Maintenance Management of Symptomatic COPD

During the evolution of COPD, patients go through stages in which they are unaware of the effects of the damage to their lungs. Then, depending upon whether they primarily experience damage to their airways (“chronic bronchitis”), or their distal air space units (“emphysema”), they typically experience various combinations of cough, excess mucus, dyspnea and exercise limitation.

Principles of Symptomatic Therapy

Treatment of COPD patients usually involves the elements identified in Table 2. The great majority of symptomatic COPD patients will benefit from management of airflow limitation and enhancement of physical conditioning. Management of hypoxemia and surgical measures to improve lung mechanics are reserved for those with more advanced disease.

Major Components of Therapy

The primary components of a COPD treatment program are noted in Tables 3 and 4. Obviously all of these interventions are not appropriate for all patients with COPD; their deployment in relation to severity of disease is depicted in Table 5.

Table 4

Table 5

Treatment Strategies in Relation to Severity of COPD

DEFINITIONS (from GOLD NHLBI/WHO Workshop Report):
I. MILD = FEV₁/FVC < 70%; FEV₁ Ž 80% predicted; with/without chronic symptoms.
II. MODERATE = FEV₁/FVC < 70%; FEV₁ Ž 30% but < 80% of predicted.
III. SEVERE = FEV₁/FVC < 70%; FEV₁ l 30% of predicted or < 50% plus respiratory failure or cor pulmonale.

Bronchodilation is the first line therapy for treatment of symptoms in COPD patients. Long-acting beta-agonists, such as salmeterol or formoterol given twice daily, establish a platform of enhanced airflow throughout the day and night. In addition, beta-agonists may accelerate ciliary beat activity, possibly aiding with mucus clearance. The bronchodilator effect may be strengthened in most patients by the addition of an anticholinergic agent which effects bronchodilation via different pathways than beta- agonists. Ipratropium is currently available in the U.S. and a longer acting agent, tiotropium (now available in many countries), may soon be available here as well. Early clinical experience suggests that inhaled tiotropium may be more effective than salmeterol in improving a variety of parameters of lung function. Neither the long-acting beta-agonists nor the anti-cholinergic agents have sufficiently rapid onset of action to relieve acute bronchospasm; a short-acting beta-agonist, such as albuterol, plus or minus a short-acting anticholinergic (ipratropium) should be used for relief of episodic breathlessness. These agents (anti-cholinergics or beta-agonists) can be used alone, but many studies show that their combined use leads to greater bronchodilation than that observed with either agent alone. This is because these agents work by different mechanisms to bronchodilate. Therefore, this leads to additive, or greater than additive (synergistic) bronchodilator effect.

The role of theophylline in COPD management is somewhat controversial today. Although this drug has demonstrated bronchodilation capacity, it is less effective than either the beta-agonist or anticholinergic agents. Additionally, the risk of toxicity, possibly related to altered hepatic elimination associated with drug-drug interactions, has created further reluctance to use the drug. However, for patients who do not enjoy consistently satisfactory control of their symptoms on beta-agonists, anticholinergics and inhaled steroids, a trial of theophylline is justified. By introducing the drug slowly in escalating dosage, some of the troublesome gastrointestinal or central nervous system side effects may be minimized. In addition to bronchodilation, other potential benefits of theophylline include improved mucociliary clearance, reinforcement of respiratory drive, and augmentation of diaphragmatic contractility/endurance. Theophylline may also help to combat inflammation, but evidence-based studies are limited on the anti-inflammatory effect in COPD.

Corticosteroids may be helpful in the management of selected COPD patients. Used commonly in the management of acute exacerbations of chronic bronchitis (AECB), chronic use of systemic steroids only results in substantial improvements in the FEV₁for about 1 in 5 COPD patients. And, a modest additional number of COPD patients will report subjective improvement while receiving oral steroids, despite a lack of improvement on spirometry. However, given the predictable and formidable sequelae of long-term systemic steroids, such treatment should be employed cautiously.

