Severe, Life–Threatening Asthma

Jill M. Baren

Asthma is responsible for > 2 million emergency department (ED) visits in the U.S. each year, and approximately 1 in 4 (∼500,000) of these visits resulted in an admission in recent years. Patients with severe, life-threatening asthma are challenging for emergency providers. The immediate goal is to prevent deterioration to respiratory or cardiopulmonary arrest. The provider must make difficult decisions about noninvasive ventilation, endotracheal intubation, and mechanical ventilation. Severe asthma exacerbations are prone to be fatal when combined with one or more asthma-related complications. These complications include tension pneumothorax (often bilateral), pneumomediastinum, pneumonia, lobar atelectasis (from mucous plugging, often of larger airways), cardiac dysfunction, and pulmonary edema.

Pathophysiology of severe, life-threatening asthma
Early management and assessment prior to intubation and respiratory arrest
Key concepts and pitfalls in management
Update on the 2007 recommendations from the National Heart, Lung and Blood Institute (NHLBI) for the management of severe asthma

Overview and Epidemiology

Asthma is a common, worldwide disease affecting 300 million people, with its highest prevalence in industrialized countries.¹ An estimated 30 million Americans (approximately 7% of adults) have been diagnosed with asthma within their lifetimes according to a 2004 National Health Interview Survey.²^,³ Asthma is responsible for > 2 million ED visits in the U.S. each year, and approximately 1 in 4 (∼500,000) of these visits resulted in an admission.⁴ The economic burden of asthma is excessive at over $12 billion annually, with over $7 billion in direct medical costs.⁵

Most patients with asthma have mild to moderate disease that can be well controlled with a combination of anti-inflammatory drugs, although they may experience intermittent exacerbation of symptoms.⁶ Exacerbations are acute worsening of disease of approximately 3 or more days’ duration, need for unscheduled health care, reduction or cessation of normal activities, and increase in treatment.⁶ The majority of these exacerbations, fortunately, are mild or moderate; however, all asthma patients are at risk for developing a severe exacerbation.⁴

A subgroup of patients with acute, severe asthma do not respond to conventional therapy and often progress rapidly to respiratory failure. Acute, severe asthma is considered to be a distinct entity or subtype of asthma that is sometimes referred to as “near-fatal asthma” or “life-threatening asthma.”²^,⁴ These terms are used interchangeably throughout this chapter. Near-fatal and fatal asthma represent the most severe clinical presentations of asthma. There are no universally agreed upon definitions, but near fatal asthma is almost always associated with the presence of hypercapnia, acidemia, altered mental status, the need for endotracheal intubation and mechanical ventilation, and a high incidence for cardiopulmonary arrest.⁷ Patients with near-fatal asthma, despite optimal treatment, typically have at least one asthma exacerbation in the year prior to the severe episode.⁷

Acute, severe asthma accounts for approximately 2% to 20% of admissions to intensive care units, with up to one third of these patients requiring intubation and mechanical ventilation.⁸ Of every 100 admissions, approximately 1 will die (5,000 deaths).⁹ Death from asthma is, therefore, not common, but there are approximately 5,000 to 6,000 deaths annually; many occur in the prehospital setting. About 1% to 7% of all patients with severe asthma will die each year; of those who survive an episode of near-fatal asthma, 17% will subsequently die from another acute severe episode.⁴

Over the last few decades guidelines developed by the National Asthma Education and Prevention Program of the NHLBI and the Global Initiative for Asthma have focused on the recognition and management of acute asthma and may have contributed to a rise in outpatient visits, a concomitant fall in hospitalizations, and improved outcomes.¹^,¹⁰^,¹¹ The latest asthma mortality data indicate that in 2003 there were just over 4,000 deaths, a 12% reduction from 1999. Gender-specific death rates still show a female preponderance (1.8:1), and asthma death
rates for blacks are approximately 2.7 per 100,000 compared with 1.2 for whites.²

Experts believe that > 50% of fatal asthma may not be recognized as such because the deaths occur at home or during transport to the hospital. Most acute episodes resulting in death are related to severe underlying disease, inadequate baseline management, and acute exacerbations of inflammation.

