This algorithm outlines the criteria for the medication treatment of COPD. The aim of therapy is to use those medications needed to maintain control and improve function and quality of life with the least risk for adverse effects. The medication plan for COPD is summarized in Table I.

1. Spirometry is essential to confirm the presence of airflow obstruction (low FEV₁ and FEV₁/VC ratio). Base therapy on symptoms, but consider alternate diagnoses (heart disease, pulmonary emboli, etc.) if out of proportion to spirometry.
   
   
2. Use the lowest level of therapy that satisfactorily relieves symptoms and maximizes activity level. Assure compliance and proper use of medications before escalating therapy.
   
   
3. Inhaled long acting beta₂-agonists should not be used as rescue therapy. Short-acting inhaled beta₂-agonist (less than 12 puffs/day) may continue to be used PRN. Nighttime symptoms are frequently better controlled with long-acting inhaled beta₂-agonist. Oral beta₂-agonists are associated with a higher rate of side effects, and should be reserved for patients who cannot take inhaled beta₂-agonist medications.
   
   
4. Theophylline should be used with caution because of potential for severe side effects. Nighttime respiratory symptoms are frequently controlled but theophylline may lead to insomnia. Theophylline should be discontinued if a symptomatic or objective benefit is not evident within several weeks.
   
   
5. A corticosteroid trial of prednisone (40 to 60mg/day) 10 to14 days, or high dose inhaled steroids (equivalent to 880 µg or more of fluticasone or 800 µg or more of budesonide) of 14 to 21 days can help identify patients who may benefit from long term steroid use. Responders to oral steroids should transition to the lowest effective dose of inhaled steroids, or to the lowest effective dose of a combination of inhaled and oral steroids, if possible, to avoid the long term complications of systemic corticosteroids. If oral steroids are used other than for an acute exacerbation, obtain spirometry prior to and after trial to confirm an objective response.

OBJECTIVE

To identify patients with COPD who may benefit from therapy.

ANNOTATION

1. Typical daily symptoms of COPD include exertional dyspnea, wheezing, or cough. Chest tightness is common, but should be further evaluated to exclude co-existing heart disease. These symptoms may occur daily or less than daily, thus resulting in different medication recommendations.
   
   
2. Routine use of ipratropium does not slow the rate of decline in pulmonary function in patients with mild COPD. Patients with symptoms less often than daily may be medicated as needed.
   
   
3. A trial of inhaled anticholinergic therapy is recommended in apparently asymptomatic patients with an FEV₁ of less than 50 percent of predicted, since this degree of obstruction is usually associated with dyspnea. A lack of symptoms may result from the patient avoiding activities and adapting to his/her disability, or from the assumption that dyspnea is part of the natural aging process.
   
   
4. Asymptomatic patients with an FEV₁ less than 50 percent predicted may benefit from regular inhaled anticholinergic therapy without a short acting inhaled beta₂-agonist (SAIBA). Symptomatic patients in this category should be prescribed both a chronic anticholinergic inhaler or SAIBA as well as a beta₂-agonist for prn use, especially prior to exertion.
   
   

EVIDENCE

Consensus recommendations on initiation of pharmacotherapy: American Thoracic Society 1995; European Respiratory Society, Siafakas 1995; British Thoracic Society 1997. LE=C, SR=IIa

Ipratropium 36 µg tid for 5 years did not affect the rate of decline in FEV₁: The Lung Health Study, Anthonisen 1994. LE=A, SR=I

OBJECTIVE

To initiate or adjust appropriate prn therapy with SAIBA.

ANNOTATION

1. Short acting beta₂-agonists are available in MDI, dry powder inhalers, nebulizer and oral forms. They can improve function and quality of life.
   
   
2. Short-acting selective inhaled beta₂-agonists such as albuterol are preferred for prn use because of demonstrated efficacy, rapid action, and selective action on airways. The short-acting adrenergic agents have similar efficacy, though inhaled beta₂ selective agents should be favored for lower side effect profiles.
   
