Status Asthmaticus

Practice Essentials

Status asthmaticus is considered a medical emergency. It is the extreme form of an asthma exacerbation that can result in hypoxemia, hypercarbia, and secondary respiratory failure. In practice, the role of the physician is to prevent this from happening through patient compliance with controller medications (eg, steroid inhalers) in an outpatient setting.

Patient education plays a very major role in preventing recurrent attacks of status asthmaticus. In a study by Rice et al, [1] inpatient asthma education was studied in children and adolescents following status asthmaticus. Subjects were enrolled in two groups. One group received the usual posthospitalization instructions and the other group received additional education by lay asthma education volunteers. The group that received the additional education had better compliance in the outpatient setting.

Background

Status asthmaticus is an acute exacerbation of asthma that remains unresponsive to initial treatment with bronchodilators. Status asthmaticus can vary from a mild form to a severe form with bronchospasm, airway inflammation, and mucus plugging that can cause difficulty breathing, carbon dioxide retention, hypoxemia, and respiratory failure. (See Prognosis and Presentation.)

Patients report chest tightness, rapidly progressive shortness of breath, dry cough, and wheezing and may have increased their beta-agonist intake (either inhaled or nebulized) to as often as every few minutes. (See Presentation.)

Typically, patients present a few days after the onset of a viral respiratory illness, following exposure to a potent allergen or irritant, or after exercise in a cold environment. Frequently, patients have underused or have been underprescribed anti-inflammatory therapy. Illicit drug use may play a role in poor adherence to anti-inflammatory therapy. (See Etiology and Presentation.)

A study published in 2004 [2] noted the number of patients with status asthmaticus requiring intensive care admissions had declined over 10 years. The trend was toward less advanced presentations. This may reflect improvements in medication compliance, education, or access to medical care. Nonetheless, concern has been raised more recently about an increase that has since been observed in the severity of asthma symptoms and the need for more intensive care management. [3] (See Prognosis, Workup, Treatment, and Medication.)

See Pediatric Status Asthmaticus for information about status asthmaticus in children.

Treatment goals

Management goals for status asthmaticus are (1) to reverse airway obstruction rapidly through the aggressive use of beta2-agonist agents and early use of corticosteroids, (2) to correct hypoxemia by monitoring and administering supplemental oxygen, and (3) to prevent or treat complications such as pneumothorax and respiratory arrest. (See Treatment and Medication.

Etiology

Exposure to an allergen or trigger causes a characteristic form of airway inflammation in susceptible individuals, exemplified by mast cell degranulation, release of inflammatory mediators, infiltration by eosinophils, and activated T lymphocytes. Multiple inflammatory mediators may be involved, including interleukin (IL)–3, IL-4, IL-5, IL-6, IL-8, IL-10, and IL-13, leukotrienes, and granulocyte-macrophage colony-stimulating factors (GM-CSFs). These, in turn, incite involvement of mast cells, neutrophils, and eosinophils. (See the diagram below.)

Figure depicting antigen presentation by the dendritic cell, with the lymphocyte and cytokine response leading to airway inflammation and asthma symptoms.

Physiologically, acute asthma has two components: an early, acute bronchospastic aspect marked by smooth muscle bronchoconstriction and a later inflammatory component resulting in airway swelling and edema.

Early bronchospastic response

Within minutes of exposure to an allergen, mast cell degranulation is observed along with the release of inflammatory mediators, including histamine, prostaglandin D2, and leukotriene C4. These substances cause airway smooth muscle contraction, increased capillary permeability, mucus secretion, and activation of neuronal reflexes. The early asthmatic response is characterized by bronchoconstriction that is generally responsive to bronchodilators, such as beta2-agonist agents.

Later inflammatory response

The release of inflammatory mediators primes adhesion molecules in the airway epithelium and capillary endothelium, which then allows inflammatory cells, such as eosinophils, neutrophils, and basophils, to attach to the epithelium and endothelium and subsequently migrate into the tissues of the airway. Eosinophils release eosinophilic cationic protein (ECP) and major basic protein (MBP). Both ECP and MBP induce desquamation of the airway epithelium and expose nerve endings. This interaction promotes further airway hyperresponsiveness in asthma. This inflammatory component may even occur in individuals with mild asthma exacerbation.

Bronchospasm, mucus plugging, and edema in the peripheral airways result in increased airway resistance and obstruction. Air trapping results in lung hyperinflation, ventilation/perfusion (V/Q) mismatch, and increased dead space ventilation. The lung becomes inflated near the end-inspiratory end of the pulmonary compliance curve, with decreased compliance and increased work of breathing.

The increased pleural and intra-alveolar pressures that result from obstruction and hyperinflation, together with the mechanical forces of the distended alveoli, eventually lead to a decrease in alveolar perfusion. The combination of atelectasis and decreased perfusion leads to V/Q mismatch within lung units. The V/Q mismatch and resultant hypoxemia trigger an increase in minute ventilation.

Complications

In the early stages of acute asthma, hyperventilation may result in respiratory alkalosis. This is because obstructed lung units (slow compartment) are relatively less numerous than unobstructed lung units (fast compartment). Hyperventilation allows carbon dioxide removal via the fast compartment. However, as the disease progresses and more lung units become obstructed, an increase in the slow compartments occurs, resulting in decreased ability for carbon dioxide removal and eventually causing hypercarbia.

Risk factors

Asthma results from a number of factors, including genetic predisposition and environmental factors. Patients often have a history of atopy. The severity of asthma has been correlated with the number of positive skin test results.

Gastroesophageal reflux disease is another risk factor for asthma, with studies indicating that the reflux of gastric contents with or without aspiration can trigger asthma in susceptible children and adults. Animal studies have shown that the instillation of even minute amounts of acid into the distal esophagus can result in marked increases in intrathoracic pressure and airway resistance. This response is thought to be due to vagal and sympathetic neural responses.

Risk factors for asthma also include the following:

• Viral infections

• Air pollutants - Such as dust, cigarette smoke, and industrial pollutants

• Medications - Including beta-blockers, aspirin, and nonsteroidal anti-inflammatory drugs (NSAIDs)

• Cold temperature

• Exercise

Epidemiology

Occurrence in the United States

Asthma affects up to 10% of the US population. Prevalence has increased by 60% in all ages in the past two decades. A significant rise in hospitalization and asthma mortality rates has accompanied the increased incidence.

Status asthmaticus is usually more common among persons in low socioeconomic groups, regardless of race, as they have less access to regular specialist medical care. [4] People who live alone are particularly affected.

International occurrence

The worldwide incidence of asthma is unclear but is estimated to be about 20 million cases. The dramatic rise in incidence has been attributed, in part, to pollution and industrialization.

Demographics

In the United States, asthma prevalence is higher among children, women, blacks, and persons with reported income below the federal poverty level. [5]

Prognosis

In general, unless a complicating illness such as congestive heart failure or chronic obstructive pulmonary disease is present, status asthmaticus has a good prognosis if appropriate therapy is administered. A delay in initiating treatment is probably the worst prognostic factor. Delays can result from poor access to health care on the part of the patient or even delays in using corticosteroids. Patients with acute asthma should use corticosteroids early and aggressively.

Complications

Complications of asthma can include the following:

• Cardiac arrest

• Respiratory failure or arrest

• Hypoxemia with hypoxic ischemic central nervous system (CNS) injury

• Pneumothorax or pneumomediastinum

• Toxicity from medications

Pneumothorax may complicate acute asthma because of increased airway pressure or as a result of mechanical ventilation. Superimposed infection can also occur in intubated patients. Patients may require a chest tube for pneumothorax or aggressive antibiotic therapy for a superimposed infection.

Mortality

The mortality rate from asthma has increased at an alarming rate. From 1993-1995, the overall annual age-adjusted death rate for asthma increased 40%. The rise in the mortality rate has been even higher among blacks, among people living in poverty, and among children aged 4 years or younger and those aged 9-16 years. More recently, asthma mortality rates are trending lower. [6]

The mortality risk is also particularly high in patients who delay medical treatment, especially treatment with systemic corticosteroids. Patients with other preexisting conditions (eg, restrictive lung disease, congestive heart failure, chest deformities) are at particular risk of death from status asthmaticus. Patients who smoke regularly have chronic inflammation of the small airways and are also at greater risk of death from status asthmaticus. Data also suggest higher mortality in persons of lower socioeconomic status, with psychiatric illness, with recent poorly controlled asthma, or with a history of prior intubation. One study links exposure to the common mold Alternaria alternata and mortality in asthma. [7]

Patient Education

Asthma is a chronic illness. Patients and their families must be provided with a team that can offer education and follow-up care. Prior to discharge, the team that provides asthma education should meet with the family and the patient to impart information regarding maintenance, monitoring, and measures for environmental control. Early identification of exacerbations and the importance of adherence with therapy are paramount.

