Changing the status of acute severe asthma

Acute severe asthma (previously known as status asthmaticus) isn't common in patients in the ICU, but is high-stakes when it occurs. Patients with acute severe asthma are challenging, especially if they need endotracheal intubation and mechanical ventilation. This article focuses on recognizing and managing acute severe asthma in adults. For details on asthma's prevalence, see Asthma by the numbers.

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The National Asthma Education and Prevention Program 2007 guidelines define asthma as a "common chronic disorder of the airways that is complex and characterized by variable and recurring symptoms, airflow obstruction, bronchial hyperresponsiveness, and an underlying inflammation. The interaction of these features of asthma determines the clinical manifestations and severity of asthma and the response to treatment." The guidelines also indicate that respiratory viral infections are a common cause of asthma development and asthma exacerbations.1 Acute severe asthma occurs when severe airway obstruction and asthma symptoms persist despite the administration of standard acute asthma therapy.2 Because this definition doesn't set a time frame for unresponsiveness following symptom onset and treatment, or aggressiveness of treatment, the term "acute severe asthma" is now more commonly used than status asthmaticus.3

Understanding asthma

Asthma is a heterogeneous disease-there's as much difference between patients as there are similarities. Inflammation is the central feature of asthma, and is characterized by many different types of cells and chemical mediators. Airflow limitation is recurrent and caused by changes that may include

* bronchoconstriction, or bronchial smooth muscle contraction that narrows airways in response to exposure to allergens and other irritants.

* airway edema secondary to inflammation.

* airway hyperresponsiveness, an exaggerated bronchoconstrictor response to stimuli. Reducing inflammation can reduce airway hyperresponsiveness.

* airway remodeling, or physiologic changes that lead to hyperplasia of submucosal and goblet cells and cause mucus hypersecretion. Mucus plugging the alveoli is a key cause of asthma death.1 For more details, see What happens in asthma.

Patients who have persistent asthma and whose asthma is only partially reversible have permanent structural changes in their airways. These changes are referred to as airway remodeling.1

Clinical management of asthma is based on the level of control that's been achieved, rather than the degree of disease severity. The level of control identifies a patient as having mild, moderate, or severe asthma.1 The American Thoracic Society expanded the definition of severe asthma based on treatment requirements, frequency of exacerbations, and pulmonary function tests (see Defining severe asthma).4,5

Outside factors that can contribute to acute severe asthma need to be excluded before these definitions can be applied. These factors include poor access to healthcare and inadequate chronic asthma control. Modifiable risk factors such as smoking, obesity, substance abuse, and occupational exposure have been associated with acute severe asthma and need to be explored in the admission assessment. Additionally, pay attention to social and behavioral health risks. Patients with asthma who perceived themselves as having poor mental health included those whose marital status was given as divorced, separated, or never married. Patients with mental illness (in particular, schizophrenia) also had proportionately higher incidences of asthma. Patient nonadherence to asthma medications and corticosteroids prescribed during an exacerbation also must be considered, as studies have found this can cause near-fatal exacerbations.6-9

More recently, attempts have been made to identify patients with asthma within phenotypes-that is, genetics coupled with environmental factors. Examples of asthma phenotypes that have been identified include childhood onset, adult onset, steroid-resistant, eosinophilic, neutrophilic, airtrapping, exacerbation-prone, and severe.10-15 Phenotypes overlap, and molecular differences haven't yet been established.16,17

Recently, a cluster analysis was able to place the various phenotypes into five clusters. The study identified 628 variables within the phenotypes and was able to reduce them to 34 core variables. After assigning the core variables to the clusters, researchers were able to show that 80% of patients could be placed in the appropriate cluster using only three variables: age of onset, and pre- and postbronchodilator forced expiratory volume in 1 second (FEV₁) percentage predicted. (See Understanding pulmonary function tests.) Most patients with severe asthma fall into the third, fourth, and fifth clusters (see Comparing asthma clusters).2

Causes of asthma exacerbations

Most asthma exacerbations, whether mild, moderate, or severe, are the result of a viral infection, usually rhinovirus (the common cold), influenza, coronavirus, or adenovirus. Other viruses associated with asthma exacerbation are respiratory syncytial virus, parainfluenza, and human metapneumovirus.10,15

The exacerbation may be made worse if a patient with a viral infection is exposed to an allergen, most commonly dog, cat, dust mite, or cockroach. Smoking, a modifiable risk factor, is related to increased hospitalizations and ED visits for asthma exacerbation.

