Bronchial biopsy specimens of patients with asthma are pathologically abnormal [13,14,15], with collagen deposition beneath the epithelial basement membranes, mucosal infiltration by eosinophils and neutrophils, mast cell degranulation, and epithelial damage. These findings occur in both severe and mild asthma, suggesting that airway inflammation is of primary importance in the pathogenesis of asthma.

Asthma exacerbations show variable pathology, reflecting at least two recognized subtypes of exacerbation—slow onset and rapid onset. Slow onset exacerbations are the most common (approximately 80% of exacerbations) and the patient presents with more than 2 to 6 hours of symptoms—often days or weeks of symptoms [16,17,18]. This suggests that most such patients should have sufficient time to seek medical attention for worsening shortness of breath [19]. At autopsy, the lungs of patients who die of “slow-onset” asthma exacerbations are hyperinflated with thick tenacious mucus filling and obstructing the lumens of the airways [4]. Microscopically, there is an eosinophilic bronchitis, with pronounced areas of mucosal edema and desquamation of the epithelium. Typically, hypertrophy and hyperplasia of smooth muscle are present and the muscle appears contracted [4].

The patient with the rapid-onset type of exacerbation presents with severe symptoms that have rapidly progressed over 2 to 6 hours [16,17,18]. These rapid-onset exacerbations may represent 8% to 14% of asthma exacerbations in general and can be fatal, leading to death in only a few hours after symptom onset [16,18]. Pathologically, airway obstruction by mucus is not prominent, and there is a neutrophil, rather than eosinophil, predominance of inflammatory cells in the airway submucosa [20]. There are no specific clinical characteristics that reliably predict which patients are prone to these rapid-onset asthma exacerbations. However, patients with rapid onset asthma exacerbations may more commonly report sensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) [18].

Asthma is a disease or group of diseases with complex underlying genetics [21]. Why airway inflammation develops in the asthmatic patient is not understood entirely, but much evidence suggests an important role for Th2 cytokines [22]. Inhaled allergens, pollutants, smoke, and viral infections all may play a role in augmenting the baseline airway inflammation present in the asthmatic airway [1,23]. When these environmental
triggers interact with the asthmatic airway, the inflammation is intensified and the released mediators have potent effects on smooth muscle cell function, epithelium and microvascular integrity, neural function, and mucus gland secretion. All these factors contribute to increased narrowing of the asthmatic airway with smooth muscle contraction, mucus secretion, epithelial cell sloughing into the lumen, and edema and inflammatory cell infiltration of the airway wall. The resulting acute increase in airway obstruction is commonly referred to as an acute exacerbation of asthma.

The major physiologic consequences of airway obstruction are hypoxemia and increased work of breathing. Understanding these physiologic disturbances is important for management of severe exacerbations of asthma.

Narrowing the caliber of airway lumens causes hypoxemia by two mechanisms. First, increases in the resistance to flow in the conducting airways result in uneven distribution of ventilation to the alveoli. Hypoxic vasoconstriction of vessels that supply underventilated alveoli partially compensates for this uneven ventilation, but overall ventilation–perfusion ([V with dot above]/[Q with dot above]) ratios remain abnormal and are the principal cause of hypoxemia in asthma [24]. Consequently, even patients with severe exacerbations of asthma usually respond well to supplemental oxygen. A second, less common cause of hypoxemia in asthma is right-to-left shunt due to atelectasis of lung distal to airways that are completely occluded by mucus or due to interatrial shunt [25,26,27].