Studies have also demonstrated the importance of an asthma education plan. Guidelines regarding this literature have been published. [8]  

Patients require instruction in the appropriate use of inhalers, to be compliant with therapy, and to practice stress-avoidance measures. Stress factors (ie, triggers of asthma attacks) include pet dander, house dust, and mold. Strongly discourage patients from smoking, this habit should be avoided at all costs.

Clinical Presentation

History

Patients with status asthmaticus have severe dyspnea that has developed over hours to days. In most cases, there is a lead time of several days. [8] Frequently, these individuals have a previous history of endotracheal intubation and mechanical ventilation, frequent emergency department visits, and previous use of systemic corticosteroids.

If the physician does not obtain a thorough history for a patient with asthma, he or she may not recognize a person with high risk factors for acute and severe decompensation. This failure may prevent the aggressive use of bronchodilators, corticosteroids, and monitoring. When obtaining the history from a patient presenting with an acute exacerbation of asthma, the following should be determined:

• Presence of current illness, such as upper respiratory tract infection or pneumonia

• History of chronic respiratory diseases (eg, bronchopulmonary dysplasia, chronic lung disease of infancy)

• Severe previous respiratory syncytial virus (RSV) disease

• History of atopy

• History of allergies

• Family history of asthma

• Presence of pets or smokers in the home

• Known triggering factors

• Home medications - Obtain a detailed list of medications being taken at home and, if possible, their timing and dosage

Risk factors for developing severe or persistent status asthmaticus include the following:

• History of increased use of home bronchodilator treatment without improvement or effect

• History of previous intensive care unit (ICU) admissions, with or without intubation and mechanical ventilatory support

• Asthma exacerbation despite recent or current use of corticosteroids

• Frequent emergency department visits and/or hospitalization (implies poor control)

• Less than 10% improvement in peak expiratory flow rate (PEFR) from baseline despite treatment

• History of syncope or seizures during acute exacerbation

• Oxygen saturation below 92% despite supplemental oxygen

• Subgroup of asthma patients who are poor perceivers of dyspnea are a greater risk of intubation and death [9]

Determine whether the patient has a severe asthma exacerbation without wheezing (ie, the silent chest). Such patients may have such severe airway obstruction or be so fatigued that they are unable to generate enough airflow to wheeze. This is an ominous sign of impending respiratory failure.

Physical Examination

Patients are usually tachypneic upon examination and, in the early stages of status asthmaticus, may have significant wheezing. Initially, wheezing is heard only during expiration, but wheezing later occurs during expiration and inspiration.

The chest is hyperexpanded, and accessory muscles, particularly the sternocleidomastoid, scalene, and intercostal muscles, are used. Later, as bronchoconstriction worsens, the wheezing may disappear, which may indicate severe airflow obstruction.

Normally, the difference in systolic blood pressure between inspiration and expiration does not exceed 15 mm Hg. In patients with severe asthma, a difference of greater than 25 mm Hg usually indicates severe airway obstruction.

An inability to speak more than one or two words at a time may also be observed in the later stages of an acute asthma episode. Ventilation/perfusion mismatch results in decreased oxygen saturation and hypoxia. Vital signs may show tachycardia and hypertension. The peak flow rate should be included in the vital signs in patients who are able to cooperate and who are able to tolerate the peak flow maneuver without significant distress.

The patient’s level of consciousness may progress from lethargy to agitation, air hunger, and even syncope and seizures. If untreated, prolonged airway obstruction and marked increase in the work of breathing may eventually lead to bradycardia, hypoventilation, and even cardiorespiratory arrest.

General examination

The peak flow rate is a standard measure of airflow obstruction and is relatively simple to perform. Most patients with more than a mild exacerbation of asthma have hypoxia and decreased oxygen saturation due to V/Q mismatch. Oxygen saturation may increase following the use of bronchodilators secondary to an increase in V/Q mismatch. Some patients prefer to remain seated and leaning forward, rather than assuming a supine position.

Retractions (ie, intercostal and subcostal) and the use of abdominal muscles may be observed in patients with status asthmaticus. The use of accessory muscles has been shown to correlate with the severity of airflow obstruction. An abnormally prolonged expiratory phase with audible wheezing can be observed. Patients with moderate to severe asthma are often unable to speak in full sentences.

Dehydration can occur in adults, but is observed less frequently than in children.

Cardiovascular symptoms may include tachycardia or hypertension in mild to moderate asthma. With worsening hypoxemia, hypercarbia, marked air trapping, and hyperinflation, the ventricular stroke volume is compromised and hypotension and bradycardia may be observed.

CNS status ranges from wide awake to lethargic and from agitated to comatose. As hypoxemia progresses, lethargy progresses to agitation caused by air hunger. As more lung units become obstructed, hypoxemia worsens and hypercarbia develops. Both hypoxemia and hypercarbia can lead to seizures and coma and are late signs of respiratory compromise.

Examination of the respiratory system

Wheezing occurs from air moving through narrowed, obstructed airways. Thus exhalation results in turbulent airflow and produces wheezes. Although asthma is the most common cause of wheezing, anything that causes airway obstruction and narrowing that results in turbulent airflow may generate wheezes. Therefore, not all wheezing is asthma.

Auscultation often reveals bilateral expiratory and possibly inspiratory wheezes and crackles. Air entry may or may not be diminished or absent, depending on severity. Remember, the silent chest may herald impending respiratory failure in a patient too obstructed or fatigued to generate wheezing.

If tension pneumothorax develops, signs of tracheal deviation to the opposite side, decreased or absent air entry on the affected side, shift of the location of heart sounds, and hypotension may be evident. Air leaks may also result in pneumomediastinum and subcutaneous emphysema.

In moderate to severe status asthmaticus, abdominal muscle use can cause symptoms of abdominal pain.

Pulsus paradoxus (a decrease in the systolic blood pressure during inspiration) results from a decrease in cardiac stroke volume with inspiration due to greatly increased left-ventricular afterload. This increase is generated by the dramatic increase in negative intrapleural and transmural pressure in a patient struggling to breathe against significant airways obstruction. Pulsus paradoxus of greater than 20 mm Hg correlates well with the presence of severe airways obstruction (ie, forced expiratory volume in 1 second [FEV1] < 60% predicted).

Differential Diagnoses

Diagnostic Considerations

Status asthmaticus can be misdiagnosed when wheezing occurs from an acute cause other than asthma. Some of these alternative causes of wheezing are discussed below.

Extrinsic compression

Airways can be compressed from vascular structures, such as vascular rings, lymphadenopathy, or tumors.

Congestive heart failure

Airway edema may cause wheezing in CHF. In addition, vascular compression may compress the airways during systole with cardiac ejection, resulting in a pulsatile wheeze that corresponds to the heart rate. This is sometimes erroneously referred to as cardiac asthma.

Differential Diagnoses

• Allergic bronchopulmonary aspergillosis

• Aspiration Syndromes

• Bronchiectasis

• Bronchiolitis

• Bronchiolitis obliterans

• Chronic bronchitis

• Chronic Obstructive Pulmonary Disease (COPD)

• Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss Syndrome)

• Croup

• Cystic Fibrosis

• Emphysema

• Foreign Bodies of the Airway

• Gastroesophageal Reflux Disease

• Heart Failure

• Idiopathic Pulmonary Arterial Hypertension

• Inhalation injury

• Pulmonary Artery Sling

• Vocal Cord Dysfunction

Workup

Approach Considerations

The selection of laboratory studies depends on historical data and patient condition. Tests that should be performed in patients with status asthmaticus include the following:

• Complete blood cell (CBC) count

• Arterial blood gas (ABG) analysis

• Serum electrolyte levels

• Serum glucose levels

• Peak expiratory flow measurement

• Chest radiography

• Electrocardiogram (in older patients)

• Blood theophylline levels (if indicated)

• IgE level in selected patients

Chest Radiography

Obtain a chest radiograph to evaluate for pneumonia, pneumothorax, pneumomediastinum, congestive heart failure (CHF), and signs of chronic obstructive pulmonary disease, which would complicate the patient's response to treatment or reduce the patient's baseline spirometry values.

