Chapter 69: Acute Asthma

Asthma is a chronic inflammatory disorder characterized by increased responsiveness of the airways to multiple stimuli. In susceptible individuals, the inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. These episodes usually are associated with widespread and varying airflow obstruction.

Although most acute attacks are reversible and improve spontaneously or within minutes to hours with treatment with symptom-free intervals in between, many asthmatic patients develop chronic airflow limitation. This impacts the diagnosis of, management of, and attempts to prevent acute exacerbations.

Asthma affects approximately 8% of the U.S. population, is the most common chronic disease of childhood (9% prevalence), affects 7% of the elderly, and has a similar prevalence in developed nations around the world.^1,2,3 Approximately one half of cases of asthma develop before the age of 10 years old, and another one third develop before the age of 40 years old.

Asthma is characterized by an abnormal accumulation of eosinophils, lymphocytes, mast cells, macrophages, dendritic cells, and myofibroblasts in airways. The pathophysiologic hallmark of asthma is a reduction in airway diameter caused by smooth muscle contraction, vascular congestion, bronchial wall edema, and thick secretions. These changes are reflected in pulmonary function changes, increased work of breathing, and abnormal distribution of pulmonary blood flow (Table 69-1). Large and small airways contain plugs composed of mucus, serum proteins, inflammatory cells, and cellular debris. On a microscopic level, airways are infiltrated with eosinophils and mononuclear cells. Evidence of microvascular leakage, epithelial disruption, and vasodilation is frequently noted. The airway smooth muscle is hypertrophied and characterized by new vessel formation, an increased number of epithelial goblet cells, and deposition of interstitial collagen beneath the epithelium. Inflammation affects all bronchial pulmonary structures.

Asthma is a continuum from acute bronchospasm to airway inflammation to permanent airway remodeling. The structural changes associated with airway remodeling, such as sub–basement membrane thickening, subepithelial fibrosis, airway smooth muscle hypertrophy and hyperplasia, angiogenesis, and mucous gland hyperplasia and hypersecretion are associated with nonreversible loss of lung function.⁴ Acute allergic bronchoconstriction results from immunoglobulin E–dependent release of mediators from mast cells. These mediators include histamine, leukotrienes, tryptase, and prostaglandins that directly contract airway smooth muscle.⁴ Bronchospasm induced by aspirin and other nonsteroidal anti-inflammatory drugs also involves mediator release from airway cells.⁴

Inflammation plays a key role in the pathophysiology of asthma regardless of disease severity. Inhaled antigens activate immunoglobulin E, mast cells, and T helper cells in the airway and induce the production of inflammatory mediators and cytokines. In turn, this initiates a cascade of reactions involving lymphocytes, mast cells, eosinophils, dendritic cells, macrophages, resident airway cells, and epithelial cells that perpetuate the inflammatory response, with further release of chemokines, cytokines, cysteinyl leukotrienes, and nitric oxide. The inflammatory process is multicellular, redundant, and self-amplifying.

Numerous host and environmental factors, such as number and type of infections in childhood, frequent antibiotic use, Western lifestyle, and repeated exposures to allergens, may contribute to the development of allergic asthma. Viral respiratory infections are among the most common of the stimuli that invoke acute asthma exacerbation.⁵ Increased airway responsiveness secondary to infection may last anywhere from 2 to 8 weeks.⁵ Exercise is another common precipitant of acute asthma. Environmental conditions, such as atmospheric pollutants and antigens noted in heavy industrial or densely populated urban areas, or increased indoor antigens, such as mold, house dust mites, cockroaches, and animal dander, are associated with higher incidence and severity of asthma. Occupational exposures, such as metal salt, wood and vegetable dust, pharmaceuticals, industrial chemicals, plastics, biological enzymes, vapors, gases, and aerosols, also may stimulate an asthma attack. Agents such as aspirin, β-blockers (including topical β-blockers), nonsteroidal anti-inflammatory drugs, sulfating agents, tartrazine dyes, and food additives and preservatives may trigger acute asthma. Exposure to cold air alone can induce acute bronchospasm. Endocrine factors, such as changing levels of estradiol and progesterone during the normal menstrual cycle and pregnancy, contribute to the level of airway reactivity.⁶ Emotional stress also can produce an asthma attack.