   
3. SAIBA should be prescribed for prn use in most symptomatic patients with COPD. The usual maximum dose in stable patients is 12 puffs per day for short-acting agents such as albuterol, metaproterenol or terbutaline. Patients who have not responded to greater than maximum doses such as 12 to 20 puffs over three to four hours during an acute exacerbation of COPD should seek medical attention.
   
   
4. Symptoms may improve without substantial improvement in FEV₁, indicating that continuation of therapy does not depend on routine assessment with spirometry. For example, SAIBA and ipratropium can improve exercise performance without necessarily improving FEV₁.
   
   
5. SAIBA, but not ipratropium, may increase the alveolar-arterial oxygen difference, and this may be a reason to decrease the dose of beta₂-agonist while titrating a patient’s medication.
   
   

EVIDENCE

Metaproterenol inhalation (5 puffs) led to an improvement in the 12-minute walk that was not present with placebo. Spirometry was not improved: Berger 1988. LE=C, SR=I

Terbutaline (2 puffs = 500 µg) decreased breathlessness: Pino-Garcia 1996. LE=B, SR=IIa

Albuterol (270 µg) decreased breathlessness with exercise: Belman 1996. LE=B, SR=I

Pirbuterol and ipratropium produced similar increases in FEV₁. Pirbuterol increased the [A-a] O₂ difference: Ashutosh 1995. LE=B, SR=I

Significant dose-related improvement in spirometry with inhaled albuterol. One mg as a single dose offered most benefit versus side effects: Vathenen 1988. LE=B, SR=I

Average dose of albuterol inhalation for optimal improvement was 430 µg (range up to 800 µg) and for terbutaline was 1,160 µg (range up to 2.5 mg): Jaeschke 1993. LE=B, SR=I

OBJECTIVE

To initiate or adjust appropriate therapy with inhaled anticholinergics.

ANNOTATION

1. Ipratropium bromide, the prototype anticholinergic bronchodilator, is available as a metered dose inhaler (MDI) or as a nebulizer solution.
   
   
2. Ipratropium bromide has similar, or according to some studies, greater efficacy than SAIBA. It has a slower onset of action, a longer duration of action, and minimal systemic absorption. It may cause fewer systemic side effects than beta₂-agonists. For these reasons, it is preferred as a regularly scheduled inhaled bronchodilator.
   
   
3. In patients with COPD, ipratropium bromide at peak effect typically increases the FEV₁ by 0.15 to 0.35 L. At high doses, ipratropium bromide can improve exercise tolerance.
   
   
4. The starting dose of ipratropium should be at least two puffs tid. Use of typical recommended doses of ipratropium (two puffs qid) produces less than maximal bronchodilation. Improvement in pulmonary function is maximal at 6 to 14 puffs as a single dose of ipratropium. If symptoms do not resolve with two to four puffs qid, up to six and possibly eight puffs qid may be needed. Improvement in level of function and in activities in daily living can be used to guide therapy. The risk of toxicity at higher doses appears to be relatively low compared to inhaled beta₂-agonists.
   
   
5. The sequence of administration of ipratropium and SAIBA does not generally make any difference in the bronchodilator benefit.
   
   

EVIDENCE

Baseline FEV₁ and FVC increased within 90 days after ipratropium initiation: Rennard 1996. LE=B, SR=IIa

Ipratropium 40 µg qid (2 puffs) or metaproterenol 1.5mg qid by inhalation were equally efficacious and safe over a 90-day period: Tashkin 1986. LE=A, SR=I

No difference between 200 µg albuterol (2 puffs) and 40 µg ipratropium in magnitude, but duration was 1 hour longer with ipratropium on day 85: Combivent 1994. LE=A, SR=I

Ipratropium produced more and longer bronchodilation than did albuterol: Braun 1989. LE=B, SR=IIa

The distance walked was greater with 7 days of albuterol (180 µg, 2 puffs) or ipratropium (36 µg) qid (2 puffs); also dyspnea was less with albuterol: Blosser 1995. LE=B, SR=IIa

