CURRENT REVIEW * ACTUALITES
Guidelines for the assessment and management of chronic obstructive pulmonary disease Canadian Thoracic Society Workshop Group Chronic obstructive pulmonary disease (COPD) is the fifth commonest cause of death in North America and is the only leading cause of death that is increasing in prevalence. Early detection and prevention through smoking cessation are essential to stem this epidemic. Once COPD is diagnosed there is a compelling rationale for vaccination against influenza and possibly pneumococcal pneumonia, although proof of efficacy is lacking. If airways obstruction is present, inhaled quaternary anticholinergic bronchodilators or inhaled 02 agonists or both may be of benefit, the former agents showing fewer side effects and often greater efficacy in elderly patients. Theophylline may enhance the effect or increase the duration of the bronchodilatation produced by an inhaled agent and may offer added nonbronchodilatory effects such as improved respiratory muscle endurance and ventilatory stimulation. If significant airflow obstruction persists, an objectively monitored trial of oral steroid therapy is required. Limitation of activity despite optimum medical therapy may be alleviated in selected patients by a supervised exercise rehabilitation program. If hypoxemia is present supplemental oxygen therapy will improve the patient's survival and quality of life. Additional therapies, from respiratory stimulants to lung transplantation, remain under
investigation. La maladie pulmonaire obstructive chronique (MPOC) vient au cinquieme rang des causes de deces pour la frequence en Amerique du Nord, et elle est la seule cause de deces dont la prevalence est en train d'augmenter. Le depistage precoce et la prevention grace au renoncement au tabac sont essentiels pour enrayer cette epidemie. Un diagnostic de MPOC constitue un motif concluant de vaccination contre l'influenza et peut-etre contre la pneumonie a pneumocoques, malgre l'absence de preuve d'efficacite. Advenant l'obstruction des voies aeriennes, l'inhalation de bronchodilatateurs anticholinergiques quaternaires, de 02 stimulants ou les deux peut representer un avantage, le premier groupe causant moins d'effets secondaires et ayant souvent une plus grande efficacit6 chez les patients ages. La theophylline peut ameliorer l'effet ou augmenter la duree de la bronchodilatation produite par un agent inhale, et elle peut amener des effets supplementaires non bronchodilatateurs, comme une amelioration de l'endurance musculorespiratoire et une stimulation ventilatoire. Si une obstruction importante de l'ecoulement de l'air se prolonge, il faut proceder a un essai objectivement surveille de la steroidotherapie par voie orale. La limitation des activites malgre un traitement medical optimal peut ere soulagee chez certains patients par un programme supervise de readaptation a l'exercice. En presence d'hypoxemie, l'oxygenotherapie d'appoint ameliorera la survie du patient et sa qualite de vie. D'autres traitements, des analeptiques respiratoires a la transplantation des poumons, demeurent a l'etude. *Members: Drs. Kenneth R. Chapman, Department of Medicine, University of Toronto, Toronto, Ont.; Dennis M. Bowie, Department of Medicine, Dalhousie University, Halifax, NS; Roger S. Goldstein, Department of Medicine, University of Toronto, Toronto, Ont.; Richard V. Hodder, Department of Medicine, University of Ottawa, Ottawa, Ont.; Marcel Julien, Department ofMedicine, University of Montreal, Montreal, Que.; Steven Kesten, Department of Medicine, University of Toronto, Toronto, Ont.; Michael T. Newhouse, Department of Medicine, McMaster University, Hamilton, Ont.; and Peter D. Pare, Department of Medicine, University of British Columbia, Vancouver, BC
Reprint requests to. Dr. Kenneth R. Chapman, Asthma Centre of the Toronto Hospital, Ste. 4-011, Edith Cavell Wing, 399 Bathurst St., Toronto, ON M5 T 2S8
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C hronic obstructive pulmonary disease (COPD) is the fifth most common cause of death in North America and the only leading cause of death that is increasing in prevalence.' Yet this modem epidemic receives scant attention in the medical or lay press, particularly when compared with the other common obstructive airways disease, asthma. Perhaps there is a widespread perception that with the decline in cigarette smoking COPD is a vanishing problem. Nothing could be further from the truth, since we are now harvesting the consequences of cigarette smoking made popular in the postwar years. Perhaps there is a perception that therapy for COPD is futile, the airways obstruction being "irreversible." This outmoded view ignores our improved understanding of the pathophysiologic features of these conditions and the many effective therapeutic options now available to COPD patients. This paper summarizes the proceedings of a workshop on COPD sponsored by the Canadian Thoracic Society. The workshop was convened to examine critically our approach to this common disease. We wished to identify diagnostic and therapeutic strategies of proven merit, strategies without merit and strategies of potential merit but requiring further investigation. In doing so, we hoped to promote more effective clinical care and to spur discussion and research in controversial areas. This paper provides an outline that can be used by the primary care practitioner to develop a treatment plan that meets the individual patient's needs.
Pathophysiologic features of COPD COPD is characterized functionally as progressive and incompletely reversible airflow obstruction. Specific forms of COPD have been described, although their identification may offer little pathophysiologically or clinically useful information.2 Chronic bronchitis is characterized by a productive cough persisting over long intervals. Although this disorder may be associated with progressive airflow obstruction and dyspnea, obstructive disease fails to develop in most patients with chronic productive cough; instead they suffer "simple chronic bronchitis." Emphysema is associated with destruction and enlargement of alveoli, a process that again may or may not be associated with significant airflow obstruction. In studies involving patients who have undergone lobectomy or pneumonectomy for focal disease, there is surprisingly poor. correlation between emphysema scores, which quantify the degree of alveolar destruction, and conventional measures of airflow obstruction such as forced expired volume in 1 second (FEV,).3 The relation between cigarette smoking and AUGUST 15, 1992
COPD is more complex than is often appreciated. Despite the strong association between the two, cigarette smoking alone appears insufficient to produce the disease. Obstructive airways disease develops in only a minority (about 15%) of long-time cigarette smokers; this implies the existence of other, unknown factors that predispose people to such airways injury. The "Dutch hypothesis" suggests that a genetic predisposition to airway injury is required before cigarette smoking causes COPD. To further complicate the relation a small number of people who have never smoked may present with an incompletely reversible obstructive airways disease indistinguishable from smoking-induced disease. Rather than attempting to categorize patients with COPD it may be more sensible to view them as suffering from some combination of the five pathophysiologic processes associated with COPD, the manifestations in each patient depending on'which of the following process or processes predominate. * Inflammatory narrowing of the respiratory and membranous bronchioles. * Proteolytic digestion of the connective-tissue framework of the lung, which results in decreased parenchymal tethering of the airways. * Loss of alveolar surface area and capillary bed. * Lung hyperinflation caused by the loss of lung elastic recoil. * Increased pulmonary vascular resistance caused by vasoconstriction and loss of the capillary bed.4 The earliest abnormalities in smoking-induced COPD are inflammatory changes in the airway walls and alveolar septa characterized by increased microvascular permeability, edema and an influx of inflammatory cells. At this stage smoking cessation, the use of anti-inflammatory medications or antioxidants, or other measures could halt the progression of airways obstruction.
Early detection In the 1970s and early 1980s there was considerable interest in the development of lung function tests sensitive to the earliest stages of obstructive lung disease. However, simple measurement of the FEV, is probably as sensitive and specific as more complex measurements in the early, reversible stages of the disease. Spirometry is a simple procedure, readily carried out in the family practitioner's office. It is recommended for those with significant occupational exposure to respiratory irritants and annually for smokers, patients with recurrent or chronic respiratory symptoms and those with a family history of pulmonary disease.5 Spirometry seems to be underused, because CAN MED ASSOC J 1992; 147 (4)
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many cases of COPD remain undiagnosed until many cases of COPD remain undiagnosed until the disease is advanced.