Latest Guidelines

Several consensus groups have developed excellent practice guidelines for the diagnosis and treatment of asthma. These groups include the National Asthma Education and Prevention Program of the National Institutes of Health,¹⁰^,¹² the Global Initiative for Asthma,¹¹ and the Canadian Association of Emergency Physicians and the Canadian Thoracic Society.¹³^,¹⁴

National Asthma Education and Prevention Program: http://www.nhlbi.nih.gov.easyaccess1.lib.cuhk.edu.hk/about/naepp/
Global Initiative for Asthma: http://www.ginasthma.com/
CAEP: http://www.caep.ca/

Life-Threatening and Fatal Asthma

Pathophysiology

Asthma represents a spectrum of disease characterized by a cascade of inflammatory mediators. The pathophysiology of asthma consists of three key abnormalities:

Bronchoconstriction
Airway inflammation
Mucous impaction

Figure 33-1 • Asthma occurs in the setting of underlying inflammation. Diffuse bronchospasm occurs, causing air passages to constrict. Hypersecretion of mucous leads to plugs, which block oxygenation and ventilation. A. Normal healthy bronchus B. Bronchiole during asthma attack.

Severe exacerbations of asthma can rapidly lead to death. Cardiac arrest in patients with asthma has been linked to a variety of pathophysiologic mechanisms that complicate exacerbations of asthma, but the most likely cause is thought to be bronchospasm with subsequent plugging of the narrowed airways by mucus.⁹ Marked airway thickening and rapid infiltration of neutrophils into the airways are consistent findings in acute, severe asthma and may differentiate these patients from those with milder disease. In fatal cases, a 25- to 30-fold greater degree of thickening of the airways has been noted.⁴ At autopsy, these patients display marked mucous plugging, airway edema, exudation of plasma proteins, hypertrophy of airway smooth muscle, and cellular activation, with increased production and activation of inflammatory mediators.¹⁵^,¹⁶^,¹⁷ Some patients experience a sudden, severe onset of bronchospasm that responds rapidly to inhaled beta₂ agonists.¹⁸ This observation suggests that marked bronchiolar smooth muscle spasm is the major component in at least some cases of fatal asthma.

Acute, severe asthma results in hypoxemia secondary to the processes of hyperinflation and regional ventilation/perfusion mismatch. Carbon dioxide retention does not typically occur until FEV₁ falls below 25% of predicted.⁴ Airway occlusion due to smooth muscle bronchoconstriction, airway edema, inflammation, and formation of mucous plugs forms the pathologic basis of the gas-exchange abnormalities observed in acute, severe asthma, and leads to the development of extensive intrapulmonary shunting. Metabolic lactic acidosis may also coexist at later stages of the disease.⁷

Bronchoconstriction and airway obstruction from mucous plugging cause hyperinflation and increased airway resistance (Fig. 33-1). As a consequence, the work of breathing
increases dramatically. For example, at an FEV₁ of 50% of predicted, the work of breathing increases to 10 times normal. At an FEV₁ of <25% of predicted, severe respiratory muscle fatigue can contribute to the development of respiratory arrest and death unless urgent treatment is provided.

Severe asthma exacerbations are prone to be fatal when combined with other asthma-related complications. These complications include tension pneumothorax (often bilateral), pneumomediastinum, pneumonia, lobar atelectasis (from mucous plugging, often of larger airways), cardiac dysfunction, and pulmonary edema. Previous suspicion that fatal cardiac arrhythmias occur from the use (or misuse) of beta-adrenergic agonists is unfounded.¹⁶^,¹⁷ In reviews of asthma-related deaths, several authors were unable to document an association between these drugs and fatal arrhythmias.¹⁸^,¹⁹^,²⁰

Table 33-1 • Risk Factors for Fatal, Near-Fatal, or Life-Threatening Asthma²

History of sudden severe exacerbation
Prior asthma exacerbation requiring intubation and mechanical ventilation
Prior admission to intensive care unit
Two or more hospitalizations for asthma exacerbation in the past year
Three or more emergency care visits for asthma exacerbation in the past year
Hospitalization or emergency care visit for asthma within the past month
Use of more than two canisters per month of inhaled short acting β₂– agonist
Current use or recent withdrawal from systemic cortico-steroids
Lack of a written asthma action plan
Lack of adherence to or compliance with therapy such as inhaled corticosteroids within the past 2 weeks
Lack of regular assessment using objective measurements of airflow obstruction
Difficulty perceiving airflow obstruction or its severity
Other comorbidity: cardiovascular, chronic obstructive pulmonary disease
Psychological problems or psychiatric disease
Low socioeconomic status
Urban/inner-city residence
Illicit drug use
Sensitivity to fungi such as Alternaria

Signs and Symptoms

Significant risk factors affecting the severity of asthma include environmental exposures, genetic polymorphisms, and especially prior asthma-related events (Table 33-1).² A history of prior hospitalization, especially if mechanical ventilation was required, is considered the greatest predictor of an episode of near-fatal asthma.⁷

Asthma Triggers

Just as patient profiles and risk factors for asthma can be identified, so too can triggers for exacerbations in many individuals. Some of these are unavoidable, but they should still be identified if possible. Some can be avoided in the future if patients and their families are aware. In other instances, they must be treated concomitantly with the asthma exacerbation (Table 33-2).