Chest radiography is indicated in patients who have an atypical presentation or in those who do not respond to therapy.

CBC Count

Obtain a CBC count and differential to evaluate for infectious causes (eg, pneumonia, viral infections such as croup), allergic bronchopulmonary aspergillosis, and Churg-Strauss vasculitis. When elevated, serum lactate levels (when obtained early at the onset of status asthmaticus) can correlate with improved lung function.

A CBC count and differential may demonstrate an elevated white blood cell count, with or without a shift to the left. The CBC count may also indicate a bacterial infection. However, beta-agonists and corticosteroids may result in demargination of white cells with an increase in the peripheral white cell count. [10, 11]

Arterial Blood Gas

An ABG value can be obtained to assess the severity of the asthma attack and to substantiate the need for more intensive care. However, the use of blood gas determination is controversial. The information generated by this measurement may be helpful in determining whether or not to intubate a patient with asthma. However, such decisions are usually made on the basis of clinical grounds in a patient who is either in respiratory arrest or impending respiratory arrest.

If a patient with acute asthma has adequate peripheral oxygen saturation, is receiving further therapy, and does not warrant immediate intubation, then the usefulness of blood gas data should be weighed against the potential pain and agitation that running this test may cause in a child. Improvement or deterioration in acute asthma can generally be followed clinically. Indwelling arterial catheters reduce the pain issue and generate highly reliable and reproducible information.

ABG determinations are indicated when the peak expiratory flow (PEF) rate or the forced expiratory volume in 1 second (FEV1) is less than or equal to 30% of the predicted value or when the patient shows evidence of fatigue or progressive airway obstruction despite treatment.

The 4 stages of blood gas progression in persons with status asthmaticus are as follows:

• Stage 1 - Characterized by hyperventilation with a normal partial pressure of oxygen (PO2)

• Stage 2 - Characterized by hyperventilation accompanied by hypoxemia (ie, a low partial pressure of carbon dioxide [PCO2] and low PO2)

• Stage 3 - Characterized by the presence of a false-normal PCO2; ventilation has decreased from the hyperventilation present in the second stage; this is an extremely serious sign of respiratory muscle fatigue that signals the need for more intensive medical care, such as admission to an ICU and, probably, intubation with mechanical ventilation.

• Stage 4 - Characterized by a low PO2 and a high PCO2, which occurs with respiratory muscle insufficiency; this is an even more serious sign that mandates intubation and ventilatory support.

Serum Electrolyte and Serum Glucose Levels

Serum electrolyte measurement, particularly of serum potassium levels, is important. Medications used to treat status asthmaticus may cause hypokalemia. A low pH may result in a transient elevation of potassium.

Serum glucose levels may become elevated from stress, the use of beta-agonist agents, such as epinephrine, and the use of corticosteroids. Because of poor stores, however, hypoglycemia may develop in younger children in response to stress.

Blood Theophylline Levels

Blood theophylline levels provide an important monitoring component in patients taking this medication (either at home or while hospitalized) and especially in patients who have received a bolus infusion of theophylline followed by continuous intravenous (IV) infusion. The volume of distribution of theophylline is 0.56 mg/L in children and adults. A dose of 1 mg/kg of theophylline raises the serum level by approximately 2 mg/dL.

If the patient has been receiving theophylline at home, obtain a serum theophylline level before therapy. Following a loading dose (if needed), obtain a serum level 30 minutes after the end of the infusion. For serum theophylline steady-state levels, obtain a serum sample at 24-36 hours in children younger than 6 months, at 12-24 hours for those aged 6 months to 12 years, and at 24 hours for children aged 12 years and older.

Factors that decrease theophylline clearance (increase levels) include cimetidine, erythromycin and other macrolide antibiotics, viral infections, cirrhosis, fever, propranolol, and ciprofloxacin.

Factors that increase theophylline clearance (decrease levels) are IV isoproterenol, phenobarbital, smoking, [12] phenytoin, and rifampin.

Pulmonary Function Testing

PEF, FEV1, and spirometry

Also see Pulmonary Function Testing.

The most important and readily available test to evaluate the severity of an asthma attack is the measurement of peak expiratory flow (PEF). PEF monitors are commonly available to patients for use at home and they provide asthmatic patients with a guideline for changes in lung function as they relate to changes in symptoms. In most patients with asthma, a decrease in peak flow as a percentage of predicted value correlates with changes in spirometry values.

Although the forced expiratory volume in one second (FEV1) is also used to monitor the degree of airway obstruction, in patients who are acutely ill, PEF monitoring is more commonly performed. Note that spirometry is more accurate (sensitive and reproducible).

According to the guidelines of the National Heart, Lung, and Blood Institute/National Asthma Education and Prevention Program, [13] hospitalization is generally indicated when the PEF or FEV1 after treatment is greater than 50%, but less than 70%, of the predicted value. Hospitalization in an ICU is dependent on the severity of symptoms, use of accessory muscles, and ABG results, as well as an FEV1 less than 50%.

A drop in the FEV1 to less than 25% of the predicted value indicates a severe airway obstruction. A patient with an FEV1 of greater than 60% of the predicted value may be treated in an outpatient setting, depending on the clinical situation. Some with associated fixed obstruction may have abnormal spirometry at baseline. Also, in very obese patients, FEV1 may be diminished. Thus, evaluation of the FEV1/FVC is quite helpful. However, if the patient's FEV1 or PEF rate drops to less than 50% of predicted, admission to the hospital is recommended.

Spirometry can be employed to monitor the progression of asthma. As the results indicate improvement, treatment may be adjusted accordingly. If a portable spirometry unit is not available, a PEF rate of 20% or less of the predicted value (ie, usually < 100 L/min) suggests severe airflow obstruction and impending respiratory failure.

Pulse oximetry

Pulse oximetry provides a continuous evaluation of oxygen saturation, which is vitally important because the primary cause of death in status asthmaticus is hypoxia.

The advantages of pulse oximetry are that pulse oximetry is readily available, it is noninvasive, it provides continuous monitoring, and it is a good indicator of hypoxemia resulting from a ventilation/perfusion mismatch.

The disadvantages of pulse oximetry are that movement artifact can be significant and the modality may provide an erroneous reading when pulsatile flow is inadequate (ie, shock with poor perfusion) or in the presence of anemia. Also, by the time desaturation occurs, there is significant reduction in oxygen and the use of a nebulized beta2 agonist can result in reduction in oxygen saturation secondary to increase in V/Q mismatch.

Other

Findings may be diminished in other pulmonary function tests (eg, maximum expiratory flow rate, mid-maximum expiratory flow rate, forced vital capacity). Functional residual capacity and residual volume increase because of air trapping, However, these tests require the child being in a body plethysmograph, which is impractical in the severely ill child.

Impulse Oscillometry Testing

In patients with reactive airways, Saadeh et al reported that impulse oscillometry detects false-negative spirometry values and provides a sensitive index of asthma control over the spectrum of mild to severe, persistent asthma. [14]

Patients can be shown the results of forced oscillation testing that occur with peripheral airway inflammation and obstruction. Review the test results with patients and show them the improvement with inhaled corticosteroids and the deterioration when they are not compliant with anti-inflammatory medications. This information may materially enhance patients' awareness of the need for continuing treatment, despite an absence of wheezing.

Technique

With forced oscillation testing using the impulse oscillometry system (IOS), patients are tested for 30-40 seconds during quiet breathing, without forced respiratory efforts. A small loudspeaker pushes "burps" of air into patients and pulls them back from the mouthpiece 5 times each second.

The measurement of airflow resistance during normal breathing requires no maximal forced expiratory efforts and does not subject patients to bronchoprovocation from forced expiration. Resistance is distributed between large airways and smaller, more peripheral airways, with distinct patterns attributable to each.

Bronchospasms and increased large-airway resistance appear as increases in resistance at higher (25-35 cycles/s) components of oscillation frequency. Additionally, a pattern of increased resistance with increasing airflow is typical of a large-airway bronchospasm. In such patients, resistance at the beginning and end of inspiration and expiration is at its minimum, with increased levels during midinspiration and midexpiration. In such patients, a deep inspiration is often followed by reflex bronchoconstriction and increased resistance for 30 seconds or more, signaling increased airway reactivity.