There has been recent interest in the use of newer, more potent inhaled steroids, to learn whether the beneficial effects can be achieved without the morbid complications.

Available data suggest that inhaled corticosteroids may both improve airflow and reduce the frequency and severity of exacerbations for moderate to severe COPD patients. Thus, it has become common practice to utilize inhaled agents to complement beta-agonists and anti-cholinergic drugs. However, the benefits of the inhaled steroids should be weighed against their potential complications and expenses. It should be noted that the benefits of inhaled steroids in COPD are only observed using high-range dosing. Long-term use of potent steroids, even inhaled, may entail risks for cataracts, osteoporosis, and adrenal suppression. Indeed, for the patient on long-term high dose inhaled steroids, it is prudent to consider ”stress” dose steroid replacement therapy if the patient must undergo general anesthesia/surgery.

The highest combination dose of salmeterol fluticasone will likely receive FDA approval for use in the maintenance management of severe COPD, but it has not received FDA approval as of the time of this printing. (6/03)

The more common problems related to inhaled steroids, especially the more potent varieties, are oral-pharyngeal or esophageal thrush and laryngeal myopathy. To lessen deposition of steroids on these proximal structures, use of spacers with MDI devices and post-inhalation rinsing after use of all steroid-delivering devices is strongly encouraged. Purpuric lesions, especially around the wrists, are seen commonly, most prominently in women.

An occasional patient will enjoy symptomatic and physiologic benefit from oral corticosteroids that cannot be duplicated with inhaled products. In these cases, it is incumbent upon the clinician to establish the minimal dosage required, usually by a gradual wean over weeks to months. In some cases, benefits can be maintained even with alternate day dosing.

Clinical research is underway to identify agents other than corticosteroids that are directed more specifically against inflammation particularly related to COPD.

Mucolytics or expectorants may be of modest benefit in patients with COPD. N-acetylcysteine (NAC) is the prototypic mucolytic agent, but due to its cost and limited utility, NAC use in its inhaled formulation in COPD is generally discouraged in the United States. However, reviews of the clinical experience in the United States and Europe suggest that there may be modest benefits from the use of oral NAC therapy among patients with symptomatic but stable COPD [see Stey]. Note that these trials, done outside the U.S., involved oral administration of MAC (total doses 400 to 600 mg/day given b.i.d. or t.i.d.). Oral tablets are not available in the U.S. Thus, one would be forced to employ the inhaled form as an oral agent, which has not been systematically studied. If inhaled NAC were to be used, logically it might be attempted in those with difficulty in clearing secretions.

By contrast, recombinant human DNAase (Dornase®), which has proven utility in patients with CF, has not resulted in benefit for patients with non-CF-related bronchial disorders.

Guaifenesin (glyceryl guaiacolate) may lessen the tenacity of respiratory secretions, aiding in their elimination. For patients who continue to have difficulty due to chronic congestion despite optimal inhaled therapy and mechanical hygiene, a trial is warranted. This medication is available in a variety of compounds, and pseudoephedrine is commonly added. To lessen side-effects, a simple formulation is generally preferable.

Mechanical hygiene involves techniques employing manual percussion or devices to augment mucus clearance, with or without postural positioning. Historically, “PD&C,” (postural drainage and clapping) was practiced in hospitals and recommended for home care. But due to inconvenience and time constraints, such recommendations were rarely adhered to after discharge. By contrast, the more user-friendly devices, such as the Flutter®, Pep®, or Acapella® valves have been received much more enthusiastically. These devices all work by generating an intermittent, vibrating energy to the airways, helping to mobilize tenacious secretions. Used after inhaled bronchodilator therapy, these devices help clear congested airways. Patients report that although they cough heavily during and shortly after such treatment, they are less likely to experience embarrassing, disruptive paroxysms of cough at work or social occasions.

To use these devices optimally, patients should be instructed in their use by respiratory therapists or other qualified healthcare professionals.

