P.M.A. Calverley
European Respiratory Journal 2001 18: 60s-66s; DOI: 10.1183/09031936.01.00229801
Until recently, inhaled bronchodilators had a relatively short duration of action with ipratropium being somewhat longer than the beta-agonists, a finding which suggested that three times daily use was adequate. This has been based more on statistical rather than clinical considerations and it seems likely that most short-acting beta-agonists have their optimum effect in the 4 h after administration, with their effects measurable from around 30 min onwards. Oral agents such as the theophylline compounds clearly can be dosed over longer periods, particularly with the availability of slow release preparations. However, the unpleasant side effects, particularly those associated with phosphodiesterase (PDE) III inhibition such as the ventricular arrhythmias have now made this therapy a third line option. Long-acting inhaled beta‐2 agonists have now been shown to be effective in terms of increasing FEV1 for around 12 h after a single dose. This effect is sustained over weeks of treatment and unlike previous reports of short-acting bronchodilators, is associated with a clinically significant improvement in health status. These findings have been established using salmeterol but currently unpublished studies with formoterol confirm these results in a wider range of subjects. There seems to be no advantage in giving higher doses of long-acting beta agonists presumably because of tremor and sleep disturbance. Four-times daily ipratropium produced a similar improvement in health status to twice daily salmeterol in one study, but this has not been confirmed using a different questionnaire in a larger investigation. There is some tantalizing evidence that the time between exacerbations can be increased by using long-acting inhaled beta-agonists. Although further prospective studies are required to establish this definitely.
The development of once daily therapy with tiotropium bromide represents a further advance. This is an exceptionally long-acting inhaled anticholinergic drug which produces significant improvements in pulmonary function over three months compared with placebo and ipratropium. Data in abstracts suggest that this also improves health status and there are clear questions to be answered about its relationship with the long-acting inhaled beta-agonists and with a further combination therapy will be the optimum way of providing maintenance bronchodilitation. There still seems to be a role for short-acting bronchodilator treatment to help with acute symptoms and high doses are often administered by wet nebulizer to patients with severe end-stage disease. The evidence that this is more beneficial than lower doses for a spacer device is limited and almost certainly requires a more detailed physiological approach than that currently used in the literature.
Anti-inflammatory therapy
The recognition of COPD is characterized by persistent airway inflammation and that as the disease advances there are an increased number of neutrophils in the alveolar structures which makes anti-inflammatory therapy both a logical and attractive approach to managing this condition. In practice this has meant using either oral or inhaled corticosteroids, and data about other forms of intervention has not, so far, extended to man. The experimental evidence in support of corticosteroid therapy in COPD, as opposed to asthma, is conflicting. Some studies report reductions in neutrophil chemotaxis and reduced numbers in induced sputum while others using a variety of oral and inhaled interventions have found no effect on important sputum markers such as interleukin‐8 and tumour necrosis factor‐α. Unpublished biopsy data suggests there may be a small reduction in the number of mast cells in airway biopsies from COPD patients treated with inhaled corticosteroids but overall the pattern of other inflammatory markers, and in particular T‐lymphocytes, is unaffected.
Empirical observations initially suggested a survival benefit for patients treated with inhaled corticosteroids and early reports pointed to a substantial improvement in patients managed this way compared with those treated with bronchodilators alone. However, these data included large numbers of people who would in other circumstances be classified as having bronchial asthma. Data studying the change in FEV1 over time was again initially encouraging with a significant improvement in prebronchodilator FEV1 a finding confirmed on a subsequent meta-analysis of European studies. Subsequent prospective investigations have used a number of inhaled corticosteroids as this route was preferred to oral therapy due to the high incidence of side-effects and evidence for corticosteroid myopathy which may contribute to mortality.
Four studies are now available which have addressed the role of inhaled corticosteroids in the long-term management of COPD. In all the studies the rate of decline of FEV1 with time has been the primary end-point and the postbronchodilator FEV1 has been chosen as the most reproducible measurement to assess this. In two of the studies patients with relatively early disease or those where it was not unduly severe were tested in the hope of preventing disease progression. In the remaining studies other end-points related to the symptoms of the disease could be considered. All the studies are in agreement in finding no beneficial effect of any of the inhaled steroids (budesonide, fluticasone propionate and triamcinolone) on the rate of decline of FEV1 with time. In two studies there was a small but statistically significant improvement in postbronchodilator FEV1 evident by three months and persistent throughout the study and this varied between 60 and 100 mL. In the Lung Health Study II there was a reduction in the number of the cases complaining of new onset breathlessness and attending for additional medical attention related to their chest problems, a surrogate for exacerbation in this group of moderately severe COPD patients.
In the Inhaled Steroids and Obstructive Lung Disease (ISOLDE) study where the patients were sicker and were already attending hospital clinics inhaled corticosteroids reduced the number of exacerbations by ∼25% with most of this benefit residing in patients with an FEV1 <50% pred. This study also showed a reduction in the rate of decline in health status with time indicating that although all patients got worse, the extent of deterioration in important clinical symptoms was substantially less in those treated with inhaled corticosteroids.
In the three studies where it was reported, skin bruising occurred in ∼5% of individuals treated with the active drug. There were no clinically significant differences in serum cortisol measurement and data about bone mineral density is conflicting, with the studies using budesonide finding no ill effects but the Lung Health Study using triamcinolone suggesting some deterioration in femoral neck bone density with time. Local side effects such as oral candidiasis and hoarse voice occurred with a frequency similar to that seen in bronchial asthma.
