1. Definitions

a. Chronic obstructive pulmonary disease (COPD) is a disorder characterized by the presence of airflow obstruction due to chronic bronchitis or emphysema; the airflow obstruction is generally progressive, may be accompanied by airway hyperreactivity, and may be partially reversible.

b. Chronic bronchitis is defined as the presence of chronic productive cough for 3 months of each of two successive years in a patient in whom other causes of chronic cough have been excluded.

c. Emphysema is defined as abnormal permanent enlargement of the air spaces distal to the terminal bronchioles, accompanied by destruction of their walls and without obvious fibrosis.

d. Asthma is by definition associated with reversible airflow obstruction. Patients with asthma whose airflow obstruction is completely reversible are not considered to have COPD. The obstruction in many patients with COPD may include a significant reversible component. Some patients with asthma may develop irreversible airflow obstruction indistinguishable from COPD.

 

2. Characterization of COPD 



a. History 


(1) Smoking - Age at initiation, quantity smoked per day, whether or not still smoker and if not, date of cessation

(2) Environmental (chronological) - May disclose important risk factors

(3) Cough (chronic, productive) - Frequency and duration, whether or not productive (especially on awakening)

(4) Wheezing

(5) Acute chest illnesses - Frequency, productive cough, wheezing, dyspnea, fever

(6) Dyspnea

 

b. Physical Examination of Chest 



(1) Airflow obstruction evidenced by:
• Wheezing during auscultation on slow or forced breathing
• Forced expiration time of more than 6 seconds
 
(2) Severe emphysema indicated by:
• Overdistention of lungs in stable state, low diaphragmatic position
• Decreased intensity of breath and heart sounds
  
  
(3) Severe disease suggested by (characteristics not diagnostic):
• Pursed-lip breathing
• Use of accessory respiratory muscles
• Indrawing of lower interspaces
 
c. Other - Unusual positions to relieve dyspnea at rest, digital clubbing (suggests possibility of lung cancer or bronchiectasis), and mild dependent edema that may be seen in absence of right heart failure

d. Laboratory 



(1) Chest radiography - Diagnostic only of severe emphysema but essential to exclude other lung diseases

(2) Spirometry (pre- and postbronchodilation) - Essential to confirm presence and reversibility of airflow obstruction and to quantify maximum level of ventilatory function (ATS 1995)

(3) Lung volumes - Measurement of more than forced vital capacity is not necessary except in special circumstances (e.g., presence of giant bullae)

(4) Carbon monoxide diffusing capacity - Unnecessary except in special instances (e.g., dyspnea out of proportion to severity of airflow limitation)

(5) Arterial blood gases are not needed in staged mild disease, but remain the standard for determining the need for oxygen therapy

(6) Alpha₁-antitrypsin (AAT) - AAT deficiency accounts for < 1 percent of COPD. Obtain a serum AAT level to screen for AAT deficiency in the following situations:

• Chronic bronchitis with airflow obstruction in a never smoker
  
  
• Bronchiectasis, especially in the absence of clear risk factors for the disease
  
  
• Premature onset of COPD with moderate or severe impairment before age 50
  
  
• A predominance of basilar emphysema; development of unremitting asthma, especially in a patient under age 50
  
  
• A family history of AAT deficiency or of COPD onset before age 50
  
  
• Cirrhosis without apparent risk factors (ATS 1995). If diagnosis of COPD or asthma is made, refer to specialist for recommendations for therapy.
  
  

 
• Symptoms on usual daily activities - Client may exhibit symptoms of dyspnea and/or wheezing. Dyspnea may be at rest or disproportionate to the degree of breathlessness expected for a given activity.

 
• If originally asymptomatic with an FEV₁ <50 percent and on therapy, then reevaluate for improvement or begin trial of therapy with inhaled anticholinergic (IAC). A trial of IAC 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. This is based on the well-known phenomenon of patients "adapting to their disability." Such a lack of symptoms may result from the patient's avoiding activities or simply thinking along the lines of "Doesn't everyone get short of breath doing this activity at my age?"
  