Of 80 responsive patients in a group of 100, 16 responded only to albuterol; 17 responded only to ipratropium; and 47 responded to both: Nisar 1992. LE=C, SR=IIa

Between 6 and 14 puffs of ipratropium (240 µg) produced maximum increase in pulmonary function: Ikeda 1995. LE=B, SR=I

160 µg of ipratropium(8-9 puffs) is needed to give maximum benefit in pulmonary function and to give any benefit at all with exercise: Ikeda 1996. LE=B, SR=I

0.4 mg of nebulized ipratropium provided a maximum response in pulmonary function. Suggested this was equivalent to 160 µg (8-9 puffs) from MDI: Gross 1989. LE=B, SR=IIa

OBJECTIVE

To initiate or adjust appropriate therapy with a combination of inhaled SAIBA.

ANNOTATION

1. Patients with COPD whose symptoms are inadequately controlled with the recommended doses of either an inhaled short acting inhaled beta₂-agonist or ipratropium should be treated with a combination of both inhaled agents. The combination at recommended doses provides added symptomatic benefit without incurring the risk of toxicity from using very high doses of single agents.
   
   
2. SAIBA may be added to ipratropium as regularly scheduled medications, typically two to four puffs qid, as well as additional prn dosing, to a usual recommended maximum of 12 puffs per day. Demonstration of an acute improvement in FEV₁ is not necessary in order to obtain clinical benefit. The lack of an immediate bronchodilator response should not preclude a clinical trial of these medications.
   
   
3. As the dose of ipratropium or inhaled SAIBA increases, the added benefit becomes less from the other agent, but some patients will have an added benefit even with high doses of each. There is no way to predict, other than in a trial of therapy, which patients will have this combined effect.
   
   
4. A product that dispenses 90 µg albuterol and 18 µg ipratropium per puff from one metered dose inhaler is available commercially (Combivent ™). This should not generally be used as a first line agent, but may provide enhanced compliance and resultant benefit in patients who require combination therapy. Patients taking a regularly scheduled combination inhaler should continue to use a SAIBA for breakthrough symptoms.
   
   

EVIDENCE

80 µg ipratropium (4 puffs) plus 400 µg (4 puffs) albuterol was better than 40 µg or 80 µg ipratropium plus 200 µg albuterol in improving FEV₁: Ikeda 1995. LE=C, SR=I

There was no added benefit of doubling the ipratropium dose or adding 1,300 µg of inhaled metaproterenol. Two of 12 patients benefited from this combination: LeDoux 1989. LE=B, SR=I

40 µg ipratropium plus 200 µg inhaled albuterol yielded a greater increase in pulmonary function than did either 40 µg ipratropium or 200 µg albuterol: Combivent 1994. LE=A, SR=I

120 µg of ipratropium or 800 µg of albuterol gives maximal bronchodilation in a single dose. Some patients may benefit from combination: Easton 1986. LE=B, SR=IIa

200 µg ipratropium added to 5 mg terbutaline or 500 µg terbutaline added to 200 µg ipratropium improved pulmonary function: Newnham 1993. LE=C, SR=IIa

OBJECTIVE

To initiate or adjust appropriate therapy with long acting inhaled beta₂-agonists.

ANNOTATION

1. The long acting inhaled beta₂-agonist, salmeterol (2 puffs or 50 µg bid), is an effective bronchodilator in COPD patients, and has been approved for use in COPD.
   
   
2. Salmeterol produces a similar peak bronchodilator response to SAIBA, but the onset is delayed. The bronchodilator effect is prolonged compared to short-acting agents. This has the potential to produce more consistent control of symptoms than SAIBA in some patients.
   
   
3. Chronic use is not associated with significant tachyphylaxis, and may decrease the need for rescue use of SAIBA.
   
   
4. Strong evidence for symptomatic benefit of salmeterol over other regularly inhaled short acting bronchodilators in patients with COPD is not currently available. Thus, its place in the scheme of therapy is not well defined at this time. It may be considered for patients whose need for SAIBA exceeds 8 to12 puffs daily.
   