This view may be unnecessarily pessimistic. First, patients with COPD who fail to show a marked response to one bronchodilating agent may show a significant response to another class of Preventive measures agents. Second, day-to-day variability in the airway Smoking cessation is the obvious and necessary obstruction of COPD results in variability in bronfirst step as a preventive measure when COPD is chodilator responsiveness.'5 Patients failing to show diagnosed. Fletcher and Peto6 have shown that the a brisk response to bronchodilator therapy one day rate of FEV, decline in ex-smokers is less than that may show it on a subsequent day. Third, the goal of of current smokers and may approach that of non- bronchodilator therapy is necessarily more modest in smokers. However, smoking cessation is a formida- COPD than in asthma. A small improvement in ble task; with organized programs relapse rates airflow in COPD patients with severe obstruction usually exceed 80% after 1 year.2 To achieve even may be of significant clinical benefit, particularly if this limited success smoking cessation programs it reduces the effort of breathing by decreasing gas must address the factors that contribute to the trapping and hyperinflation. Finally, some bronsmoking habit, such as learned behaviours, environ- chodilators are reputed to have useful extrapulmental influences and, for many, chemical depen- monary effects that would not be evident during dence.7'8 The use of nicotine gum or transdermal simple bronchodilator testing. Inhaled bronchodilators are often preferred in patches may be a useful adjunctive measure for selected patients who exhibit symptoms of physical the management of obstructive airways disease beaddiction to nicotine.9 Aversive therapy may be of cause of the rapid response and minimal systemic benefit to selected patients. Clonidine, administered side effects compared with oral agents. Two classes orally or transdermally, may diminish some addic- of inhaled bronchodilator, anticholinergic and f2 tive behaviours.'0 Hypnosis, acupuncture and laser agonist, are available for the management of COPD. In most patients who have COPD, inhaled quaternatherapy have not been shown to be effective.2 The importance of other preventive measures is ry anticholinergic agents offer bronchodilatation at less well established. Annual influenza vaccination is least equal to and often greater than that seen with 2 recommended for those with chronic cardiopulmo- agonists and produce fewer side effects.'6"18 This nary disease. Although its role in COPD has not efficacy appears to be unblunted over years of been assessed in large-scale clinical trials, the ra- regular, uninterrupted use. tionale for its use is appealing, and the risk-benefit The often greater bronchodilating effect of antiratio is thought to be low. Less certain is the status cholinergic drugs compared with adrenergic agents of polyvalent pneumococcal vaccines. I ', 2 Although in COPD is opposite to the result in patients with pneumococcus is one of two bacteria cultured fre- asthma. This may be a consequence of aging. There quently from the sputum of COPD patients, there is a relative decline in the number or sensitivity or are no data to show that pneumococcal bacteremia is both of adrenergic receptors with age; this leaves the more common or more lethal in COPD patients than cholinergic system more readily manipulated for in the general population. Pneumococcal vaccine, purposes of bronchodilatation.19 designed to thwart fulminant pneumococcal sepsis, Both classes of inhaled bronchodilator have must be regarded as potentially useful but unproven minimal side effects. Ipratropium bromide, the most therapy for COPD. Orally administered Haem- extensively studied of the quaternary anticholinergic ophilus influenzae vaccines have shown promise in bronchodilators, is poorly absorbed after inhalation small-scale studies in reducing exacerbations of and consequently produces no atropine-like side chronic bronchitis, but such vaccines are currently effects and no significant measurable cardiovascular unavailable in Canada.'3'14 effects.20 Despite its atropinic heritage it has no apparent effect on mucociliary transport, sputum Bronchodilator therapy volume or sputum viscosity.2' The drug may cause minor topical effects such as dry mouth, particularly If patients with COPD have significantly limited at high dosages. Such topical effects may be reduced airflow after smoking cessation bronchodilators are by the use of a spacing device that minimizes usually prescribed. Acute bronchodilator challenges oropharyngeal deposition. Adrenergic agents are in the pulmonary function laboratory often fail to similarly benign, although tremor is a common, show the marked responsiveness considered charac- minor side effect that appears to diminish with teristic of asthma. This has led to the use of the term continued use. "irreversible" airflow obstruction and has caused Inhaled O2 agonists may be absorbed systemicalmany to question the rationale for continued bron- ly to some extent and stimulate an increase in chodilator therapy for COPD. cardiac output, primarily as a consequence of per422
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ipheral vasodilatation and afterload reduction.22 Pulmonary vasodilatation will also occur, with consequent ventilation-perfusion mismatch. This accounts for the observation that the partial pressure of oxygen in arterial blood (Pao2) may fall slightly when COPD patients are given a 12 agonist.23 Systemic absorption of 12 agonists may also produce mild hypokalemia, an effect of uncertain clinical significance. Concerns that long-term $2-agonist therapy in asthma patients may heighten airway instability24 may or may not also be relevant in COPD patients. Studies designed to test the long-term effect of such therapy for COPD have involved relatively small numbers of patients, although recent results suggest that the phenomenon may be present.25 Adjunctive use of 12 agonists as needed would obviate such concerns. Although two puffs from a metered-dose inhaler four times daily is a common first step for either class of inhaled agent, greater benefit may be achieved with four or six puffs at each administration. The use of a higher dose, particularly with a spacer, will obviate the need for nebulizers in most if not all patients. Oral theophylline therapy also produces bronchodilatation in COPD patients, although the effects are more modest than with either inhaled anticholinergic or 12-agonist agents.26-28 The advantages of theophylline are ease of administration and better compliance with sustained-release formulations given once or twice daily. The means by which theophylline produces bronchodilatation remain unknown, although some aspects of the treatment are understood. The bronchodilator potency of theophylline is correlated with its level in the blood; however, the relation is not linear. Some bronchodilatation is noticeable when the blood theophylline concentration exceeds 25 to 30 ,mol/L; it is most evident in the "low therapeutic" range (55 to 85 ,umol/L), and relatively little additional benefit is observed when the level climbs to the "highest therapeutic" range (85 to 110 ,umol/L).29 Thus, attempts to increase the dosage to the upper limit result in diminished returns and increase the risk of adverse effects. Interest in theophylline therapy has been rekindled by reports of beneficial nonbronchodilator effects. The drug is said to prevent and relieve respiratory muscle fatigue, an effect readily demonstrated in the laboratory but of uncertain clinical relevance.30-32 Theophylline (and 132-adrenergic drugs) stimulates mucociliary transport in the healthy airway, although effects on diseased airways are likely to be minor.33 Finally, theophylline is a respiratory stimulant, a feature that may be of benefit to COPD patients who hypoventilate, particularly overnight.34 AUGUST 15, 1992
Interest in these nonbronchodilator effects of theophylline should be balanced by an awareness of the drug's possible adverse effects. Approximately 10% to 15% of patients receiving theophylline will experience gastrointestinal upset, insomnia or other minor side effect. In an overdose, theophylline remains the only drug in the treatment plan that can be lethal. Both major and minor side effects are less likely if one resists the temptation to push the blood theophylline level into the high therapeutic range. Combination bronchodilator therapy (e.g., with inhaled anticholinergic and adrenergic agents) may be more effective than monotherapy in some COPD patients.35 The combination of theophylline with either an anticholinergic agent or a 12 agonist has also been shown to be beneficial in some cases; this again emphasizes the need to tailor therapy to the individual patient's needs and responses.26
Corticosteroid therapy The role of corticosteroids in COPD remains controversial. Although there is clear evidence of airway inflammation in COPD it is less clear that COPD patients, in general, benefit from steroids either taken systemically or inhaled. Studies that have attempted to address this question are complicated by a number of factors: defining the study population so as to exclude people with asthma, detecting beneficial effects against a varying baseline with various outcome measures, determining duration and dosage of corticosteroid therapy and ensuring that the COPD patients are being assessed at a clinically stable time. In addition, published studies have not always included a sufficient number of patients to exclude type II error. Although the question remains to be answered definitively, a review of published studies and a recent meta-analysis suggest that only a few COPD patients (10% to 20%) benefit from either systemic or inhaled corticosteroid therapy.35-44 As well, some patients with apparent COPD show such marked responses to steroids that they may subsequently be viewed as having asthma. The results of pulmonary function tests for steroid-responsive COPD patients may resemble those for patients with asthma; that is, there may be marked acute bronchodilator responses. However, even patients with minimal acute bronchodilator responsiveness may sometimes benefit from steroids. A reasonable clinical approach is to assess each patient's response to steroids if airway obstruction and symptoms persist despite smoking cessation and optimum bronchodilator therapy. The steroid response trial must be based on objective end points and must be undertaken only at a time of clinical
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During maximum bronchodilator therapy the patient is given prednisone, approximately 0.5 mg/kg, or equivalent, for 2 to 3 weeks, after which pulmonary function tests are repeated. An improvement in the FEVY of at least 20% and 0.2 L is regarded as evidence of steroid responsiveness; some experts regard an improvement of at least 30% as a more appropriate criterion.37 If the patient is deemed steroid responsive the next difficult decision is how to maintain this benefit. The benefits of long-term corticosteroid therapy must be weighed against its known hazards. One approach is to reduce the oral dose to the minimum needed to maintain the measured benefit. One could also consider the use of inhaled steroids. However, data on the response to inhaled steroids in COPD are conflicting,37"44 and more research is required.
Rehabilitation programs If patient activities are limited despite optimum pharmacologic therapy an exercise-based rehabilitation program may be useful. Well-motivated patients and those who do not have concomitant medical illnesses are likely to benefit from rehabilitation programs.45 Conditioning exercises may include stair climbing, treadmill walking or cycling, but to some extent the improvement in exercise tolerance is task specific. Thus, walking is the preferred form of exercise for most patients. Initial performance can be quantified with the use of standard exercise protocols, but simple and reproducible walking tests of 6 or 12 minutes' duration are a low-cost method for monitoring exercise performance. Initial exercise tests should be monitored by means of oximetry to identify patients who would benefit from supplemental oxygen therapy during the conditioning program. Optimum conditioning programs require that patients exercise for at least 20 to 30 minutes three times per week. The goal is not cardiovascular conditioning, because ventilatory limitations usually prevent the patient from reaching target heart rates needed for such an effect. Instead, conditioning increases exercise duration, reduces dyspnea and enhances the sense of well-being while leaving blood gas tensions and pulmonary function unchanged. Improvements in exercise tolerance may disappear rapidly if regular exercise is discontinued. Improvements in the strength and endurance of the respiratory muscles have been attempted directly. Repeated inspiration against resistance can improve exercise performance, but the basis of improvement is not understood.46 Explanations vary from true improvement in muscle performance to 424
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blunting of the patient's perception of dyspnea. Breathing retraining is an attempt to teach patients simple respiratory manoeuvres such as pursed-lip breathing and the use of abdominal muscles to assist expiration. Retraining does not lead to the unconscious adoption of such breathing patterns but, rather, offers the patient a coping mechanism for times of acute dyspnea.47 Another useful component of rehabilitation programs is instruction in energy conservation, a technique for minimizing workloads during common daily activities. Such efforts help to reduce the fear of breathlessness for many patients, thus further enhancing their quality of life. Patient education concerning lung disease, general health habits, nutrition, medication and emergencies is also useful for the same reason.