  
Ipratropium (without prn inhaled beta2-agonist, since it is not needed for rescue medication) is generally the first choice in a trial of therapy, with improvement in function or activities of daily living being used to guide therapy (see Annotation G). If ipratropium is ineffective or produces a less-than-optimal effect, add a short-acting inhaled beta2-agonist on a regular schedule (i.e., not prn) as combination therapy. A long-acting inhaled beta2-agonist may be substituted for the short-acting inhaled beta2-agonist if usage warrants. For further details on use of ipratropium and beta2-agonists, see Annotations E, F, and G. If there is no improvement or if symptoms worsen, the trial should be discontinued.

Ipratropium and short-acting inhaled beta2-agonists in typical doses (2 to 4 inhalations) on a scheduled rather than prn use are generally equally effective as bronchodilators, although some studies suggest that ipratropium has a greater peak and a longer duration of action. The side effects of each are similar, except for increases in heart rate and tremor (neither of which is typical at these doses) occur almost exclusively with beta2-agonists. Dyspnea may be improved to a greater extent with inhaled beta2-agonist. Some patients will have a response to one but not the other, so in any trial of therapy, both should be tried if improvement is not optimal with the first choice. There is evidence that ipratropium improves baseline pulmonary function (after withholding ipratropium for 6 to 12 hours) whereas beta2-agonists do not.

C. Patient on Maximum Steroids with SRT, LAIBA, SAIBA, IAC - If no contraindications, oral steroids can be used (40 to 60 mg/day) for 2 to 3 weeks with remeasure of FEV₁. If response, continue qod and decrease to lowest effective dose, with institution of high-dose inhaled steroids (HDIS) as part of the taper, with the ultimate goal of the lowest effective dose of inhaled steroids. An alternative is HDIS (see table on doses below) with measurement of FEV₁ after 2 to 3 weeks; if less-than-optimal response, add oral steroids, with eventual adjustment to lowest effective dose or stopping of steroids if not effective.

A response is defined as one of the following: 

1. Symptoms resolve and FEV₁ increases 20 percent on oral steroids, high-dose inhaled steroids, or a combination of oral and HDIS.
   
   
2. Symptoms improve and FEV₁ increases 20 percent on oral steroids or a combination of oral steroids and HDIS.
   
   

Measurement of peak expiratory flow rate by patients at home, at least in the morning and at night, can be used to follow progress of treatment, since many investigators measured daily home PEF and found that it was higher with oral or inhaled steroids than on placebo.

Oral steroids can improve pulmonary function in patients with COPD. The number of patients who improve placebo-controlled studies is not presently precisely defined but appears to be in the 10 percent range, with some studies showing no improvement over placebo and other studies having as much as 38 percent of patients who have a 20-percent or more increase in FEV₁ over baseline. The increase is determined by dividing the difference between posttreatment and pretreatment FEV₁ (in liters) by the pretreatment value and multiplying by 100. The dose is from 30 to 80 mg of prednisone or equivalent every day or every other day, although two cohort studies suggest that long-term use (years) may be effective with doses as low as 10 mg/day of prednisolone or the equivalent. Every-other-day oral steroids appear to be as effective as daily oral steroids in stable COPD clients. Many patients with a response to oral steroids have a dramatic response (> 50 percent) that almost never occurs with placebo.

Inhaled steroids produce significant improvement in pulmonary function compared to placebo in a number of patients. The percent who improve is not precisely defined. The dose of inhaled steroids is important, with doses greater than 800 g/day of budesonide or beclomethasone being necessary to produce improvement in groups of COPD patients. Several long-term studies (2 years of inhaled steroid treatment) show a reduction in the decline in FEV₁, fewer symptoms, and fewer dropouts with medium- (800 g/day) to high-dose (1,600 g/day) inhaled steroids. Response to high-dose inhaled steroids is predictive of response to oral steroids and inhaled steroids can be used as initial steroid therapy, with addition of oral steroids if there is a partial response.

Patients with predominant emphysema appear to respond as well or nearly as well as those with predominant chronic bronchitis.

It may take more than 2 weeks to determine responsiveness to either oral or inhaled steroids.

Patients with a response to inhaled beta2-agonists prior to the use of steroids may be more likely to respond to oral or inhaled steroids, but not all studies confirm this and the sensitivity and specificity are not sufficient in most studies to justify a decision to treat.

D. Consider Adding Sustained-Release Theophylline - Sustained-release theophylline (SRT) can be added to improve pulmonary function, symptoms, or activities. The blood level of theophylline should be measured, with a therapeutic target of 10 g/ml (range of 5 to 12 g/ml). If the theophylline level is difficult to regulate, if adverse symptoms occur, or if there is significant preexisting cardiovascular disease, avoid use.