   
5. The principle advantage of salmeterol is its long duration of action, which may be of benefit in treating nocturnal dyspnea. Additionally, enhanced compliance with a twice daily rather than qid regimen may provide smoother symptomatic control.
   
   
6. Because the onset and duration of action are both prolonged compared to SAIBA, salmeterol should not be used for prn, rescue use. Patients should be educated to continue to use SAIBA prn.
   
   
7. Oral forms of beta₂-agonists may be useful in patients who cannot use any inhaled form, although such cases are rare. The risk of systemic adverse reactions is increased significantly with oral beta₂-adrenergic bronchodilators.
   
   
8. Inhaled salmeterol should be continued only in those patients who experience symptomatic benefit from its addition to their regimen.
   
   

EVIDENCE

Four weeks of 50 µg bid (or 2 puffs) salmeterol led to an increase in FEV₁: Grove 1996. LE=B, SR=I

16 weeks of treatment with 50 µg bid salmeterol added to existing regimen improved FEV₁ and symptoms: Boyd 1997. LE=A, SR=I

16 weeks of 50 µg bid (but not 100 µg bid) salmeterol improved health related quality of life: Jones 1997. LE=A, SR=I

Salmeterol acute dose response curve plateaus at 50 µg: Cazzola 1995. LE=B, SR=I

4 weeks of 50 µg bid salmeterol improved peak flow and symptoms: Ulrik 1995. LE=A, SR=I

Combination of salmeterol (50 µg) and ipratropium was no different than either alone for peak effect; duration was similar to that for salmeterol: Matera 1996. LE=B, SR=IIb

Single-dose 50 µg salmeterol caused more prolonged acute bronchodilation than 200 but not 400 µg oxitropium inhaler: Cazzola 1998. LE=B, SR=IIa

OBJECTIVE

To initiate or adjust appropriate therapy with oral theophylline.

ANNOTATION

1. Theophylline can be added to improve pulmonary function, symptoms, or activities in patients with COPD who do not achieve adequate symptom control with inhaled bronchodilators.
   
   
2. Many theophylline preparations are available, but sustained release formulations may provide longer control and better benefit for nocturnal dyspnea.
   
   
3. Theophylline has a narrow therapeutic index, with the potential for dose related adverse reactions that include insomnia, anxiety, nausea, vomiting, tremor, arrhythmias, delirium, seizures, and death.
   
   
4. Typical starting doses are 400-600 mg daily, but blood levels should be measured carefully at the start of therapy. The therapeutic target for most patients should be a blood level of 10 µg/ml (range 5-12 µg/ml). In some cases, if benefit has been demonstrated and with careful monitoring, a blood level of 15 µg/ml of theophylline can be a therapeutic target. However, with an increase in concentrations over 12 µg/ml, the risk to benefit ratio increases, especially in older patients. After initial stability, repeat levels should be obtained when symptoms change, acute illness develops, potentially interacting drugs are added, non-compliance is suspected, dose adjustments are made, or symptoms suggestive of toxicity develop.
   
   
5. Drug interactions with theophylline are common, and may either increase or decrease theophylline metabolism. All changes in medical regimens should be evaluated for potential impact on theophylline levels.
   
   
6. Theophylline should be continued only in patients who demonstrate a symptomatic benefit, such as improved dyspnea or exercise tolerance. The improvement in function from theophylline may not be evident in pulmonary function testing. However, therapy should be discontinued in patients who demonstrate no subjective or objective improvement after several weeks of theophylline therapy.
   
   

DISCUSSION

Mechanisms of Benefit

EVIDENCE

Theophylline is usually a bronchodilator: Fragoso 1993. LE=A, SR=I

Mucociliary clearance improved in some patients: Fragoso 1993. LE=C, SR=IIa

Some patients have an improvement in respiratory muscle performance: Fragoso 1993. LE=B, SR=IIa

Generally consistent improvement in function of the right heart: Fragoso 1993. LE=C, SR=IIa

