration. All patients with a severe exacerbation should immediately receive oxygen, high doses of an inhaled, short-acting, beta-2 adrenergic agonist, and systemic corticosteroids. A brief, focused history pertinent to the exacerbation can be completed while treatment is given. More detailed assessments usually add little in the early phase of management.

Because severe asphyxia is a common cause of death, oxygen therapy is extremely important. Supplemental oxygen should be given to maintain SaO₂ above 90% or PaO₂ above 60 mm Hg. Concern over oxygen-induced hypoventilation is not warranted; in fact, the goal is to oxygenate effectively even at the expense of ventilation. Rapid reversal of airflow obstruction should be attempted by using repetitive or continuous administration of an inhaled, short-acting, beta-2 adrenergic agonist. Frequent, high-dose delivery of such an agent is indicated and is usually well tolerated in severe airway obstruction.

While some studies suggest that continuous therapy is more effective than intermittent administration of short-acting beta-2 adrenergic agonists, there is no clear consensus as long as similar doses are administered. Continuous-flow nebulization of albuterol generally translates to about 7.5 to 10 mg of the drug over one hour. While the precise dose equivalent is uncertain, the effectiveness of 4 to 10 puffs of albuterol delivered from a metered-dose inhaler (MDI) via an inhalation device is generally considered to be equivalent to one nebulizer treatment. Ipratropium can be nebulized along with the beta-2 agonist.

At least three MDI or nebulizer treatments should be given in the first hour of therapy. Thereafter, the frequency of administration varies according to improvement in airflow and associated symptoms and side effects.

Because of the immediately life-threatening nature of severe asthma exacerbations, all patients with serious exacerbations should be treated in the emergency department, where they can receive prompt therapy and careful monitoring. Prevention of recurrent severe airflow obstruction is best achieved by intensifying overall asthma care. A short course of systemic corticosteroids is necessary. The medications that are typically administered during acute exacerbations of asthma are summarized in the table below.

Serial monitoring of patients with severe exacerbations should be made after the initial dose of inhaled bronchodilator and again after three more doses have been administered (60 to 90 minutes after treatment is initiated). The response to initial treatment is a better predictor of the need for hospitalization than the severity of an exacerbation on initial presentation. For adults, improvement in PEFR or FEV₁ after 30 minutes of treatment correlates significantly with several alternative indicators of severity. Repeated measurement of airflow in the emergency department can be used to assess the need for hospital admissions for asthma exacerbations.

PATIENT DISPOSITION

Decisions regarding patient disposition should take into consideration a combination of subjective parameters such as resolution of wheezing and improved gas exchange as assessed by auscultation, objective measures such as PEFR or FEV₁, and factors such as compliance and history of emergency department visits and hospitalizations. The ideal combination of factors needed for a successful discharge with minimal risk of early relapse has not yet been determined. Some degree of residual airflow obstruction, airway lability, and inflammation persist after treatment in the emergency department and after discharge. However, adult patients with a PEFR above 300 L/min may generally be discharged home.

Patients with an incomplete response to therapy (PEFR or FEV₁ at or more than 50% but less than 70% of predicted or personal best) and with mild symptoms should be assessed individually to determine whether it is appropriate to send them home. Most asthmatics treated in the emergency department fall into this category. The decision to discharge or hospitalize a patient should be based on the duration and severity of symptoms, severity of airflow obstruction, course and severity of prior exacerbations, medication use at the time of the exacerbation, access to medical care and medications, adequacy of social support and home conditions, and the presence of psychiatric illness.

Although beta-2 agonists and corticosteroids help reduce relapse among patients discharged from the emergency department, patients with a history of previous emergency department visits and hospitalization remain at highest risk for relapse regardless of management and medications prescribed for home use. No single treatment program can be recommended for all patients discharged from the emergency department.

Once the patient’s PEFR or FEV₁ has returned to 70% of predicted or personal best or higher (or more than 300 L/min in an adult patient) and the response is sustained 60 minutes after the last treatment and associated with a normal physical examination, the patient may be discharged home. Interventions to be initiated in the outpatient setting include inhaled beta-2 agonists, a course of oral steroids, patient education, and review of medication use.

