Managing acute severe asthma, part 1: What therapies to try, and when
The initial assessment of acute severe asthma includes confirmation of the diagnosis and rapid assessment of mental status and degree of respiratory distress. The severity of airflow obstruction is best determined by forced expiratory volume in 1 second or peak expiratory flow rate. While inhaled ß2-agonists are the initial therapy, the combination of ipratropium and a ß2-agonist can enhance results in some patients. There also is evidence that inhaled corticosteroids can lead to a more rapid improvement in pulmonary function. (J Respir Dis. 2007;28(2):57-64)
Acute asthma is a major problem in the United States and a common cause of morbidity and mortality. Despite numerous advances in the diagnosis and treatment of asthma, in the past 2 decades, the prevalence of this disorder worldwide has continued to increase. It is estimated that 2% to 12% of adults have asthma.1 In the United States, an estimated 17 million persons had asthma in 1998.2
Acute severe asthma accounts for almost 2 million emergency department (ED) visits, 500,000 hospital admissions, and 5000 deaths every year.3 Asthma mortality rates among children and adults in the United States and other Western nations increased from the 1940s to the 1990s despite an increased understanding of the pathophysiology of this clinical condition.2,4-7 Data suggest that in the past few years the mortality rate from asthma has reached a plateau and may be decreasing.8,9
In the United States, mortality rates for acute severe asthma differ markedly by region and ethnicity, with the highest case-fatality rates reported among black men who live in inner cities.5 Known risk factors for death from acute severe asthma include:
•Previous mechanical ventilation.
•Admission to an ICU.
•A history of recurrent hospitalizations for asthma.
Unfortunately, fewer than half of the patients who die of acute severe asthma have any of these risk factors.5,10 It has been estimated that the primary reason for death from asthma is the delay in seeking medical assistance, since most asthma deaths occur at home or in transit to the hospital.5,10-12
In this article, we will review the assessment and management of acute severe asthma. In a subsequent issue of The Journal of Respiratory Diseases, we will continue our review of treatment, including the indications for noninvasive positive pressure ventilation.
PATHOPHYSIOLOGY
By definition, asthma is a lung disease characterized by airway hyperresponsiveness, reversible expiratory airflow limitation, and chronic inflammatory changes in the submucosa of the airways.13,14 Acute severe asthma (status asthmaticus) has been defined by some as asthma that is life-threatening, does not respond to conventional therapy, and requires hospitalization.14-17 Many patients with asthma are "labeled" as having status asthmaticus when they do not respond to treatment with ß2-agonists, corticosteroids, and anticholinergics and have received invasive interventions, such as mechanical ventilation.18
The major component of acute severe asthma is airway inflammation and mucous plugging.19,20 Autopsies of patients who died of acute severe asthma reveal proteinaceous materials in the airways; mucosal and submucosal edema; and eosinophils, neutrophils, plasma cells, and lymphocytes infiltrating small airways.21 The number of neutrophils found in the airways has been correlated with the sudden onset of fatal asthma.22,23 In patients with a large number of neutrophils in the bronchial mucosa, the airways tend to be "dry" as opposed to "plugged" (Figure).
Although the exact mechanisms by which an acute asthma episode is initiated and perpetuated are not completely understood,20 cell activation and production of potent mediators of inflammation are believed to be central to the pathophysiology of asthma. Almost all of the inflammatory cells in the bronchial wall and lumen have been implicated in the pathogenesis of mucosal inflammation in asthma.
ASSESSMENT
The initial assessment and management of an acute severe asthma episode occur simultaneously and include:
•Confirmation of the diagnosis of acute severe asthma.
•A brief history, whenever possible, with attention to the onset and duration of symptoms and history of previous exacerbations (provided the patient can speak).
•Rapid assessment of mental status and degree of respiratory distress (reflected by respiratory rate, use of accessory muscles, vital signs, pulsus paradoxus, and sympathetic tone).
