Introduction

• The following practice guidance article primarily includes acute care pharmacotherapy recommendations from open-access resources provided by GINA 2022 (Global Initiative for Asthma)(2) and treatment recommendations from the ACEP 2023 expert panel committee (3). 

• Please note that certain information may vary within sections, so it is highly advised to review the full-text articles in order to gain a comprehensive understanding of the topic.
  
  

Definition (2)

• Asthma is a heterogeneous disease, usually characterized by chronic airway inflammation. It is defined by the history of respiratory symptoms, such as wheeze, shortness of breath, chest tightness and cough, that vary over time and in intensity, together with variable expiratory airflow limitation. Airflow limitation may later become persistent.

• Asthma is usually associated with airway hyperresponsiveness and airway inflammation, but these are not necessary or sufficient to make the diagnosis.
  
  

Pathophysiology (1)

• The presence of inflammation in asthma is supported by autopsy and bronchial biopsy findings, which show infiltration of immune cells, structural changes in the airways, and the presence of inflammatory cytokines in respiratory samples.

• Asthma is categorized into allergic and non-allergic types based on the presence or absence of specific antibodies. Exposure to microbes and allergens during early life may have a protective effect against developing allergies and asthma, supporting the hygiene hypothesis.

• Severe exacerbations of asthma are life-threatening medical emergencies, which are most safely managed in an acute care setting. 

Assessment (2)

History

A brief history and physical examination should be conducted concurrently with the prompt initiation of therapy. Include:

• Time of onset and cause (if known) of the present exacerbation.

• Severity of asthma symptoms.

• Any symptoms of anaphylaxis.

• Risk factors for asthma-related death.

• All current reliever and controller medications, including doses and devices prescribed, adherence pattern, any recent dose changes, and response to current therapy.

Physical examination

The physical examination should assess:

• Signs of exacerbation severity, including vital signs (e.g. level of consciousness, temperature, pulse rate, respiratory rate, blood pressure, ability to complete sentences, use of accessory muscles).

• Complicating factors (e.g. anaphylaxis, pneumonia, atelectasis, pneumothorax or pneumomediastinum).

• Signs of alternative conditions that could explain acute breathlessness (e.g. cardiac failure, inducible laryngeal obstruction, inhaled foreign body or pulmonary embolism).

Objective assessments

• Oxygen saturation: this should be closely monitored, preferably by pulse oximetry. This is especially useful in children if they are unable to perform PEF. In children, oxygen saturation is normally >95%, and saturation <92% is a predictor of the need for hospitalization (Evidence C). Saturation levels <90% in children or adults signal the need for aggressive therapy. Subject to clinical urgency, saturation should be assessed before oxygen is commenced, or 5 minutes after oxygen is removed or when saturation stabilizes.

• Arterial blood gas measurements are not routinely required: They should be considered for patients with PEF or FEV1 <50% predicted, or for those who do not respond to initial treatment or are deteriorating. Supplemental controlled oxygen should be continued while blood gases are obtained. During an asthma exacerbation PaCO2 is often below normal (<40 mmHg). Fatigue and somnolence suggest that pCO2 may be increasing and airway intervention may be needed. PaO2<60 mmHg (8 kPa) and normal or increased PaCO2 (especially >45 mmHg, 6 kPa) indicate respiratory failure.

• Chest X-ray (CXR) is not routinely recommended: In adults, CXR should be considered if a complicating or alternative cardiopulmonary process is suspected (especially in older patients), or for patients who are not responding to treatment where a pneumothorax may be difficult to diagnose clinically. Similarly, in children, routine CXR is not recommended unless there are physical signs suggestive of pneumothorax, parenchymal disease or an inhaled foreign body. Features associated with positive CXR findings in children include fever, no family history of asthma, and localized lung examination findings.

The following treatments are usually administered concurrently to achieve rapid improvement:

• Oxygen
  To achieve arterial oxygen saturation of 93–95% (94–98% for children 6–11 years), oxygen should be administered by nasal cannula or mask. In severe exacerbations, controlled low flow oxygen therapy using pulse oximetry to maintain saturation at 93–95% is associated with better physiological outcomes than with high concentration (100%) oxygen therapy  (Evidence B). However, oxygen therapy should not be withheld if pulse oximetry is not available (Evidence D). Once the patient has stabilized, consider weaning them off oxygen using oximetry to guide the need for ongoing oxygen therapy.

  • When managing a severe asthmatic crisis, specially a “crashing” asthmatic patient, EMDrugs recommend initiating high flow oxygen with a non-reflow mask for both oxygenation and “preoxygenation” anticipating the probability of advance emergency airway management.