The symptoms of asthma include dyspnea, wheezing, and cough. Many, but not all, patients will relay the history of asthma upon presentation. Early in the attack, patients will complain of a sensation of chest constriction and cough. As the exacerbation progresses, wheezing becomes apparent, expiration becomes prolonged, and accessory muscle use may ensue. A thorough history can be helpful in guiding care for asthma exacerbations^7,8,9,10 (Table 69-2). Acute asthma exacerbations are categorized based on clinical features^7,8,9,10 (Table 69-3).

Physical examination findings are variable. Patients presenting with a severe asthma attack may be in respiratory distress, with rapid breathing and loud wheezing, whereas patients with mild exacerbation may present with only cough and end-expiratory wheezing. At times, wheezing may be audible without a stethoscope. Other conditions may present with wheezing and mimic asthma (Table 69-4). The use of accessory muscles of inspiration indicates diaphragmatic fatigue. The appearance of paradoxical respiration, which is chest deflation and abdominal protrusion during inspiration followed by chest expansion and abdominal deflation during expiration, is a sign of impending ventilatory failure. Alteration in the mental status (e.g., lethargy, exhaustion, agitation, or confusion) also heralds respiratory arrest.

Directed physical examination reveals hyperresonance to percussion, decreased intensity of breath sounds, and prolongation of the expiratory phase, usually with wheezing. Although wheezing results from the movement of air through narrowed airways, the intensity of the wheeze may not correlate with the severity of airflow obstruction. The "silent chest" reflects very severe airflow obstruction, with air movement insufficient to promote an audible wheeze. A pulsus paradoxus (change in blood pressure during inspiration) >20 mm Hg is also indicative of severe asthma, although it is not specific for asthma. Although tachycardia and tachypnea are usually seen with acute asthma, a normal heart rate, a normal respiratory rate, and the absence of a pulsus paradoxus do not indicate complete relief of airway obstruction.

DIAGNOSIS AND PATIENT MONITORING

Bedside spirometry provides a rapid, objective assessment of patients and guides therapy. The forced expiratory volume in 1 second (FEV₁) and the peak expiratory flow rate (PEFR) rate directly measure the degree of large airway obstruction. Sequential measurements help assess severity and determine response to therapy. A flow-volume loop can help distinguish asthma from vocal cord dysfunction; the latter is often treated as asthma, sometimes with repeated visits. Vocal cord dysfunction responds to the moisture, not the drug, in a nebulized treatment, and "fails" metered-dose inhaler outpatient therapy because moisture is not a part of that delivery system. If not documented, obtain a full spirometry assessment only in patients with frequent outpatient failures.

Signs on physical examination and the subjective symptoms do not necessarily correlate well with the severity of airflow obstruction, making objective measures valuable. Patient cooperation is essential for these tests to be reliable, limiting the value of spirometry in severe exacerbations or in noncooperative patients.^7,8,9,10

Pulse oximetry assesses oxygen saturation during treatment. Arterial blood gas measurement is not needed in most patients with mild to moderate asthma exacerbation, and it should be reserved for suspected hypoventilation with carbon dioxide retention and respiratory acidosis. With acute attacks, ventilation is stimulated, resulting in a decrease in partial pressure of arterial carbon dioxide (Paco₂). Therefore, a normal or slightly elevated Paco₂ (e.g., >42 mm Hg) indicates extreme airway obstruction and fatigue and may herald the onset of acute ventilatory failure. Patients with impending respiratory failure almost always have clinical evidence of severe attacks or spirometry demonstrating a PEFR or FEV₁ <25% predicted.¹¹ The use of capnography in acute asthma management is unclear. One small study reported good concordance between expired carbon dioxide levels measured by capnography and arterial carbon dioxide concentration,¹² but another reported differences of up to 10 mm Hg or more between the two measurements.¹³

Radiography is indicated only if there is clinical suspicion of pneumothorax, pneumomediastinum, pneumonia, or other cause for symptoms (e.g., acute heart failure) or complication of asthma. For admitted asthma patients, less than one third of patients have an abnormal chest radiograph.¹⁴

A CBC is not routinely needed and likely will show modest leukocytosis secondary to administration of β-agonist therapy or corticosteroids. For those few patients taking theophylline, measure the serum level. Routine ECG is also unnecessary but may reveal right ventricular strain, abnormal P waves, or nonspecific ST- and T-wave abnormalities, which resolve with treatment. Older patients, especially those with coexisting heart disease, should have cardiac monitoring during treatment.