A recommendation for close medical follow-up should be made. Follow-up care should be arranged to ensure resolution of symptoms and to review the long-term medication plan for the management of chronic asthma. High relapse rates despite the routine use of corticosteroid treatment strongly suggest the need for follow-up within days of the initial visit. Patients must have an appropriate written plan of action that provides instruction for effectively conducting self-assessment, maintains routine care, and includes an action plan for managing recurrence of airflow obstruction. Education about discharge medications and their appropriate use, inhaler technique, and PEFR monitoring are issues that physicians must review with patients before discharge.

While inhaled bronchodilator therapy may provide sufficient short-term symptomatic relief, corticosteroids appear to have the greatest potential to limit the acute airway hyperresponsiveness associated with recurrences of asthma. Referral to an asthma specialist for consultation should be considered for patients with frequent exacerbations or for those who have required emergency or hospital care.

Current guidelines to help determine hospitalization versus discharge are based on patient response to aggressive treatment. Patients with a poor response to treatment are those with persistent symptoms and a PEFR or FEV₁ below 50% of predicted values or personal best measurements. An exacerbation in these patients is classified as severe; it is usually associated with severe symptoms and accessory muscle use. This scenario typically results from a combination of worsening airflow obstruction and respiratory muscle fatigue and indicates impending respiratory failure. These patients can deteriorate rapidly and should be admitted and closely monitored in a critical care setting. An inhaled, short-acting, beta-2 adrenergic agonist should be continued hourly, along with an inhaled anticholinergic. Oxygen and systemic steroid therapy should also be continued.

In children and infants, the response to beta-2 adrenergic agonist therapy can be variable and is a relatively unreliable predictor of improvement. Because of their increased risk of respiratory failure, infants who do not quickly respond to treatment should be hospitalized for close monitoring and treatment.

When the decision to admit a patient has been made, the next key decision is whether the patient should be admitted to an intensive care unit (ICU). At the time of admission, certain clinical features are predictive of poor outcome and can be used to triage patients to general inpatient or intensive care. Critically ill asthmatic patients should be cared for in an ICU that is appropriate to the patient’s age. Alterations in mental status or indicators of respiratory dysfunction are reliable harbingers of respiratory failure and provide a strong justification for ICU admission (see box).

NONINVASIVE POSITIVE PRESSURE VENTILATION

When a patient with a severe exacerbation of asthma is admitted, noninvasive positive pressure ventilation (NIPPV) may be considered to alleviate respiratory distress and avoid the need for mechanical ventilation. When the patient’s PEFR or FEV₁ decreases to 50% of baseline, there is an associated 7- to 10-fold increase in inspiratory muscle work. At this point assisted ventilation may be required. Noninvasive positive pressure ventilation has been shown to decrease the work of breathing, improve oxygenation, and reduce the need for intubation. Continuous positive airway pressure decreases the work of breathing, causes bronchodilatation, reexpands atelectatic lungs, promotes removal of secretions, and relaxes the inspiratory muscles; it also offsets intrinsic positive end-expiratory pressure (PEEP) and decreases the adverse hemodynamic effects of large, negative, inspiratory pleural pressures.

Noninvasive positive pressure ventilation should be tried in alert, cooperative patients, before intubation, when they have not improved with aggressive medical therapy. It should generally not be used in patients who are unresponsive, confused, rapidly deteriorating, hemodynamically unstable, or otherwise unable to protect their airway or those who have excessive mucus production.

Despite the physician’s best efforts to manage acute severe asthma, symptoms may worsen and respiratory arrest may become imminent. The timing of intubation is one of clinical judgment. Fortunately, less than 1% of asthmatic patients require mechanical ventilation. A high PaCO₂ alone is not an indication for intubation, especially if the patient is alert and cooperative. The true criteria for intubation and mechanical ventilation are detailed in the box.

Patients meeting these criteria for intubation should be intubated as soon as it is deemed necessary, regardless of the setting. (Direct oral intubation is preferred over the nasotracheal route.) Patients who present with apnea or coma should be intubated immediately. Similarly, endotracheal intubation should not be delayed; it is recommended for airway protection and for patients who present with altered mental status or shock. Intubation of a critically ill asthma patient is difficult and is best done semi-electively, before the crisis of a respiratory arrest, in a controlled setting and by a physician with extensive experience in intubation techniques and airway management.

At the time of intubation, close attention should be paid to maintenance or replacement of intravascular volume because hypotension commonly occurs when the patient is sedated and positive pressure ventilation is initiated. Also, these patients are often already dehydrated due to poor oral intake.