Theophylline may increase respiratory drive: Ashutosh 1998. LE=B, SR=IIa

Theophylline Therapy

EVIDENCE

Two months of theophylline at 14.8 µg/ml led to less dyspnea, an increase in PaO_{2 ,} a decrease in PaCO₂ , and an increase in vital capacity and FEV₁: Murciano 1989. LE=A, SR=IIa

Pulmonary function and exercise performance were improved on 9.5 mg/L of theophylline: Newman 1994. LE=B, SR=IIa

17 mg/L improved pulmonary function and symptoms: McKay 1993. LE=B, SR=IIa

Withdrawal of theophylline (11 mg/L) led to a decline in pulmonary function, an increase in symptoms, and less distance in the 6-minute walk test: Kristen 1993. LE=A, SR=IIa

Theophylline at 12.2 mg/L improved FVC₁, MVV, and exercise: Fink 1994. LE=B, SR=IIa

Higher awake PaO₂ , lower awake PaCO₂ , higher sleep SaO₂,, improved FEV₁, and lower trapped gas volume were seen with a theophylline level of 11.8 mg/L: Mulloy 1993. LE=B, SR=IIa

Theophylline (14.2 mg/L) improved FEV₁; SaO₂ increased during non-rapid eye movement (NREM) sleep. There were fewer arousals; sleep architecture was unaffected: Berry 1991. LE=B, SR=IIa

Twice-a-day theophylline (15 µg/ml) improved FEV₁ more than once a day (11 µg/ml). No effect on arterial saturation or sleep architecture: Martin 1992. LE=B, SR=IIa

Theophylline (9.2 µg/ml) improved pulmonary function, reduced nocturnal wheezing, and improved nocturnal saturation. Sleep quality unaffected: Man 1996. LE=B, SR=IIa

Theophylline Combination Therapy

EVIDENCE

Theophylline (12.5 mg/L) significantly improved FEV₁ and PEF (daily) to a small degree, even after the inhalation of salbutamol and ipratropium: Nishimura 1993. LE=B, SR=IIa

In combination with 400 µg salbutamol qid and 80 µg (or 4 puffs) ipratropium qid, theophylline (15 mg/L) had a small additive effect on FEV₁ and PEF: Thomas 1992. LE=B, SR=IIa

Theophylline (12.9 mg/L) and salbutamol improved pulmonary function; the combination was better than either alone: Thomas 1992. LE=B, SR=IIa

Combination theophylline (12 to 18mg/L), albuterol, and ipratropium improved pulmonary function more than did theophylline and albuterol or ipratropium alone: Karpel 1994. LE=A, SR=IIa

OBJECTIVE

To initiate or adjust appropriate therapy with corticosteroids in patients with COPD.

ANNOTATION

1. Unlike the high response rate seen in asthma, in patients with COPD a response to chronic oral corticosteroid use is beneficial in less than about 20 to 25 percent. The benefit from inhaled steroids is not precisely defined.
   
   
2. Patients on maximal bronchodilator therapy who have not had a satisfactory response may be considered candidates for a corticosteroid trial. An objective measure of improvement should be sought in all patients undergoing a steroid trial. A response may be defined as an improvement in symptoms and an increase in FEV₁ of > 20 percent from baseline. An objective measurement of the steroid effects can only be obtained in patients who are otherwise stable.
   
   
3. A typical trial of oral prednisone is 40 to 60 mg/day for 10 to 14 days. There is less published experience with high-dose inhaled steroids, but in some patients this may be a reasonable alternative. The appropriate dose of inhaled steroids has not been determined, but a trial for 14 to 21 days of the equivalent of beclomethasone 1500 µg/day (30 puffs) or fluticasone 880 µg /day has been suggested.
   
   
4. Patients who show no objective response to a steroid trial should have their steroids promptly discontinued. Patients who have a response should be tapered to the lowest possible dose. Supplementation or substitution with a high-dose inhaled steroid may allow further reduction or discontinuation of the oral steroid.
   
   
5. Adverse effects of oral corticosteroids are numerous and include: hypertension, hyperglycemia, weight gain, immunosupression, skin thinning, personality, purpura, mental status changes, depression, glaucoma, cataracts, and adrenal suppression. Patients requiring long-term steroids should be evaluated for risk of osteoporosis and preventive measures instituted, such as calcium and vitamin D supplements, weight-bearing exercise and hormone replacement therapy if appropriate. The risks of long-term treatment should be discussed with the patient.
   