The goal is rapid reversal of airflow obstruction by repetitive or continuous administration of inhaled β₂-agonists, ensuring adequate oxygenation, and relieving inflammation.^7,8,9,10 Figure 69-1 shows the National Asthma Education and Prevention Program Expert Panel ED treatment algorithm.¹⁰ The following categories of medications are used in the treatment of acute asthma: β-adrenergic agonists, anticholinergics, and glucocorticoids. Treatments for impending or actual respiratory arrest are discussed below in "Status Asthmaticus."

ADRENERGIC AGENTS

β-Adrenergic agonists with rapid onset are the preferred initial rescue medication for acute bronchospasm (Table 69-5). Stimulation of β₁-receptors increases rate and force of cardiac contraction and decreases small intestine motility and tone, whereas β₂-adrenergic stimulation promotes bronchodilation, vasodilation, uterine relaxation, and skeletal muscle tremor.

β-Adrenergic drugs cause bronchodilation by stimulation of the enzyme adenyl cyclase, which converts intracellular adenosine triphosphate into cyclic adenosine monophosphate. This action enhances the binding of intracellular calcium to cell membranes, reducing the myoplasmic calcium concentration, and results in relaxation of bronchial smooth muscle. β-Adrenergic drugs also inhibit mediator release and promote mucociliary clearance.

The most common side effect of β-adrenergic drugs is skeletal muscle tremor. Patients also may experience nervousness, anxiety, insomnia, headache, hyperglycemia, palpitations, tachycardia, and hypertension. Clinical toxicity is rare and less common than undertreatment complications. Provoking dysrhythmias or myocardial ischemia is rare, especially in those without a prior history of coronary artery disease. The older catecholamine bronchodilators, such as epinephrine, are not β₂ specific and have a short duration of action.

Albuterol is a 50:50 racemic mixture (equal amounts of left and right isomers); it is now available in the hydrofluoroalkane formulation, which has increased the cost and the effectiveness. The R isomer has great binding affinity for the β₂-receptor and is responsible for bronchodilation. The S isomer has no bronchodilatory effect but has a long half-life (12 hours); this isomer may be responsible for late paradoxical bronchospasm in some patients. Levalbuterol (Xopenex^®) is the pure R isomer form of the drug, intended to improve effectiveness and limit side effects such as tachycardia and rhythm change. Both racemic albuterol and levalbuterol can be given as intermittent or continuous nebulizations. Levalbuterol costs 5 to 25 times more than albuterol, and it has no clear advantage over albuterol regarding symptom change, admission, or tachycardia.^15,16,17

Nonprescription racemic epinephrine (Asthmanefrin^®) replaced Primatene^® as an over-the-counter medication, and the cost is less than for prescription β₂-adrenergics. Asthmanefrin^® contains 11.25 milligrams of racemic epinephrine/0.5 mL. In one study, subjects recruited through local pharmacies reported no worse asthma outcomes than individuals treated with prescription β-agonists.¹⁸ No other data exist to guide use of Asthmanefrin^® versus prescribed agents.

Aerosol therapy with β₂-adrenergic drugs produces excellent bronchodilation and is favored over oral or parenteral routes. The aerosol route achieves topical administration of a relatively small dose of drug, thereby producing local effects with minimum systemic absorption and fewer side effects. Aerosol delivery occurs with a metered-dose inhaler coupled to a spacing device or with a compressor-driven nebulizer.²⁰ A spacing device attached to the inhaler improves drug deposition; when optimally used, metered-dose inhaler therapy delivers the most drug to target airways, better than nebulized therapy. Even with optimum technique, a maximum of 15% of the drug dose is retained in the lungs, regardless of the aerosol method used.