The second physiologic consequence of severe airway obstruction is increased work of breathing. During acute exacerbations, respiratory muscles must expend increased energy, generating large changes in pleural pressure to overcome high airway resistance [28]. The resulting discordance between respiratory effort and the change in thoracic volume also plays a role in the patient’s sensation of dyspnea and central drive to increase minute ventilation. The ensuing rapid respirations further increase the work of breathing and worsen air trapping behind narrowed airways that prematurely close during expiration. The dynamic hyperinflation of the lung itself leads to increased respiratory muscle energy costs because it restricts vital capacity to high thoracic volumes where alveolar dead space is increased, the respiratory muscles are at suboptimal mechanical advantage, and the lung is less compliant. All of these factors contribute to the enormous increase in the work of breathing. Thus, the respiratory muscles must expend more energy to achieve the same alveolar ventilation. Initially, the respiratory muscles may be able to exert the force needed to maintain alveolar ventilation but the muscles may fatigue if airway resistance increases rapidly, is sustained, or if there is inadequate oxygen delivery to theses muscles [29,30]. Dynamic hyperinflation due to severe airway obstruction also may impair cardiac performance by increasing afterload, decreasing venous return to the heart, and causing diastolic dysfunction [7,27].

Baseline pulmonary function tests that show persistent decreases in the forced expired volume of air in 1 second (FEV₁), loss of lung elastic recoil, and hyperinflation at total lung capacity are associated with increased risk of near-fatal asthma [38]. A recent history of poorly controlled asthma (increases in dyspnea and wheezing, frequent nocturnal awakenings due to shortness of breath, increased use of beta-adrenergic rescue medications, increased diurnal variability in peak expiratory flow, and recent hospitalizations or emergency department visits) and any history of a prior near-fatal asthma exacerbation (prior admission to an intensive care unit or intubation for asthma) are the two most important predictors of a patient’s propensity for severe life-threatening asthma exacerbations [39,40,41,42,43,44]. Patient complaints of severe breathlessness or chest tightness or difficulty walking more than 100 feet (30.48 m) also suggest severe airway obstruction. Cigarette smoking also has been associated with higher in-hospital and posthospitalization mortality [43]. In general, patients are somewhat better judges of the severity of their airway obstruction during an attack of asthma than are physicians who elicit their history at the bedside [45]. However, the patient’s own assessment of airway obstruction should never be the exclusive means of assessing the severity of airway obstruction. Notably, patients with a history of severe asthma often have a blunted perception of dyspnea [46,47,48,49]. In assessing risk for fatal asthma, other important historical details include identification of current medications and coexisting illnesses, such as psychiatric disease, that interfere with medical follow-up and cardiopulmonary disease. A history of known coronary artery disease is important because the patient may be more sensitive to the stimulatory effects of β₂-adrenergic agonists and to the cardiac complications of hypoxemia [50]. These patients may also be receiving β₂-adrenergic antagonists that are making control of their asthma worse.

Physical examination is important for excluding other causes of dyspnea (see Differential Diagnosis section) and assessing the degree of airway obstruction [44]. Tachycardia (greater than 120 beats per minute), tachypnea (greater than 30 breaths per minute), diaphoresis [51], bolt-upright posture in bed, pulsus paradoxus greater than 10 mm Hg, and accessory respiratory muscle use all should be regarded as signs of severe airway obstruction [52]. However, because the absence of these signs does not rule out severe obstruction, physical examination cannot be relied on exclusively to estimate the severity of airway obstruction. The amount of wheezing heard on auscultation of the chest is a notoriously poor method of assessing the severity of airway obstruction [53]. Cyanosis is a late, insensitive finding of severe hypoxemia. Abnormal thoracoabdominal motion (e.g., respiratory muscle alternans, abdominal paradox) and depressed mental status due to hypoxemia and hypercapnia are ominous indicators and can herald the necessity for mechanical ventilation [54].

To evaluate patients who are having an acute exacerbation of asthma, an objective measure of maximal expiratory airflow should be performed. An exception to this is the patient who is unable to perform a testing maneuver due to a severe, life-threatening exacerbation with obvious airway compromise and cyanosis [44]. Peak expiratory airflow rate (PEFR) and FEV₁ are equally good bedside measures to quantify the degree of airway obstruction [55]. These tests are invaluable for the initial assessment and for following responses to therapy [44,56]. In general, a PEFR or FEV₁ of less than 40% of baseline (either the predicted value or the patient’s best-known value) indicates severe obstruction and a severe exacerbation of asthma (Table 48.2).