• Inhaled short-acting beta2-agonists

  • Inhaled SABA therapy should be administered frequently for patients presenting with acute asthma. The most cost- effective and efficient delivery is by pMDI with a spacer (Evidence A). Evidence is less robust in severe and near- fatal asthma. Systematic reviews of intermittent versus continuous SABA in acute asthma, which mostly used nebulized SABA, provide conflicting results. Use of nebulizers can disseminate aerosols and potentially contribute to spread of respiratory viral infections. Currently, inhaled albuterol is the usual bronchodilator in acute asthma management.

    • Following the position of other emergency medicine experts, EMDrugs recommends the use of continuous SABA administration in the crashing asthmatic. 

  • Similar efficacy and safety have been reported from emergency department studies with formoterol, and in one study of budesonide-formoterol. More studies of ICS-formoterol in emergency department management are needed.

  •  Current evidence does not support the routine use of intravenous beta2-agonists in patients with severe asthma exacerbations (Evidence A).

• Epinephrine (for anaphylaxis)
  Intramuscular epinephrine (adrenaline) is indicated in addition to standard therapy for acute asthma associated with anaphylaxis and angioedema. It is not routinely indicated for other asthma exacerbations.

  • EMDrugs recommends considering the administration of parenteral epinephrine in the crashing asthmatic (when anaphylaxis is not suspected) with the objective of providing bronchial beta-agonism in cases of extreme airflow restriction.

• Systemic corticosteroids

  • Systemic corticosteroids speed resolution of exacerbations and prevent relapse, and in acute care settings should be utilized in all but the mildest exacerbations in adults, adolescents and children 6–11 years. (Evidence A). Where possible, systemic corticosteroids should be administered to the patient within 1 hour of presentation. Use of systemic corticosteroids is particularly important in the emergency department if: 

    • Initial SABA treatment fails to achieve lasting improvement in symptoms

    • The exacerbation developed while the patient was taking OCS

    • The patient has a history of previous exacerbations requiring OCS.

  • Route of delivery: oral administration is as effective as intravenous. The oral route is preferred because it is quicker, less invasive and less expensive. For children, a liquid formulation is preferred to tablets. OCS requires at least 4 hours to produce a clinical improvement. Intravenous corticosteroids can be administered when patients are too dyspneic to swallow; if the patient is vomiting; or when patients require non-invasive ventilation or intubation. In patients discharged from the emergency department, an intramuscular corticosteroid may be an alternative to a course of OCS for preventing relapse, especially if there are concerns about adherence with oral therapy. However, current evidence does not demonstrate a benefit of intramuscular over oral corticosteroids.

  • Dosage: daily doses of OCS equivalent to 50 mg prednisolone as a single morning dose, or 200 mg hydrocortisone in divided doses, are typically used for adults. For children, a prednisolone dose of 1–2 mg/kg up to a maximum of 40 mg/day is suggested.

  • Duration: 5- and 7-day courses in adults have been found to be as effective as 10- and 14-day courses respectively (Evidence B), and a 3–5-day course in children is usually considered sufficient for most. A small number of studies examined oral dexamethasone 0.6 mg/kg, given once daily for 1-2 days in children and adults; the relapse rate was similar to that with prednisolone for 3–5 days, with a lower risk of vomiting. Oral dexamethasone should not be continued beyond 2 days because of concerns about metabolic side-effects. If there is a failure of resolution, or relapse of symptoms, consideration should be given to switching to prednisolone. Evidence from studies in which all patients were taking maintenance ICS after discharge suggests that there is no benefit in tapering the dose of OCS, either in the short term or over several weeks (Evidence B).

• Inhaled corticosteroids

  • Within the emergency department: high dose ICS given within the first hour after presentation reduces the need for hospitalization in patients not receiving systemic corticosteroids (Evidence A). When added to systemic corticosteroids, evidence is conflicting in adults. In children, administration of ICS with or without concomitant systemic corticosteroids within the first hours of attendance to the emergency department might reduce the risk of hospital admission and need for systemic corticosteroids (Evidence B). Overall, add-on ICS are well tolerated; however, cost may be a significant factor, and the agent, dose and duration of treatment with ICS in the management of asthma in the emergency department remain unclear. Patients admitted to hospital for an asthma exacerbation should continue on, or be prescribed, ICS-containing therapy.

  • On discharge home: patients should be prescribed ongoing ICS-containing treatment since the occurrence of a severe exacerbation is a risk factor for future exacerbations (Evidence B), and ICS-containing medications significantly reduce the risk of asthma-related death or hospitalization (Evidence A). SABA-only treatment of asthma is no longer recommended. For short-term outcomes such as relapse requiring admission, symptoms, and quality of life, a systematic review found no significant differences when ICS were added to systemic corticosteroids after discharge. There was some evidence, however, that post-discharge ICS were as effective as systemic corticosteroids for milder exacerbations, but the confidence limits were wide. (Evidence B). Cost may be a significant factor for patients in the use of high dose ICS, and further studies are required to establish their role.