GOALS OF MECHANICAL VENTILATION

The main goals of mechanical ventilation are to ensure adequate oxygenation and to avoid barotrauma. Plateau airway pressures are generally kept below 35 cm H₂O and peak pressures below 50 cm H₂O. Severe airflow obstruction will prolong expiratory time, resulting in dynamic hyperinflation. These patients must be ventilated with low tidal volumes (6-8 ml/kg), rapid flow rates, and a reduced respiratory rate (6-8/min) that allows more time for expiration and a low inspiratory-expiratory ratio. Intrinsic PEEP should be limited, if possible, to less than 10 cm H₂O; it may be added to reduce the work of breathing and adjusted to the value of auto-PEEP.

Permissive hypercapnia may be employed with severe airway obstruction without concern for normalizing the hypercapnic acidosis. Arterial pH should be maintained above 7.2. Sodium carbonate must be avoided because it eventually increases intracellular carbon dioxide and acidosis attributable to a fixed rate of carbon dioxide elimination.

USE OF OXYGEN AND BRONCHODILATORS

Oxygen, bronchodilators, and anti-inflammatory drugs can be used to treat most asthma exacerbations, regardless of severity. The table on page 25 lists the dosages of drugs for asthma exacerbations that require emergency care or hospitalization. The review of medications should provide an opportunity to advise the patient about their appropriate use and to address any questions the patient may have about these agents. The toxicity and adverse effects of these medications should be discussed with the patient and outpatient personnel who may assist with management.

Supplemental oxygen therapy should be given to all patients with symptoms of a moderate-to-severe asthma exacerbation until an accurate assessment of their arterial oxygenation can be made. Patients who are hypoxemic (SaO₂ at or below 90% or PaO₂ below 60 mm Hg) should receive supplemental oxygen to maintain SaO₂ levels above 90% or PaO₂ levels above 60 mm Hg. Pregnant women and patients with heart disease should have their SaO₂ levels maintained above 95%. Oxygen may be delivered via nasal cannula or face mask. In more severe asthma exacerbations, endotracheal intubation and mechanical ventilation may be required to deliver the high fractions of inspired oxygen that may be needed to achieve target levels of oxygenation.

Bronchodilators have been shown to be an effective primary treatment for all patients with asthma exacerbations. Short-acting beta-2 adrenergic agonists, anticholinergic agents, and methylxanthines have been thoroughly evaluated in this patient population. Short-acting beta-2 adrenergic agonists are the most effective bronchodilators for treating asthma exacerbations and should be used in all patients. The medical literature does not support use of one agent over another based on efficacy. However, given concerns about cardiotoxicity, beta-2-selective agents should be used because they produce less cardiac stimulation than agents that have mixed beta-1 or -2 effects. Currently available short-acting beta-2-selective adrenergic agonists include albuterol, terbutaline, pirbuterol, and bitolterol. Salmeterol, a long-acting beta-2 adrenergic agonist, should not be used for the primary treatment of exacerbations of asthma; its properties render it more applicable as an agent for maintenance of asthma control.

Inhaled beta-2 adrenergic agonist therapy is as effective as oral or parenteral therapy in relaxing airway smooth muscle and improving acute asthma attacks. It offers the advantages of rapid onset of action (less than five minutes) and fewer systemic side effects. In addition, repetitive administration produces incremental bronchodilatation. Intravenous (IV) and subcutaneous routes of administration should be reserved for patients who are unable to inhale medications. Occasionally, parenteral agents may be required when very severe airflow obstruction limits delivery of inhaled agents and the patient is not responding. However, a number of studies suggest that patients who do not respond to inhaled beta-2 adrenergic agonist therapy remain unresponsive when treated with the same agent via the parenteral route.

WET NEBULIZATION VERSUS MDIs

There is a mistaken impression that wet nebulization offers more effective delivery of beta-2 adrenergic agonists than MDIs. This misunderstanding is in part attributable to differences in drug delivery contingent on the delivery method. With most beta-2 adrenergic agonists, the recommended dose by nebulizer for acute asthma (albuterol, 2.5 mg) is 25 to 30 times that delivered by a single activation of an MDI (albuterol, 0.09 mg). Although direct comparison of these doses is not possible due to differences in the delivery method and patient respiration patterns, many practitioners assume the significantly smaller standard dose from an MDI will be insufficient. Nevertheless, studies show that equivalent bronchodilatation can be achieved by either high doses (6 to 12 puffs) of a beta-2 adrenergic agonist delivered by an MDI with an inhalation chamber, under the supervision of trained personnel, or by nebulizer therapy. Nebulizer therapy may be more effective, however, in patients who are unable to coordinate inhalation of medication from an inhaler because of age, agitation, or symptom severity.