Peripheral airway inflammation and obstruction are signaled by increased resistance at low (5 cycles/s) oscillation frequencies that are decreased at higher oscillation frequencies (15 or 20 cycles/s). In association with the fall in resistance from 5-15 cycles per second, the magnitude of respiratory reactance in peripheral airway inflammation and obstruction increases.

Careful attention must be paid to whether patients have their lips fully closed around the mouthpiece. Patients with acute dyspnea may feel constrained when breathing through a mouthpiece and may reflexively open their mouths to increase airflow during late inspiration. This is analogous to flaring alae nasi with dyspnea and results in characteristic airflow leak patterns. This causes underestimation of true airflow resistance. IOS tests with such airflow leak patterns must be repeated after reassuring the patient and ensuring closure of the lips around the mouthpiece.

Histologic Findings

Autopsy results from patients who died from status asthmaticus of brief duration (ie, developed within hours) show neutrophilic infiltration of the airways. In contrast, results from patients who developed status asthmaticus over days show eosinophilic infiltration; this is more common and is associated with eosinophil up-regulation. Autopsy results also show extensive mucus production and severe bronchial smooth muscle hypertrophy. However, the predominant response, based on results from bronchoalveolar lavage studies, is eosinophilic in nature.

The eosinophil itself can lead to epithelial destruction through its own degrading products (eg, cationic proteins). This destruction can result in inflammation and, later, a neutrophilic response.

Staging

The 4 stages of status asthmaticus are based on ABG progressions in status asthma. Patients in stage 1 or 2 may be admitted to the hospital, depending on the severity of their dyspnea, their ability to use accessory muscles, and their PEF values or FEV1 after treatment (>50% but < 70% of predicted values).

Patients with ABG determinations characteristic of stages 3 and 4 require admission to an ICU. The PEF value or FEV1 is less than 50% of the predicted value after treatment.

Stage 1

Patients are not hypoxemic, but they are hyperventilating and have a normal PO2. Data suggest that to possibly facilitate hospital discharge, these patients may benefit from ipratropium treatment via a handheld nebulizer in the emergency setting as an adjunct to beta-agonists.

Stage 2

This stage is similar to stage 1, but patients are hyperventilating and hypoxemic. Such patients may still be discharged from the emergency department, depending on their response to bronchodilator treatment, but will require systemic corticosteroids.

Stage 3

These patients are generally ill and have a normal PCO2 due to respiratory muscle fatigue. Their PCO2 is considered a false-normal value and is a very serious sign of fatigue that signals a need for expanded care. This is generally an indication for elective intubation and mechanical ventilation, and these patients require admission to an ICU. Parenteral corticosteroids are indicated, as is the continued aggressive use of an inhaled beta2-adrenergic bronchodilator. These patients may benefit from theophylline.

Stage 4

This is a very serious stage in which the PO2 is low and the PCO2 is high, signifying respiratory failure. These patients have less than 20% of predicted lung function or FEV1 and require intubation and mechanical ventilation.

Patients in stage 4 should be admitted to an ICU. Switching from inhaled beta2-agonists and anticholinergics to metered-dose inhalers (MDIs) via mechanical ventilator tubing is indicated. Parenteral corticosteroids are essential, and theophylline may be added, as with patients in stage 3.

Treatment & Management

Approach Considerations

After confirming the diagnosis and assessing the severity of an asthma attack, direct treatment toward controlling bronchoconstriction and inflammation. Beta-agonists, corticosteroids, and theophylline are mainstays in the treatment of status asthmaticus. Sevoflurane, a potent inhalation agent, was successful in a single case report in which it was used when conventional treatment failed in a woman aged 26 years. [15]

Fluid replacement

Hydration, with intravenous normal saline at a reasonable rate, is essential. Special attention to the patient's electrolyte status is important.

Hypokalemia may result from either corticosteroid use or beta-agonist use. Correcting hypokalemia may help to wean an intubated patient with asthma from mechanical ventilation. Hypophosphatemia may result from poor oral intake and is also an important consideration when weaning such patients.

Antibiotics

The routine administration of antibiotics is discouraged. Patients are administered antibiotics only when they show evidence of infection (eg, pneumonia, sinusitis). In some situations, sinus imaging using computed tomography (CT) scanning or plain radiography [16, 17] may be essential to rule out chronic sinusitis. [18]

Oxygen monitoring and therapy

Monitoring the patient's oxygen saturation is essential during the initial treatment of status asthmaticus. Arterial blood gas (ABG) values are usually used to assess hypercapnia during the patient's initial assessment. Oxygen saturation is then monitored via pulse oximetry throughout the treatment protocol. Oxygen saturation may increase following the use of bronchodilators secondary to an increase in V/Q mismatch.

Oxygen therapy is essential, with hypoxia being the leading cause of death in children with asthma. Oxygen therapy can be administered via a nasal canula or mask, although patients with dyspnea often do not like masks. With the advent of pulse oximetry, oxygen therapy can be easily titrated to maintain the patient's oxygen saturation above 92% (>95% in pregnant patients or those with cardiac disease).

In the event of significant hypoxemia, non-rebreathing masks may be used to deliver as much as 98% oxygen. Tracheal intubation and mechanical ventilation are indicated for respiratory failure.

Chest tube placement

Chest tube placement may be necessary in the management of pneumothorax.

Nitrate oxide

Nitrate oxide has been employed in a child with refractory asthma. The future role of this therapy remains to be determined.

Leukotriene modifiers

Leukotriene modifiers are useful for treating chronic asthma but not acute asthma. This treatment may be beneficial if used via a nebulizer, but it remains experimental. Most studies have examined intravenous use. [19, 20]  Montelukast can be used as an add-on treatment for asthma in general. It is mostly used for improving the quality of life as an add-on therapy to inhaled corticosteroids and not necessarily just for status asthmaticus. There has been one study that showed minimal to no effect of using montelukast in the emergency department setting for patients with status asthmaticus. [21, 22] In general, it did not show any significant benefit. It is not used specifically for status asthmaticus prevention.

ICU admission criteria

Indications for ICU admission include the following:

• Altered sensorium

• Use of continuous inhaled beta-agonist therapy

• Exhaustion

• Markedly decreased air entry

• Rising PCO2 despite treatment

• Presence of high-risk factors for a severe attack

• Failure to improve despite adequate therapy

Surgery

Status asthmaticus is generally managed by means of medical therapy, with some exceptions. For example, thoracostomy is indicated in pneumothoraces.

Some children may have asthma that is primarily exacerbated by gastroesophageal reflux disease. Some patients can be treated with a combination of antireflux (eg, proton pump inhibitors) and histamine 2 (H2)–receptor antagonist agents. However, surgery, such as Nissen fundoplication, is occasionally required.

Anesthesia support is needed if inhaled anesthetic agents are considered for refractory severe intubated status asthmaticus.

If all other support modalities fail and extracorporeal membrane oxygenation (ECMO) is required, surgical support for cannula placement should take place at an established pediatric ECMO center.

Diet

Some children with asthma may have episodes triggered by food allergies. Consultation with a nutritionist may be necessary to provide appropriate dietary management.

Beta2-Agonists

The first line of therapy is bronchodilator treatment with a beta2-agonist, typically albuterol. Handheld nebulizer treatments may be administered either continuously (10-15 mg/h) or by frequent timing (eg, q5-20min), depending on the severity of the bronchospasm.

The dose of albuterol for intermittent dosing is 0.3-0.5 mL of a 0.5% formulation mixed with 2.5 mL of normal saline. Many of these preparations are available in a premixed form with a concentration of 0.083%.

Studies have also demonstrated an excellent response to the well-supervised use of albuterol via an MDI with a chamber. The dose is 4 puffs, repeated at 15- to 30-minute intervals as needed. Most patients respond within 1 hour of treatment.