Aerosol treatments may be administered every 15 to 20 minutes or on a continuous basis.²¹ Subcutaneous epinephrine and terbutaline are options for patients unable to coordinate aerosolized or metered-dose inhaler treatments, seen often in severe airflow-limited states. IV β-agonist infusions offer no advantage over aerosolized or metered-dose inhaler–delivered agents and carry increased risk.²²

Salmeterol xinafoate and formoterol are β₂-adrenoreceptor agonists that bind with greater affinity to the β₂-receptor site than albuterol. They are indicated for twice-daily maintenance therapy. Neither drug should be used for acute asthma exacerbations. Bronchodilator effects last at least 12 hours, and tachyphylaxis has not been reported with long-term use. The number of asthma-related deaths among patients receiving salmeterol, especially in African Americans, has increased for unknown reasons, although this may be due to failure to recognize the need for or use rescue short-acting agents and to seek care appropriately. Long-acting β₂-adrenoreceptor agonists are an effective treatment for long-term control of asthma, especially in conjunction with inhaled corticosteroids. Short-acting β₂-adrenoreceptor agonists are used for infrequent or breakthrough symptoms that occur despite the use of long-acting β₂-adrenoreceptor agonists.^7,8,9,10,21

CORTICOSTEROIDS

Corticosteroids are a cornerstone of asthma treatment. Steroids produce beneficial effects by restoring β-adrenergic responsiveness and reducing inflammation. The peak anti-inflammatory effect occurs at least 4 to 8 hours after IV or PO administration, but early use is wise to enhance care quickly; corticosteroids given within 1 hour of arrival in the ED reduce the need for hospitalization.²³ Although there is disagreement over the optimal dose in acute asthma, an initial dose of PO prednisone of 40 to 60 milligrams or IV methylprednisolone of 1 milligram/kg is sufficient, and higher-dose corticosteroid therapy offers no advantage.²⁴ Admitted patients should receive additional daily corticosteroids until subjective and objective improvements are achieved. Patients who are being discharged home with an FEV₁ or PEF of <70% predicted after aggressive ED treatment should be prescribed a 5- to 10-day nontapering course of prednisone (40 to 60 milligrams/d in a single daily dose or its equivalent) or a 2-day course of oral dexamethasone (16 milligrams/d in a single daily dose).^{7,8,9,10,19,25,26} A single dose of depot methylprednisolone, 150 milligrams IM, is another option if compliance is a concern.²⁷

Current recommendations favor inhaled corticosteroids for all patients with mild persistent asthma or more severe asthma.^7,8,9,10 This means discharging patients with mild persistent or more severe asthma on maintenance inhaled corticosteroids in addition to any systemic bursts.^28,29,30,31 Inhaled corticosteroid options are beclomethasone, 80 to 240 micrograms/d; budesonide, 180 to 600 micrograms/d; flunisolide, 500 to 1000 micrograms/d; fluticasone, 88 to 264 micrograms/d; mometasone, 200 micrograms/d; and triamcinolone acetonide, 300 to 750 micrograms/d.

ANTICHOLINERGICS

The effects of anticholinergics used in combination with β-adrenergic agents are additive. Anticholinergics affect large, central airways, whereas β-adrenergic drugs dilate smaller airways. Anticholinergic drugs competitively antagonize acetylcholine at the postganglionic junction between the parasympathetic nerve terminal and effector cell. This process blocks the bronchoconstriction induced by vagal cholinergic-mediated innervation to the larger central airways. In addition, anticholinergics reduce concentrations of cyclic guanosine monophosphate in airway smooth muscle, further promoting bronchodilation.