Analysis of arterial blood gases (ABGs) have a role in assessing and managing severe asthma exacerbations (see Chapter 11) and should be performed for suspected hypoventilation, severe respiratory distress, or when spirometric test results are less than 25% predicted [44]. Also, any patient who fails to respond to the first 30 to 60 minutes of intensive bronchodilator therapy should have an ABG analysis performed. Although ABG values are not predictive of overall patient outcome [55], there is some correlation between hypoxemia and hypercapnia and the degree of airway obstruction measured by FEV₁ [57]. A partial pressure of arterial oxygen (PaO₂) less than 60 mm Hg or a pulse oximeter oxygen saturation value less than 90% on room air should be regarded as additional evidence of severe airway obstruction. Therefore, although ABG analysis is not recommended as routine in the initial evaluation of asthma, it should be done for the evaluation of severe cases. One study found that the frequency of ABG analysis in cases of severe asthma actually decreased from 1997 to 2000, a trend needing improvement [58].

Understanding the expected changes in the partial pressure of arterial carbon dioxide (PaCO₂) during an asthma exacerbation is important for recognition of a rapidly deteriorating course. With modest airway obstruction, the patient’s mild dyspnea stimulates an increase in minute ventilation that meets or exceeds the level required to maintain normal alveolar ventilation. Thus, patients with modest obstruction have a normal or slightly below normal PaCO₂. As airway obstruction worsens, dyspnea becomes more severe and the central nervous system drive to increase minute ventilation becomes intense. Typically, the increase in minute ventilation exceeds the level required to maintain constant alveolar ventilation; consequently, patients with moderate-to-severe obstruction have lower than normal PaCO₂ and respiratory alkalosis. As the airway obstruction becomes more severe and prolonged, high minute ventilation can no longer be maintained by the respiratory musculature and alveolar ventilation decreases. As a result, the PaCO₂ rises toward normal and then continues to climb, resulting in hypercapnia and respiratory acidosis. Thus, a normal or high PaCO₂ (greater than 40 mm Hg) during a severe exacerbation of asthma is a potentially ominous finding, often signifying the impending need for mechanical ventilation. Any coexisting conditions (malnutrition, advanced age) or medications (sedatives) that weaken respiratory muscle function or depress respiratory drive should be expected to accelerate the onset of hypercapnic ventilatory failure during acute exacerbations of asthma.

For acute exacerbations of asthma, routine chest radiographs reveal few abnormalities other than hyperinflation [59]. However, although not recommended for routine assessment, for severe exacerbations chest radiography can be helpful when there is clinical suspicion of other causes of dyspnea and wheezing (see Differential Diagnosis section) or complications of severe airway obstruction [44]. Chest radiographs should be examined for evidence of enlarged cardiac silhouette, upper lung zone redistribution of blood flow, pleural effusions, and alveolar or interstitial infiltrates because any one of these findings suggests a diagnosis other than or in addition to acute asthma. In addition, chest radiography allows the early detection of common complications of severe airway obstruction, including pneumothorax, pneumomediastinum, and atelectasis. Also, lung infiltrates on chest radiographs can be compatible with a diagnosis of asthma complicated by either allergic bronchopulmonary aspergillosis or Churg–Strauss syndrome.

In the elderly, in patients with severe hypoxemia, and in individuals with suspected cardiac ischemia or arrhythmia, an electrocardiogram should be performed. Sinus tachycardia is common during acute exacerbations of asthma, but less common and transient findings include right-axis deviation, right ventricular hypertrophy and strain, P pulmonale, ST- and T-wave abnormalities, right bundle-branch block, and ventricular ectopic beats [60].