Viruses are responsible for triggering the vast majority of asthma exacerbations. They are accompanied by lower airway neutrophilia and have been linked to asthma mortality. Although patients with severe asthma do not seem to have more viral infections than patients without asthma or those with mild asthma, the effect of viruses on their lower airways seems to be more substantial.⁶ Certain bacteria (e.g., Chlamydia pneumoniae and Mycoplasma pneumoniae) are also associated with asthma exacerbations and, in the case of patients with severe asthma, also lead to a more intense inflammatory response than is seen in asthma patients without such infections.⁶

Aeroallergens and pollutants are other triggers for asthma exacerbation and are all associated with increased rates of hospitalization and health care expenditures.⁶

Allergen exposure is also an important environmental factor in triggering asthma exacerbations: dust mites, cockroaches, and fungi such as Alternaria have all been strongly implicated.²¹ Cigarette smoke is another widely cited trigger
for an asthma exacerbation. Sinusitis episodes are common triggering events as well.²¹ Drugs such as aspirin, beta-blockers, and nonsteroidal anti-inflammatory agents may predispose to asthma exacerbations. In the subset of asthma patients who require mechanical ventilation, almost 10% have aspirin use as a precipitating factor. Heroin, cocaine, and alcohol intoxication are also frequently reported in association with asthma death.⁷

Table 33-2 • Triggers of Fatal and Near Fatal Asthma Exacerbations

Environment:
- extremes of temperature
- high humidity and dew points
- episodic contaminants (smoke, cigarette smoke)
Upper respiratory infections (viruses and bacteria)
Allergens (pollens and molds)
Exercise (cold-induced)
Other medical conditions (COPD, GE reflux)
Drugs (aspirin, beta-blockers, nonsteroidal anti-inflammatory medications)

COPD, chronic obstructive pulmonary disease; GE, gastroesophageal.

Asthma Facts

The number of patients with severe asthma exacerbations who present to the ED at night is ten times greater than the number who present during the day; 2% of patients with acute asthma who present at night require intubation. Most deaths from asthma occur at home or during transport to an ED.

Those groups at increased risk for near-fatal and fatal asthma include:

Patients who fail to recognize the severity of their exacerbation
Patients who attempt to treat themselves during an exacerbation without notifying their primary provider
Patients with a high level of denial about their disease on psychological evaluation
Patients who receive suboptimal treatment from their primary care provider
Patients who are depressed or anxious
Patients whose asthma was diagnosed when they were < 5 years of age

Based on studies of risk factors, the patient with near-fatal asthma has a somewhat stereotypical picture of noncompliance, inadequate medication regimen, and denial. But that stereotype is inaccurate for about half of life-threatening asthma events.²² Nearly half of near-fatal and fatal asthma episodes occur suddenly and unexpectedly, outside the hospital, in stable, younger, atopic patients who are reportedly compliant with their medical plan of care, using inhaled corticosteroids on a daily basis.²²

Based on clinical presentation, there seem to be two distinct phenotypes of acute, severe asthma. Type 1, or slowly progressive asthma, is characterized by a prolonged, slow onset of symptoms with late arrival for medical care. This type is more common and represents about 80% to 85% of acute, severe asthma patients; it is generally considered to be preventable. These patients have excess mucous plugging and tend to perceive symptoms early despite delay in seeking treatment, and they also tend to have a slow response to treatment. Type 2, or sudden asphyxic asthma, is characterized by the rapid onset of symptoms with sudden, severe deterioration; it is seen in the remaining 15% to 20%. Such patients are characterized by a history of unstable disease that is partially responsive to treatment. They have hyperacute or acute asphyxic symptoms leading to the development of respiratory failure within 2 hours of symptom onset. These patients also tend to have massive allergen exposure as well as emotional distress. The airways tend to be empty of secretions and there is a late perception of symptoms but an often rapid response to treatment if the patient is able to get to emergency medical care.²^,⁷

Signs and Symptoms: Assessing Severity

Asthma exacerbations are acute or subacute episodes of progressively worsening shortness of breath, cough, wheezing, or chest tightness or a combination of several of these symptoms. The hallmark finding that characterizes an asthma exacerbation is a decrease in expiratory airflow that can be documented by spirometry or peak expiratory flow measurement. It is important to use these objective measures to more reliably gauge the severity of an exacerbation (Table 33-3).