Treating exacerbations with drugs

Oxygen is administered to maintain an Spo₂ greater than 90% (or 95% in pregnant women and patients with heart disease), regardless of oxygen delivery system.1,18 For most patients, Spo₂ and serial peak expiratory flow (PEF) or FEV₁ measurements are adequate for monitoring oxygenation. These measurements may not be possible or accurate in patients with severe asthma. Also, if the patient's Spo₂ is less than 94%, an arterial blood gas analysis is indicated to assess for acidosis and hypercapnia. These findings represent a worsening of the exacerbation. Monitor the patient's oxygenation until the patient responds to bronchodilator therapy.

In the early acute phase of an asthma exacerbation, the patient's ABGs will indicate respiratory alkalosis with hypoxemia. The patient will hyperventilate in an effort to improve oxygenation. Carbon dioxide is blown off, resulting in a low PaCO₂. A PaCO₂ in the upper range of normal (40 to 45 mm Hg) or higher indicates impending respiratory failure.1,19

Short-acting beta-agonists (SABAs) and corticosteroids are the cornerstone of care for asthma exacerbations. SABAs are extremely effective bronchodilators, and are given by nebulization so that large doses can be delivered to the lungs very rapidly. SABAs also can be given via metered dose inhaler (MDI), but, in severe asthma, the patient might not be able to use an MDI effectively.

Administer a nebulized SABA either every 20 minutes (for up to three treatments), or, if indicated, continuously, until the patient shows improvement.1 Although the duration of effectiveness of SABAs is unknown, it's shorter in patients with acute severe asthma than in patients with stable asthma. Titrate the drug based on an objective measure such as FEV₁ or PEF.1,18,20

Racemic albuterol, the SABA most commonly given for asthma exacerbation, comprises two isomers. The R-isomer acts on beta₂-agonist receptor sites, causing bronchodilation. The S-isomer has been shown to increase airway hyperreactivity and contract smooth muscle, causing bronchoconstriction. It appears to also have proinflammatory effects.

Levalbuterol, which contains only the R-isomer, may be more effective in reversing bronchoconstriction in patients with a severe asthma exacerbation who've been taking their rescue inhaler before arrival at the hospital. Studies have shown that administering levalbuterol to a patient with an asthma exacerbation can reduce the need for hospitalization. The drug's effect in improving FEV₁ can last as long as 60 minutes after the last dose. Because levalbuterol is effective at lower doses than albuterol, beta-agonist adverse effects of tachycardia and tremor are minimized.3,21,22

Adding ipratropium, an anticholinergic, to the SABA nebulizer solution provides additional bronchodilation. Because ipratropium relaxes smooth muscle through a different pathway than albuterol, it causes few adverse reactions. Recent studies indicate that ipratropium may significantly reduce airway obstruction and hospital admissions when used early in treatment. Once the patient has been stabilized and admitted, ipratropium hasn't been shown to be beneficial.1,3,18,22

Corticosteroids such as prednisone, prednisolone, and methylprednisolone effectively reduce the airway inflammation found in virtually all patients with asthma. These corticosteroids are equally effective when administered either orally or I.V. The oral route is preferred, but may not be possible if the patient is too dyspneic, vomiting, or obtunded. Corticosteroids are most effective when given within the first hour after the patient arrives at the ED, and can reduce hospital admissions. Recent studies indicate that doses of prednisone or methylprednisolone greater than 80 mg don't show any additional benefits in outcomes. Improvement of symptoms indicating reduction of inflammation may not be seen for 2 to 6 hours.3,20

Patients with asthma commonly take inhaled corticosteroids, usually in combination with a long-acting beta-agonist (LABA), as a maintenance medication, but this medication hasn't been shown to be effective during an acute asthma exacerbation. However, further study, including effective dosing, has been recommended.1

A single dose of I.V. magnesium sulfate has been shown to be safe and effective in adults with acute severe asthma.19 Magnesium blocks smooth muscle-cell calcium channels and inhibits muscle contraction, but isn't effective in milder exacerbations and isn't a first-line drug. Magnesium should be considered after 1 hour of conventional therapy. Although the drug is considered very safe, monitor the patient for depressed reflexes and bradycardia.