β₂-Adrenergic agonists bind to β₂-adrenergic receptors on airway smooth muscle cells and cause relaxation of the muscle cell. Although the primary cellular target of β₂-adrenergic agonists is airway smooth muscle, other cell types in the airways also express β₂-adrenergic receptors that may regulate mediator release by mast cells, epithelial cells, and nerves.

There are two general classes of β₂-adrenergic agonists. Short-acting β₂-adrenergic agonists (SABA) have bronchodilatory effects that last for 3 to 5 hours. They include
epinephrine, isoproterenol, terbutaline, metaproterenol, albuterol, and fenoterol. These short-acting agents have an onset of action less than 5 minutes and are the mainstay of bronchodilator therapy for acute asthma. These agents differ in their selectivity for β₂-adrenergic receptors, the rank order of selectivity being epinephrine < isoproterenol < metaproterenol < fenoterol, terbutaline, and albuterol [63]. However, all of these agents have approximately equal efficacy in the treatment of asthma. Another class of drugs, the long-acting β₂-adrenergic agonists (LABA), have bronchodilatory effects for at least 12 hours, but these agents are not currently recommended in the treatment of acute exacerbations [1,2,44]. There has been significant controversy on whether chronic use of these long-acting agents predisposes patients to increased severe, life-threatening, or fatal asthma exacerbations [64].

Among the short-acting β₂-adrenergic agonists, a single-isomer preparation (i.e., R-albuterol or levalbuterol) is available. The potential advantage of this preparation is that the S-enantiomer present in racemic albuterol, does not contribute to bronchodilation and might have deleterious effects in the airways. However, although some studies of levalbuterol (R-albuterol) in the emergency department setting have suggested that levalbuterol is a more efficacious bronchodilator than racemic preparations, there have been no large, randomized, double-blind and controlled trials in adults to confirm these findings [65,66,67].

The major side effects of β₂-adrenergic agonists during the treatment of severe asthma exacerbations are tremor, cardiac stimulation, and hypokalemia [68]. Case reports have associated lactic acidosis with the use of β₂-adrenergic agonists as well [69]. These side effects are potentially serious, especially in the elderly, who frequently have underlying cardiac disease. Cardiac toxicity can be minimized by using agonists with high β₂-adrenergic receptor selectivity, by avoiding systemic administration of β₂-adrenergic agonists, and by maintaining adequate oxygenation [50,70]. β₂-Adrenergic agonists can be administered to patients by inhaled, subcutaneous, or intravenous routes. Numerous studies have shown that the bronchodilator effects of inhaled β₂-adrenergic agonists are rapid in onset and equal to the effect achieved by systemic delivery [71]. Because the inhaled route allows administration of comparatively small doses directly to the airways with minimal systemic toxicity, this route is almost always preferable to systemic delivery [1,2].

Several options exist for the delivery of inhaled β₂-adrenergic agonists (see Chapter 62). A small-volume nebulizer is widely used. However, studies have shown that metered-dose inhalers (MDIs) equipped with spacer devices are as effective as small-volume nebulizers in the treatment of acute asthma, although some patients may have difficulty coordinating MDI use, especially during an acute exacerbation with severe respiratory distress [1,72,73]. Frequent, multiple inhalations of the medication may allow for progressively deeper penetration of the drug into peripheral airways [74]. In fact, continuous administration by nebulizer may be more effective in severely obstructed patients [75,76]. For administration of inhaled albuterol in the treatment of severe exacerbations of asthma, National Institutes of Health guidelines recommend treatment with MDI (90 μg per puff; four to eight puffs every 20 minutes up to 4 hours, then every 1 to 4 hours as needed) or nebulizer treatments, either intermittent (2.5 to 5.0 mg every 20 minutes for 3 doses, then every 1 to 4 hours as needed) or continuous (10 to 15 mg per hour) [1] (see Management section).

