Corticosteroids - clinical applications: exacerbations of asthma in adults

Summary
Corticosteroids are essential to reverse the eosinophilic airway inflammation which causes symptomatic exacerbations of asthma. Much of the current variation in clinical practice is not justified by data from clinical trials. Oral prednisolone is as effective as intravenous therapy and very high doses of corticosteroid are no better than modest doses (30-50 mg prednisolone). Corticosteroids should be given twice a day for optimum effect. Therapy does not need to be tapered, but can be ceased abruptly after 10 days in most patients who are also taking high -dose inhaled corticosteroids. There is an increasing role for inhaled corticosteroids in the management of mild exacerbations of asthma. The dose, route and duration of therapy need to be defined for each patient and written down as part of an action plan to enable early intervention in future exacerbations.

Introduction
An exacerbation of asthma is a common and sometimes life -threatening complication which may require hospital admission. Although corticosteroids have been used for symptomatic exacerbations of asthma for many years, there is considerable variability in how they are used. There are probably as many corticosteroid regimens as there are physicians treating asthma. Clinical guidelines are attempting to standardise the approach to management, but they still have their problems.

Pathogenesis
An exacerbation of asthma involves

• bronchospasm
• airway inflammation with cellular infiltration and oedema
• mucus plugging.

Recognised triggers for asthma exacerbations include respiratory tract infections, allergens, occupational chemical exposure and non-specific triggers such as irritants and emotional factors. The aims of treatment are to prevent death, to relieve hypoxaemia, to normalise lung function as quickly as possible, and to prevent future relapses. Corticosteroids are of proven benefit for eosinophilic airway inflammation, and bronchodilators are given to reverse bronchospasm. Specific therapy is not available for the poorly understood mucus plugging.

Action plans
In most cases the exacerbation progressively worsens over several days, or occurs on a background of chronic poor asthma control. This provides an opportunity to intervene early in order to reduce the severity of the exacerbation. When a patient presents with acute asthma, this is an important occasion to review background asthma control, and to provide the patient with an asthma action plan. The main approach is the early use of sufficient corticosteroid and bronchodilator therapy to reverse the exacerbation. This approach needs to be defined individually for each person with asthma, and written down as an action plan. Action plans instruct the patient

• when to increase treatment
• how to increase treatment
• for how long to take the increased treatment
• when to call the doctor.

Failure to specify and adhere to each component of the action plan can result in treatment failure. Corticosteroids are particularly important in step 2, 'How to increase treatment'.

Are corticosteroids necessary?
Corticosteroids are generally considered to be beneficial in exacerbations of asthma, although some studies have found minimal or no benefit. The clinical course of an asthma exacerbation varies from one patient to another. This may relate to the type of trigger, the presence (or absence) of corticosteroid responsive pathology (eosinophilic bronchitis) versus the degree of mucus plugging. There can be resolution with bronchodilators alone, a delayed response to corticosteroid, or treatment failure with no response to corticosteroid. The literature therefore contains some trials showing that corticosteroids have no effect. The technique of meta-analysis has been used to deal with these variations in the published literature, so that the results of many clinical trials can be pooled to give a single measure of effect. A meta -analysis of corticosteroid use in acute asthma shows that they are effective in reducing hospital admission rates, improving pulmonary function, and reducing relapses of asthma.¹ For these reasons, and because it is not possible to predict those patients who will resolve spontaneously, corticosteroids should be offered to each patient who presents with an exacerbation of asthma. The important issues are to define which corticosteroid, in what dose, how often, and by what route.

Which corticosteroid to use?
Many corticosteroids have been used to treat acute asthma. Overall, the drugs appear to be of similar efficacy when used at comparable doses. The main differences in the drugs relate to their cost and adverse effect profile. Intravenous hydrocortisone is more expensive and has more associated mineralocorticoid properties than dexamethasone. Oral drugs are cheaper than intravenous treatment, and prednisone or prednisolone is commonly used. In the absence of liver disease, there is no evidence that oral prednisone is less effective than prednisolone which does not require activation by hydroxylation in the liver.

Drug dosage
A dose-response relationship for corticosteroids has been difficult to find in acute asthma. Of 12 controlled clinical trials which examined the dose-response of corticosteroids^2,3, only two studies were able to show a difference between doses. In general, the literature does not support the use of high dose corticosteroids in acute asthma. Hydrocortisone 50 mg 4 times a day for 48 hours, followed by oral prednisone, was as effective as 200 mg or 500 mg of hydrocortisone followed by high dose prednisone.³ The effective dose of oral prednisolone is between 30 mg and 50 mg daily.⁴ High doses of corticosteroids are associated with increased adverse effects, in particular mood disturbance and myopathy.