Heliox, a mixture of helium and oxygen, produces a lower-density gas that can carry bronchodilating medication deeper into the lungs. Additionally, heliox overcomes the turbulent airflow that occurs with obstruction, and which increases the work of breathing.22 Although study results have been conflicting regarding heliox use, the 2007 asthma guidelines recommend it for patients with severe asthma exacerbation that hasn't improved within 1 hour.1 Heliox can be administered via non-rebreather mask and nebulizer. Monitor the patient's Spo₂ during administration; afterward, measure the patient's PEF, FEV_1, and pulsus paradoxus to assess the therapy's effectiveness.1,3,18,21

Antibiotics aren't indicated unless the patient has a fever and purulent sputum. If pneumonia or bacterial sinusitis is suspected, antibiotics are appropriate.1

Avoiding intubation

Most patients experiencing an asthma exacerbation can be treated without intubation and mechanical ventilation. Taking steps to avoid the need for intubation is important because once the patient is placed on mechanical ventilation, the risk of mortality increases.19

One intervention that shows promise in reducing the need for mechanical ventilation is noninvasive positive pressure ventilation (NPPV). This therapy wasn't recommended in the 2007 asthma guidelines because of lack of evidence on which to base a recommendation. However, recent studies have shown that NPPV and nebulization can improve PEF, forced vital capacity (FVC), and FEV₁ in patients with severe asthma.23,24 Studies using continuous positive airway pressure (CPAP) and bilevel positive airway pressure (BiPAP) have shown increased functional residual capacity (FRC) and improved oxygenation.25 The continuous, high positive pressure of CPAP makes inspiration easier for patients and keeps the airways open during end-exhalation. BiPAP provides high inspiratory positive airway pressure (which increases tidal volume and alveolar ventilation) and a low expiratory positive pressure (which, like CPAP, increases FRC and improves oxygenation).26 Because of the complications of mechanical ventilation, healthcare providers should consider using NPPV in selected patients with severe asthma.27,28

Clinician expertise is an important aspect for successful use of NPPV. Ensure that the NPPV mask fits properly. An orofacial mask is best for a patient with severe asthma. The mask should fit well enough to prevent air leaks, but not so tight that it may cause nasal or facial skin breakdown. You should be able to insert one or two fingers between patient's face and the mask's straps.

Assess the patient for signs or symptoms of claustrophobia (from the mask) and hypotension (secondary to positive-pressure ventilation). Administer I.V. fluids to support the patient's BP. If the patient's clinical status doesn't improve, prepare for elective intubation.

Table. Comparing ast... - Click to enlarge in new window

Table. Comparing asthma clusters

When ventilation is needed

The decision to intubate and mechanically ventilate a patient with severe asthma is a matter of clinical judgment. Altered mental status, progressive exhaustion, a quiet chest, normalization or elevation of PaCO₂, severe hypoxia, a pulsus paradoxus greater than 25 mm Hg, and hemodynamic instability are signs of impending respiratory failure. Because respiratory failure can progress rapidly, early recognition and elective intubation is key to good outcomes.1,3,18,19,28

Laryngeal and bronchial hyperresponsiveness can become more severe during intubation. To prevent this, administer inhaled beta-agonist and anticholinergic medications before intubation, as prescribed. The patient also should be sedated to treat the hyperresponsiveness and to make intubation more comfortable. Midazolam, propofol, or ketamine can be used, although midazolam, a benzodiazepine, has a prolonged and unpredictable wear-off time.19

Propofol can be titrated to deep sedation, and has a short half-life, as well as some bronchodilatory properties. If your patient is hypotensive, fluids or vasopressors may be indicated. Ketamine, which also has bronchodilatory properties, is indicated in patients with severe bronchoconstriction during intubation.3 Succinylcholine, a depolarizing neuromuscular blocking drug (NMBD), is often used as a paralytic during intubation because of its rapid onset and short duration. But before using it, confirm that the patient isn't hyperkalemic as a result of respiratory acidosis because the succinylcholine can increase potassium levels and cause cardiac dysrhythmias.19

Nondepolarizing NMBDs such as vecuronium or cisatracurium may be used instead of succinylcholine, but are longer acting.19 Sustained paralysis with NMBDs can cause myopathy, particularly in patients on corticosteroids, so don't administer NMBDs over more than 24 hours if at all possible.19,28

Hypotension after intubation can be a result of increased hyperinflation, which decreases venous return and cardiac output. Removing the patient from the ventilator for about 1 minute and closely watching Spo₂ should improve BP. Reconnect the patient to the ventilator, but at a lower tidal volume and respiratory rate.19,28 Administer fluids. If the patient doesn't improve, suspect tension pneumothorax and intervene appropriately.19,28