Theophylline is a bronchodilator and improves symptoms. Combination therapy with a short-acting inhaled beta2-agonist provides added improvement. Theophylline may improve mucociliary clearance in the airways, may improve respiratory muscle strength, and may improve right ventricular and left ventricular ejection fraction, decrease pulmonary artery pressure, and increase heart rate.

In some cases, if benefit has been demonstrated and with careful monitoring under guidance of a specialist, a blood level of 15 g/ml of theophylline can be a therapeutic target.

If the theophylline level is difficult to regulate, if adverse symptoms occur, or if there is significant preexisting cardiovascular disease, avoid use.

Theophylline levels of 14 mg/L or higher improve pulmonary function, decrease dyspnea, improve exercise, improve PaO₂, decrease gas trapping, may decrease PaCO₂, and have no obvious deleterious effects on sleep. Theophylline levels around 10 mg/L usually improve pulmonary function and arterial blood gases while awake or asleep and consistently improve exercise performance without impairing cognitive function. Attempts to withdraw theophylline, even at lower levels, should be done cautiously, since deterioration in pulmonary function and exercise performance may occur, with more shortness of breath, more wheezing, and more symptoms. Theophylline is a stimulant, and some patients have difficulty sleeping; however, in moderate to severe COPD, the overall effect is negligible and may even be beneficial, perhaps by reducing nocturnal symptoms from dyspnea, wheezing, and arterial oxygen desaturation.

Combination therapy of theophylline, a short-acting inhaled beta2-agonist, and ipratropium can be used to improve pulmonary function and possibly symptoms.

Theophylline (12.5 to 15 g/ml) improves pulmonary function when used in combination with short-acting inhaled beta2-agonists and ipratropium. Symptomatic improvement may not occur. 

Use of oral beta2-agonist in COPD has not been studied to a significant degree with respect to pulmonary function. However, one well-done study in a small number of subjects suggests that there is substantial additive effect when combinated with theophylline.

Should symptoms not resolve, the short-acting inhaled beta2-agonist can be increased to regularly scheduled dosing qid, with additional prn dosing for rescue. The typical dose is 2 to 4 inhalations, not to exceed 12 per day. However, as much as 1 mg of albuterol (or the equivalent of other short-acting beta2-agonists) may be required acutely to provide maximal bronchodilation for rescue.

The side effects include tremor, increase in heart rate, and reduced arterial oxygen saturation. When SAIBA is used as rescue medication, doses that are generally considered large (up to 10 inhalations) when used over a short time (minutes) may be necessary to alleviate acute shortness of breath or wheezing. In such cases, patients should seek medical advice to determine whether other measures are needed (see also Module A3, Acute Exacerbation).

Some patients can be maintained on a regularly scheduled short-acting inhaled beta2-agonist and ipratropium, 2 to 4 puffs of each four to five times a day.

Should the number of inhalations of beta2-agonist exceed 12 per day (the usually recommended maximum dose of inhaled short-acting beta2-agonist), addition of long-acting inhaled beta2-agonist is recommended (see Annotation F), with continuation of short-acting inhaled beta2-agonist as rescue medication.

The sequence of administration of ipratropium and a short-acting inhaled beta2-agonist does not generally make any difference in the bronchodilator benefit.

Improvement in pulmonary function is maximal at 6 to 14 puffs of ipratropium. Improvement in exercise performance generally requires a minimum of 6- to 8-puffs (108 to 144 g). 

Salmeterol is an effective bronchodilator in patients with COPD at 50 micrograms bid. The degree appears to correlate with the amount of acute reversibility to short-acting inhaled beta2-agonists. Chronic dosing up to 16 weeks produces a benefit that does not diminish. Symptomatic improvement occurs with salmeterol as well as improvement in spirometry. The 100-microgram dose may not be effective in chronic dosing. Combination of usual doses of ipratropium with usual doses of salmeterol may not improve pulmonary function, suggesting that lack of improvement with the combination should not, in itself, prevent implementation of further therapeutic steps in patients responsive to at least one of ipratropium or salmeterol. Salmeterol decreases but does not eliminate prn short acting beta2-agonist rescue.