Supplemental oxygen therapy This therapy is unique in COPD because it has been shown to reduce the risk of death in selected patients. In COPD patients with hypoxemia who have cor pulmonale, long-term oxygen therapy may increase the life span by 6 to 7 years.48 Improved survival has been demonstrated in patients with chronic hypoxemia when oxygen is administered for at least 12 hours per day (including the nocturnal hours); greater survival benefit has been shown when oxygen is administered continuously.49,50 Patients likely to benefit are those whose daytime resting PaO2 while they are breathing room air is less than 55 mm Hg or whose arterial oxygen saturation is less than 90%.1' Such measurements should be made at a time of clinical stability; long-term oxygen therapy should not be decided on during or immediately after an exacerbation or hospital stay. Patients whose Pao2 is between 55 and 59 mm Hg may also benefit from supplemental oxygen therapy if there is indirect evidence of hypoxemic end-organ damage such as cor pulmonale or polycythemia. The benefits of long-term oxygen therapy may not be realized in patients who continue to smoke and thereby continue to have high levels of carboxyhemoglobin.52 Supplemental oxygen is usually given through nasal prongs at a flow rate sufficient to produce a resting Pao2 between 65 and 80 mm Hg. Flow rates are often increased by 1 or 2 L/min during exercise and sleep. Oximetry during these activities may aid in determining the right flow rate. Transient nocturnal episodes of hypoxemia are common in COPD. Among 135 COPD patients with normal daytime oxygenation 27% experienced periods of desaturation during sleep, although most were brief.53 No single daytime pulmonary function measurement or blood gas variable predicted these LE 15 AOUJT 1992
events. Do such transient hypoxemic episodes warrant oxygen therapy? Although animal studies have shown that transient hypoxemia can lead to sustained pulmonary hypertension,54 these results cannot be extrapolated freely to the clinical situation. Given the scope of the COPD epidemic and the cost of supplemental oxygen therapy a large multicentre clinical trial is warranted.
Exacerbations of COPD Such events are poorly understood in clinical terms and not easily defined in laboratory terms. Patients will often report a change in sputum colour, volume or viscosity accompanied by increased dyspnea. There may or may not be systemic symptoms and signs, such as fever and neutrophilia. Most often chest x-ray films show no focal change. The presumed mechanism of such exacerbations is a viral respiratory tract infection, but other processes must be considered, especially in patients who are elderly and chronically ill. Patients presenting with apparent exacerbations of COPD may have suffered a pulmonary embolism, myocardial infarction, episode of congestive heart failure or perhaps recurrent episodes of gastroesophageal reflux. In addition to considering such possibilities the physician must be alert to iatrogenic causes such as respiratory failure resulting from the unwitting administration of sedatives or ,8-blockers. Continued cigarette smoking may predispose the patient to recurrent episodes of acute on chronic respiratory failure. Exacerbations of COPD are treated with appropriate supplemental oxygen therapy, aggressive bronchodilator therapy, corticosteroids and antibiotics. Supplemental oxygen therapy should be administered carefully, but concerns about worsening respiratory failure due to the abolishment of hypoxic ventilatory drive may be misplaced.55 The rise in the partial pressure of carbon dioxide (Pco2) seen when a patient with COPD is given supplemental oxygen is generally attributed to depression of the hypoxic ventilatory drive. However, some investigators have attributed much of the hypercapnia to the Haldane effect and changes in ventilation-perfusion matching.56 Some studies have suggested that most COPD patients have a higher than normal rather than a blunted drive to breathe.57 Regardless of the mechanism or mechanisms of the hypercapnia, patients must not be kept profoundly hypoxemic for fear that oxygen therapy will induce CO2 retention. Arterial blood must, however, be sampled regularly to monitor the pH and the Pco2, particularly if the patient becomes disoriented or stuporous. Bronchodilators may be administered with the use of either a nebulizer or a metered-dose inhaler with spacing devices.28 Combination therapy AUGUST 15, 1992
with a #2 agonist and an anticholinergic agent would seem reasonable, although the bronchodilator effect with any regimen may be minimal during acute exacerbation.58 The prompt administration of corticosteroids seems to hasten improvements in the FEVy, although no effect on survival has been shown.59 The use of orally administered antibiotics when sputum is purulent also hastens resolution of the event.60 Many of the older antibiotics appear as effective as the newer, more expensive ones. Intravenous aminophylline therapy is controversial; it appears to offer little, if any, added bronchodilator benefit and may cause troublesome side effects.6' Should a patient with COPD who is suffering exacerbation be mechanically ventilated if respiration worsens? Fears that the patient will be difficult to wean from mechanical ventilation discourage many physicians from this course. However, physicians are poor at predicting survival in this setting.62 Most patients suffering an acute reversible process pose little weaning difficulty and may have reasonable functional recovery.63 In contrast, patients presenting with respiratory failure due to an inexorable decline in lung function and those with a recurrent pattern of respiratory failure must be assessed carefully to determine whether there is reasonable hope of recovery after mechanical ventilation.64 The ideal time for such assessment is when the patient is clinically stable and out of hospital.
Compliance Compliance is important in COPD because therapy is administered regularly and for years at a time. Moreover, drugs are often prescribed in combination. At least one report suggested that compliance is poor, approximately half of patients underusing their maintenance drugs.65 More worrisome, particularly if theophylline is prescribed, is the observation that about half of patients will overuse medications at times of exacerbation. Also, the use of a metereddose inhaler may be a problem for some patients. Two steps may be useful in addressing these issues. First, whenever possible regimens should be simplified. For example, the dosage of a single inhaled bronchodilator should be maximized before the addition of a second inhaled agent is considered; many patients will be treated adequately with one. Similarly, patients should receive long-term corticosteroid therapy only if an oral corticosteroid trial has shown objective benefit. Approximately 80% of patients will thus be spared the need for steroid inhalers or tablets. Second, patients should receive some education with their prescribed therapy. Forewarned, patients can avoid such hazards as taking excessive amounts CAN MED ASSOC J 1992; 147 (4)
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of theophylline at times of worsening and can emphysema if there are features to suggest familial improve their care by early self-administration of deficiency, such as emphysema of early onset, simiantibiotics at times of exacerbation. larly afflicted family members or the presence of emphysema without a significant history of cigarette Treatments under investigation smoking. The Canadian Thoracic Society Standards Committee has addressed this issue in detail, calling Mucolytics, though widely used in many Euro- for a national registry of people with a,-antitrypsin pean countries, have shown little objective benefit in deficiency and discouraging the clinical use of proclinical trials.66 Iodinated glycerol has been shown in tein replacement therapy until efficacy is assessed a large trial to be of modest symptomatic benefit in a rigorously through a large-scale, multicentre randomwell-defined group of patients with chronic bronchi- ized controlled trial.7' Noninvasive mechanical ventilatory assistance tiS.67 The importance of this observation is unclear, and the practice has not been adopted widely. Some overnight via a face or nasal mask with positive orally administered mucolytic agents are said to pressure or via cuirass or poncho with negative have a useful antioxidant benefit, an effect of unde- pressure can, in the short term, improve arterial termined clinical importance but perhaps more rele- blood gas tensions in patients with respiratory failure vant to patients who continue to smoke.68 secondary to COPD.7273 These devices may also be Ventilatory stimulants have been studied as of use in avoiding mechanical 'ventilation in some adjunctive therapy for alveolar hypoventilation (al- cases of acute exacerbation. It remains to be seen though, as noted earlier, most COPD patients have whether long-term use of nocturnal ventilatory assisan enhanced ventilatory drive). Agents studied have tance can improve quality of life or reduce the death included the methylxanthines, narcotic antagonists, rate. The most dramatic treatment option in cases of progesterone, acetazolamide and analeptics such as doxapram and almitrine bismesylate. Although sev- severe COPD is lung transplantation. Improved eral of these improve minute ventilation their use is surgical techniques, improved immunosuppressive limited by the potential for adverse effects. The most regimens, early recognition and treatment of rejeceffective agent of this group has been almitrine, tion, and the use of preventive antibiotics have all several studies clearly demonstrating an improve- contributed to the increased success of transplantament in arterial blood gas tensions. Almitrine ap- tion. Overall, a 2-year survival rate of 60% to 70% pears to increase peripheral chemoreceptor sensitivi- can be expected.74 Double-lung transplantation has ty and to improve ventilation-perfusion matching by been performed more frequently, but single-lung enhancing vasoconstriction in underventilated lung transplantation has also been used successfully in segments. However, the latter effect has been shown COPD. Hyperinflation of the native lung with comto increase pulmonary artery pressures with conse- pression of the transplanted lung is still of some quent increased strain on the right ventricle, an concern, although not to the extent originally expectadverse effect outweighing any potential clinical ed.74 This technique above all has the potential for benefit of the drug.69 This agent is not currently "reversing the irreversible," but the prevalence rate available in Canada and may not become so given of COPD and the scarcity of donor lungs would the adverse effects. preclude transplantation for all but a few afflicted For patients with emphysema induced by patients. The current status of lung transplantation is a,-antitrypsin deficiency purified a,-antitrypsin pro- the subject of a Canadian Thoracic Society position tein is available for supplemental administration paper.75 intravenously. This therapy is both costly and cumbersome, and its use is limited solely to patients with Conclusions this type of emphysema. The drug is available by prescription in North America, although it has not Because the dyspnea of COPD may not be been shown conclusively to retard the progress of present until the airways are markedly obstructed, emphysema in deficient patients. Instead, injections early detection is most likely to be achieved through produce blood and alveolar levels of protein that are spirometric screening of high-risk patients. The prithought to be protective on theoretic grounds.70 At a ority of any therapeutic plan for the patient who has cost of approximately $30 000 per year such a series COPD is avoidance of further pulmonary damage. of injections is best undertaken by specialized cen- This makes smoking cessation the necessary first tres after thorough patient assessment and educa- step in a successful treatment strategy. tion. Annual influenza vaccination and vaccination The availability of this protein should encourage against pneumococcal pneumonia may be useful primary care physicians to measure blood levels of supplementary measures. If bronchodilator therapy a,-antitrypsin protein in patients with panlobular is required inhaled agents including anticholinergic 426
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and p2-agonist agents offer the greatest benefit with the fewest side effects. Anticholinergic agents may offer greater benefit in older patients. If combination bronchodilator therapy is needed the order of adding adrenergic agents, theophylline or both is best determined by preference and tolerance. If the condition of a nonsmoking COPD patient has been stabilized with a bronchodilator regimen but disabling symptoms persist the response to oral corticosteroid therapy may be assessed over 2 to 3 weeks by appropriate pulmonary function testing. If, despite such measures, exercise tolerance remains poor and reasonable daily activities are hampered a comprehensive exercise rehabilitation program may be useful. Finally, if despite all other avenues of treatment hypoxemia persists supplemental oxygen therapy remains the only proven way to reduce the death rate. We thank the Canadian Thoracic Society Standards Committee for reviewing this manuscript and providing many helpful suggestions. This study was sponsored by the Canadian Thoracic Society and supported by an educational grant from Boehringer Ingelheim Canada Ltd.