The US Food and Drug Administration (FDA) approved the use of the R isomer of albuterol, known as levalbuterol, for treating patients with acute asthma. This isomer has fewer effects on the heart rhythm (ie, tachyarrhythmia) and is associated with fewer occurrences of tremors, while having the same or greater clinical bronchodilator effects as racemic albuterol. The decreased prevalence of adverse effects with this single isomer medication may allow physicians to use nebulizer therapy in patients with acute asthma more frequently, with less concern over the adverse effects that occur with other bronchodilators (eg, albuterol, metaproterenol). The dose of levalbuterol is either a 0.63-mg vial for children or a 1.26-mg vial for adults. A study in 2009 documented that although a slight decrease may have occurred in the duration of continuous nebulizer treatment with levalbuterol compared with albuterol, the difference was not statistically significant. [23]

The above drugs, especially albuterol, are safe to use during pregnancy. Beta2-agonists act via stimulation of cyclic adenosine monophosphate (AMP)–mediated bronchodilation. The airway is rich in beta receptors; the stimulation of these receptors relaxes airway smooth muscles, increases mucociliary clearance, and decreases mucous production.

The nebulized, inhaled route of administration is generally the most effective route of delivery for beta2-agonists. Inhaled beta-agonists can be administered intermittently or as continuous, nebulized aerosol in a monitored setting. Some patients with severe, refractory status asthmaticus may benefit from the addition of beta-agonists delivered intravenously.

Beta-agonists are generally most effective in the early asthma reaction phase. However, patients who present with status asthmaticus despite frequent use of beta-agonists at home may have tachyphylaxis and may exhibit resistance to these agents. Similar issues may be seen in patients using long-term inhaled long-acting beta-agonists. Therefore, these patients may not respond as well when these agents are given in the hospital setting.

Endotracheal adrenaline in patients who are intubated has been associated with variable success in different studies. However, based on the current literature, no specific advantage can be gained at this point by using endotracheal adrenaline. [24]

Continuous inhaled albuterol and intravenous methylprednisolone are considered important in the management of status asthmaticus. In a report by Beach et al, [25] a 40-year-old patient with status asthmaticus acquired an accelerated idioventricular rhythm while on this treatment. The rhythm resolved after the condition was controlled and the treatment was discontinued. Three months’ follow-up showed no sequelae. Therefore, this type of rhythm appears to be benign and should not pose a significant alarm.

High-dose albuterol has been started in a limited fashion in children with status asthmaticus. The high dose was defined as 150 mg/h and the lower dose was 75 mg/h. The higher dose resulted in low rate of subsequent mechanical ventilation and a short pediatric intensive care unit length of stay. There was no evidence of toxicity.

Nonselective beta2-agonists

Patients whose bronchoconstriction is resistant to continuous, handheld nebulizer treatments with traditional beta2-agonists may be candidates for nonselective beta2-agonists (eg, epinephrine [0.3-0.5 mg] or terbutaline [0.25 mg]) administered subcutaneously. [26] However, systemic therapy has no proven advantage over aerosol therapy with selective beta2 agents.

Exercise caution in patients with other complicating factors (eg, congestive heart failure (CHF), history of cardiac arrhythmia). Intravenous isoproterenol is not recommended for the treatment of asthma, because of the risk of myocardial toxicity. [27]

Some practitioners advocate monitoring cardiac enzyme levels in patients who receive prolonged, significant infusions of intravenous beta-agonists. Small studies in children have documented that enzymes such as troponin I may be elevated during terbutaline infusion, although these levels normalize as terbutaline is discontinued. The clinical significance of such enzyme elevation remains unclear. [28, 29]

Anticholinergics

Anticholinergic agents are believed to work centrally by suppressing conduction in vestibular cerebellar pathways. They may have an inhibitory effect on parasympathetic nervous system. They may also decrease mucus production and improve mucociliary clearance

Ipratropium bromide

Ipratropium bromide (Atrovent), a quaternary amine that does not cross the blood-brain barrier, is the recommended anticholenergic parasympatholytic agent of choice. This synthetic ammonium compound is very similar structurally to atropine. It comes in premixed vials at 0.2%, is administered every 4-6 hours, and can be synergistic with albuterol or other beta2-agonists when treating severe acute asthma exacerbations.

Ipratropium may also be used as an alternative bronchodilator in patients who are unable to tolerate inhaled beta2-agonists. Because children appear to have more cholinergic receptors, they are more responsive to parasympathetic stimulation than adults.

Atropine, a tertiary amine, may also be used and nebulized. However, the drug may cause CNS effects because it may cross the blood brain barrier.

Glucocorticosteroids

Glucocorticosteroids are the most important treatment for status asthmaticus. [30] These agents can decrease mucus production, improve oxygenation, reduce beta-agonist or theophylline requirements, and activate properties that may prevent late bronchoconstrictive responses to allergies and provocation.

In addition, corticosteroids can decrease bronchial hypersensitivity, reduce the recovery of eosinophils and mast cells in bronchioalveolar lavage fluid, decrease the number of activated lymphocytes, and help to regenerate the bronchial epithelial cells.

Corticosteroids may be administered intravenously or orally. Although most practitioners administer corticosteroids intravenously during status asthmaticus, some studies indicate that early administration of oral corticosteroids may be just as effective.

Corticosteroid action usually requires at least 4-6 hours to occur following corticosteroid administration because protein synthesis is required before the initiation of a corticosteroid’s anti-inflammatory effects. Because of this, patients with status asthmaticus must depend on other supportive measures (eg, beta2-agonists, oxygen, adequate ventilation) in their initial treatment while awaiting the action of corticosteroids. The usual dose is oral prednisone at 1-2 mg/kg daily.

Methylprednisolone is used to treat inflammatory and allergic reactions. By reversing increased capillary permeability and suppressing polymorphonuclear (PMN) cell activity, it may decrease inflammation. Other corticosteroids may be used in equivalent dosages. In some authors' experience, methylprednisolone provides excellent efficacy in pediatric patients when given intravenously at 1 mg/kg/dose every 6 hours. [31, 32]

Corticosteroid treatment for acute asthma is necessary but has potential adverse effects. The serum glucose value must be monitored. Insulin can be administered on a sliding scale if needed. Monitoring a patient's electrolyte levels, especially potassium, is essential. Hypokalemia can cause muscle weakness, which may worsen respiratory distress and cause cardiac arrhythmias.

Adverse effects of pulse therapy, in some authors' experience, are minimal and are comparable to those of the traditional doses of intravenous corticosteroids. The adverse effects may include hyperglycemia, which is usually reversible once steroid therapy is stopped, increased blood pressure, weight gain, increased striae formation, and hypokalemia. Long-term adverse effects depend on the duration of steroid therapy after the patient leaves the hospital.

Nebulized steroids

The use of nebulized corticosteroids for treating status asthmaticus is controversial. Data comparing nebulized budesonide with prednisone in children suggest that the latter therapy is more effective for treating status asthmaticus.

No good scientific evidence supports using nebulized dexamethasone or triamcinolone via a handheld nebulizer. In fact, in some authors' experience, more adverse effects, including a cushingoid appearance and irritative bronchospasms, have occurred with these nebulizers.

Other Bronchodilators

Methylxanthines

The role of methylxanthines, such as theophylline or aminophylline, in the treatment of severe acute asthma has been diminished since the advent of potent selective beta-agonists and their use at higher doses. [33] At therapeutic doses, methylxanthines are weaker bronchodilators than beta-agonists and have many undesirable adverse effects, such as frequent induction of nausea and vomiting. Furthermore, most studies have failed to show additional benefit when methylxanthines are administered to patients who are already receiving frequent beta-agonists and corticosteroids.

Nevertheless, several prospective, randomized, controlled studies in children with refractory status asthmaticus have reexamined the role of the methylxanthines theophylline and aminophylline and have demonstrated improvement in the clinical asthma scores when compared with placebo control.

One study compared intravenous theophylline with intravenous terbutaline in critically ill children with refractory asthma and demonstrated equal therapeutic efficacy but significantly lower costs associated with theophylline use. [34]

Theophylline

Among the effects of theophylline that are important in managing asthma are bronchodilatation, increased diaphragmatic function, and central stimulation of breathing.

Usually, theophylline is given parenterally, but it can also be given orally, depending on the severity of the asthma attack and the patient's ability to take medications. This class of drugs can induce tachycardia and decrease the seizure threshold (especially in children); therefore, therapeutic monitoring is mandatory.

In the past the typical theophylline therapeutic levels ranged from 10-20 mcg/mL. However, adverse effects can occur even with therapeutic levels. A lower therapeutic range of 8-15 mcg/mL has therefore been adopted by many institutions. Seizures have occurred even with levels below 10 mcg/mL.