Once the patient is intubated and placed on mechanical ventilation, continue sedation as prescribed, usually as a continuous I.V. infusion. Opioids also should be prescribed, for patient comfort and to suppress ventilatory drive sufficiently so that NMBDs aren't needed. Avoid naturally occurring opiates, such as morphine, which can cause histamine release and subsequent bronchoconstriction and vasodilation. Synthetic opioids, such as fentanyl, are much less likely to cause histamine release, and are a better choice.19,28

Most experts agree that volume-controlled ventilation, such as commonly used in assist-control mode, is preferred. Use sedation as prescribed in order to limit patient-ventilator dyssynchrony and control hyperinflation, which can be worsened by spontaneous breathing.19,28 Ventilator settings must take into consideration the airtrapping commonly seen in severe asthma. The recommended initial settings are a tidal volume of 7 to 8 mL/kg of ideal body weight, a respiratory rate of 8 to 10 breaths/minute, positive end-expiratory pressure (PEEP) of 0 cm H₂O, and inspiratory: expiratory ratio (I:E ratio) of 1:3. FiO₂ should initially be set at 1.0, then titrated to maintain the patient's Sao₂ greater than 90%.3,19,28

The main goal of these settings is to maintain adequate gas exchange and prevent further increases in lung hyperinflation. In asthma, severe airway narrowing significantly increases airflow resistance, prolonging the expiratory phase and trapping air in the alveoli. This results in hyperinflation and increased end-expiratory alveolar pressure, called auto-PEEP or intrinsic PEEP.19,29 Adding ventilator-set PEEP in this situation can worsen the auto-PEEP.

Complications of auto-PEEP include hypotension and barotrauma. Monitoring and controlling auto-PEEP significantly decreases the risk of these complications. Interventions include decreasing respiratory rate and reducing tidal volume. Of these, reducing tidal volume may be more effective. Here's why: Airflow decreases progressively throughout exhalation, and airway closure may occur prematurely, limiting alveolar emptying. So lowering the respiratory rate may not sufficiently lower auto-PEEP.

Increasing the flow rate can also be an effective way to reduce auto-PEEP. Shortening inspiratory time will lengthen the expiratory time. Using a decelerating waveform configuration initially may achieve this goal by providing higher pressure at the beginning of inspiration, then tapering the pressure down to avoid auto-PEEP. Once the patient is over the crisis and ready to be weaned from the ventilator, or if the patient's auto-PEEP and hyperinflation is under control, a square waveform may be used.19,29

Decreasing respiratory rate and tidal volume can decrease auto-PEEP, but also causes hypercapnia. However, hypercapnia is preferred over a normal PaCO₂ to avoid hyperventilation and alveolar damage. Interventions permitting an arterial pH as low as 7.20 and a PaCO₂ level up to 90 mm Hg have been used successfully in severe asthma.19

Patients with increased intracranial pressure (ICP) aren't candidates for hypercapnia strategies, as CO₂ dilates cerebral vessels, increasing blood volume and further elevating ICP. Patients with severe cardiac dysfunction also can't tolerate hypercapnia because it can cause a decrease in cardiac contractility.19

Discharge planning

Before your patient goes home, plan interventions that focus on asthma control. For patients with a history of sinusitis-related exacerbations, controlling these infections can improve their asthma. Patients whose asthma is triggered by gastroesophageal reflux benefit from proton pump inhibitors such as pantoprazole and esomeprazole, as well as elevating the head of the bed.

For maintenance therapy, leukotriene modifiers such as zafirlukast and montelukast may be considered as an alternative to inhaled corticosteroids or in combination with them, depending on the severity of the patient's symptoms. Leukotriene modifiers have been shown to be beneficial for patients with asthma and allergic rhinitis and are recommended for these patients.

In patients who remain symptomatic despite aggressive interventions, treatment with a monoclonal immunoglobulin G1 blocking antibody such as omalizumab may be indicated. Omalizumab inhibits IgE binding to mast cell and basophil receptors, limiting the release of allergic response mediators. The patient may need subcutaneous injections two to four times weekly for as long as a year. Effectiveness is determined by a decrease in frequency of exacerbations, decreased asthma symptoms, improved lung function, and patient perception of improved quality of life.30

Stress the importance of follow-up. A patient who's had an asthma exacerbation severe enough to require endotracheal intubation is at significant risk for death from a subsequent asthma exacerbation. Talk to the patient about the need for prompt activation of emergency medical services, and not to rely on someone driving him or her to the hospital by car if another exacerbation occurs.31