References 1. Higgins MW: Chronic airways disease in the United States: trends and determinants. Chest 1989; 96 (suppl 3): 328S-
329S 2. American Thoracic Society: Standards-for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. Am Rev Respir Dis 1987; 136: 225-244 3. Wright JL, Pare PD, Wiggs BJR et al: Ranking the severity of emphysema on whole lung slices: concordance of upper lobe, lower lobe and entire lung rank. Am Rev Respir Dis 1986; 133: 930-931 4. Moreno R, Hogg J, Pare PD: Perspective: mechanics of airway narrowing. Ibid: 1171-1180 5. Tames P: Breathing to Live: a Physician's Companion to Managing COPD and Counselling Patients, Grosvenor, Toronto, 1991: 43-44 6. Fletcher C, Peto R: The natural history of chronic airflow obstruction. BMJ 1977; 1: 1645-1648 7. Fisher EB, Bishop DB, Mayer J et al: The physician's contribution to smoking cessation in the workplace. Chest 1988; 93 (suppl 2): 56S-65S 8. Fisher EB, Bishop DB, Goldmuntz J et al: Implications for the practising physician of the psychosocial dimensions of smoking. Ibid: 69S-78S 9. Tonnesen P, Fryd V, Hansen M et al: Effect of nicotine chewing gum in combination with group counselling on the cessation of smoking. NEnglJMed 1988; 318: 15-18 10. Omish SA, Zisook S, McAdams LA: Effects of transdermal clonidine treatment on withdrawal symptoms associated with smoking cessation: a randomized, controlled trial. Arch Intern
Med 1988; 148: 2027-2031
11. Williams JH: Continuing controversy: pneumococcal vaccine
and COPD. Chest 1987; 92: 193-194 12. Davis AL, Aranda CP, Schiffman G et al: Pneumococcal infection and immunologic response to pneumococcal vaccine in chronic obstructive pulmonary disease: a pilot study. Ibid: 204-211 AUGUST 15, 1992
13. Lehmann D, Coakley KJ, Coakley CA et al: Reduction in the incidence of acute bronchitis by an oral Haemophilus influenzae vaccine in patients with chronic bronchitis in the highlands of Papua New Guinea. Am Rev Respir Dis 1991; 144: 324-330 14. Clancy R, Cripps A, Murree-Allen K et al: Oral immunization with killed Haemophilus influenzae for protection against acute bronchitis in chronic obstructive lung disease. Lancet 1985; 2: 1395-1397 15. Anthonisen N, Wright E: Response to inhaled bronchodilators in COPD. Chest 1987; 91 (suppl 5): 36S-39S 16. Gross NJ, Skorodin MS: Anticholinergic, antimuscarinic bronchodilators. Am Rev Respir Dis 1984; 129: 856-870 17. Pakes GE, Brogden RN, Heel RC et al: Ipratropium bromide: a review of its pharmacologic properties and therapeutic efficacy in asthma and chronic bronchitis. Drugs 1980; 20: 237-266 18. Gross NJ: Anticholinergic agents in COPD. Chest 1987; 91 (suppl 5): 52S-57S 19. Ullah MI, Newman GB, Saunders KB: Influence of age on response to ipratropium bromide and salbutamol in asthma. Thorax 1981; 36: 523-529 20. Chapman KR, Smith DL, Rebuck AS et al: Hemodynamic effects of inhaled ipratropium bromide, alone and combined with an inhaled beta2 agonist. Am Rev Respir Dis 1985; 132: 845-847 21. Wanner A: Effect of ipratropium bromide on airway mucociliary function. Am J Med 1986; 81 (suppl 5A): 23-27 22. Chapman KR, Smith DL, Rebuck AS et al: Hemodynamic effects of an inhaled beta2 agonist. Clin Pharmacol Ther 1984; 35: 762-767 23. Gross NJ, Bankwala Z: Effects of an anticholinergic bronchodilator on arterial blood gases of hypoxemic patients with chronic obstructive pulmonary disease: comparison with a beta adrenergic agent. Am Rev Respir Dis 1987; 136: 10911094 24. Sears MR, Taylor DR, Print CG et al: Regular inhaled beta-agonist treatment in bronchial asthma. Lancet 1990; 336: 1391-1396 25. Van Schayck CP, Graafsma SJ, Visch MB et al: Increased bronchial hyperresponsiveness after inhaling salbutamol during 1 year is not caused by subsensitization to salbutamol. JAllergy Clin Immunol 1990; 86: 793-800 26. Bleecker ER, Johns M, Britt EJ: Greater bronchodilator effects of ipratropium compared to theophylline in chronic airflow obstruction. Chest 1988; 94 (suppl 1): 3S 27. Barclay J, Whiting B, Addis GJ: The influence of theophylline on maximal response to salbutamol and severe chronic obstructive pulmonary disease. Eur J Clin Pharmacol 1982; 22: 389-393 28. Newhouse MT, Dolovich M: Aerosol therapy of reversible air flow obstruction: concepts and clinical applications. Chest 1987; 91 (suppl 5): 58S-64S 29. Rogers RM, Owens GR, Pennock BE: The pendulum swings again: toward a rational use of theophylline. Chest 1985; 87: 280-282 30. Aubier M, DeTroyer A, Sampson M et al: Aminophylline improves diaphragmatic contractility. N Engl J Med 1981; 305: 249-252 31. Murciano D, Aubier M, Lecocgiv Y et al: Effects of theophylline on diaphragmatic strength and fatigue in patients with chronic obstructive pulmonary disease. N Engl J Med 1984; 311: 349-352 32. Murciano D, Auclair MH, Pariente R et al: A randomized, controlled trial of theophylline in patients with severe chronic obstructive pulmonary disease. N Engl J Med 1989; 320: 1521-1525 33. Wanner A: Effects of methylxanthines on airway mucociliary function. Am JMed 1985; 79 (suppl 6A): 16-21 34. Berry RB, Desa MM, Branum JP et al: Effect of theophylline on sleep and sleep-disordered breathing in patients with CAN MED ASSOC J 1992; 147 (4)
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chronic obstructive pulmonary disease. Am Rev Respir Dis 1991; 143: 245-250 Filuk RB, Easton PA, Anthonisen NR: Responses to large doses of salbutamol and theophylline in patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1985; 132: 871-874 Mendella LA, Manfreda J, Warren CPW et al: Steroid response in stable chronic obstructive pulmonary disease. Ann Intern Med 1982; 96: 17-21 Callaghan CM, Dittus RS, Katz BP: Oral corticosteroid therapy for patients with stable chronic obstructive pulmonary disease. Ann Intern Med 1991; 114: 216-223 Weir DC, Gove RI, Robertson AS et al: Corticosteroid trials in non-asthmatic chronic airflow obstruction: a comparison of oral prednisolone and inhaled beclomethasone dipropionate. Thorax 1990; 45: 112-117 Syed A, Hoeppner VJ, Cockcroft DW: Prediction of nonresponse to corticosteroids and stable chronic airflow obstruction. Clin Invest Med 1991; 14: 28-34 Eliasson 0, Hoffman J, Trueb FD et al: Corticosteroids in COPD: a clinical trial and reassessment of the literature. Chest 1986; 89: 484-490 Mitchell DM, Gildeh P, Dimond AH et al: Value of serial peak expiratory flow measurements in assessing treatment response in chronic airflow limitation. Thorax 1986; 41: 606610 Blair GP, Light RW: Treatment of chronic obstructive pulmonary disease with corticosteroids. Chest 1984; 86: 524528 Lam WK, Shun YS, Yu DYC: Response to oral corticosteroids in chronic airflow obstruction. Br J Dis Chest 1983; 77: 189-198 Shim C, Stovere DE, Williams MH: Aerosol beclomethasone in patients with steroid-responsive chronic obstructive pulmonary disease. Am JMed 1985; 78: 655-658 Jones NL: Physical therapy - present state of the art. Am Rev Respir Dis 1974; 110 (suppl): 132-136 Sonne L, Davis J: Increased exercise performance in patients with severe COPD following inspiratory resistive training. Chest 1982; 81: 436-439 Campbell EJM, Friend J: Action of breathing exercises in pulmonary emphysema. Lancet 1955; 1: 325-329 Cooper CB, Waterhouse J, Howard P: Twelve year clinical study of patients with hypoxic cor pulmonale given long term domiciliary oxygen therapy. Thorax 1987; 42: 105-1 10 Medical Research Council Working Party: Long-term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema. Lancet 1981; 1:681-686 Nocturnal Oxygen Therapy Trial Group: Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease: a clinical trial. Ann Intern Med 1980; 93: 391398 Anthonisen NR: Long-term oxygen therapy. Ann Intern Med 1983; 99: 519-527 Calverley PMA, Legett RJ, McElderry L et al: Cigarette smoking and secondary polycythemia in hypoxic cor pulmonale.AmRevRespirDis 1982; 125: 507-510 Fletcher EC, Miller J, Divine GW et al: Nocturnal oxyhemoglobin desaturation in COPD patients with arterial oxygen tensions about 60 mm Hg. Chest 1987; 92: 604-608 Nattie EE, Bartlett D Jr, Johnson K: Pulmonary hypertension and right ventricular hypertrophy induced by intermittent hypoxia and hypercapnia in the rat. Am Rev Respir Dis 1978; 118: 653-658 Sassoon CS, Hassell KT, Mahutte CK: Hyperoxic-induced hypercapnia in stable chronic obstructive pulmonary disease. Am Rev Respir Dis 1987; 135: 907-911 Lenfant C: Arterial-alveolar difference in Pco2 during air and