Signs and symptoms
The classic triad of asthma is wheezing, cough, and dyspnea.14 However, patients with acute severe asthma may present with any combination of these symptoms--or with none of them. The presence of audible wheezing correlates poorly with the degree of airflow limitation.24-27 In fact, a silent chest may be a sign that there is insufficient ventilation and airflow for wheeze to occur. The development of wheezing in a patient who had a silent chest generally indicates improved airflow. In contrast, areas of localized wheezing or crackles on chest auscultation may represent mucous plugging or atelectasis, pneumonia, pneumothorax, endobronchial lesions, or a foreign body.13
In patients with acute severe asthma, cough may range from nonproductive to productive with tenacious mucoid sputum that is very difficult to clear. As airflow obstruction increases, the use of accessory muscles and an upright sitting position may be observed in some patients. In many studies and in our personal experience, the symptoms and clinical signs of acute severe asthma may provide a poor indication of the severity of airway obstruction and should not be used as the only means of assessing obstruction.13,24-27
Possible complications of acute severe asthma include subcutaneous emphysema in the case of barotraumas or unilateral breath sounds in pneumothorax or in major bronchi mucous plugging.28
Vital signs may not be reliable indicators of the severity of illness in patients with acute severe asthma. Although tachycardia initially occurs in most patients, the heart rate decreases with the development of hypoxemia; this is an ominous sign. The same principle applies to the respiratory rate. A pulsus paradoxus of more than 12 mm Hg is found in most patients in the late stages of an acute severe asthma exacerbation.
Spirometry
To assess the severity of airway limitation, clinicians must rely on spirometric maneuvers in patients who can perform them. Many patients may have near-normal physical findings and yet show clinically important signs of airflow limitation on spirometric evaluation. Similarly, changes in clinical signs after bronchodilator treatment do not always reflect changes in spirometric results.13
The forced expiratory volume in 1 second (FEV1) and the peak expiratory flow rate (PEFR) are direct reflections of the severity of airflow obstruction and are the standard measures used in emergency situations to assess the severity of airflow obstruction.14,24,29,30 Patients who present to the hospital with an acute severe asthma exacerbation usually have an FEV1 between 30% and 80% of predicted.14,31
The NIH Guidelines for the Diagnosis and Management of Asthma (National Asthma Education and Prevention Program [NAEPP] guidelines) have defined a moderate exacerbation of asthma as an FEV1 or PEFR of 50% to 80% of predicted or personal best and a severe exacerbation as an FEV1 or PEFR of less than 50% of predicted or personal best.14 FEV1 and PEFR measurements are not needed in moribund patients or in those who appear confused, cyanotic, or exhausted.
Other diagnostic tests
Oxygen saturation must be assessed via pulse oximetry in all patients presenting with acute asthma.28 In patients in whom arterial blood gas measurements are obtained, mild asthma is usually associated with a normal PaO2 and normal to low PaCO2. As the severity of airflow obstruction increases, ventilation-perfusion mismatching results in arterial hypoxemia in patients breathing room air. Hypercapnia (PaCO2 greater than 40 mm Hg) generally develops only when the FEV1 is less than 25% of predicted. Therefore, in a patient with acute severe asthma, the presence of normocapnia and normal arterial pH indicates a poor prognosis, because it may represent an impending respiratory arrest.
The chest radiograph is only a complement to the clinical assessment and should be obtained in patients in whom a complicating cardiopulmonary process is suspected. Examples include pneumothorax, pneumomediastinum, pneumonia, lobar atelectasis, and congestive heart failure.14
TREATMENT
Time is a major factor in managing acute severe asthma. As with other severely ill patients, initial assessment of patients with acute severe asthma begins with the ABCs: airway, breathing, and circulation.14 A stepwise approach is suggested for all patients with acute asthma exacerbations; however, endotracheal intubation should not be delayed and is recommended for airway protection or for patients who present with altered mental status or circulatory shock.
For patients who are not intubated, supplemental oxygen is given, preferably by face mask. Hypoxemia is easily corrected if patients are in the early stages of an acute severe asthma exacerbation, since these patients have a ventilation-perfusion mismatch.32
Because the patient's condition is not static, continuing clinical evaluations, including measurement of FEV1 or PEFR, must be made while different therapeutic interventions are administered.
ß
2
-Agonists
The most effective and safest initial choice of therapy to relieve airflow obstruction in a patient with acute severe asthma is a selective ß2-agonist.14,16,17,33,34 Inhaled ß2-agonists are more effective and are safer than ß2-agonists given intravenously.35 These agents have an onset of action of approximately 5 minutes and a duration of action ranging from 3 to 6 hours.36
It has been well documented in clinical trials that metered-dose inhalers (MDIs) with a spacer device are equivalent in effective- ness to nebulized therapy.37,38 Compared with nebulizers, MDIs that have a spacer device offer the advantage of greater cost savings, faster access to therapy, more efficient use of staff time, and quicker achievement of maximal bronchodilatation.39-41 Albuterol administered via an MDI with a spacer device achieves bronchodilatation in about 2 to 3 minutes for each treatment, compared with 10 to 20 minutes for each treatment with a nebulizer. However, most EDs use nebulizers preferentially.