• • Ipratropium bromide
    For adults and children with moderate-severe exacerbations, treatment in the emergency department with both SABA and ipratropium, a short-acting anticholinergic, was associated with fewer hospitalizations (Evidence A for adults; Evidence B for adolescents/children) and greater improvement in PEF and FEV1 compared with SABA alone. (Evidence A, adults/adolescents) For children hospitalized for acute asthma, no benefits were seen from adding ipratropium to SABA, including no reduction in length of stay,667 but the risk of nausea and tremor was reduced.
    
    

  • Aminophylline and theophylline (not recommended)
    Intravenous aminophylline and theophylline should not be used in the management of asthma exacerbations, in view of their poor efficacy and safety profile, and the greater effectiveness and relative safety of SABA. Nausea and/or vomiting are more common with aminophylline. The use of intravenous aminophylline is associated with severe and potentially fatal side-effects, particularly in patients already treated with sustained-release theophylline. In adults with severe asthma exacerbations, add-on treatment with aminophylline does not improve outcomes compared with SABA alone.
    
    

  • Magnesium
    Intravenous magnesium sulfate is not recommended for routine use in asthma exacerbations; however, when administered as a single 2 g infusion over 20 minutes, it reduces hospital admissions in some patients, including adults with FEV1 <25–30% predicted at presentation; adults and children who fail to respond to initial treatment and have persistent hypoxemia; and children whose FEV1 fails to reach 60% predicted after 1 hour of care (Evidence A). Randomized, controlled trials that excluded patients with more severe asthma showed no benefit with the addition of intravenous or nebulized magnesium compared with placebo in the routine care of asthma exacerbations in adults and adolescents or children (Evidence B).
    
    

  • Helium oxygen therapy
    A systematic review of studies comparing helium-oxygen with air–oxygen suggests there is no role for this intervention in routine care (Evidence B), but it may be considered for patients who do not respond to standard therapy; however, availability, cost and technical issues should be considered.
    
    

  • Leukotriene receptor antagonists (LTRAs)
    There is limited evidence to support a role for oral or intravenous LTRAs in acute asthma. Small studies have demonstrated improvement in lung function but the clinical role and safety of these agents requires more study.
    
    

  • ICS-LABA combinations
    The role of these medications in the emergency department or hospital is unclear. One study showed that high dose budesonide-formoterol in patients in the emergency department, all of whom received prednisolone, had similar efficacy and safety profile to SABA, but more studies are needed. Another study examined addition of salmeterol to OCS for hospitalized patients, but was not adequately powered to support a recommendation.
    
    

  • Antibiotics (not recommended)
    Evidence does not support the routine use of antibiotics in the treatment of acute asthma exacerbations unless there is strong evidence of lung infection (e.g. fever or purulent sputum or radiographic evidence of pneumonia).
    
    

  •  Sedatives (must be avoided)
    Sedation should be strictly avoided during exacerbations of asthma because of the respiratory depressant effect of anxiolytic and hypnotic drugs. An association between the use of these drugs and avoidable asthma deaths has been reported.
    
    

  • Non-invasive ventilation (NIV)
    The evidence regarding the role of NIV in asthma is weak. A systematic review identified five studies involving 206 participants with acute severe asthma treated with NIV or placebo. Two studies found no difference in need for endotracheal intubation but one study identified fewer admissions in the NIV group. No deaths were reported in either study. Given the small size of the studies, no recommendation is offered. If NIV is tried, the patient should be monitored closely (Evidence D). It should not be attempted in agitated patients, and patients should not be sedated in order to receive NIV (Evidence D).

Summary of Standard Pharmacotherapy: The First Hour in the ED

• All patients should receive inhaled beta agonist therapy (e.g., albuterol).

• Combined nebulized albuterol (2.5-5.0 mg) and ipratropium bromide (0.5 mg) can be administered three times within the first hour. Alternatives include 4-8 puffs of albuterol (90 mcg/puff) and ipratropium bromide (18 mcg/puff) three times within the first hour via pMDI with spacer.

• In severe cases, consider continuous nebulized albuterol at 10-20 mg/hr.

• Corticosteroids such as dexamethasone 0.6 mg/kg/day, max 16 mg/day or prednisone 40-80 mg (1-2 mg/kg pediatric, max 60 mg) should be administered as early as possible, ideally within the first hour. 

• Intravenous corticosteroids may be preferred in severe cases although the literature supporting this is sparse.

• Intravenous magnesium (typically 2 mg over 20 minutes) can be added to standard therapy for severe/refractory cases.
  