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oxygen breathing. JAppi Physiol 1966; 21: 1356-1362 57. Aubier M, Murciano D, Fournier M et al: Central respiratory drive in acute respiratory failure of patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1980; 122: 191-199 58. Rebuck AS, Chapman KR, Abboud R et al: Nebulized anticholinergic and sympathomimetic treatment of asthma and chronic obstructive airways disease in the emergency room. Am JMed 1987; 82: 59-64 59. Albert RK, Martin TR, Lewis SW: Controlled clinical trial of methylprednisolone in patients with chronic bronchitis and acute respiratory insufficiency. Ann Intern Med 1980; 92: 753-758 60. Anthonisen NR, Manfreda J, Warren CPW et al: Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med 1987; 106: 196-204 61. Rice KL, Leatherman JW, Duane PG et al: Aminophylline for acute exacerbations of chronic obstructive pulmonary disease. Ann Intern Med 1987; 107: 305-309 62. Pearlman RA: Variability in physician estimates of survival for acute respiratory failure in chronic obstructive pulmonary disease. Chest 1987; 91: 515-521 63. Martin TR, Lewis SW, Albert RK: The prognosis of patients with chronic obstructive pulmonary disease after hospitalization for acute respiratory failure. Chest 1982; 82: 310-314 64. Menzies R, Gibbons W, Goldberg P: Determinants of weaning and survival among patients with COPD who require mechanical ventilation for acute respiratory failure. Chest 1988; 95: 398-405 65. Dolce JJ, Crisp C, Manzella B et al: Medication adherence patterns in chronic obstructive pulmonary disease. Chest 1991; 99: 837-841 66. Guyatt GH, Townsend M, Kazim F et al: A control trial of ambroxol in chronic bronchitis. Chest 1987; 92: 618-620 67. Petty TL: The National Mucolytic Study. Results of a randomized, double-blind, placebo-controlled study of iodinated glycerol in chronic obstructive bronchitis. Chest 1990; 97: 75-83 68. Glennow C: Reduced exacerbation frequency in chronic bronchitis: short review. In Oxidative Stress in the Lung. Intervention with Thiols, Draco, London, 1986: 39-40 69. MacNee W, Connaughton J, Rhind JB et al: A comparison of the effects of almitrine or oxygen breathing on pulmonary arterial pressures and right ventricular ejection fraction in hypoxic chronic bronchitis and emphysema. Am Rev Respir Dis 1986; 134: 559-565 70. Wewers MD, Casolaro MA, Sellers SE et al: Replacement therapy of alpha, antitrypsin deficiency associated with emphysema. N Engl J Med 1987; 316: 1055-1062 71. Ad Hoc Committee on Alpha- 1-Antitrypsin Replacement Therapy of the Standards Committee, Canadian Thoracic Society: Current status of alpha-1-antitrypsin replacement therapy: recommendations for the management of patients with severe hereditary deficiency. Can Med Assoc J 1992; 146: 841-844 72. Carroll N, Branthwaite MA: Control of nocturnal hypoventilation by nasal intermittent positive pressure ventilation. Thorax 1988; 43: 349-353 73. Brochard L, Isabey D, Piquett J et al: Reversal of acute exacerbations of chronic obstructive lung disease by inspiratory assistance with a face mask. N Engl J Med 1990; 323: 1523-1530 74. Patterson GA, Maurer JR, Williams TJ.et al: Comparison of outcomes of double and single lung transplantation for obstructive lung disease. J Thorac Cardiovasc Surg 1991; 101: 623-632 75. Standards Committee: The Indications for Lung Transplantation, Canadian Thoracic Society, Toronto, 1991
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Guidelines for the assessment and management of chronic obstructive pulmonary disease Canadian Thoracic Society Workshop Group Chronic obstructive pulmonary disease (COPD) is the fifth commonest cause of death in North America and is the only leading cause of death that is increasing in prevalence. Early detection and prevention through smoking cessation are essential to stem this epidemic. Once COPD is diagnosed there is a compelling rationale for vaccination against influenza and possibly pneumococcal pneumonia, although proof of efficacy is lacking. If airways obstruction is present, inhaled quaternary anticholinergic bronchodilators or inhaled 02 agonists or both may be of benefit, the former agents showing fewer side effects and often greater efficacy in elderly patients. Theophylline may enhance the effect or increase the duration of the bronchodilatation produced by an inhaled agent and may offer added nonbronchodilatory effects such as improved respiratory muscle endurance and ventilatory stimulation. If significant airflow obstruction persists, an objectively monitored trial of oral steroid therapy is required. Limitation of activity despite optimum medical therapy may be alleviated in selected patients by a supervised exercise rehabilitation program. If hypoxemia is present supplemental oxygen therapy will improve the patient's survival and quality of life. Additional therapies, from respiratory stimulants to lung transplantation, remain under
investigation. La maladie pulmonaire obstructive chronique (MPOC) vient au cinquieme rang des causes de deces pour la frequence en Amerique du Nord, et elle est la seule cause de deces dont la prevalence est en train d'augmenter. Le depistage precoce et la prevention grace au renoncement au tabac sont essentiels pour enrayer cette epidemie. Un diagnostic de MPOC constitue un motif concluant de vaccination contre l'influenza et peut-etre contre la pneumonie a pneumocoques, malgre l'absence de preuve d'efficacite. Advenant l'obstruction des voies aeriennes, l'inhalation de bronchodilatateurs anticholinergiques quaternaires, de 02 stimulants ou les deux peut representer un avantage, le premier groupe causant moins d'effets secondaires et ayant souvent une plus grande efficacit6 chez les patients ages. La theophylline peut ameliorer l'effet ou augmenter la duree de la bronchodilatation produite par un agent inhale, et elle peut amener des effets supplementaires non bronchodilatateurs, comme une amelioration de l'endurance musculorespiratoire et une stimulation ventilatoire. Si une obstruction importante de l'ecoulement de l'air se prolonge, il faut proceder a un essai objectivement surveille de la steroidotherapie par voie orale. La limitation des activites malgre un traitement medical optimal peut ere soulagee chez certains patients par un programme supervise de readaptation a l'exercice. En presence d'hypoxemie, l'oxygenotherapie d'appoint ameliorera la survie du patient et sa qualite de vie. D'autres traitements, des analeptiques respiratoires a la transplantation des poumons, demeurent a l'etude. *Members: Drs. Kenneth R. Chapman, Department of Medicine, University of Toronto, Toronto, Ont.; Dennis M. Bowie, Department of Medicine, Dalhousie University, Halifax, NS; Roger S. Goldstein, Department of Medicine, University of Toronto, Toronto, Ont.; Richard V. Hodder, Department of Medicine, University of Ottawa, Ottawa, Ont.; Marcel Julien, Department ofMedicine, University of Montreal, Montreal, Que.; Steven Kesten, Department of Medicine, University of Toronto, Toronto, Ont.; Michael T. Newhouse, Department of Medicine, McMaster University, Hamilton, Ont.; and Peter D. Pare, Department of Medicine, University of British Columbia, Vancouver, BC
Reprint requests to. Dr. Kenneth R. Chapman, Asthma Centre of the Toronto Hospital, Ste. 4-011, Edith Cavell Wing, 399 Bathurst St., Toronto, ON M5 T 2S8
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C hronic obstructive pulmonary disease (COPD) is the fifth most common cause of death in North America and the only leading cause of death that is increasing in prevalence.' Yet this modem epidemic receives scant attention in the medical or lay press, particularly when compared with the other common obstructive airways disease, asthma. Perhaps there is a widespread perception that with the decline in cigarette smoking COPD is a vanishing problem. Nothing could be further from the truth, since we are now harvesting the consequences of cigarette smoking made popular in the postwar years. Perhaps there is a perception that therapy for COPD is futile, the airways obstruction being "irreversible." This outmoded view ignores our improved understanding of the pathophysiologic features of these conditions and the many effective therapeutic options now available to COPD patients. This paper summarizes the proceedings of a workshop on COPD sponsored by the Canadian Thoracic Society. The workshop was convened to examine critically our approach to this common disease. We wished to identify diagnostic and therapeutic strategies of proven merit, strategies without merit and strategies of potential merit but requiring further investigation. In doing so, we hoped to promote more effective clinical care and to spur discussion and research in controversial areas. This paper provides an outline that can be used by the primary care practitioner to develop a treatment plan that meets the individual patient's needs.
