The Early Recognition and
|1 or 2 puffs b.i.d. of
MDI1 blister inhaled b.i.d.
1 capsule inhaled b.i.d.
Slow onset of
do not use for acute episodes
(Ventolin®, MDI)(Proventil®, MDI)
|1 or 2 puffs
q 4 to 6
|Use for relief of acute dyspnea
|1 blister inhaled
|see comments below|
|(Albuterol & ipratropium)
COMBIVENT ® MDI
|1 or 2 puffs
q 4 to 6
|This combination provides better
bronchodilation than the single agents
|1 or 2 puffs q 4 to 6
|Useful in maintenance
|1 dry powder inhaler
|More useful than Salmeterol
b.i.d. in COPD [see Donohue].
|1 or 2 puffs
q 4 to 6 hours
(Flovent® MDI: 44, 110, 220)
|MDI: 2 puffs b.i.d.||see comments below|
|(Flovent® Diskus: 50, 100, 250)
||Diskus: 1 blister
|(Flovent® Rotadisk: 50, 100,
|Rotadisk: 1 blister b.i.d.
|1 or 2 puffs b.i.d.
|2 puffs b.i.d.||The Aerobid-M has a menthol
flavor which some find more tolerable
|(Aerobid-M®, MDI)||2 puffs b.i.d.|
|1 or 2 puffs b.i.d.||A unique inhalation device;
|(Qvar®, MDI)||1 or 2 puffs b.i.d.||Qvar® comes in 40 or 80 mcg
||Vanceril® comes only in 42 mcg
strength [Oral and Intravenous agents and doses not included]
|3 to 5 ml of 20% or 6 to 10 ml
of 10% solution t.i.d. via nebulizer
|May irritate airways in high
compounds; see PDR)
|200 mg po t.i.d. or
|Caution: note accompanying drugs
including pseudoephedrine; see PDR
|Average daily dose is about 400
mg; may give in b.i.d. or q.d. according to compound
|Given the innate variability in
catabolism and potential for drug-drug interactions, it is essential
that drug levels be monitored regularly and peak levels be
kept below 20 mcg/ml; see PDR.
COMMENTS: Evidence suggests that the
500/50 dose of Advair is efficacious in COPD – 500 ug bid of fluticasone
in several studies, including ISOLDE, was used for efficacy. * Evidence of
benefit from lower doses of inhaled corticosteroids is lacking. In the
Lung Health Study of triamcinolone, evidence of a reduction in bone
density was found. Thus long term surveillance for developing osteoporosis
and preventive therapy is strongly suggested. *Pending FDA approval for use in
moderate to advanced COPD, i.e., FEV1 <50% of predicted.
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.
|I. MILD||II. MODERATE||III. SEVERE|
|Theophylline||–||As needed||As needed|
|Systemic||–||As needed||As needed|
|Guaifenesin||–||As needed||As needed|
|Mechanical hygiene||–||As needed||As needed|
|Supplemental oxygen||–||As needed||As
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)
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 FEV1
for 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.
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
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
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
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
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
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.
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
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
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
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
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
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
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.