There is no standard dose of a beta-2 agonist for patients who present with acute severe asthma. The dose should be based on the patient’s symptoms and measured response to treatment. The initial dose may be as high as four to eight puffs from an MDI every 15 to 20 minutes or two 5-mg treatments with nebulized albuterol given at 40-minute intervals. Levalbuterol, an R-isomer of racemic albuterol, has all the pharmacologic bronchodilator properties of racemic albuterol and may be as effective, with fewer side effects. The S-isomer may increase airway reactivity and hyperresponsiveness and may have proinflammatory effects. The S-isomer is metabolized 10 times more slowly than levalbuterol and may accumulate with frequent dosing.

Beta-2 adrenergic agonists used today have predominant beta-2 specificity compared to older catecholamines such as isoproterenol and epinephrine. A spacer device attached to the inhaler can improve drug deposition. Dry powder delivery devices and MDIs using hydrofluoroalkane as a propellant have recently replaced chlorinated fluorocarbon-driven devices. Patients who cannot tolerate or are unable to use inhalation therapy may have parenteral epinephrine (0.3 to 0.5 mg subcutaneously every 20 minutes for three doses) or terbutaline (0.25 mg subcutaneously every 20 minutes for three doses). Despite potential concerns, significant cardiovascular side effects are uncommon.

Anticholinergic agents may be useful adjuncts to inhaled, short-acting, beta-2 adrenergic agonists and may be considered for patients with moderate-to-severe asthma exacerbations. Ipratropium is a quaternary anticholinergic agent that limits its systemic absorption and side effects. It does not increase heart rate, a relative advantage supporting its use. High doses of inhaled ipratropium bromide (0.5 mg in adults, 0.25 mg in children) may cause additional bronchodilatation in some patients with severe airway obstruction and has led to an important reduction in hospital admission rates. Ipratropium may be mixed in the same nebulizer as albuterol and is given 0.5 mg every 30 minutes for three doses, then every two to four hours as needed. Ipratropium may be administered by an MDI (four to eight puffs every two to four hours as needed).

TREATMENT WITH ANTI-INFLAMMATORY AGENTS

Anti-inflammatory agents are an effective primary treatment for patients with moderate-to-severe exacerbations or for patients who fail to respond promptly and completely to inhaled beta-2 adrenergic agonist therapy. They may also be useful for patients with less severe exacerbations. Corticosteroids are the most important anti-inflammatory agents.

Inhaled corticosteroids. Generally very beneficial in all patients with asthma exacerbations, inhaled corticosteroids increase airway caliber and decrease bronchial hyperreactivity and appear to work more rapidly and sometimes more effectively than systemic corticosteroids. However, the maximum response from inhaled corticosteroids may not be observed for months, so immediate initiation of therapy and consistent use are necessary. Patients should be counseled about the importance of complying with instructions for regular, uninterrupted use of inhaled corticosteroids, even when their symptoms appear to be improving.

Patients with asthma exacerbations who are not taking inhaled corticosteroids should be started on an inhaled agent, and patients who are already using inhaled corticosteroids should be instructed to increase the dose. Because of limited data directly comparing the available inhaled corticosteroids and individual patient variability, the most important determinants of agent selection and appropriate dosing are the clinician’s judgment of the patient’s status and response to treatment.

Systemic corticosteroids. Systemic corticosteroids are recommended for patients with moderate-to-severe exacerbations and those who fail to respond promptly and completely to inhaled beta-2 adrenergic agonist therapy. These agents are a mainstay of treatment for severe, life-threatening asthma. Although their mechanism of action is not completely understood, many believe that corticosteroids restore beta-2 adrenergic responsiveness and reduce airway inflammation. Systemic corticosteroids appear to speed up the resolution of airflow obstruction and reduce the rate of relapse. As with inhaled corticosteroids, prompt initiation of therapy during the course of an exacerbation is important to gain maximum benefit, especially in infants and children.