Pathophysiologic features of COPD COPD is characterized functionally as progressive and incompletely reversible airflow obstruction. Specific forms of COPD have been described, although their identification may offer little pathophysiologically or clinically useful information.2 Chronic bronchitis is characterized by a productive cough persisting over long intervals. Although this disorder may be associated with progressive airflow obstruction and dyspnea, obstructive disease fails to develop in most patients with chronic productive cough; instead they suffer "simple chronic bronchitis." Emphysema is associated with destruction and enlargement of alveoli, a process that again may or may not be associated with significant airflow obstruction. In studies involving patients who have undergone lobectomy or pneumonectomy for focal disease, there is surprisingly poor. correlation between emphysema scores, which quantify the degree of alveolar destruction, and conventional measures of airflow obstruction such as forced expired volume in 1 second (FEV,).3 The relation between cigarette smoking and AUGUST 15, 1992
COPD is more complex than is often appreciated. Despite the strong association between the two, cigarette smoking alone appears insufficient to produce the disease. Obstructive airways disease develops in only a minority (about 15%) of long-time cigarette smokers; this implies the existence of other, unknown factors that predispose people to such airways injury. The "Dutch hypothesis" suggests that a genetic predisposition to airway injury is required before cigarette smoking causes COPD. To further complicate the relation a small number of people who have never smoked may present with an incompletely reversible obstructive airways disease indistinguishable from smoking-induced disease. Rather than attempting to categorize patients with COPD it may be more sensible to view them as suffering from some combination of the five pathophysiologic processes associated with COPD, the manifestations in each patient depending on'which of the following process or processes predominate. * Inflammatory narrowing of the respiratory and membranous bronchioles. * Proteolytic digestion of the connective-tissue framework of the lung, which results in decreased parenchymal tethering of the airways. * Loss of alveolar surface area and capillary bed. * Lung hyperinflation caused by the loss of lung elastic recoil. * Increased pulmonary vascular resistance caused by vasoconstriction and loss of the capillary bed.4 The earliest abnormalities in smoking-induced COPD are inflammatory changes in the airway walls and alveolar septa characterized by increased microvascular permeability, edema and an influx of inflammatory cells. At this stage smoking cessation, the use of anti-inflammatory medications or antioxidants, or other measures could halt the progression of airways obstruction.
Early detection In the 1970s and early 1980s there was considerable interest in the development of lung function tests sensitive to the earliest stages of obstructive lung disease. However, simple measurement of the FEV, is probably as sensitive and specific as more complex measurements in the early, reversible stages of the disease. Spirometry is a simple procedure, readily carried out in the family practitioner's office. It is recommended for those with significant occupational exposure to respiratory irritants and annually for smokers, patients with recurrent or chronic respiratory symptoms and those with a family history of pulmonary disease.5 Spirometry seems to be underused, because CAN MED ASSOC J 1992; 147 (4)
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many cases of COPD remain undiagnosed until many cases of COPD remain undiagnosed until the disease is advanced.
This view may be unnecessarily pessimistic. First, patients with COPD who fail to show a marked response to one bronchodilating agent may show a significant response to another class of Preventive measures agents. Second, day-to-day variability in the airway Smoking cessation is the obvious and necessary obstruction of COPD results in variability in bronfirst step as a preventive measure when COPD is chodilator responsiveness.'5 Patients failing to show diagnosed. Fletcher and Peto6 have shown that the a brisk response to bronchodilator therapy one day rate of FEV, decline in ex-smokers is less than that may show it on a subsequent day. Third, the goal of of current smokers and may approach that of non- bronchodilator therapy is necessarily more modest in smokers. However, smoking cessation is a formida- COPD than in asthma. A small improvement in ble task; with organized programs relapse rates airflow in COPD patients with severe obstruction usually exceed 80% after 1 year.2 To achieve even may be of significant clinical benefit, particularly if this limited success smoking cessation programs it reduces the effort of breathing by decreasing gas must address the factors that contribute to the trapping and hyperinflation. Finally, some bronsmoking habit, such as learned behaviours, environ- chodilators are reputed to have useful extrapulmental influences and, for many, chemical depen- monary effects that would not be evident during dence.7'8 The use of nicotine gum or transdermal simple bronchodilator testing. Inhaled bronchodilators are often preferred in patches may be a useful adjunctive measure for selected patients who exhibit symptoms of physical the management of obstructive airways disease beaddiction to nicotine.9 Aversive therapy may be of cause of the rapid response and minimal systemic benefit to selected patients. Clonidine, administered side effects compared with oral agents. Two classes orally or transdermally, may diminish some addic- of inhaled bronchodilator, anticholinergic and f2 tive behaviours.'0 Hypnosis, acupuncture and laser agonist, are available for the management of COPD. In most patients who have COPD, inhaled quaternatherapy have not been shown to be effective.2 The importance of other preventive measures is ry anticholinergic agents offer bronchodilatation at less well established. Annual influenza vaccination is least equal to and often greater than that seen with 2 recommended for those with chronic cardiopulmo- agonists and produce fewer side effects.'6"18 This nary disease. Although its role in COPD has not efficacy appears to be unblunted over years of been assessed in large-scale clinical trials, the ra- regular, uninterrupted use. tionale for its use is appealing, and the risk-benefit The often greater bronchodilating effect of antiratio is thought to be low. Less certain is the status cholinergic drugs compared with adrenergic agents of polyvalent pneumococcal vaccines. I ', 2 Although in COPD is opposite to the result in patients with pneumococcus is one of two bacteria cultured fre- asthma. This may be a consequence of aging. There quently from the sputum of COPD patients, there is a relative decline in the number or sensitivity or are no data to show that pneumococcal bacteremia is both of adrenergic receptors with age; this leaves the more common or more lethal in COPD patients than cholinergic system more readily manipulated for in the general population. Pneumococcal vaccine, purposes of bronchodilatation.19 designed to thwart fulminant pneumococcal sepsis, Both classes of inhaled bronchodilator have must be regarded as potentially useful but unproven minimal side effects. Ipratropium bromide, the most therapy for COPD. Orally administered Haem- extensively studied of the quaternary anticholinergic ophilus influenzae vaccines have shown promise in bronchodilators, is poorly absorbed after inhalation small-scale studies in reducing exacerbations of and consequently produces no atropine-like side chronic bronchitis, but such vaccines are currently effects and no significant measurable cardiovascular unavailable in Canada.'3'14 effects.20 Despite its atropinic heritage it has no apparent effect on mucociliary transport, sputum Bronchodilator therapy volume or sputum viscosity.2' The drug may cause minor topical effects such as dry mouth, particularly If patients with COPD have significantly limited at high dosages. Such topical effects may be reduced airflow after smoking cessation bronchodilators are by the use of a spacing device that minimizes usually prescribed. Acute bronchodilator challenges oropharyngeal deposition. Adrenergic agents are in the pulmonary function laboratory often fail to similarly benign, although tremor is a common, show the marked responsiveness considered charac- minor side effect that appears to diminish with teristic of asthma. This has led to the use of the term continued use. "irreversible" airflow obstruction and has caused Inhaled O2 agonists may be absorbed systemicalmany to question the rationale for continued bron- ly to some extent and stimulate an increase in chodilator therapy for COPD. cardiac output, primarily as a consequence of per422