Clinical evaluation of severe asthma must occur immediately, and the medical history should not differ substantially from that of patients with a less severe presentation other than the fact that those who are severely ill may be too dyspneic to provide much information prior to initial therapy. Common symptoms reported are dyspnea, cough, and wheezing, but presentations are variable and dyspnea can be absent in up to 18% of cases.² Wheezing can be a poor indicator of functional impairment.

The patient’s report of subjective symptoms is often an inaccurate gauge of asthma severity. Reported severity correlates poorly with objective severity scoring systems. Some patients with severe, life-threatening asthma have an impaired response to hypercapnia and hypoxia. Their perception of dyspnea appears to be blunted. These patients may present with severe abnormalities of oxygenation as well as with respiratory acidosis.²³

The priority of the clinical examination is to confirm the diagnosis of asthma and to assess its severity. Most of the relevant physical examination can be determined from the vital signs and by direct observation of the patient. Physical signs and symptoms include tachypnea, tachycardia, wheezing, accessory muscle use, diaphoresis, cyanosis, and altered mental status. Auditory wheezing or wheezing heard through auscultation is present in almost all cases with the exception of those patients who have severely diminished air movement; in such cases, the chest is “quiet” and may represent severe obstruction. Although physical examination findings do not always correlate well with severity, they

should be used as a guide to determining severity. For example, an asthmatic patient who is sitting upright to breathe and using accessory inspiratory muscles in the neck and chest, is at risk for sudden respiratory failure. Somnolence, mental confusion, and a moribund or exhausted appearance are ominous signs that respiratory arrest is imminent.

Table 33-3 • Formal Evaluation of Asthma Exacerbation Severity in the Urgent or Emergency Care Setting

	Mild	Moderate	Severe	Subset: Respiratory Arrest Imminent
Symptoms
Breathlessness	While walking	While at rest(infant— softer, shorter cry, difficulty feeding)	While at rest (infant— stops feeding)
Breathlessness	Can lie down	Prefers sitting	Sits upright
Talks in	Sentences	Phrases	Words
Alertness	May be agitated	Usually agitated	Usually agitated	Drowsy or confused
Signs
Respiratory rate	Increased	Increased	Often >30/minute
		Guide to rates of breathing in awake children:
		Age	Normal rate
		<2 months	<60/minute
		2–12 months	<50/minute
		1–5 years	<40/minute
		6–8 years	<30/minute
Use of accessory muscles; suprasternal retractions	Usually not	Commonly	Usually	Paradoxical thoracoabdominal movement
Wheeze	Moderate, often only end expiratory	Loud; throughout exhalation	Usually loud; throughout inhalation and exhalation	Absence of wheeze
Pulse/minute	<100	100–120	> 120	Bradycardia
		Guide to normal pulse rates in children:
		Age	Normal rate
		2–12 months	<160/minute
		1–2 years	<120/minute
		2–8 years	<110/minute
Pulsus paradoxus	Absent <10 mm Hg	May be present 10–25 mm Hg	Often present > 25 mm Hg (adult) 20–40 mm Hg (child)	Absence suggests respiratory muscle fatigue
Functional Assessment
PEF percent predicted or percent personal best	≥70 percent	Approx. 40–69 percent or response lasts <2 hours	<40 percent	<25 percent Note: PEF testing may not be needed in very severe attacks
PaO₂ (on air)	Normal (test not usually necessary)	≥60 mm Hg (test not usually necessary)	<60 mm Hg: possible cyanosis
and/or PCO₂	<42 mm Hg (test not usually necessary)	<42 mm Hg (test not usually necessary)	≥42 mm Hg possible respiratory failure (See pages 393–394, 399)
SaO₂ percent (on air) at sea level	> 95 percent (test not usually necessary)	90–95 percent (test not usually necessary)	<90 percent
	Hypercapnia (hypoventilation) develops more readily in young children than in adults and adolescents.
Key PaO₂, arterial oxygen pressure; PCO₂, partial pressure of carbon dioxide; PEF, peak expiratory flow; SaO₂, oxygen saturation. Notes: The presence of several parameters, but not necessarily all, indicates the general classification of the exacerbation. Many of these parameters have not been systematically studied, especially as they correlate with each other. Thus, they serve only as general guides. From the National Heart, Lung, and Blood Institute National Asthma Education and Prevention Program Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma, 2007.