Theophylline also has significant drug interactions with medications such as ciprofloxacin, digoxin, and warfarin. These interactions may decrease the rate of theophylline clearance by interfering with P-450 site metabolism. On the other hand, phenytoin and cigarette smoking can increase the rate of metabolism of theophylline and, therefore, can decrease the therapeutic level of the drug.

Manage the theophylline dose in persons who quit smoking fewer than 6 months previously as if they are still smoking. Patients who smoke or those on phenytoin require higher loading and maintenance doses of theophylline. Other adverse effects can include nausea, vomiting, and palpitations.

The usual loading dose of theophylline is 6mg/kg, followed by maintenance doses of 1mg/kg/h in the emergent setting. In patients who smoke, the maintenance dose may be higher and the loading dose may be slightly higher. Patients on phenytoin should also receive increased maintenance doses of theophylline. Patients with liver disease or elderly patients may require a maintenance dose as low as 0.25mg/kg/h.

Aminophylline

Conflicting reports on the efficacy of aminophylline therapy have made it controversial. Starting intravenous aminophylline may be reasonable in patients who do not respond to medical treatment with bronchodilators, oxygen, corticosteroids, and intravenous fluids within 24 hours. [35]

Data suggest that aminophylline may have an anti-inflammatory effect in addition to its bronchodilator properties. The loading dose is usually 5-6 mg/kg, followed by a continuous infusion of 0.5-0.9 mg/kg/h.

Magnesium sulfate

Intravenous magnesium sulfate infusion has been advocated in the past for the treatment of acute asthma. Magnesium can relax smooth muscle and hence may cause bronchodilation by competing with calcium at calcium-mediated smooth muscle ̶ binding sites. Usually 1 gram or a maximum of 2.5 grams during the initiation of therapy may be considered.

One double-blind, placebo-controlled study reported a significant increase in PEF, FEV1, and forced vital capacity in children who had asthma and were treated with a single 40-mg/kg dose of magnesium sulfate infused over 20 minutes, along with steroids and inhaled bronchodilators, compared with control subjects who received saline placebo. [36] In addition, patients who received intravenous magnesium (8 of 16 patients) were significantly more likely to be discharged home from the presenting emergency department than were control subjects (0 of 14 patients).

No data regarding duration of effect or efficacy with repeated doses are available, and no guidelines describe the monitoring of serum magnesium levels if more than an initial magnesium dose is administered. In one small study of four children who received 40-50 mg/kg of magnesium sulfate, serum magnesium levels were all less than 4 mg/dL, whereas electrocardiographic changes are generally not seen until levels exceed 4-7 mg/dL. Adverse effects may include facial warmth, flushing, tingling, nausea, and hypotension.

This therapy can be tried, especially in pregnant women, as an adjunct to beta2 bronchodilator therapy. However, more studies have not confirmed the effectiveness of this treatment, [37, 38] and its use is still controversial.

Inhaled magnesium sulfate has generated some interest with regard to the treatment of status asthmaticus, when combined with beta-agonist use. [39]

In a retrospective study by Vaiyani and Irazuzla, [40] magnesium sulfate infusion for status asthmaticus in children was evaluated. Two groups of patients were identified. Nineteen of the first group received high-dose prolonged magnesium infusions consisting of 75 mcg/kg if the weight was less than 30 kg. If the weight was more than 30 kg, the dose was 50 mg/kg. In both situations, the infusion of magnesium sulfate was continuous over 4 hours given at 40 mg/kg/h. In the second group, no loading dose was given. The dose was 50 mg/kg/h over 5 hours. There was no difference in the magnesium concentration in the serum in both of these groups, and the amount of bronchodilation was similar. Based these and other data, magnesium sulfate remains an important regimen in the treatment of status asthmaticus, with excellent tolerability. [41]

Sedatives

Patients may benefit from sedatives in very small doses and under controlled, monitored settings. Sedatives should be used judiciously, if at all. For example, lorazepam (0.5 or 1 mg intravenously) could be used for patients who are very anxious and are undergoing appropriate and aggressive bronchodilator therapy. More powerful agents (eg, oxybutynin) can be administered to intubated patients to achieve sedative, amnestic, and anxiolytic effects.

In the past several years, new therapies have been developed in patients with severe and resistant status asthmaticus despite mechanical ventilation.

Anesthetics

Ketamine

Ketamine is a short-acting pentachlorophenol derivative that exerts bronchodilatory effects because it leads to an increase in endogenous catecholamine levels, which may bind to beta receptors and cause smooth muscle relaxation and bronchodilation.

Ketamine was used in the management of status asthmaticus in a prospective trial in patients with respiratory failure who did not respond adequately to mechanical ventilation. [42] This agent improved airway resistance, particularly the lower airways, as well as improve lung compliance. Significant improvement in oxygenation and hypercarbia has been reported, even 15 minutes after the administration of ketamine.

Case reports have also described the use of ketamine as a sedative to reduce anxiety and agitation that can exacerbate tachypnea and work of breathing and potentially obviate further respiratory failure in small children with status asthmaticus.

Ketamine as a continuous infusion may induce relaxation of the airways with limited anesthesia. However, its role is still limited in status asthmaticus. Central nervous system sedation, which may require intubation, is a limitation in its use. It is also noted that its use has been limited to the pediatric population and at a very low dosage. [43, 44, 45]

Inhaled anesthetic agents

Inhaled anesthetic agents, such as halothane, isoflurane, and enflurane, have been used with varying degrees of success in refractory, intubated patients with severe asthma. The mechanism of action is unclear but they may have direct relaxant effects on airway smooth muscle. [46, 47]

Other inhaled anesthetics that have been studied include propofol and sevoflurane. Prolonged propofol administration, however, may be complicated by generalized seizure, increased carbon dioxide production, and hypertriglyceridemia.

Sevoflurane has been employed more commonly than halothane and isoflurane. Care must be used with this medication, even though it is relatively safe, because of the risk of hepatotoxicity and renal tubular injury. In children, sevoflurane has been shown in some studies to be safe and effective. In adults, careful monitoring of liver and kidney function, as well as serum fluoride concentration, is helpful for avoiding toxic levels of sevoflurane. [48]

Other agents

Neuromuscular blockers may be used with caution in patients who are well sedated but exhibiting severe anxiety and tachycardia, as well as in those who are intolerant of intubation. [3, 24]

In isolated case reports, nitric oxide has also been used in the treatment of status asthmaticus and has been effective when mechanical ventilation is not adequate. [49, 50]

Additionally, the use of nebulized lidocaine in combination with albuterol or levalbuterol is effective in helping the vocal cord dysfunction that may accompany status asthmaticus (this is an unpublished observation by an author in clinical practice). Data have shown that lidocaine in asthma may have efficacy. [51, 52] It helps in reducing the cough component and has been shown to be an eosinophilic apoptotic agent with clinical efficacy in chronic cough.

Extracorporeal Life Support

Mikkelsen and colleagues reported the successful use of extracorporeal life support in patients with status asthmaticus and severe secondary asphyxia in any patient who otherwise was not responsive to aggressive pulmonary support. [53]

The role of extracorporeal life support has been studied and implemented in several institutions and should be considered in patients at high risk of developing refractory status asthmaticus. [54, 55] This includes, but is not limited to, patients with a history of multiple intubations, respiratory failure requiring intubation within 6 hours of admission, hemodynamic instability, neurologic impairment at the time of admission, and duration of respiratory failure greater than 12 hours despite maximal medical therapy. [56]

Noninvasive Ventilation

Noninvasive ventilation, such as bilevel positive airway pressure, can be considered in patients with impending respiratory failure, in order to avoid intubation. In contrast to patients with chronic obstructive respiratory disease exacerbation and respiratory failure, however, asthma patients tend to require more invasive means of ventilation with intubation when they are in status asthmaticus. The presence of severe bronchoconstriction with multiple secretions and inflammatory processes are contributors to the need for more aggressive ventilation. [56]

Ram et al demonstrated that the effectiveness of noninvasive positive pressure ventilation was affected by meta-analysis. [57] Ueda et al reported using noninvasive positive pressure ventilation to wean a patient with refractory status asthmaticus who also had developed atelectasis. [58]

Steinack et al report that venoocclusive extracorporeal membrane oxygenation (ECMO) was effective in a 25-year-old pregnant woman. [59] The patient failed to respond to the usual therapeutic modalities for status asthmaticus, including the typical medications discussed as well as pressure control ventilation with high inspiratory pressures. ECMO as mentioned should always be considered with status asthmaticus and respiratory failure with inadequate response to pressure control ventilation, antimuscarinic drugs, intravenous beta-agonists, intravenous methylprednisolone, and magnesium sulfate. Continuous positive airway pressure therapy has been used for support of status asthmaticus. Noninvasive positive-pressure ventilation has been shown to "splint" the airways, allowing for better exhalation and emptying. [60]

Leatherman et al reported that prolongation of the expiratory time can decrease dynamic inflation in patients with status asthmaticus and may have a minor positive effect on weaning in these patients. [61]

One should also consider that noninvasive ventilation may have a significant role in managing patients with status asthmaticus. This has been shown to be mostly effective in the pediatric population. [62]

Mechanical Ventilation

Consider mechanical ventilation as a salvage therapy in patients with status asthmaticus. Mechanical ventilation in patients with asthma requires careful monitoring, because these patients have high end-expiratory pressure and, therefore, are at high risk for pneumothorax.