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ipheral vasodilatation and afterload reduction.22 Pulmonary vasodilatation will also occur, with consequent ventilation-perfusion mismatch. This accounts for the observation that the partial pressure of oxygen in arterial blood (Pao2) may fall slightly when COPD patients are given a 12 agonist.23 Systemic absorption of 12 agonists may also produce mild hypokalemia, an effect of uncertain clinical significance. Concerns that long-term $2-agonist therapy in asthma patients may heighten airway instability24 may or may not also be relevant in COPD patients. Studies designed to test the long-term effect of such therapy for COPD have involved relatively small numbers of patients, although recent results suggest that the phenomenon may be present.25 Adjunctive use of 12 agonists as needed would obviate such concerns. Although two puffs from a metered-dose inhaler four times daily is a common first step for either class of inhaled agent, greater benefit may be achieved with four or six puffs at each administration. The use of a higher dose, particularly with a spacer, will obviate the need for nebulizers in most if not all patients. Oral theophylline therapy also produces bronchodilatation in COPD patients, although the effects are more modest than with either inhaled anticholinergic or 12-agonist agents.26-28 The advantages of theophylline are ease of administration and better compliance with sustained-release formulations given once or twice daily. The means by which theophylline produces bronchodilatation remain unknown, although some aspects of the treatment are understood. The bronchodilator potency of theophylline is correlated with its level in the blood; however, the relation is not linear. Some bronchodilatation is noticeable when the blood theophylline concentration exceeds 25 to 30 ,mol/L; it is most evident in the "low therapeutic" range (55 to 85 ,umol/L), and relatively little additional benefit is observed when the level climbs to the "highest therapeutic" range (85 to 110 ,umol/L).29 Thus, attempts to increase the dosage to the upper limit result in diminished returns and increase the risk of adverse effects. Interest in theophylline therapy has been rekindled by reports of beneficial nonbronchodilator effects. The drug is said to prevent and relieve respiratory muscle fatigue, an effect readily demonstrated in the laboratory but of uncertain clinical relevance.30-32 Theophylline (and 132-adrenergic drugs) stimulates mucociliary transport in the healthy airway, although effects on diseased airways are likely to be minor.33 Finally, theophylline is a respiratory stimulant, a feature that may be of benefit to COPD patients who hypoventilate, particularly overnight.34 AUGUST 15, 1992
Interest in these nonbronchodilator effects of theophylline should be balanced by an awareness of the drug's possible adverse effects. Approximately 10% to 15% of patients receiving theophylline will experience gastrointestinal upset, insomnia or other minor side effect. In an overdose, theophylline remains the only drug in the treatment plan that can be lethal. Both major and minor side effects are less likely if one resists the temptation to push the blood theophylline level into the high therapeutic range. Combination bronchodilator therapy (e.g., with inhaled anticholinergic and adrenergic agents) may be more effective than monotherapy in some COPD patients.35 The combination of theophylline with either an anticholinergic agent or a 12 agonist has also been shown to be beneficial in some cases; this again emphasizes the need to tailor therapy to the individual patient's needs and responses.26
Corticosteroid therapy The role of corticosteroids in COPD remains controversial. Although there is clear evidence of airway inflammation in COPD it is less clear that COPD patients, in general, benefit from steroids either taken systemically or inhaled. Studies that have attempted to address this question are complicated by a number of factors: defining the study population so as to exclude people with asthma, detecting beneficial effects against a varying baseline with various outcome measures, determining duration and dosage of corticosteroid therapy and ensuring that the COPD patients are being assessed at a clinically stable time. In addition, published studies have not always included a sufficient number of patients to exclude type II error. Although the question remains to be answered definitively, a review of published studies and a recent meta-analysis suggest that only a few COPD patients (10% to 20%) benefit from either systemic or inhaled corticosteroid therapy.35-44 As well, some patients with apparent COPD show such marked responses to steroids that they may subsequently be viewed as having asthma. The results of pulmonary function tests for steroid-responsive COPD patients may resemble those for patients with asthma; that is, there may be marked acute bronchodilator responses. However, even patients with minimal acute bronchodilator responsiveness may sometimes benefit from steroids. A reasonable clinical approach is to assess each patient's response to steroids if airway obstruction and symptoms persist despite smoking cessation and optimum bronchodilator therapy. The steroid response trial must be based on objective end points and must be undertaken only at a time of clinical
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During maximum bronchodilator therapy the patient is given prednisone, approximately 0.5 mg/kg, or equivalent, for 2 to 3 weeks, after which pulmonary function tests are repeated. An improvement in the FEVY of at least 20% and 0.2 L is regarded as evidence of steroid responsiveness; some experts regard an improvement of at least 30% as a more appropriate criterion.37 If the patient is deemed steroid responsive the next difficult decision is how to maintain this benefit. The benefits of long-term corticosteroid therapy must be weighed against its known hazards. One approach is to reduce the oral dose to the minimum needed to maintain the measured benefit. One could also consider the use of inhaled steroids. However, data on the response to inhaled steroids in COPD are conflicting,37"44 and more research is required.
Rehabilitation programs If patient activities are limited despite optimum pharmacologic therapy an exercise-based rehabilitation program may be useful. Well-motivated patients and those who do not have concomitant medical illnesses are likely to benefit from rehabilitation programs.45 Conditioning exercises may include stair climbing, treadmill walking or cycling, but to some extent the improvement in exercise tolerance is task specific. Thus, walking is the preferred form of exercise for most patients. Initial performance can be quantified with the use of standard exercise protocols, but simple and reproducible walking tests of 6 or 12 minutes' duration are a low-cost method for monitoring exercise performance. Initial exercise tests should be monitored by means of oximetry to identify patients who would benefit from supplemental oxygen therapy during the conditioning program. Optimum conditioning programs require that patients exercise for at least 20 to 30 minutes three times per week. The goal is not cardiovascular conditioning, because ventilatory limitations usually prevent the patient from reaching target heart rates needed for such an effect. Instead, conditioning increases exercise duration, reduces dyspnea and enhances the sense of well-being while leaving blood gas tensions and pulmonary function unchanged. Improvements in exercise tolerance may disappear rapidly if regular exercise is discontinued. Improvements in the strength and endurance of the respiratory muscles have been attempted directly. Repeated inspiration against resistance can improve exercise performance, but the basis of improvement is not understood.46 Explanations vary from true improvement in muscle performance to 424
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blunting of the patient's perception of dyspnea. Breathing retraining is an attempt to teach patients simple respiratory manoeuvres such as pursed-lip breathing and the use of abdominal muscles to assist expiration. Retraining does not lead to the unconscious adoption of such breathing patterns but, rather, offers the patient a coping mechanism for times of acute dyspnea.47 Another useful component of rehabilitation programs is instruction in energy conservation, a technique for minimizing workloads during common daily activities. Such efforts help to reduce the fear of breathlessness for many patients, thus further enhancing their quality of life. Patient education concerning lung disease, general health habits, nutrition, medication and emergencies is also useful for the same reason.
Supplemental oxygen therapy This therapy is unique in COPD because it has been shown to reduce the risk of death in selected patients. In COPD patients with hypoxemia who have cor pulmonale, long-term oxygen therapy may increase the life span by 6 to 7 years.48 Improved survival has been demonstrated in patients with chronic hypoxemia when oxygen is administered for at least 12 hours per day (including the nocturnal hours); greater survival benefit has been shown when oxygen is administered continuously.49,50 Patients likely to benefit are those whose daytime resting PaO2 while they are breathing room air is less than 55 mm Hg or whose arterial oxygen saturation is less than 90%.1' Such measurements should be made at a time of clinical stability; long-term oxygen therapy should not be decided on during or immediately after an exacerbation or hospital stay. Patients whose Pao2 is between 55 and 59 mm Hg may also benefit from supplemental oxygen therapy if there is indirect evidence of hypoxemic end-organ damage such as cor pulmonale or polycythemia. The benefits of long-term oxygen therapy may not be realized in patients who continue to smoke and thereby continue to have high levels of carboxyhemoglobin.52 Supplemental oxygen is usually given through nasal prongs at a flow rate sufficient to produce a resting Pao2 between 65 and 80 mm Hg. Flow rates are often increased by 1 or 2 L/min during exercise and sleep. Oximetry during these activities may aid in determining the right flow rate. Transient nocturnal episodes of hypoxemia are common in COPD. Among 135 COPD patients with normal daytime oxygenation 27% experienced periods of desaturation during sleep, although most were brief.53 No single daytime pulmonary function measurement or blood gas variable predicted these LE 15 AOUJT 1992
events. Do such transient hypoxemic episodes warrant oxygen therapy? Although animal studies have shown that transient hypoxemia can lead to sustained pulmonary hypertension,54 these results cannot be extrapolated freely to the clinical situation. Given the scope of the COPD epidemic and the cost of supplemental oxygen therapy a large multicentre clinical trial is warranted.