Oral corticosteroids should be available for early administration at home in properly educated patients with asthma. Administration of a corticosteroid within one hour of arrival in the emergency department reduces the need for hospitalization. Oral administration of corticosteroids produces results identical to those of IV administration when the total daily dose is comparable. The onset of action is delayed for at least four to eight hours following IV or oral administration. However, it may be prudent to administer corticosteroids to a critically ill patient intravenously to avoid concerns about altered gastrointestinal absorption and to keep the stomach empty in case the patient eventually needs to be intubated.

The minimal effective dose of a systemic corticosteroid for asthma patients has not been identified. Outpatient prednisone “burst” therapy is typically 40 to 60 mg/day in a single dose or two divided doses for adults (for children, 1 to 2 mg/kg/day up to a maximum of 60 mg/day) for 3 to 10 days. Severe exacerbations typically require 120 to 180 mg/day of methylprednisolone equivalents administered in three or four divided doses for adults (for children, 1 mg/kg every six hours) for at least 48 hours or longer if the PEFR or FEV₁ has not returned to at least 50% of predicted or personal best. The dose is then decreased to 60 to 80 mg/day for adults (for children, 1 to 2 mg/kg/day up to a maximum of 60 mg/day in two divided doses) until the PEFR reaches 70% of predicted or personal best.

No clear advantage has been found for higher doses of corticosteroids in severe exacerbations, and there is no evidence that tapering the dose of an oral corticosteroid following symptom and airflow improvement prevents a relapse. Short-term therapy should continue until the patient achieves a PEFR at 80% of predicted or personal best. In our experience, it usually requires at least 3 to 10 days of therapy to achieve this objective. Current recommendations favor continuation of inhaled corticosteroids as maintenance for all patients with chronic asthma that is classified as mild persistent or more severe.

METHYLXANTHINES NOT RECOMMENDED

Methylxanthines are not generally recommended for the treatment of asthma exacerbations. Aminophylline has clearly been shown to be less effective than beta-2 adrenergic agonists when used as monotherapy for acute asthma and has the disadvantage of potential toxicity. For patients taking an agent containing theophylline, their serum theophylline concentration should be determined to exclude theophylline toxicity. Aminophylline is reserved for patients in whom other agents have failed. The National Heart, Lung, and Blood Institutes’ expert panel recommends that IV aminophylline not be administered for emergency management of asthma, except in what is considered a life-threatening asthma attack. Theoretically, aminophylline may be a useful adjunct, providing more sustained bronchodilatation, improved respiratory muscle endurance, and resistance to fatigue. Recent data suggest an anti-inflammatory mechanism of action.

Leukotriene-modifying drugs are either leukotriene receptor antagonists or inhibitors of leukotriene synthesis. When administered with corticosteroids, these drugs have a complementary anti-inflammatory effect and have been shown to reduce the need for hospitalization in patients with acute asthma. In a single trial, IV montelukast was demonstrated to cause rapid bronchodilatation when used as adjuvant therapy for acute asthma. However, additional studies are needed to determine the indications for and the dosages of these drugs when they are used in patients with severe asthma exacerbations.

Antibiotics are also not recommended for asthma treatment during asthma exacerbations, but they may be necessary for comorbid conditions. Bacterial, chlamydial, and Mycoplasma respiratory tract infections are thought to contribute only infrequently to exacerbations of asthma. The use of antibiotics should be reserved for patients with fever and purulent sputum and for those with evidence of pneumonia or suspicion of bacterial sinusitis. Clinicians must be aware that purulent sputum may not indicate infection but may be due to eosinophils in respiratory secretions.

Hydration, contrary to common belief, does not alter the viscosity of sputum and should be given only if clinically indicated. Because patients with acute exacerbations may have experienced poor intake prior to presentation, volume status should be assessed and hypovolemia treated accordingly.

Magnesium has bronchodilating effects in animals and may also increase the responsiveness of airway receptors that regulate bronchial tone. Patients receiving magnesium sulfate have demonstrated nonsignificant improvements in peak expiratory flow rates and FEV₁, but it does not reduce the overall hospital admission rate except in the most severe subgroup of treated asthmatic patients. However, no clinically important changes in vital signs or adverse effects have been reported.

Current evidence does not support the routine use of IV magnesium sulfate in all patients with acute asthma presenting to the emergency department. However, this agent appears to be safe and beneficial in patients who present with severe acute asthma. It should not be substituted for standard therapy. The dose is 1 to 2 grams IV over 30 minutes. Because magnesium is excreted principally by the kidneys, caution must used in patients with renal insufficiency. In such patients, serum magnesium levels should be monitored and a dose of the antidote calcium gluconate should be kept available to ameliorate magnesium toxicity.