Indications for intubation and mechanical ventilation include the following:

• Apnea or respiratory arrest

• Diminishing level of consciousness

• Impending respiratory failure marked by significantly rising PCO2 with fatigue, decreased air movement, and altered level of consciousness

• Significant hypoxemia that is poorly responsive or unresponsive to supplemental oxygen therapy alone

Mechanical ventilation, when used in patients with asthma, is usually required for less than 72 hours. In occasional patients with severe bronchospasm, however, mechanical ventilation can be prolonged. In these situations, consultation with a pulmonologist or another expert in mechanical ventilatory techniques is recommended.

Because asthma is a disease of airway obstruction (ie, increased airway resistance), resulting in prolongation of the time constant (the time needed for lung units to fill and empty), low ventilator rates are usually needed.

Considerations in mechanical ventilation

The decision to intubate a patient with asthma should be made with extreme caution. Positive pressure ventilation in a patient with asthma is complicated by the severe airway obstruction and air trapping, which results in hyperinflated lungs that may resist further inflation and places the patient at high risk of barotrauma. Therefore, mechanical ventilation should be undertaken only in the face of continued deterioration despite maximal bronchodilatory therapy.

In the face of high peak airway pressures, the principle of mechanical ventilation in status asthmaticus is controlled hypoventilation with toleration of higher levels of PCO2 in order to minimize tidal volume and peak inspiratory pressures. Permissive hypercapnia can be tolerated as long as the patient remains adequately oxygenated. A longer inspiration/expiration (I/E) ratio, often greater than 1:3-4, helps to allow time for optimal exhalation, facilitating ventilation and avoiding an excessive amount of further air trapping (auto–positive end-expiratory pressure [auto-PEEP]).

Keep in mind, however, that patients may be uncomfortable and air hungry while ventilated with low respiratory rates, prolonged exhalation times, and hypercapnia due to a strategy of controlled hypoventilation.

The use of positive end-expiratory pressure (PEEP) is controversial. A patient with status asthmaticus who is in respiratory failure and on mechanical ventilation usually has a significant amount of air trapping that results in intrinsic PEEP, which may be worsened by maintaining PEEP during exhalation. However, some patients may benefit from the addition of PEEP, perhaps owing to the maintenance of airway patency during exhalation. Thus, in a patient who remains refractory to the initial ventilatory settings with no or very low PEEP, cautiously increasing the PEEP may prove beneficial.

Traditionally, slow, controlled ventilation with heavy sedation, often with muscle relaxation, has been used to ventilate patients with status asthmaticus. Caution is warranted, however, as the use of muscle relaxants with high-dose corticosteroids has been associated with the development of prolonged paralysis.

Alternatively, some practitioners report ventilating children with status asthmaticus with pressure support alone. This strategy may allow the patient to set his or her own respiratory rate as determined by the physiologic time constant, while assisting ventilation and relieving the fatigue due to significantly increased work of breathing.

Invasive mechanical ventilation is associated with increased hospital resource use, with prolonged length of stay and even a higher risk of developing pneumonia. The research for noninvasive ventilation should help in minimizing the frequency of invasive mechanical ventilation. [63] In addition, a single case report showed that status asthmaticus in a 12-year-old boy with subcutaneous emphysema and pneumomediastinum resulted in worsening of both of the conditions with noninvasive ventilation. Further research is needed in this area. [64] When in doubt, mechanical invasive ventilation should be considered first in patients with significant respiratory distress who are not responding to the usual aggressive pharmacological and appropriate oxygenation. It is considered the safest approach in a patient who is in severe status asthmaticus, particularly with secondary respiratory failure. It is not, however, without adverse effects or complications. Pneumothorax and idiopathic hemothorax have both been reported. [65]

Monitoring and support

Patients require supportive measures and monitoring during mechanical ventilation. Ideally, monitor flow-volume loops to ascertain if adequate time is provided for exhalation to avoid breath stacking, which occurs if the next breath is delivered before exhalation is completed. Monitoring exhaled tidal volume and auto-PEEP is also important.

Fluids and electrolytes should be monitored. Before arrival in the hospital, children with status asthmaticus have often had diminished oral intake and may have been vomiting because of respiratory difficulty or adverse effects from their medications. This leads to decreased intravascular volume status that may be potentiated by the effects of positive pressure ventilation. Moreover, serum electrolyte levels should be monitored because medications used to treat asthma can result in significant kaliuresis.

In addition, cardiac output may be decreased because of decreased preload that results from air trapping and auto-PEEP. This decreased cardiac output and intravascular volume may be accompanied by metabolic acidosis. Intravascular fluid expansion is needed to treat hypoperfusion, hypotension, or metabolic acidosis.

In addition, diastolic hypotension may occasionally result from high doses of beta-agonists. A vasoconstrictor (ie, norepinephrine, phenylephrine) may be considered if significant diastolic hypotension in the face of adequate intravascular volume persists.

Catheter placement

Placement of an indwelling arterial catheter may be considered for blood gas sampling and continuous blood pressure measurement in patients with mechanical ventilation but is not generally recommended. The arterial waveform can also be used for measurement of pulsus paradoxus.

Heliox

Other treatments have been used in patients with severe acute asthma, but none is well proven. A combination of helium and oxygen known as heliox (ie, 30/70 mixture) has been studied, but this treatment should only be considered in patients who are able to take deep breaths, because the treatment is dependent on inspiratory flow. [66]

Helium is an inert gas that is less dense than nitrogen. The administration of a heliox reduces turbulent airflow across narrowed airways, which can help to reduce the work of breathing. This, in turn, can result in improved gas exchange and improve pH and clinical symptoms. [67, 68] It does not improve the caliber of the narrowed airway. Because of its low density, helium is more fluid under conditions of turbulence. This results in minimizing airway pressure and facilitating reoccurrence of laminar flow. Therefore, oxygenation becomes easier in the presence of increased airway resistance.

Some data suggest that nebulized-size particles may be more uniformly distributed in the distal airways when nebulization treatments are administered via heliox than with a standard oxygen-nitrogen mixture. [69]

Heliox can be administered via a well-fitting face mask at flows high enough to prevent entrainment of room air. The effectiveness of heliox in reducing the density of administered gas and improving laminar airflow depends on the helium concentration of the gas. The higher the helium concentration, the more effective the result. Therefore, an 80/20 mixture of helium-oxygen is most effective.

Heliox loses most of its clinical utility when the FiO2 is greater than 40%, reducing the percentage of helium to less than 60%. Therefore, the limitation to the use of heliox is the amount of supplemental oxygen the patient requires to maintain adequate oxygen saturation.

Heliox has also been used with mechanical ventilation to lower the dynamic peak inspiratory pressures.

Heliox is a low-density gas that allows better oxygenation into the small airways. It should be considered in patients who are not adequately responding to conventional pharmacological therapy, and it may aid in preventing intubation. [70]

Deterrence and Prevention

Status asthmaticus can usually be prevented if patients are compliant with their medications and avoid triggers and stress factors. However, this condition can occur even when patients are compliant and doing well as outpatients. In such situations, search for an occult infection (eg, respiratory syncytial virus [RSV] in children but rarely in adults or an occult sinus infection).