Close contact with the healthcare provider is essential for asthma control. The healthcare provider and patient should mutually develop goals to improve modifiable risk factors such as obesity and smoking.30 Teach the patient about the importance of taking the prescribed daily medications. A plan of care that includes self-treatment with prednisone for exacerbations, without the need for a physician office or ED visit, can help to prevent a poor outcome from future exacerbations. Each visit should include an assessment of medication use and understanding, review of the patient's recordings of peak flow measurements, discussion of environmental controls, and general health.32

Future treatments

Future treatment of acute severe asthma is focused on continued identification of asthma phenotypes. By targeting the specific pathophysiologic causes of a severe asthma exacerbation in individual patients, outcomes can be improved and exacerbations prevented, improving patients' quality of life. Continued research in asthma pathophysiology, phenotype identification, and role of genetics can help to direct the development of treatments specific to individual asthma exacerbations.1

Asthma by the numbers

* 16.4 million adults in the United States, or 7.3% of all American adults, had been diagnosed with asthma as of 2008, the last year for which statistics are available.

* 13.3 million visits to physician offices, hospital outpatient clinics, and EDs in 2006 were for asthma treatment. Discharges with first-listed diagnosis of asthma totaled 444,000, with an average length of stay of 3.2 days.

* 3,613 Americans died of asthma in 2006, an average of 1.2 deaths per 100,000 population. Two-thirds of these deaths occurred outside the hospital.

* 4.2% of patients admitted to the hospital for severe asthma in 2000 required endotracheal intubation, and 0.5% of patients admitted to the hospital for asthma died.

* 10.2% of Blacks have asthma, the greatest percentage by race or ethnicity. In comparison, 7.6% of Whites and 6.8% of Hispanics are affected.

* 8.9% of women have asthma, compared with 6.5% of men.

* 5% to 10% of patients with asthma have severe asthma.

What happens in asthma

Asthma is mediated by the immune system. Airway inflammation in asthma is a constant, even if the patient's symptoms are episodic. The relationship between the various inflammatory cells and mediators is complex.

Mast cells, activated by allergens, release bronchoconstrictors including histamine.

Eosinophils release proteins that can damage airway epithelial cells.

T lymphocytes stimulate production of immunoglobulin E (IgE), the antibody involved in activating the allergic response. Th2 cytokines also promote the increases in eosinophils that are almost always present in acute asthma exacerbations.5

Neutrophils are the predominant inflammatory cell in airway secretions during acute exacerbation.

Asthma exacerbations can be characterized by either eosinophilic or neutrophilic inflammation. The eosinophilic asthma phenotype is mediated by Th2 cytokines, and represents half of patients with asthma; non-Th2 mechanisms are in operation in the remaining 50%, who are considered the neutrophilic phenotype.

Defining severe asthma

The American Thoracic Society lists these criteria for severe or refractory asthma.

Major criteria (need one or more)

* Treatment with continuous or near-continuous (50% of the year or more) oral corticosteroids.

* Requires treatment with high-dose inhaled corticosteroids.

* Minor criteria (need two or more)

* Needs additional daily treatment with a controller medication (LABA, theophylline, or leukotriene antagonist).

* Has asthma symptoms requiring daily or near-daily use of SABAs.

* Persistent airway obstruction, defined as an FEV₁ of less than 80% of predicted value, and greater than 20% diurnal PEF variability.

* One or more urgent care visits for asthma per year.

* Three or more oral steroid "bursts" per year.

* Prompt deterioration with a 25% or less reduction in oral or inhaled corticosteroid use.

* Near-fatal asthma even in the past.

Understanding pulmonary function tests

* FVC-the maximum amount of air that can be rapidly and forcefully exhaled from the lungs after full inspiration.

* FEV1-or the volume of air exhaled during the first second of FVC.

* Percentage of FVC-volume of air expired in the first second, expressed as a percentage of FVC.

* Maximal voluntary ventilation-maximum amount of air that can be breathed in a given time.

* Forced midexpiratory flow rate (FEF25%-75%)-the average midexpiratory flow rate, determined by finding the points corresponding to 25% and 75% of FVC on the volume-time curve recording obtained during FVC, then drawing a straight line through these points. The slope of the line is the FEF_25%-75%.

* Forced inspiratory flow rate (FIF25%-75%)-the volume inspired from residual volume at the point of measurement. FIF_25%-75% is the slope of the line between the points on the volume pressure curve corresponding to 25% and 75% of inspired volume.