OTHER MEDICATIONS

Other investigational agents have not yet been established as accepted therapy for patients with asthma exacerbations. Glucagon produces smooth muscle relaxation by stimulating cyclic AMP production and could theoretically be beneficial in asthmatic patients. Nitroglycerin may produce bronchodilatation in patients unresponsive to conventional agents through prostacyclin production and stimulation of adenyl cyclase. Calcium is an important trigger in the release of mast cell mediators in asthma. Calcium channel blockers prevent entry of calcium into the cell via voltage-dependent channels and may likewise facilitate bronchodilatation.

Changes in bronchial osmolarity can induce bronchoconstriction. Inhaled diuretics may be bronchoprotective by preventing changes in bronchial osmolarity. Heparin is a nonspecific blocker of inositol triphosphate receptors, by which mechanism it may modulate degranulation of mast cells and attenuate the bronchoconstrictor response in asthma. Through its effect on central and peripheral beta-2 adrenergic receptors, inhaled clonidine improves basal respiratory function and reduces inflammatory reactions induced by allergens in extrinsic asthma. Cromolyn and nedocromyl block chlorine channels, thus modulating mast cell mediator release and eosinophil recruitment. Their role is mainly preventive, and these agents are not indicated for acute exacerbations of asthma. Mucolytic agents, such as N-acetylcysteine and potassium iodide, should be avoided because they may worsen cough or airflow obstruction. Anxiolytic and hypnotic drugs are contraindicated in critically ill asthma patients because of their respiratory depressant effects.

General anesthetics have been used in cases of refractory asthma. Several inhalational anesthetics have intrinsic bronchodilator properties. Isoflurane decreases auto-PEEP and airway resistance. Ketamine causes bronchodilatation by endogenous catecholamine release. There is anecdotal data for the use of halothane, ether, droperidol, and enflurane. However, controlled studies substantiating improved results are lacking.

Helium is a low-density gas that lowers airway resistance, the work of breathing, and peak airway pressures in patients with bronchospasm. Considerable expertise is required, however, for helium administration. Studies have shown variable results and this agent cannot replace standard therapy. Extracorporeal membrane oxygenators are not indicated because oxygenation is usually not a problem in acute severe asthma. The data for bronchoscopy also is anecdotal; it may be used if a patient does not improve after several days of mechanical ventilation, especially if central airway obstruction is suspected or refractory lobar obstruction is noted on chest x-rays.

Suggested Reading Afzal M and Tharratt RS: Mechanical ventilation in severe asthma. Clin Rev Allergy Immunol 20(3):385, 2001. Beveridge RC, et al.: Guidelines for the emergency management of asthma in adults: CAEP/CTS asthma advisory committee. CMAJ 155(1):25, 1996. Chesnutt MS and Lazarus SC: Asthma therapy in the nineties: focus on inflammation. Hosp Formul 27(2):466, 1992. Corbridge TC and Hall JB: The assessment and management of adults with status asthmaticus. Am J Respir Crit Care Med 151(5):1296, 1995. Manthous CA: Management of severe exacerbations of asthma. Am J Med 99(3):298, 1995. Marik PE, et al.: The management of severe asthma. J Emerg Med 23(3):257, 2002. National Asthma Education and Prevention Program: Expert panel report 2: Guidelines for the diagnosis and management of asthma. National Heart, Lung, and Blood Institute, National Institute of Health. NIH publication 97-4051, 1997. National Asthma Education and Prevention Program: Guidelines for the diagnosis and management of asthma—update on selected topics 2002. National Heart, Lung, and Blood Institute, National Institute of Health. NIH publication 02-5075, 2002. Rudnitsky GS, et al.: Comparison of intermittent and continuously nebulized albuterol for treatment of asthma in an urban emergency department. Ann Emerg Med 22(12):1842, 1993. Rowe BH, et al.: Early emergency department treatment of acute asthma with systemic corticosteroids. Cochrane Database Syst Rev (1):CD002178, 2001. Turner MO, et al.: Risk factors for near fatal asthma: a case control study in hospitalized patients with asthma. Am Rev Respir Crit Care Med 157(6 pt 1):1804, 1997.