Prevention of status asthmaticus may be aided with monitoring forced oscillation test results rather than spirometry findings. This is particularly true for children younger than 12 years. However, adults with reactive airways may be undertreated if the criterion for stability and normality is a spirometric FEV1 of greater than 80% of the predicted value.

Among the important preventive considerations are home medications, such as anti-inflammatory agents. Corticosteroids are now considered the mainstays of asthma maintenance therapy. Studies indicate that the underuse of anti-inflammatory agents is related to more severe asthma. This is thought to be due to airway remodeling and the persistence of inflammatory changes.

Identify specific patients who are at risk for asthma exacerbation, such as younger children and adults older than 60 years. Bronchodilators are recommended for acute exacerbations. Environmental management is also necessary in children with environmental allergies.

A retrospective analysis showed that the severity of asthma at baseline and the age of the patient are the most important determining factors in the risk for recurrent status asthmaticus and for predicting the severity of the attack. [71] In other words, patients older than 60 years who are also characterized as having either moderate persistent asthma or severe persistent asthma are at high risk of developing status asthmaticus.

Therefore, compliance with the National Institutes of Health (NIH) guidelines for the treatment and management of patients with asthma should theoretically be an effective prophylaxis against the development of status asthmaticus.

Inpatient education by trained lay volunteers in patients who are admitted with status asthmaticus was associated with improvement in posthospitalization and better adherence to their inhaler management. [1]

In a study by Miller et al, [72] an asthma protocol developed by the hospital and based on the guidelines of the National Institutes of Health in children with status asthmaticus resulted in improved time to treatment and better outcome. This was studied in children aged 3-11 years.

Consultations

Consult allergists or pulmonologists because these specialists can provide comprehensive follow-up care with the appropriate therapy, allergy testing (if indicated), control of environmental factors, and consistent follow-up testing and manipulation of medications, as required. Consultation with a surgeon may be required if the child can benefit from fundoplication.

Hospital admission for asthma should be considered the result of a failure of outpatient management. Better outpatient therapy is necessary to prevent subsequent admissions.

Consultation with a member of social services can provide support in the complex management of a chronic illness. Adolescents who have severe, uncontrolled asthma and are nonadherent or have depression or significant behavioral issues may require the services of a psychiatrist or psychologist.

Long-Term Monitoring

Appropriate follow-up is important, as is checking the patient's peak flow meter and forced expiratory volume in 1 second (FEV1) at home or in the office, respectively.

Children with asthma commonly present with normal (FEV1), and, accordingly, more sensitive lung function testing should be undertaken with regular impulse oscillometry system (IOS) assessments. Medication titration may be usefully guided by IOS resistance and reactance values.

Outpatient follow-up and continued care of a patient who has been hospitalized in the pediatric ICU because of severe status asthmaticus is important in optimizing long-term outcome and quality of life and in minimizing recurrent episodes of severe asthma exacerbation. Follow-up is best provided by a specialist in the treatment of asthma. The subgroup of patients who are poor perceivers of dyspnea are at increased risk for future exacerbations. An at-home peak flow meter may be valuable in this poor-perceiver population. [8]

Complications

In adults with status asthmaticus, the clinical presentation with overt acidemia was significantly associated with higher rate of invasive ventilation and prolonged hospital stay with complications and mortality. This was based on a retrospective analysis in patients aged 33-70 years. [73] Hypokalemia was noted in a minority of these patients but, for the most part, did not require supplementation. [74]

Medication

Medication Summary

The following agents are used in the pharmacologic treatment of status asthmaticus:

• Beta2-agonists - The first line of therapy in status asthmaticus

• Anticholinergics - Are believed to work centrally by suppressing conduction in vestibular cerebellar pathways

• Glucocorticosteroids - Among other therapeutic activities, can decrease mucus production, improve oxygenation, reduce beta-agonist or theophylline requirements, and activate properties that may prevent late bronchoconstrictive responses to allergies and provocation

• Bronchodilators - Methylxanthines are weaker bronchodilators than beta-agonists and have many adverse effects. Intravenous magnesium sulfate can relax smooth muscle and hence cause bronchodilation by competing with calcium at calcium-mediated smooth muscle binding sites.

Enoximone is an imidazole phosphodiesterase III inhibitor that has been used in patients with heart failure. In a limited report of eight patients with status asthmaticus, and after exhausting maximal treatment in six of these patients, enoximone was noted to be effective via intravenous administration. [75] It allowed the patients to improve without the need of invasive treatment such as mechanical ventilation. Its role in the future needs to be further investigated.

Beta2-Agonist

Class Summary

These agents relax airway smooth muscle, thus causing bronchodilation in patients with reversible airway obstruction, such as asthma.

Albuterol (Proventil HFA, Ventolin HFA, ProAir HFA)

Albuterol relaxes bronchial smooth muscle by action on beta2 receptors with little effect on cardiac muscle contractility. Administer continuous nebulization with a pump-driven aerosol or via a small-particle aerosol generator

Levalbuterol (Xopenex, Xopenex HFA)

Levalbuterol is a selective beta2-agonist. Albuterol is a racemic mixture, while levalbuterol contains only the levo isomer of albuterol. The safety and efficacy of levalbuterol have not been determined in children under 12 years; multicenter trials in children aged 12 years and younger are ongoing.

Terbutaline

Terbutaline is a selective beta2-adrenergic agent. It produces relaxation of airway smooth muscle, resulting in bronchodilation in patients with asthma.

Anticholinergic, Respiratory

Class Summary

These agents are used for bronchodilation in patients with bronchospasm associated with asthma or chronic obstructive pulmonary disease.

Ipratropium bromide (Atrovent HFA)

Ipratropium bromide is chemically related to atropine. It has antisecretory properties and, when applied locally, inhibits secretions from serous and seromucous glands lining the nasal mucosa. Ipratropium bromide inhibits acetylcholine at parasympathetic sites in bronchial smooth muscle, resulting in bronchodilation.

Corticosteroids

Class Summary

These agents decrease the inflammatory response observed in asthma. They also decrease capillary leak and augment beta-receptor response to beta-adrenergic agents.

Prednisone

Prednisone decreases inflammation by suppressing the production of leukotrienes and the migration of polymorphonuclear leukocytes and by reducing capillary permeability.

Prednisolone (Pediapred, Millipred, Orapred)

Prednisolone decreases inflammation by suppressing the production of leukotrienes and the migration of polymorphonuclear leukocytes and by reducing capillary permeability.

Methylprednisolone (Solu-Medrol, Depo-Medrol, A-Methapred, Medrol)

Prednisone and methylprednisolone interfere with arachidonic acid metabolism and the production of leukotrienes, reduce microvascular leakage, reduce cytokine production, and prevent the migration of inflammatory cells.

Xanthine Derivatives

Class Summary

These agents are used as additional therapy for patients who remain in refractory status asthmaticus despite maximal inhalational therapy and the use of corticosteroids. These medications may be administered intravenously.

Theophylline (Theo-24, Elixophyllin Elixir)

Theophylline is a bronchodilator that is used in patients with reversible bronchospasm associated with asthma or chronic obstructive pulmonary disease. The mechanism of action of theophylline is unclear, but its beneficial effects in asthma are thought to result from bronchodilation partly caused by phosphodiesterase inhibition, improved diaphragmatic inotropicity, CNS stimulation of the respiratory drive, and possible anti-inflammatory effects.

Start oral (eg, Theo-24, Theochron, Elixophyllin Elixir) dosing when the patient is stable on continuous IV dose.

Aminophylline

Aminophylline causes bronchodilation by increasing tissue concentrations of cAMP. It can be administered intravenously. However, intravenous aminophylline is generally used for refractory status asthmaticus because of the severity of the patient's asthma, which results in the decision to add methylxanthines to the treatment regimen. The theophylline dose is 79% of the aminophylline dose. To convert a theophylline dose to aminophylline, the theophylline dose needs to be divided by 0.80.

Pulmonary, Other

Class Summary

Asthma patients that respond poorly to beta-agonists may benefit from adjunctive use in the treatment of acute exacerbations of severe asthma.

Magnesium sulfate

Magnesium sulfate relaxes smooth muscle and may lead to adjunctive bronchodilation. Its mechanism of action is unknown, but magnesium sulfate may compete with calcium for smooth muscle binding sites, leading to relaxation.

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