Intermittent positive-pressure breathing devices to deliver aerosols were once popular but are not used today because many patients with severe asthma cannot tolerate the device and because the devices are no more effective than small-volume nebulizers [77]. Furthermore, the risk of barotrauma is significantly increased with intermittent positive-pressure breathing devices, and pneumothorax resulting in death has been reported [78].

Because of its lower density than oxygen, heliox-powered nebulizer treatments have the potential to improve penetration of aerosols into the lungs. Adult patients with severe asthma exacerbations had greater improvements in peak expiratory flow rates and dyspnea scores when albuterol was delivered using heliox, rather than oxygen, driven nebulization [79,80]. Current National Institute of Health Guidelines suggest that heliox-driven albuterol nebulization be considered for patients with life-threatening exacerbations or for those with severe exacerbations even after 1 hour of intensive conventional therapy [1].

Theoretically, systemic administration of beta-adrenergic agonists could deliver drugs via the bloodstream to obstructed airways that are poorly accessible to inhaled aerosols. However, this theoretical advantage has not been supported by most studies [71]. Subcutaneous epinephrine (adults, 0.3 mL of a 1 to 1,000 solution every 20 minutes for three doses) was a traditional therapy for acute asthma in emergency departments, but it is not more effective than aerosol delivery of β₂-adrenergic agonists [81]. A major concern with the use of subcutaneous epinephrine in adults has been cardiac toxicity [82]. More selective β₂-adrenergic agonists, such as terbutaline, are available for subcutaneous use, but cardiac toxicity in elderly individuals is still a significant concern even with these more selective agents. Formerly, intravenous isoproterenol (0.05 to 1.50 μg per kg per minute) was often used to treat severe exacerbations of asthma [83]. However, intravenous delivery of β₂-adrenergic agonists is no longer recommended for the routine treatment of even severe exacerbations of asthma [1,2]. No convincing evidence has shown intravenous administration to be superior to inhaled delivery of β₂-adrenergic agonists. The lack of enhanced efficacy and the potential cardiac toxicity of intravenous β₂-adrenergic agonists have led most authorities to reserve intravenous delivery for those rare patients who continue to deteriorate on mechanical ventilation despite maximal routine therapy with inhaled β₂-adrenergic agonists [83]. Intravenous β₂-adrenergic agonists should be used only in closely monitored adults because myocardial ischemia can occur [84]. It is important to emphasize again that intravenous β₂-adrenergic agonists are not recommended in current NIH guidelines and are unlikely to be any more effective than inhaled β₂-adrenergic agonists such as albuterol [1].

The muscarinic cholinergic antagonists (e.g., atropine, ipratropium and tiotropium) are less effective and more slowly acting bronchodilators than β₂-adrenergic agonists [85,86,87]. In general, these agents should not be used as the sole bronchodilator therapy for acute asthma. Exceptions may be bronchospasm induced by acetylcholinesterase inhibitors or β₂-adrenergic antagonists and patients with severe cardiac disease who are unable to tolerate β₂-adrenergic agonists.

However, inhaled cholinergic antagonists have a low incidence of side effects and are a recommended adjunct to β₂-adrenergic agonists in the initial emergency department treatment of severe exacerbations of asthma [1,88]. Because even small improvements in airflow could prove clinically significant in the severely obstructed and deteriorating patient, it is recommended that ipratropium be routinely added to β₂-adrenergic agonist therapy during the initial treatment of severe asthma exacerbations in the emergency department [1] (see Management section). However, although comparable trials for adults do not exist, controlled trials in children have not shown a benefit of continuing ipratropium treatment once the patient is hospitalized [89,90]. Therefore, inhaled ipratropium bromide currently is not recommended for hospitalized
patients with severe exacerbations of asthma [1]. The long-acting anticholinergic, tiotropium, has a role in treating outpatients with difficult to control asthma, but whether it has a role in treating hospitalized patients with acute exacerbations of asthma is not yet known [91].