Preventing lower respiratory tract infections is an important element of COPD care. All patients should receive Pneumovax, and if they have not been vaccinated in the past 10 years, they should be revaccinated to both boost immunity and take advantage of the additional serotypes included in recent vaccines.

Persons with COPD should receive the ‘flu” vaccine every fall when it first becomes available. If they miss the vaccine and are exposed to someone with presumed influenza, they should take prophylactic anti-influenza therapy with agents such as amantadine, rimantadine, zanamivir (Relenza ®) or oseltamivir (Tamiflu®). Or, if they have been vaccinated but nevertheless are coming down with an illness presumed to be influenza, such therapy may lessen the severity and duration of the illness.

Finally, persons with COPD should be cautioned to avoid unnecessary contact with persons known to be infected or at very high risk of viral respiratory infections (e.g., grandchildren in primary school or large gatherings during “flu season”).

Long term oxygen therapy (LTOT), pulmonary rehabilitation and surgery are discussed in the next section.

Sleep disordered breathing may complicate the health of persons with COPD. Individuals who report daytime somnolence, snoring, restless sleep, or spouse-described apneas should be considered for evaluation. Other warning signs include new onset hypertension and/or erythrocytosis.

Nutritional issues may also be important for persons with COPD. Typically, with advancing COPD—commonly with emphysema-dominant disease—patients begin to lose weight. In some respects, this may be seen as a physiological adjustment to diminished lung capacity. But, in extreme cases, the weakness which ensues may be deleterious. Nutritional counseling and special enriched diets may be beneficial.

At the other extreme, some patients with bronchitis-dominant disease may suffer from obesity which compromises their mobility and endurance. Weight loss may prove beneficial.

Depression is common among persons whose lives have been compromised by COPD. Psychological counseling and sex-education may prove helpful. However, in a substantial portion of cases, pharmacotherapy may be essential to relieve the pall of depression.

Gastro-esophageal reflux disease (GERD) becomes increasingly common among persons with progressive COPD. Over half of those with advanced COPD (FEV₁ < 50% predicted) have GERD and/or disordered esophageal motility. This is relevant in terms of the differential diagnosis of retrosternal chest pain (i.e., is it cardiac ischemia or GERD?). It is also important to remember that several commonly used COPD medications, including beta-agonists, theophylline, and corticosteroids, can exacerbate GERD.

Osteoporosis is typically found in persons with advanced COPD. Special risk factors include female gender and slender body habitus. Additional hazards secondary to chronic use (systemic or inhaled) include diminished exercise capacity and compromised nutrition.

Summary

Patients who are symptomatic with stable COPD require a variety of interventions to optimize their life styles and survival. Depending on their particular circumstances, they may benefit from maximizing airflow, reducing and clearing secretions, physical rehabilitation, preventing infections, and assuring adequate oxygenation. The various elements can be introduced over time with careful observation to determine which intervention has favorable (or unfavorable) effects. Awareness of other disorders that are common among those with COPD will aid in early recognition, treatment, or prevention. Prompt recognition and effective management of acute exacerbations of chronic bronchitis are essential.

References

Barnes PJ: Chronic obstructive pulmonary disease. N Engl J Med 2000;343:269-280. A state of the art review of all aspects of COPD including conventional and future novel therapies.

Barnes PJ: Theophylline: new perspectives on an old drug. Am J Respir Crit Care Med 2003;167;813-818. A review on the mechanisms of action of theophylline. It may promote steroid action in COPD.

Brus R. Effects of high-dose inhaled corticosteroids on plasma cortisol concentrations in healthy adults. Arch Intern Med 1999;159:1903-1908. A study demonstrating that single-dose exposure to beclomethasone triamcinolone, budesonide and fluticasone resulted in significant suppression of cortisol AUC over 24 hours.

Burge PS, Calverley PMA, Jones PW, et al: Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ 2000;320: 1297-1303. The results of the ISOLDE trial in Europe showing that inhaled fluticasone resulted in elevated FEV ₁(vs. placebo) throughout the trial reduced the frequency of AECB by 25% and resulted in lessened deterioration of health status.