   
6. The role of chronic inhaled corticosteroids in COPD remains under investigation. Preliminary work suggests that chronic inhaled steroid use may slow the rapid decline in FEV₁ typically seen in patients with COPD. Response to an oral steroid trial, as well as a brisk bronchodilator response may help identify patients who will respond better to inhaled steroids.
   
   
7. The use of MDI spacers and rinsing of the mouth after drug use is recommended to help improve drug delivery to the lung and avoid local complications, such as hoarseness or oral candidiasis.
   
   

DISCUSSION

EVIDENCE

Oral steroid meta-analysis: 10 percent of patients with COPD using oral steroids (30 to 80 mg/day or equivalent prednisone) had a 20 percent improvement in FEV₁: Callahan 1991. LE=A, SR=I

Alternate-day oral steroids (64 mg) as effective as daily oral steroids (8 mg qid): Blair 1984. LE=A, SR=I

Equal or more than 7.5 mg/day oral prednisolone slows decline of FEV₁ and improves survival in severe COPD: Postma 1985. LE=C, SR=IIa

7.5 mg/day oral prednisolone or more decreases decline in FEV₁ in moderately severe COPD: Postma 1988. LE=C, SR=IIa

40 mg/day of prednisolone added to inhaled beclomethasone of 1,500 and 3,000 µg/day did not further improve pulmonary function: Weir 1993. LE=A, SR=IIa

It can take more than 2 weeks to reach maximum benefit from oral (40 mg prednisolone) or inhaled (1,500 µg beclomethasone) steroids: Weir 1990. LE=A, SR=I

Emphysema and nonemphysema COPD respond similarly to oral prednisolone (40 mg/day) and inhaled beclomethasone (1,500 µg/day): Weir 1991. LE=B, SR=I

20 of 100 subjects responded to 30 mg prednisolone for 2 weeks, 17 of whom responded to ipratropium or albuterol and 3 of whom were nonresponders: Nisar 1992. LE=C, SR=IIa

Inhaled beclomethasone (1,500 µg/day) produced 2/3 the response of oral prednisolone. Response to oral correlated with response to inhaled steroid: Weir 1990. LE=A, SR=I

Response to high-doses inhaled beclomethasone (1,500 g/day) predicts which patients will respond to oral prednisolone (30 mg/day): Wardman 1988. LE=C, SR=IIa

Addition of oral prednisolone (30 mg/day) produces further improvement in responders to inhaled beclomethasone (1,500 g/day): Wardman 1988. LE=C, SR=IIa

Meta-analysis: More than 800 µg of inhaled beclomethasone or budesonide was required for improvement in pulmonary function or symptoms: Van Schayck. LE=B, SR=IIa

Two years of 800 µg/day of budesonide plus either albuterol or ipratropium reduced the decline in FEV₁ and improved symptoms: Dompeling 1993. LE=C, SR=IIa

800 µg/day of budesonide for 12 weeks decreased cough but did not improve any other measure or symptom: Engel 1989. LE=B, SR=IIa

Two years of budesonide at 1,600 µg/day improved symptoms, and there were fewer dropouts for pulmonary reasons compared to placebo: Renkema 1996. LE=A, SR=IIa

Six weeks of 800 µg/day of budesonide improved 5 of 8 beta2-agonist acute responders and 1 of 22 nonresponders to beta2-agonist: Weiner 1995. LE=B, SR=IIa

Inhaled fluticasone (500 µg bid) for 6 months improved FEV₁, peak flow, 6 minute walk, symptoms and severity of exacerbations: Paggiaro 1998. LE=A, SR=IIa

OBJECTIVE

To apply precautions and educate patients about the use of medications.