Symptoms may be improved without substantial improvement in FEV₁, indicating that continuation of therapy does not depend on routine assessment with spirometry. For example, short-acting inhaled beta2-agonists and ipratropium can improve exercise performance without necessarily improving FEV₁. Also, it may be difficult to reduce high-dose ipratropium, since such doses may be needed to improve exercise performance. Inhaled short-acting beta2-agonists can improve dyspnea, and the benefit may be related to this action. Short-acting inhaled beta2-agonists but not ipratropium increase the alveolar-arterial oxygen difference and may be a reason to decrease the dose of beta2-agonists in titrating a patient's medication.

H. Be Aware of Precautions and Recommendations for Use of Medications and Aerosols

1. Precautions when Using Beta2-Agonists 



• Watch for nonimprovement or paradoxical deterioration with aerosol use.
  
  
• Use spacers to improve compliance.
  
  
• Avoid overuse; check the number of metered dose inhalers (MDIs) used per month against the number of puffs per MDI (200 to 300+, depending on brand).
  
  
• Instruct the patient on the maximum number of puffs per day (usually 8 to 12) and on the number allowed during an exacerbation (e.g., 12 to 24 over 3 to 4 hours) before additional intervention is required.
  
  
• If a long-acting agent is used, caution the patient that frequent use must be avoided.
  
  
• Home updraft nebulizers with inhalant solutions providing large dosages are rarely needed.
  
  
2. Precautions when Using Theophylline 


• Initiate treatment with a low dose (e.g., 400 mg) and adjust after a few days.
  
  
• Reduce the dosage if drug clearance is likely to be impaired because of illness, liver malfunction, or concomitant drugs.
  
  
• Do not allow any additional theophylline preparation to be taken.
  
  
• Drug must be taken at the same time each day with respect to meals.
  
  
• When symptoms change, acute illness develops, new drugs are added, or symptoms suggestive of toxicity develop, check the serum level of theophylline.
  
  
• Aim for a serum level of 5 to 12 g/ml; adjust the dosage and follow the serum level when indicated.
  
  
3. Precautions when Using Ipratropium 


• Patients should use a spacer and avoid spraying into eyes.
  
  
• Be prepared to increase the dose, if necessary, from 2 to 3 puffs 3 to 4 times a day to 6 to 8 puffs 3 to 4 times a day, if tolerated.
  
  
• Caution the patient that the onset of effect is relatively slow; additional doses should not be taken for acute symptom relief.
  
  
• Monitor for side effects, e.g., tachycardia, dry mouth, glaucoma, prostatism, or bladder neck obstruction.
  
  
4. Precautions when Using Oral Steroids 


• Reduce the dosage to the lowest effective daily dose or to alternate-day dosing as quickly as symptoms allow.
  
  
• Monitor for hypertension, diabetes, weight gain, mental changes, infections, central polar cataracts, skin thinning, purpura, osteoporosis, and osteonecrosis.
  
  
• Distinguish psychological benefit from true pulmonary benefit by following FEV₁ for 2 weeks after initiating therapy.
  
  
• Administer prophylactic calcium therapy to women; treat osteoporosis appropriately.
  
  
• Steroid-dependent patients require steroid coverage during any crisis for many months after stopping steroids.
  
  
• Repeatedly evaluate the patient to determine whether steroid therapy can be discontinued.
  
  
5. Precautions when Using Aerosol Steroids
 
• Seek objective evidence of the value of this therapy, because its use may decrease compliance with other aerosol usage.
  
  
• Use a spacer; monitor for oral thrush and laryngeal dysfunction.
  
  
• Be aware that aerosol steroid side effects may occur in skin, bone, etc.
  
  
• When introducing aerosol steroids in a patient on an oral steroid, wean him or her slowly off the oral drug.
  
  

6. Recommendation - The fewest inhalers with the fewest inhalations at the least frequent interval consistent with the patient's inhaler needs should be used to improve compliance. A similar principle applies to oral medications.

7. Recommendation - MDI with, if necessary, a spacer is preferred unless not recommended by the manufacturer; a hand-held nebulizer should be used only if the patient is unable to use an MDI.

Nebulizers generally require between 2 and 12 times as much beta2-agonist to produce the same effect as an MDI, depending on the nebulizer used. Adherence with nebulizers is similar to that with MDI. There is no obvious advantage in using a nebulizer in a stable COPD patient who can properly use an MDI.