There is no standard ß2-agonist dose for patients who present with acute severe asthma. The dose should be based on patients' symptoms and measured response to treatment.42 Some studies have recommended an initial dose of 4 to 8 puffs of an MDI every 15 to 20 minutes.16 The initial suggested dose of nebulized albuterol is 2.5 mg every 20 minutes for 1 hour.14,43 However, McFadden and colleagues44 have demonstrated that two 5-mg treatments with nebulized albuterol given at a 40-minute interval may result in a more rapid improvement in lung function than the standard dosing regimen.
Levalbuterol, an R-isomer of racemic albuterol, also is available for the treatment of acute severe asthma. The results of clinical studies suggest that levalbuterol may be a more effective bronchodilator with fewer adverse effects than racemic albuterol.45,46 Biopharmacologic data suggest that all of the bronchodilator properties of racemic albuterol reside in the R-isomer, while the S-isomer may increase airway reactivity.47
It has been postulated that S- albuterol increases intracellular calcium with smooth muscle contraction, enhances experimental airway hyperresponsiveness, and may have proinflammatory effects.47,48 Also, S-albuterol is metabolized 10-fold more slowly than levalbuterol; thus, the S-isomer may accumulate with frequent dosing.49
Many patients cannot tolerate or are unable to use inhalation therapy (for example, they cannot coordinate MDI actuation). In these patients, subcutaneous epinephrine or intravenous terbutaline may be indicated.13 Despite the concerns of many practitioners who use these agents, significant cardiovascular complications are uncommon. In a study of 95 patients with acute severe asthma who received subcutaneous epinephrine, Cydulka and coworkers50 found significant improvement in the PEFR and few adverse effects in most of their patients. Other investigators have found no clinically significant cardiac toxicity (as measured by serum troponin) from the use of intravenous terbutaline in children.51
Anticholinergics
The use of these agents for managing respiratory conditions was introduced into Western medicine in the early 1800s by British military officers who had learned of the use of atropine (from the leaves and roots of the plant Datura stramonium) in India.52,53 By blocking muscarinic receptors in airway smooth muscles, these agents inhibit vagal cholinergic tone, resulting in bronchodilatation. Nonselective anticholinergic agents, such as atropine, ipratropium, and oxitropium, block both the prejunctional and postjunctional receptors.
Ipratropium is a quaternary anticholinergic agent, which limits its systemic absorption and adverse effects, and is available as an MDI. The drug is topically active and does not appear to affect mucus secretion or ciliary movement. In addition, ipratropium does not increase heart rate.54
In patients who have acute asthma exacerbations, the combination of ipratropium with a ß2-agonist has been shown to be superior to a ß2-agonist alone.55-61 The use of multiple-dose ipratropium regimens in the initial treatment of adults and children has led to an important reduction in hospital admission rates.53
Corticosteroids
Since airway inflammation is a major culprit in acute severe asthma, anti-inflammatory agents are commonly used. Because of their potent anti-inflammatory effects, corticosteroids have become regarded as the cornerstone of management of both acute and chronic asthma. However, despite more than 4 decades of corticosteroid use in acute severe asthma, many issues remain unresolved.
It has been suggested that both systemic and inhaled corticosteroids reduce the number of relapses in patients following an acute asthma attack and in patients with chronic asthma.62 However, in a meta-analysis, Rodrigo and Rodrigo63 suggest that the administration of parenteral corticosteroids to patients with acute severe asthma neither improves airflow obstruction nor reduces the need for hospitalization. The main reason for the failure of corticosteroids in the early treatment of acute severe asthma is that it may take up to 24 hours before the effects become evident.
Inhaled corticosteroids are a reasonable alternative for patients who can tolerate them during the acute phase of an asthma exacerbation. Some studies have suggested that the use of inhaled corticosteroids is associated with a more rapid improvement in FEV1 and a lower likelihood of hospital admission.64,65 Rodrigo and Rodrigo66 demonstrated that extremely high doses of inhaled corticosteroids in patients with acute asthma treated in emergency settings improved pulmonary function within 3 hours. The addition of an inhaled corticosteroid to an oral corticosteroid regimen reduces the number of relapses in patients with acute asthma discharged from EDs.67
While the ideal dosing of corticosteroids has not been determined, McFadden68 suggests that 10 to 15 mg/kg/d of hydrocortisone, or its equivalent, is effective therapy for patients with acute severe asthma. This translates into a dosage of 120 to 180 mg/d of methylprednisolone, which is the dosage recommended by the NAEPP expert panel and the Canadian guidelines for the emergency management of asthma in adults (Canadian Association of Emergency Physicians/Canadian Thoracic Society Asthma Advisory Committee).14,16 Despite these recommendations, a dosage of 60 to 125 mg of methylprednisolone every 6 hours is commonly used.15,17
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