  

Overview

• The guiding principle of emergency management of asthma exacerbations is the prompt reversal of airway obstruction.

• Inhaled short-acting beta agonists (SABAs) and systemic corticosteroids mark the cornerstones of acute care for asthma exacerbations.

• Inhaled anticholinergic agents are typically considered the third standard intervention to supplement SABA-mediated bronchodilation.

• Adjunct therapies, such as intravenous magnesium, might be helpful additions to routine therapy, particularly in moderate to severe cases.

• Proper technique is critically important for medications given via inhaler. If response to unwitnessed inhaled therapies is limited, consider whether the treatment was properly received.
  
  

Beta Agonists

• Inhaled short-acting beta agonist (SABA) therapy (e.g., albuterol) is the main bronchodilator medication that should be used for all asthma exacerbations in the ED.

• SABAs work through agonism of beta 2 adrenergic receptors, with the primary effect to relax smooth muscle in the airway to relieve bronchospasm/obstruction.

• Albuterol can be administered via pressurized metered-dose inhaler (with a spacer) or with a nebulizer (gas flow rate typically set at 6-8 L/min).

• Inhaler: 4-8 puffs (90 mcg/puff) every 20 minutes during the first 4 hours

• Nebulizer: 2.5-5.0 mg every 20 minutes for the first hour (sometimes referred to as “stacked”), followed by 2.5-10 mg every 1-4 hours as needed.

• Continuous albuterol can be administered via nebulizer in severe cases, typically started at 10-20 mg/hr. Experts typically recommend starting higher and weaning as tolerated, rather than starting lower and gradually increasing.

Corticosteroids

• Systemic corticosteroids exert their effect by reducing inflammation, edema, and secretions, thereby relieving airway obstruction.

• Systemic corticosteroids take time to reach peak effect to combat prolonged inflammatory processes, so prompt administration (i.e., within 1 hour) is critically important.

• If the patient arrived by EMS, ask whether systemic corticosteroids have already been administered.

• Intravenous corticosteroid options include methylprednisolone 40-125 mg (1-2 mg/kg pediatric, max 60 mg) or dexamethasone 16mg (0.6 mg/kg pediatric, max 16 mg) daily, and oral options include prednisone or prednisolone 40-80 mg (1-2 mg/kg pediatric, max 60 mg) daily.

• Inhaled corticosteroids should not be used as a substitute for systemic corticosteroids and are not generally considered helpful in management of asthma exacerbation.

• When administering corticosteroids, consider comorbid conditions that can be exacerbated, such as diabetes, psychiatric disorders, and hypertension.

• Corticosteroid therapy should be continued daily for several days, regardless of ED disposition.

Anticholinergics

• Inhaled anticholinergic agents (most commonly ipratropium bromide) are an effective addition to inhaled SABA therapy (but not a substitute).

• Inhaler: 18 mcg/puff (with spacer), 4-8 puffs every 20 minutes for the first 3 hours

• Nebulizer: 0.5 mg every 20 minutes for the first hour, followed by 0.5 mg every 6 hours

• Many EDs offer a combined formulation of ipratropium bromide and albuterol, which can be administered together simultaneously via nebulizer every 20 minutes during the first hour (2.5 mg albuterol and 0.5 mg ipratropium bromide per dose).

Magnesium

• Magnesium exerts its bronchodilator effect by inhibiting calcium influx into smooth muscle cells and through anti-inflammatory activity.

• Intravenous magnesium sulfate (typically 2 g over 20 minutes) can be used to supplement routine therapy in severe cases.

• Inhaled magnesium is generally not considered helpful for asthma exacerbations.

Epinephrine

• Nebulized epinephrine is not routinely used, as inhaled albuterol is the preferred bronchodilator agent to treat asthma exacerbations.

• Systemic epinephrine (typically intramuscular or subcutaneous but occasionally intravenous) is not typically recommended for asthma exacerbations but can be used in severe cases especially when anaphylaxis is considered a likely alternative diagnosis to asthma.

• Risks associated with intravenous epinephrine use, especially in vulnerable patients (e.g., cardiac risk factors), should be considered prior to administration.

Other agents

• Methylxanthines (e.g., theophylline) and leukotriene modifiers are generally not considered helpful in acute care for asthma.

• Ketamine stimulates bronchodilation but is not generally recommended for use solely for its bronchodilator effect. However, it is generally preferred over other sedative agents to facilitate noninvasive positive pressure ventilation or intubation when needed.

• Heliox is a mixture of helium (typically 60-80%) and oxygen that is meant to reduce airway resistance, thereby improving air movement and work of breathing. In the absence of clear supportive evidence, Heliox is generally not prioritized and only attempted in severe cases where the capability exists.

• Antibiotics are only indicated when bacterial infection (e.g., pneumonia) is suspected.