Vital signs during an acute, severe asthma exacerbation typically show tachypnea > 30 breaths per minute and tachycardia. Blood pressure can fluctuate depending on the degree of hemodynamic compromise secondary to lung hyperinflation and on the degree of dehydration.⁴ Increasing heart rate has close correlation with worsening asthma severity; do not assume that tachycardia is only due to beta-agonist treatment, because studies have shown that adequate bronchodilator response has been associated with a decrease in heart rate.²⁶

The assessment of severity and prediction of treatment requirements, including the need for hospitalization, depends on repeated clinical assessments. In adults, repeated objective measures of lung function are helpful; but in children, this type of monitoring will depend on age. Many clinical scoring systems to gauge the severity of asthma have been developed, but none are 100% predictive for hospitalization. The benefit of using clinical asthma severity scores is primarily to highlight the importance of regular comprehensive assessments.

Close monitoring includes serial measurement of lung function. Every effort should be made to obtain objective measures of lung function. These include forced expiratory volume in 1 second (FEV₁) and peak expiratory flow rate (PEFR), which are useful for predicting the need for hospitalization in adults. FEV₁ is preferred but usually less available in EDs than PEFR. The PEFR and FEV₁ are not equivalent in terms of the percentage of predicted values; FEV₁ is on average about 5 to 10 points lower than the PEFR (FEV₁ of 30% is equivalent to a PEFR of 35%–40%).²⁶ The only patients who do not warrant a peak flow or FEV₁ measurement are those with life-threatening exacerbations, during which the clinical assessment should suffice. Otherwise the FEV₁ or PEFR should be obtained initially and then 30 to 60 minutes after initial treatment (NHLBI). An FEV₁ or PEFR that is < 25% of predicted, that improves only < 10% after treatment, or that shows very wide fluctuation, is a potential indication for admission to an intensive care unit (ICU); such patients should be very carefully observed.¹⁰ Some patients can appear deceptively well despite the presence of severe airflow obstruction; this underscores the importance of objective lung function measurements.²⁶

For children > 5 years of age, either FEV₁ or PEFR may be useful; but neither may be feasible during an exacerbation.¹⁰ Only 65% of children 5 to 18 years of age and virtually no children < 5 years can perform these tests.²⁷

A peak flow meter provides a quick, accurate, and reproducible measure of PEFR in cooperative adults and children; it is also not influenced by the person supervising the test.²⁸ EDs should consider PEFR as a vital sign for an asthma patient. Store the PEFR device with a small box of disposable mouthpieces and a copy of the expected normal flow rate values for men, women, and children.

Pulse oximetry has been shown to be useful in infants and children in determining the severity of an exacerbation but not for predicting hospitalization unless repeated.¹⁰ Measurement of pulse oximetry should be made in all patients with severe asthma. Arterial oxygen desaturation and hypercarbia occurring concurrently may indicate the need for endotracheal intubation and may portend a life-threatening situation.²⁶

Most often, other diagnostic tests will not be necessary. Even if specific laboratory tests are deemed necessary, they should not delay treatment. The primary purpose of diagnostic testing in the setting of asthma is to hasten the detection of respiratory failure or confirm suspected complications of asthma exacerbations, such as pneumonia. The following laboratory tests can be considered.

Arterial blood gases are not necessary for most patients but can provide information about respiratory reserve, metabolic disturbances, and degree of hypoxemia. The most common abnormality is respiratory alkalosis, but as lung function drops, hypercarbia and respiratory acidosis develop, with a subset of patients also having metabolic acidosis; the latter is thought to be due to accumulating lactate from respiratory muscle fatigue and tissue hypoxia.⁴

Chest radiography is also not routinely needed for the assessment and management of all asthma patients. Abnormalities other than hyperinflation and atelectasis are rarely found (<5%).⁴ In acute, severe asthma, where barotrauma is a significant consideration, more frequent use of chest radiography is justified.⁴ About one third of chest radiographs in one series of admitted asthma patients were found to indicate major abnormalities that needed intervention.⁴ Most of these were cases of pneumonia treated with antibiotics. The same principle applies to children, where the clinical significance of a chest radiograph during the first presenting episode of asthma was very limited.²⁹

Complete blood count may be useful in patients with fever and/or the presence of purulent sputum to support the diagnosis of infection as a trigger of asthma.⁷ Some of the electrocardiographic (ECG) changes noted in acute, severe asthma are right axis deviation and evidence of right ventricular hypertrophy, which usually resolves with effective therapy.

Differential Diagnosis

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