Describe the standard medical therapies and discuss some of the controversies related to each.

1. The effect of supplemental oxygen on hypoxic drive in asthmatics.
2. Beta agonists: What is the best mode of drug delivery in asthma, nebulizers or metered-dose inhalers (MDIs)? Are Beta₂ (B₂) -agonists association with increased mortality in the acute setting?
3. What dose of which corticosteroid is optimal?
4. What is the role of anticholinergic agents in the acute setting.
5. What is the role of the theophylline
6. What is the role of the newer leukotriene inhibitors in the acute setting?

1. Oxygen

Supplemental oxygen (FiO2 < 0.4 is usually all that is required) during acute episodes helps correct hypoxemia and improves hypoxic pulmonary vasoconstriction. It is vitally important to realise that hypoventilation because of relief of hypoxic drive is extremely unusual and should not deter one from correcting hypoxemia, the main cause of death in fatal asthma. Refractory hypoxemia should lead one to a search for additional pathology such as a pneumothorax, pneumonia, aspiration or lobar collapse.

2. Beta₂ - agonists

Inhaled B₂-agonist are the mainstay of bronchodilator therapy in acute exacebations and should be started immediately on presentation. The standard regime for initial care is albuterol 2.5mg by continuous flow nebulization (0.5ml of a 0.5% solution in 2.5ml of normal saline) every 20 minutes for three doses, and then aproximately hourly as dictated by the patients condition. If very severe bronchoconstriction is present albuterol may be nebulized at higher doses (5mg) and even at times continuously until an adequate clinical response is seen or one is limited by adverse side-effects (agitation, tremor, tachycardia or arrhythmias). However recent reports suggest that metered-dose inhalers (MDIs) combined with a spacer are as effective or even better at drug delivery and improvement in lung function than nebulizers. The larger particle size generated by continuous flow nebulizers and loss of medication inherent in the technique make it a much less efficient mode of delivery than MDIs (1). The recommendation is 4 to 8 puffs every 20 minutes (felt to be equivalent to one nebulizer treatment) but up to 40 to 60 puffs may be given in certain situations. An important point to be noted was that physicians monitored for correct inhaler technique in all of these Nebulizer versus MDI studies. Patient cooperation is minimally required for continuous nebulizer treatments.

Systemic administration (especally intravenously) of B₂-agonists confers no special advantage over inhaled techniques and may actually result in a higher incidence of side effects. In dire circumstances where patients are not responding to inhaled beta-agonists, epinepherine (0.3ml of a 1:1000 solution) given subcutaneously is the drug of choice.

B₂ agonists have been associated with an increased mortality in the chronic but not in the acute setting. However these studies have been difficult to interpret and an increased B₂ agonist use may be merely selecting out a sicker population. B₂ agonists are, and remain, the mainstay of initial bronchodilator treatment in the acute setting.

3. Corticosteroids

Corticosteroids are the most potent means of reducing airway inflammation. However objective improvement in airway obstruction takes at least 6 to 12 hours, thus the first dose should be administered as early as possible. The slowness of the response does not diminish the importance of these agents. Proposed mechanisms of action include potentiating the beta-responsiveness of airway smooth muscle, reducing mucosal edema, reducing inflammatory cell infiltration and decreasing mucus secretion.

The optimum dose remains controversial. Recent reviews have recommended 150-225 mg/day prednisone or the equivalent (e.g. 40mg methylprednisolone IV q6h, 125 mg hydrocortisone IV q6h or 60 mg prednisone PO q6h) (2). Steroids should be continued until recovery of lung function. The is no widely accepted method of tapering steroids and they are associated with a large number of well known side effects.

4. Anticholinergics

Anticholinergics (e.g. Ipatropium or glycopyrrolate) are not considered a first line therapy. A recent expert panel suggested the use of an inhaled anticholinergic agent in combination with a beta-agonist for patients not responding to a beta-agonist alone. Anticholinergic agents achieve their effect through the copious efferent, cholinergic, parasympathetic innervations of the bronchi. They are slower in their onset and have less bronchodilation than do the beta agonists. However there are reports that the combination produces greater bronchodilation than beta agonists alone, especially in severe cases (3). Theoretical concerns of inhibition of mucociliary clearance in the airways have not been borne out clinically. Ipatropium may be given via continuous nebulizer (0.5 mg diluted in 2.5 ml of normal saline) or via MDI (18 mcg/puff).

5. Theophyllines

The use of theophyllines to treat asthma is very controversial. As a monotherapy, theophyllines are inferior to B₂ agonists in the acute setting. However many physicians continue to use intravenous aminophylline or theophylline in sick asthmatic patients when conventional therapy is not working. A meta-analysis of theophyllines use in the emergency room came to the conclusion that there is insufficient evidence to support or reject its use in this situation (4). Apart from its bronchodialtor effects, it is thought to both improve respiratory muscle function and to have an anti-inflammatory action. The usual loading dose for aminophylline is 5-6mg/kg over 30 minutes, followed by a continuous infusion of 0.6mg/kg/hr. Target serum levlas are 8&endash;15 mcg/ml. Toxicity results in a high incidence of nausea, tremors, palpitations and arrhythmias.

6. Anti- leukotriene agents.

This relatively new class of drugs inhibits the synthesis of leukotrienes which are known potent bronchoconstrictors that also cause both pulmonary vascular leakage and inflammatory cell infiltration of the airways. Despite much excitement engendered around their arrival, currently they are only approved for chronic use in mild persistent disease and, to date, no evidence supports their use in acute asthma.