Initial pharmacological therapy for the patient with severe asthma includes oxygen and inhaled bronchodilators. Low-flow oxygen is generally sufficient to achieve adequate arterial oxygenation. Severe hypoxemia may be due to additional complications such as atelectasis, pneumonia, and barotrauma. Bronchodilator therapy and corticosteroids are the most important treatments in status asthmaticus (table I).[1,17,18]
2.1 β-Adrenoceptor Agonist (β-Agonist) Therapy
2.1.1 Inhaled β-Agonists
β-Adrenoceptor agonist (β-agonist) therapy is the cornerstone of the initial management of status asthmaticus. β-agonists relax airway smooth muscle and decrease mucosal edema. The onset of action is rapid. Albuterol (salbutamol) is the most commonly used β2 selective inhaled bronchodilator in the United States. Inhaled therapy may be administered via a nebulizer or metered-dose inhaler (MDI) with a spacer (table II). Nebulization of 2.5mg (in 2ml of saline) or four puffs (0.36mg) of albuterol have been shown to be equivalent. The onset of bronchodilator action is rapid, occurring within 5 minutes, with peak effect within 30 minutes. The medication may be administered every 20 minutes for three doses and then hourly. For some adult patients with severe acute asthma, higher doses of albuterol and continuous inhaled therapy are required. Administration of β2-agonist via an MDI may be effective; however, in patients with severe airflow obstruction administration via a nebulizer may provide greater subjective relief.
Dosage and frequency of administration of inhaled albuterol (salbutamol) in patients with status asthmaticus[1,17–20]
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The administration of inhaled therapy to patients who are intubated is challenging.[17,20] Higher doses are required for an adequate amount of drug delivery to the lower airways. Many factors affect aerosol deposition in the airways of intubated patients including ventilator settings, ventilator circuit, humidification, location of device, amount of drug, endotracheal tube dimensions, severity of airways disease, and patient effort and synchrony. Nebulized albuterol 2.5mg is administered with the nebulizer placed 30cm distal to the Y connector with an airflow rate of 6–8 L/min. The use of an MDI with a spacer placed 10cm from the Y connector for the administration of 6–8 puffs of albuterol has also been advocated. MDI actuation directly into the endotracheal tube has been found to supply the least effective bronchodilation, as more drug impacts on the endotracheal tube and large airways.
The best approach is to assess the effect of a drug dose or delivery system for the individual patient.[1,17] Corbridge and Hall recommend assessing changes in airflow resistance. The ventilatory parameter of peak-to-plateau airway pressure gradient may be examined for the effect of the administered bronchodilator. A fall in the gradient of >15% indicates a significant effect on airflow resistance. The drug can then be administered every 30 or 60 minutes. With improvement, the time interval between doses can be lengthened.
Potential adverse effects of inhaled β-agonist therapy include arrhythmias, tremor, and hypokalemia.
2.1.2 Parenteral β-Agonist Therapy
Although patients with status asthmaticus have severe airflow obstruction, inhaled medications are still generally effective in reaching the lower airways. Epinephrine (adrenaline) or terbutaline given subcutaneously have not been shown to provide greater bronchodilatory effect compared with an inhaled β-agonist. Such therapy may be considered in younger patients (<40 years) who demonstrate refractory status asthmaticus. Epinephrine 0.3ml of 1 : 1 000 solution can be administered subcutaneously every 20 minutes for 3 doses. Terbutaline 0.25mg subcutaneously every 20 minutes for three doses is preferred in the pregnant patient. Complications include metabolic disturbances such as hypokalemia and lactic acidosis, cardiac arrhythmias and myocardial ischemia. In adults with status asthmaticus, intravenous β-agonist administration has shown no improvement in bronchodilation compared with the inhaled route, and is not recommended.
There is rarely a need for parenteral β-agonist therapy in status asthmaticus. Oral β-agonists are not useful in status asthmaticus. Status asthmaticus will usually respond to appropriate inhaled therapy, corticosteroids and supportive measures.
Corticosteroid therapy is a mainstay of treatment of status asthmaticus. Corticosteroids decrease synthesis of inflammatory mediators such as leukotrienes and prostaglandins, inhibiting macrophage and T cell mediator release, and decreasing endothelial adhesion molecules. Corticosteroids thus decrease airway wall inflammation and mucus production and also improve responsiveness to β-agonist therapy. Their mechanism of action involves binding to cell cytosol receptors and regulating gene transcription; the latter effects are not seen for 6–12 hours. Corticosteroids should be administered early and may be administered as methylprednisolone 60–125mg intravenously or prednisone 30–40mg orally every 6 hours.[1,18] Aerosolized corticosteroids are not generally administered for status asthmaticus.
Complications related to corticosteroid administration include hyperglycemia, hypertension, and psychosis. Myopathy is a specific complication of corticosteroid use in patients intubated for status asthmaticus who are receiving neuromuscular blocking agents.
2.3 Anticholinergic Agents
Inhaled anticholinergic agents may be useful in status asthmaticus, particularly in those patients refractory to inhaled β-agonist and corticosteroid therapy.[1,18] Ipratropium blocks acetylcholine action at muscarinic receptors on airway smooth muscle. Peak effect occurs within 90 minutes and lasts up to 6 hours. Anticholinergic agents alone are weak bronchodilators but may enhance bronchodilation provided by β-agonists. A recent study found significant benefit from the addition of ipratropium to albuterol, via a MDI, as initial therapy in the emergency department for adult patients with acute asthma.
There is little systemic toxicity related to inhaled ipratropium. Its use may be of particular importance in patients with β-blockade. Ipratropium bromide may be administered as a 0.5mg solution via nebulization alone or in combination with albuterol 2.5mg. Ipratropium may be administered as 4–10 puffs via a MDI with spacer.
Theophylline has a long history of use in the treatment of asthma with the potential beneficial effects of potentiation of β-agonist-induced bronchodilation, improved diaphragmatic contractility, inotropic and diuretic effects. Recent work also suggests an immunomodulatory role of theophylline in inhibiting activation of airway T lymphocytes. However, theophylline has not been demonstrated to benefit patients with status asthmaticus when added to standard bronchodilator therapy. Adverse effects include tachycardia, nausea and tremor, and there are many drug interactions to consider.
2.5 Magnesium Sulfate
Magnesium has been administered as a bronchodilator in patients with severe status asthmaticus. Magnesium may work by inhibiting calcium-mediated as well as parasympathetic nerve-mediated constriction of airway smooth muscle. A meta-analysis of seven trials using intravenous magnesium sulfate in the emergency department for the treatment of asthma indicated that although routine use was not beneficial, use in patients with severe asthma led to improvement in peak expiratory flow rates. Therefore, individual patients with status asthmaticus may benefit from intravenous magnesium. Magnesium sulfate is administered as a 2g intravenous infusion over 20 minutes.
Heliox is a mixture of helium and oxygen which is less dense than air and thus may produce less resistance in airways with turbulent air flow. Heliox does not affect airway inflammation or bronchoconstriction. The objective of administering heliox is to reduce the work of breathing while giving time for pharmacological therapy to become effective. Several small studies have shown improvement in peak flow and reduction in pulsus paradox, as well as an improvement in respiratory acidosis. At this time there is insufficient evidence to recommend the use of heliox in status asthmaticus.