Donohue, JF, van Noord, JA, Bateman, ED, et al: A 6-month, placebo-controlled study comparing lung function and health status changes in COPD patients treated with tiotropium or salmeterol. Chest 2002;122: 47-55. In a head-to-head comparison with a placebo control arm, tiotropium 18 mcg inhaled once daily outperformed salmeterol 50 mcg twice-daily in terms of FEV₁improvement and other markers of respiratory status. The major side-effect was dry mouth, reported in 10%.

Garbe E, Suissa S, LeLorier J. Association of inhaled corticosteroid use with cataract extraction in elderly patients. JAMA 1998;280:539-543. A study from Canada showing that long-term (±2 years) use of high dose inhaled steroids resulted in a significantly increased risk of cataract development.

Hattotuwa KL, Gizycki MJ, Ansari TW, et al: The effects of inhaled fluticasone on airway inflammation in chronic obstructive pulmonary disease. A double-blind, placebo-controlled biopsy study. Am J Respir Crit Care Med 2002;165:1592-1596. A study demonstrating that inhaled steroids (fluticasone) lessened symptoms and resulted in fewer AECB episodes; the unique element was pre- and post-treatment bronchial biopsy and lavage showing alterations in inflammatory cells with fluticasone.

Mahler DA, Wire P, Horstman D, et al: Effectiveness of fluticasone propionate and salmeterol combination delivered via the Diskus device in the treatment of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002;166: 1084-1091. The combination produced lung function improvement and relieved dyspnea better than the individual components or placebo. A randomized clinical trial.

Martin RJ, Szefler SJ, Chinchilli VM, et al: Systemic effect comparisons of six inhaled corticosteroid preparations. Am J Respir Crit Care Med 2002;165: 1377-1383. A careful, comprehensive study comparing the systemic bioavailability of inhaled steroids as well as the effects on plasma cortisol dynamics. The fluticasone dry powder inhaler had relatively low systemic effects. These data suggest awareness of possible adrenal suppression with long-term high-dose use of inhaled steroids.

Paggiaro PL, Dahle R, Bakran I, et al: Multicentre randomised placebo-controlled trial of inhaled fluticasone propionate in patients with chronic obstructive pulmonary disease. Lancet 1998;351:773-780. Demonstrated that inhaled fluticasone resulted in fewer severe AECB events during treatment. Also, there were modest improvements in physiology and endurance.

Pauwels RA, Löfdahl C-G, Laitinen LA, et al: Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking. N Engl J Med 1999;340:1948-1953. Among COPD patients who continued to smoke, inhaled steroids resulted in modest improvements of the FEV₁but did notalter the long term decline. Purpura was seen among recipients.

Pauwels R. Inhaled glucocorticosteroids and chronic obstructive pulmonary disease. How full is the glass? Am J Respir Crit Care Med 2002;165:1579-1580. An overview of the recent experience and possibly beneficial mechanisms of inhaled steroids.

Soriano JB, Vestbo J, Pride NB, et al: Survival in COPD patients after regular use of fluticasone propionate and salmeterol in general practice. Eur Respir J 2002;20: 819-825. Evidence of improved survival in COPD patients with the regular use of both agents.

Stey C, Steurer J, Bachmann S, et al: The effect of oral N-acetylcysteine in chronic bronchitis: a quantitative systematic review. Eur Respir J 2000;16:253-262. A review of multiple studies examining the efficacy of inhaled NAC in patients with “chronic bronchitis”. This analysis indicated fewer exacerbations and amelioration of symptoms among those receiving extended courses of NAC. However the authors noted that the expense may not justify the modest benefits.

Van Noord JA, deMunck DRAJ, Bantje ThA, et al: Long-term treatment of chronic obstructive pulmonary disease with salmeterol and the additive effect of ipratropium. Eur Respir J 2000;15:878-885. A single-dose and longer term therapeutic trial comparing salmeterol, ipratropium and a combination of the two in COPD. The combination was more effective in improving airflow and appeared to lessen the risk of AECB.