ANNOTATION

Method of administering aerosols

1. Metered-Dose Inhalers (MDI).
   
   
   1. Inhaled bronchodilators are preferred to oral medications to reduce the risk of systemic adverse effects.
      
      
   2. Ensure proper education and technique in the use of MDIs (see DISCUSSION).
      
      
   3. Use spacers as required to enhance drug delivery.
      
      
   4. Emphasize the maximum doses of bronchodilators to avoid overuse.
      
      
   5. Educate the patient to use bronchodilators before exercise.
      
      
   6. Compliance declines when inhaler regimens become complicated.
      
      
   7. Consider other drug delivery systems (such as dry powder inhalers) if patient cannot use MDI with spacer.
      
      
2. Small Volume Nebulizer.
   
   
   1. There is little evidence that nebulizer delivery offers improvement in control over adequate MDI delivery for management of the stable COPD patient.
      
      
   2. Situations where a nebulizer is preferable include difficulty in managing a MDI (with spacer) due to impaired hand strength or dexterity, visual impairment, cognitive problems, or severe dyspnea.
      
      
3. Precautions when using beta₂-agonists.
   
   
   1. Inhaled beta₂-agonists may cause tremor, increased heart rate, insomnia, restlessness, hypokalemia, or a paradoxical reduction in arterial oxygenation.
      
      
   2. Avoid overuse. Check number of metered dose inhalers (MDIs) used per month against number of puffs per MDI (200 to 300+, depending on brand).
      
      
   3. Instruct patients on maximum number of puffs per day (usually 8 to 12) and on number allowed during an exacerbation (e.g., 12 to 24 over 3 to 4 hours) before additional intervention is required.
      
      
   4. If a long-acting agent is used for maintenance therapy, educate the patient that only SAIBA should be used for breakthrough symptoms.
      
      
   5. Home nebulizers with inhalant solutions providing large dosages are rarely needed.
      
      
4. Precautions when using ipratropium
   
   
   1. Inhaled ipratropium may cause dry mouth or increased heart rate, or exacerbate glaucoma, benign prostatic hypertrophy or other conditions potentially worsened by the drug’s anti-cholinergic activity.
      
      
   2. Patients should generally use a spacer and should avoid spraying into eyes.
      
      
   3. Caution patients that onset of effect is relatively slow compared to SAIBA, and that additional doses should not be taken for acute symptom relief.
      
      
   4. In general, dose related systemic side effects of inhaled anticholinergics are less severe when using ipratropium than those produced by inhaled beta₂-agonists.
      
      
5. Precautions when using theophylline.
   
   
   1. Theophylline has dose related side effects that include insomnia, anxiety, nausea, vomiting, tremor, arrhythymias, delirium, seizures, and death.
      
      
   2. Drug interactions with theophylline are common, and all changes in a patient’s medical regimen should be reviewed for their potential impact on serum theophylline levels.
      
      
   3. Initiate treatment with a low dose (e.g., 400 mg/day) and adjust after a few days.
      
      
   4. Aim for a serum level of 5 to 12 µg/ml; adjust dosage and follow serum level when indicated.
      
      
   5. Check the serum level of theophylline when symptoms change, acute illness develops, new drugs are added, or symptoms suggestive of toxicity develop.
      
      
   6. Reduce dosage if drug clearance is likely to be impaired because of illness, liver malfunction, or concomitant drugs.
      
      
   7. Instruct patients not to take additional theophylline preparations.
      
      
   8. Theophylline should be taken at the same time each day with respect to meals.
      
      
   9. Attempts to withdraw theophylline, even at lower plasma levels, should be done cautiously, since deterioration in pulmonary function and exercise performance may occur.
      
      
6. Precautions when using oral corticosteroids.
   
   
   1. Adverse effects of oral corticosteroids include hypertension, hyperglycemia, weight gain, personality changes, depression, immunosuppression, glaucoma, cataracts, skin thinning, purpura, osteoporosis, osteonecrosis, and adrenal supression. In general, side effects are more common with prolonged therapy.
      
      
   2. Reduce dosage to lowest effective daily dose or to alternate-day dosing as quickly as symptoms allow.
      
      
   3. Administer stress dose steroid therapy to patients with severe illness or injury who have received prolonged oral corticosteroid treatment. Adrenal insufficiency may extend for up to a year following the discontinuation of steroids.
      