Dose interval
A single daily dose of corticosteroid may be inappropriate for exacerbations of asthma. There are several reasons for this. The duration of action of corticosteroid on lung function in unstable asthma peaks at 9 hours and falls after this (Fig. 1).⁵ A single 8 a.m. dose of prednisone will not prevent the nocturnal increase in airway inflammation or airway obstruction which accompanies nocturnal asthma, whereas an afternoon dose will.⁶ Hence, some patients given a single daily dose will continue to experience night-time asthma. A convenient dose interval is therefore 12 hours.

Which route of administration?

Oral or intravenous
Although hydrocortisone is commonly injected for acute asthma, the routine use of this drug may be unnecessary. Prednisolone is rapidly absorbed and has a high bioavailability (75-100%). Several randomised trials have compared oral to intravenous therapy for the treatment of acute asthma. These studies showed no difference in efficacy between the oral and intravenous route. The intravenous route is more costly, but is indicated when the oral route is unavailable. A convenient regimen for moderately severe exacerbations of asthma is
50 mg prednisolone orally as an immediate dose, followed by 25 mg twice daily.

Oral or inhaled
Asthma exacerbations of moderate severity (FEV1 <60% predicted) require therapy with an oral corticosteroid. However, the vast majority of asthma exacerbations are mild. Many people are concerned about the adverse effects of corticosteroids, but these drugs are essential to reverse the eosinophilic inflammation which accompanies even mild exacerbations of asthma. An alternative is to give an inhaled corticosteroid because of its favourable adverse effect profile. In mild exacerbations of asthma (FEV1 >60% predicted), high dose inhaled corticosteroids reduce airway inflammation, improve airway responsiveness, and shorten the duration of the exacerbation.⁷ A recent study has found high-dose inhaled corticosteroid therapy to be as effective as oral prednisolone.⁸ More clinical trials are needed to confirm the use of inhaled corticosteroids in exacerbations.

Inhaled corticosteroid therapy is therefore an option for patients who present with a mild exacerbation of asthma. Once asthma severity is assessed and the patient is defined as having a mild exacerbation, then the approach which I use is based upon a 'rule of twos'. High dose inhaled corticosteroid (beclomethasone or budesonide) is administered twice daily, for two weeks, in a dose of 2 mg daily, or at least twice the maintenance dose (whichever is the greater). Oral prednisolone is added if there is

• a recent history of a severe exacerbation
• a history of treatment failure with inhaled corticosteroid
• an unreliable inhalation technique
• no response after several days.

Dose reduction
The common practice of tapering the dose of oral corticosteroid after recovery from an exacerbation is complex for the patient and may be unnecessary. Several studies have compared abrupt cessation of corticosteroid after 7-10 days' therapy with a tapering dose.⁹ There was no difference in lung function or relapse rate between the steroid tapering group and the abrupt cessation group. Tapering is not necessary provided that the patient is not using oral corticosteroids chronically, and is protected by high-dose inhaled corticosteroid after the oral steroid is stopped. It takes an average of 7-10 days for symptoms and lung function to stabilise after an asthma exacerbation.^7,9 Because of this, immediately tapering the corticosteroid could actually lead to rebound asthma. Although biochemical evidence of partial hypothalamic-pituitary axis suppression can be detected after short courses of oral corticosteroid, this is rarely of clinical significance unless the patient has been taking steroids long term.

Tapering the dose is still indicated in the occasional patient who is chronically dependent upon oral corticosteroid as well as inhaled steroid for asthma control. In these circumstances, the dose is tapered at weekly intervals (or longer) until symptoms begin to recur. This is done in order to identify the minimum maintenance dose of corticosteroid to maintain control of the asthma. When suppression of the hypothalamic -pituitary-adrenal axis has occurred from chronic corticosteroid usage, dose tapering should proceed very slowly over 6-15 months with monitoring of plasma cortisol.¹⁰

Controlled studies have not yet defined the best way to reduce the dose of inhaled steroids after exacerbations. One approach is to reduce the dose at weekly intervals in order to identify the minimum maintenance dose of inhaled steroid.

Inadequate response
Inadequate response is not infrequent during exacerbations of asthma.8 The most common causes are non-compliance or a delay in starting corticosteroid therapy. These can be addressed by education and preparing an asthma action plan. As there is no specific therapy for mucus plugging in asthma, there may be a slow response to therapy when this is present. The clinical relevance of individual variations of corticosteroid metabolism remains undefined.

Influences on treatment
There are a number of additional factors to consider when choosing therapy for patients. Oral prednisolone is preferred if there is a history of severe asthma, life-threatening asthma, non-response to inhaled corticosteroids, or chronic use of high-dose inhaled corticosteroids or daily oral steroids. In mild exacerbations, oral steroids are avoided if there is a history of adverse reactions, non-compliance, steroid phobia, or diabetes mellitus.