Current guidance incorporated in the GOLD report suggest that inhaled corticosteroids should be considered in patients with an FEV1 <50% pred who have at least one exacerbation per year. Additionally, there are data suggesting that ∼10% of individuals will show significant spirometric improvement after oral corticosteroids, which can be sustained with time. GOLD suggests that patients who show such an improvement in post bronchodilator FEV1 also merit inhaled corticosteroid therapy although the robustness of this particular recommendation still requires testing.
Management of acute exacerbations
COPD is characterized by periodic worsening of the symptoms sustained for more than 48 h commonly described as an exacerbation. This can occur at all stages of the disease and vary from a troublesome increase in cough and sputum production to severe breathlessness and respiratory failure. The therapy offered is dictated by the severity of the symptoms and the background severity of the COPD but falls broadly under four headings.
Treatment of the precipitating factor
Viral or bacterial infection are thought to be the most common precipitants of exacerbation and antimicrobial therapy is indicated in patients in whom there is an increase in breathlessness accompanied by an increase in sputum volume purulence. The evidence in favour of treating less severe episodes is scant although new anti-viral therapies are available, they have not been fully evaluated in terms of COPD patients and in particular whether they shorten the duration of exacerbations. This could be a potentially important intervention for the various neuraminidase inhibitors, which have now been licensed for use in North America and Europe. Preventing exacerbations is clearly important and there is indirect, but powerful evidence that regular influenza vaccination based on the prevailing strain can do this. In contrast, the benefit of immunization against the pneumococcus is much more controversial, with conflicting data from North America and Western Europe. At present, this is not routinely recommended.
Increased bronchodilator therapy
In general bronchodilator therapy has increased in intensity particularly in patients where breathlessness is prominent. Thus, patients with mild disease who become breathless can be treated by regular inhaled bronchodilators or the introduction of long-acting therapy, while those already receiving this treatment due to more severe background disease may need one or more days of nebulized bronchodilators. There is no clear advantage to initiating therapy with the beta agonist or an anticholinergic when nebulized drugs are used and it has been argued, based on FEV1 criteria, that adding in ipratropium to salbutamol is not beneficial during the clinical course of patients who are hospitalized. Despite this, it is common practice to use combination bronchodilators in the early stages of exacerbations of severe COPD and more data are needed about the appropriateness of this and the physiological benefits. Nebulizers tend to be used because they do not need patient cooperation and they provide therapy high on the dose-response relationship. Side effects such as tremor with beta-agonists are much more common, particularly in elderly patients were caution should also be used in those with a history of glaucoma when they are given anticholinergic drugs.
Anti-inflammatory therapy
Unlike the situation in chronic disease, there is now clear evidence that oral corticosteroids increase the rate of resolution of acute exacerbations of COPD and shorten hospital stay. This has been shown in outpatients and in two large studies of inpatients where similar effects were produced despite substantially different doses and duration’s of oral corticosteroid therapy. In general, medication with 0.6 mg·kg−1 of prednisolone (usually equivalent of 30 mg taken once daily) for 10 days appears to produce equivalent benefit to larger doses and mostly for longer periods. Whether oral corticosteroids are useful in patients with less severe symptoms is not yet established. There is no benefit in giving this medication intravenously and it can be stopped without complications in most cases. Caution is needed in patients who have had recurrent causes of oral corticosteroids where a reducing dose may be required to prevent corticosteroid withdrawal effects.
Other medications
A wide range of other therapies have been developed for treatment in COPD, of these the most promising are the mucolytic drugs, although initial assumptions that they would improve the troublesome cough and sputum that characterizes mild-to-modern disease have not been well founded. Indeed it has been difficult to demonstrate any objective benefit in many of the studies conducted where outcomes such as lung function symptoms or health status have been examined. However, there is an increasing body of data, which has been collated by a good meta-analysis and has a selective review of the literature to support the view that these agents reduce the number of exacerbations of chronic bronchitis symptoms experienced by COPD patients. Most of these data are driven by studies involving N‐acetyl cysteine, which is more properly described as an antioxidant drug. There are attractive theoretical grounds for believing that this drug could be effective although the levels of air within the airways and alveoli appear to be very low on current oral dosing regimes. There are no data using currently available leukotriene antagonists or enzyme inhibitors to support a role in COPD although a substantial number of prescriptions with this indication are issued in North America. Antagonism of leukotriene B‐4 may have a role in reducing the number of exacerbations and specific inhibitors are in clinical trial. There appears to be no role for nedocromil or related agents nor is there good evidence for benefits from current cough suppressants although these are often purchased by patients.
Intravenous aminophylline is frequently used in the management of acute COPD although there are no good clinical trials to demonstrate its benefit in patients who have received adequate doses of nebulized bronchodilators. It can accentuate the toxicity in patients who are already receiving oral therapy and should be used with caution, ideally with the availability of plasma theophylline levels. Respiratory failure can be managed by giving parental respiratory stimulants with doxapram hydrochloride being the favourite drug. Reports over 30 years ago suggest that this might improve blood gas tensions, but more recent studies have found it inferior to noninvasive positive pressure ventilation in the management of significant hypercapnic exacerbations of COPD.
Conclusions
There is now substantial evidence that through good clinical practice in the management of chronic obstructive pulmonary disease patients, it is possible to lessen the symptoms and intervene positively for these patients. Further progress will be dependent on the ability to understand and categorize the processes which underline chronic obstructive pulmonary disease both in terms of its progression and the patients’ symptoms. As this knowledge accumulates more rational therapy will be possible.
English