Exacerbations of COPD Such events are poorly understood in clinical terms and not easily defined in laboratory terms. Patients will often report a change in sputum colour, volume or viscosity accompanied by increased dyspnea. There may or may not be systemic symptoms and signs, such as fever and neutrophilia. Most often chest x-ray films show no focal change. The presumed mechanism of such exacerbations is a viral respiratory tract infection, but other processes must be considered, especially in patients who are elderly and chronically ill. Patients presenting with apparent exacerbations of COPD may have suffered a pulmonary embolism, myocardial infarction, episode of congestive heart failure or perhaps recurrent episodes of gastroesophageal reflux. In addition to considering such possibilities the physician must be alert to iatrogenic causes such as respiratory failure resulting from the unwitting administration of sedatives or ,8-blockers. Continued cigarette smoking may predispose the patient to recurrent episodes of acute on chronic respiratory failure. Exacerbations of COPD are treated with appropriate supplemental oxygen therapy, aggressive bronchodilator therapy, corticosteroids and antibiotics. Supplemental oxygen therapy should be administered carefully, but concerns about worsening respiratory failure due to the abolishment of hypoxic ventilatory drive may be misplaced.55 The rise in the partial pressure of carbon dioxide (Pco2) seen when a patient with COPD is given supplemental oxygen is generally attributed to depression of the hypoxic ventilatory drive. However, some investigators have attributed much of the hypercapnia to the Haldane effect and changes in ventilation-perfusion matching.56 Some studies have suggested that most COPD patients have a higher than normal rather than a blunted drive to breathe.57 Regardless of the mechanism or mechanisms of the hypercapnia, patients must not be kept profoundly hypoxemic for fear that oxygen therapy will induce CO2 retention. Arterial blood must, however, be sampled regularly to monitor the pH and the Pco2, particularly if the patient becomes disoriented or stuporous. Bronchodilators may be administered with the use of either a nebulizer or a metered-dose inhaler with spacing devices.28 Combination therapy AUGUST 15, 1992
with a #2 agonist and an anticholinergic agent would seem reasonable, although the bronchodilator effect with any regimen may be minimal during acute exacerbation.58 The prompt administration of corticosteroids seems to hasten improvements in the FEVy, although no effect on survival has been shown.59 The use of orally administered antibiotics when sputum is purulent also hastens resolution of the event.60 Many of the older antibiotics appear as effective as the newer, more expensive ones. Intravenous aminophylline therapy is controversial; it appears to offer little, if any, added bronchodilator benefit and may cause troublesome side effects.6' Should a patient with COPD who is suffering exacerbation be mechanically ventilated if respiration worsens? Fears that the patient will be difficult to wean from mechanical ventilation discourage many physicians from this course. However, physicians are poor at predicting survival in this setting.62 Most patients suffering an acute reversible process pose little weaning difficulty and may have reasonable functional recovery.63 In contrast, patients presenting with respiratory failure due to an inexorable decline in lung function and those with a recurrent pattern of respiratory failure must be assessed carefully to determine whether there is reasonable hope of recovery after mechanical ventilation.64 The ideal time for such assessment is when the patient is clinically stable and out of hospital.
Compliance Compliance is important in COPD because therapy is administered regularly and for years at a time. Moreover, drugs are often prescribed in combination. At least one report suggested that compliance is poor, approximately half of patients underusing their maintenance drugs.65 More worrisome, particularly if theophylline is prescribed, is the observation that about half of patients will overuse medications at times of exacerbation. Also, the use of a metereddose inhaler may be a problem for some patients. Two steps may be useful in addressing these issues. First, whenever possible regimens should be simplified. For example, the dosage of a single inhaled bronchodilator should be maximized before the addition of a second inhaled agent is considered; many patients will be treated adequately with one. Similarly, patients should receive long-term corticosteroid therapy only if an oral corticosteroid trial has shown objective benefit. Approximately 80% of patients will thus be spared the need for steroid inhalers or tablets. Second, patients should receive some education with their prescribed therapy. Forewarned, patients can avoid such hazards as taking excessive amounts CAN MED ASSOC J 1992; 147 (4)
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of theophylline at times of worsening and can emphysema if there are features to suggest familial improve their care by early self-administration of deficiency, such as emphysema of early onset, simiantibiotics at times of exacerbation. larly afflicted family members or the presence of emphysema without a significant history of cigarette Treatments under investigation smoking. The Canadian Thoracic Society Standards Committee has addressed this issue in detail, calling Mucolytics, though widely used in many Euro- for a national registry of people with a,-antitrypsin pean countries, have shown little objective benefit in deficiency and discouraging the clinical use of proclinical trials.66 Iodinated glycerol has been shown in tein replacement therapy until efficacy is assessed a large trial to be of modest symptomatic benefit in a rigorously through a large-scale, multicentre randomwell-defined group of patients with chronic bronchi- ized controlled trial.7' Noninvasive mechanical ventilatory assistance tiS.67 The importance of this observation is unclear, and the practice has not been adopted widely. Some overnight via a face or nasal mask with positive orally administered mucolytic agents are said to pressure or via cuirass or poncho with negative have a useful antioxidant benefit, an effect of unde- pressure can, in the short term, improve arterial termined clinical importance but perhaps more rele- blood gas tensions in patients with respiratory failure vant to patients who continue to smoke.68 secondary to COPD.7273 These devices may also be Ventilatory stimulants have been studied as of use in avoiding mechanical 'ventilation in some adjunctive therapy for alveolar hypoventilation (al- cases of acute exacerbation. It remains to be seen though, as noted earlier, most COPD patients have whether long-term use of nocturnal ventilatory assisan enhanced ventilatory drive). Agents studied have tance can improve quality of life or reduce the death included the methylxanthines, narcotic antagonists, rate. The most dramatic treatment option in cases of progesterone, acetazolamide and analeptics such as doxapram and almitrine bismesylate. Although sev- severe COPD is lung transplantation. Improved eral of these improve minute ventilation their use is surgical techniques, improved immunosuppressive limited by the potential for adverse effects. The most regimens, early recognition and treatment of rejeceffective agent of this group has been almitrine, tion, and the use of preventive antibiotics have all several studies clearly demonstrating an improve- contributed to the increased success of transplantament in arterial blood gas tensions. Almitrine ap- tion. Overall, a 2-year survival rate of 60% to 70% pears to increase peripheral chemoreceptor sensitivi- can be expected.74 Double-lung transplantation has ty and to improve ventilation-perfusion matching by been performed more frequently, but single-lung enhancing vasoconstriction in underventilated lung transplantation has also been used successfully in segments. However, the latter effect has been shown COPD. Hyperinflation of the native lung with comto increase pulmonary artery pressures with conse- pression of the transplanted lung is still of some quent increased strain on the right ventricle, an concern, although not to the extent originally expectadverse effect outweighing any potential clinical ed.74 This technique above all has the potential for benefit of the drug.69 This agent is not currently "reversing the irreversible," but the prevalence rate available in Canada and may not become so given of COPD and the scarcity of donor lungs would the adverse effects. preclude transplantation for all but a few afflicted For patients with emphysema induced by patients. The current status of lung transplantation is a,-antitrypsin deficiency purified a,-antitrypsin pro- the subject of a Canadian Thoracic Society position tein is available for supplemental administration paper.75 intravenously. This therapy is both costly and cumbersome, and its use is limited solely to patients with Conclusions this type of emphysema. The drug is available by prescription in North America, although it has not Because the dyspnea of COPD may not be been shown conclusively to retard the progress of present until the airways are markedly obstructed, emphysema in deficient patients. Instead, injections early detection is most likely to be achieved through produce blood and alveolar levels of protein that are spirometric screening of high-risk patients. The prithought to be protective on theoretic grounds.70 At a ority of any therapeutic plan for the patient who has cost of approximately $30 000 per year such a series COPD is avoidance of further pulmonary damage. of injections is best undertaken by specialized cen- This makes smoking cessation the necessary first tres after thorough patient assessment and educa- step in a successful treatment strategy. tion. Annual influenza vaccination and vaccination The availability of this protein should encourage against pneumococcal pneumonia may be useful primary care physicians to measure blood levels of supplementary measures. If bronchodilator therapy a,-antitrypsin protein in patients with panlobular is required inhaled agents including anticholinergic 426
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and p2-agonist agents offer the greatest benefit with the fewest side effects. Anticholinergic agents may offer greater benefit in older patients. If combination bronchodilator therapy is needed the order of adding adrenergic agents, theophylline or both is best determined by preference and tolerance. If the condition of a nonsmoking COPD patient has been stabilized with a bronchodilator regimen but disabling symptoms persist the response to oral corticosteroid therapy may be assessed over 2 to 3 weeks by appropriate pulmonary function testing. If, despite such measures, exercise tolerance remains poor and reasonable daily activities are hampered a comprehensive exercise rehabilitation program may be useful. Finally, if despite all other avenues of treatment hypoxemia persists supplemental oxygen therapy remains the only proven way to reduce the death rate. We thank the Canadian Thoracic Society Standards Committee for reviewing this manuscript and providing many helpful suggestions. This study was sponsored by the Canadian Thoracic Society and supported by an educational grant from Boehringer Ingelheim Canada Ltd.
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