      
   4. Prevent or treat osteoporosis with calcium, vitamin D, hormone replacement therapy or other therapies as appropriate for patients on prolonged oral corticosteroid therapy.
      
      
7. Precautions when using inhaled corticosteroids.
   
   
   1. Adverse effects of inhaled corticosteroids include oral candidiasis, hoarseness, and possible adrenal suppression at high doses.
      
      
   2. Instruct patients to use a spacer and rinse the mouth after use to decrease the likelihood of local complications.
      
      
   3. Be aware that systemic effects of corticosteroids may occur in skin, bone, eyes, and other organs, especially with the use of high dose inhaled corticosteroids.
      
      
   4. Stress dose oral or intravenous corticosteroids may be necessary in some patients with severe illness or injury who have been treated with high dose inhaled corticosteroids.
      
      
   5. Seek objective evidence of the value of this therapy, because its use may decrease compliance with other aerosol usage.
      
      
   6. When introducing aerosol steroids in a patient taking an oral steroid, wean slowly off the oral drug.
      
      

DISCUSSION

Metered dose inhaler technique (Newman 1984).

1. Remove the cap and shake the inhaler thoroughly.
   
   
2. Breathe out slowly.
   
   
3. Hold the inhaler upright.
   
   
4. Place the mouthpiece two cm (approximately two fingers) in front of the lips. (Placing the mouthpiece between the lips with the teeth and tongue out of the way is also acceptable.) The use of a spacer instead is highly recommended.
   
   
5. Press down on the inhaler while inhaling slowly and deeply.
   
   
6. Hold the breath for 10 seconds, if possible.
   
   
7. Breathe out slowly through nose or pursed lips.
   
   
8. Take one puff at a time. Pause at least 20 seconds before the next inhalation.

EVIDENCE

Precautions when using pharmacotherapy: ATS 1995. LE=C, SR=IIa

MDI technique: Newman 1984. LE=C, SR=IIa

52 percent used an MDI once or less daily rather than the required three times daily: Rand 1995. LE=C, SR=I

Adherence with intermittent positive pressure breathing (IPPB) or nebulizers was 50.6 percent: Turner 1995. LE=C, SR=I

Maximum bronchodilation was similar between nebulizer and MDI beta2-agonist. Nebulizer dose of twice MDI dose to produce same effect: Mestitz 1989. LE=B, SR=I

Dose of nebulized albuterol producing the same bronchodilation was about 10 times higher than with MDI: Jenkins 1987. LE=B, SR=I

No difference in outcome between nebulizer and MDI. Nebulized metaproterenol dose was about seven times higher than with the MDI: Turner 1988. LE=B, SR=I

It takes about 12.5 times as much nebulized albuterol to achieve the same increase in FEV₁ as with an MDI: Harrison 1983. LE=B, SR=I

ADDITIONAL REFERENCES

Ashutosh K; et al. Effects of theophylline on respiratory drive in patients with chronic obstructive pulmonary disease. J Clin Pharmacol 1997 Dec;37(12):1100-7

Boyd G; et al. An evaluation of salmeterol in the treatment of chronic obstructive pulmonary disease (COPD). Eur Respir J 1997 Apr;10(4):815-21

Cazzola M; et al. Effects of formoterol, salmeterol or oxitropium bromide on airway responses to salbutamol in COPD. Eur Respir J 1998 Jun;11(6):1337-41

Newman SP; Clarke SW. The proper use of metered-dose inhalers. Chest 1984; 86:342-3

Paggiaro PL; et al. Multicentre randomised placebo-controlled trial of inhaled fluticasone propionate in patients with chronic obstructive pulmonary disease. International COPD Study Group. Lancet 1998 Mar 14;351(9105):773-80

Veterans Health Administration. The pharmacologic management of chronic obstructive pulmonary disease. Department of Veterans Affairs Veterans Health Administration Publication No. 980012, Nov 1998.