The anticholinergic commonly used is inhaled ipratropium bromide. Ipratropium is available as a nebulized solution and a metered-dose inhaler or in combination with albuterol^7,8,9,10 (Table 69-5). Use an aerosolized ipratropium bromide solution, 0.5 milligrams, in patients with moderate to severe exacerbation.^7,8,9,10 Adding multiple doses of ipratropium bromide to a short-acting selective β-agonist may improve bronchodilation and decrease the need for hospitalization among severely obstructed asthmatics,³² although this benefit is not universal.³³ Potential side effects with anticholinergics include dry mouth, thirst, and difficulty swallowing. Less commonly, tachycardia, restlessness, irritability, confusion, difficulty in micturition, ileus, blurring of vision, or an increase in intraocular pressure can occur. Long-acting anticholinergic agents have no role in acute care.

Status asthmaticus is an acute severe asthma attack that does not improve with usual doses of inhaled bronchodilators and steroids. Signs and symptoms include hypoxemia, tachypnea, tachycardia, accessory muscle use, and wheezing. Wheezing may be absent when airflow is severely reduced. Rapid treatment is the key to preventing cardiopulmonary arrest. In addition to usual and ongoing bronchodilators coupled with early steroids, other treatment adjuncts exist.

MAGNESIUM

IV magnesium sulfate is indicated in the management of acute, very severe asthma (FEV₁ <25% predicted).³⁴ The magnesium dose is 1 to 2 grams IV over 30 minutes. Nebulized magnesium is effective and may also improve pulmonary function in severe asthma when it follows aggressive β-agonist and steroid therapy.^34,35,36 Dosing regimens vary; one regimen is 95 milligrams of nebulized magnesium sulfate in four divided doses 20 minutes apart, and another is 384 milligrams of nebulized magnesium sulfate in sterile water.³⁷ When using magnesium in any form, monitor blood pressure and deep tendon reflexes during administration³⁷ because hypotension or neuromuscular blockade may occur, although this is exceptionally rare in the doses recommended.

NONINVASIVE POSITIVE-PRESSURE VENTILATION

Noninvasive positive-pressure ventilation (see chapter 28, "Noninvasive Airway Management") improves airflow and respirations compared with usual care, and despite little research, it is commonly used in clinical practice for acute life-threatening asthma.^38,39 Noninvasive positive-pressure ventilation decreases the need for intubation, results in clinical improvement, and decreases the need for hospitalization.³⁹ Do not institute noninvasive positive-pressure ventilation if intubation is indicated or in patients with suspected pneumothorax.

KETAMINE

Ketamine inhibits reuptake of noradrenaline and thus increases circulating catecholamines, aiding some with severe asthma. An IV bolus dose of 0.2 milligram/kg followed by an infusion of 0.5 milligram/kg/h is sometimes used;⁴⁰ higher doses are validated.⁴¹ If intubation is needed, ketamine is a good agent to aid during the procedure and after mechanical ventilation starts. Controlled trials substantiating ketamine's efficacy in treating severe acute asthma are lacking.

EPINEPHRINE

Although epinephrine is standard treatment for anaphylactic asthma, it is overlooked as an adjunct to treat status asthmaticus. Epinephrine can be given SC or IM, 0.5 milligram in adults (standard adult EpiPen^® dose), in refractory situations.⁴¹

MECHANICAL VENTILATION

If the patient manifests progressive hypercarbia or acidosis or becomes exhausted or confused, intubation and mechanical ventilation (see chapter 29, "Intubation and Mechanical Ventilation") are necessary to prevent respiratory arrest. Mechanical ventilation does not relieve the airflow obstruction—it merely eliminates the work of breathing and enables the patient to rest while the airflow obstruction is resolved.

The potential complications of mechanical ventilation in asthmatic patients include extremely high peak airway pressures with subsequent barotrauma and hemodynamic impairment. Mucous plugging is frequent, leading to increased airway resistance, atelectasis, and pulmonary infection. Due to the severity of airflow obstruction during the early phases of treatment, the tidal volume may be larger than the returned volume, leading to air trapping and increased residual volume (intrinsic positive end-expiratory pressure). Using rapid inspiratory flow rates at a reduced respiratory frequency (12 to 14 breaths/min) and allowing adequate time for the expiratory phase can mitigate these effects. Also, it is reasonable to target adequate arterial oxygen saturation (≥90%) without concern for "normalizing" the hypercarbic acidosis. This approach is called controlled mechanical hypoventilation or permissive hypoventilation.

Ventilation of asthmatic patients requires sedation. Neuromuscular blocking agents may be required, but extended use may cause postextubation muscle weakness.⁴² See chapter 111, Intubation and Ventilation in Infants and Children for further discussion.

AGENTS OF UNCERTAIN OR NO BENEFIT IN STATUS ASTHMATICUS

Heliox

A mixture of 80% helium and 20% oxygen (heliox) can lower airway resistance and act as an adjunct in the treatment of severe asthma exacerbations.⁴³ Heliox does not reliably avert tracheal intubation, change intensive care and hospital admission rates and duration, or decrease mortality in severe asthma.⁴³

Methylxanthines

Aminophylline is no longer a first- or second-line treatment for acute asthma.⁴⁴ The most common side effects of methylxanthines are nervousness, nausea, vomiting, anorexia, and headache. At plasma levels >30 milligrams/mL, there is a risk of seizures and cardiac arrhythmias.

Other Agents

Mast cell modifiers, such as cromolyn and nedocromil, exert their anti-inflammatory action by blockage of chlorine channels, modulating mast cell mediator release and eosinophil recruitment. These agents also inhibit early and late responses to allergen challenge and exercise. Neither is indicated for treatment of acute bronchospasm.

Leukotrienes are potent proinflammatory mediators that contract airway smooth muscle, increase microvascular permeability, stimulate mucus secretion, decrease mucociliary clearance, and recruit eosinophils into the airway. Several leukotriene modifiers, namely montelukast, zafirlukast, and zileuton, are available as oral tablets for the treatment of asthma. Leukotriene modifiers improve lung function, diminish symptoms, and diminish the need for short-acting β₂-agonists. They may be used as an alternative to low-dose inhaled corticosteroid therapy in mild persistent asthmatics and as steroid-sparing agents with inhaled corticosteroids in moderate persistent asthmatics.^7,8,9,10 Despite one trial with adjuvant IV montelukast for acute asthma,⁴⁵ there is no indication for the use of any of the leukotriene modifiers in the ED.

Disposition decisions should take into account a combination of subjective parameters, such as resolution of wheezing and improvement in air exchange, as assessed by auscultation and patient opinion; objective measures, such as normalization of FEV₁ or PEFR; and historical factors, such as compliance, history of ED use, and hospitalization. Some degree of residual airflow obstruction, airway lability, and inflammation persists after treatment and discharge from the ED.

Advise discharged patients to use a short-acting β-agonist on a scheduled basis for several days and to complete any oral corticosteroids regimens. Add inhaled corticosteroids in patients with a history of persistent asthma who are not already using this regimen.^28,29,30

A good response to treatment resolves symptoms and results in a PEFR or FEV₁ of >70% predicted; these patients can be safely discharged home. Patients with a poor response to treatment have persistent symptoms and FEV₁ or PEFR of <40% predicted; these patients are usually best observed or admitted. An incomplete response to treatment, the middle ground, is defined as some persistence of symptoms and a PEF or FEV₁ between 40% and 69% predicted. Most asthmatics treated in the ED fall into this category and may be discharged home safely, although some benefit from prolonged observation or admission^7,8,9,10 (Table 69-2).

Patients who fail to improve adequately over a period of several hours because they are in the late phase of their exacerbation and those with significant risk factors for death from asthma are best placed in an observation unit or hospital bed. Many patients can be successfully treated in an ED observation unit with evidence-based care protocols.⁴⁶ Intubated patients require intensive care unit admission.

Arrange follow-up care to ensure resolution and to review the long-term medication plan for the chronic management of asthma. High previous relapse rates suggest the need for follow-up within 1 to 4 weeks of the ED visit.^7,8,9,10 Deliver an appropriate written discharge plan of action that addresses routine care and care of worsening symptoms (Table 69-6). Educate patients on asthma triggers, and review all discharge medications and the correct use of the inhaler and a peak flow meter (for daily tracking).