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Chronic obstructive pulmonary disease
• A disorder characterized by abnormal tests of expiratory flow that do not change markedly over periods of several months duration (intended to distinguish COPD from asthma).
• The obstruction may be structural or functional.• Bronchial hyperreactivity may be present in patients with COPD as measured by an improvement in airflow following the inhalation of beta-adrenergic agents or worsening after inhalation of methacholine or histamine.
Three disorders are incorporated into COPD:
Emphysema
A condition of the lung characterized by abnormal permanent enlargement of the airspaces distal to the terminal bronchiole, accompanied by destruction of their walls, and without obvious fibrosis
Chronic bronchitis
Chronic or recurrent excess mucus secretion into the bronchial tree occurring on most days for at least three months/year for at least two successive years
Peripheral airways disease
Inflammation of the terminal and respiratory bronchioles, fibrosis of the airway walls, and goblet cell metaplasia. These changes may represent early or preclinical COPD:
• Affects 15,000,000 Americans
• 4th leading cause of death in the US Mortality rate 10 years after diagnosis is 50%
Emphysema
A pathological diagnosis supported by PFTs that characteristically show airflow obstruction, air trapping, and reduced DLCO, thus the diagnosis is made on clinical grounds
Pathogenesis of emphysema
• Intratracheal elastase causes development of experimental emphysema (Gross, 1965)
• a1-antitrypsin deficiency is associated with development of early emphysema Protease-antiprotease theory, Janoff
• Diagnosis of al-protease inhibitor deficiency:
Young individual (<40 years) with progressive dyspnea, severe obstruction on
PFrs, hyperlucent lungs on CXR especially in lower lung fields
Chronic bronchitis
Can occur with or without airflow obstruction (the latter is termed simple chronic bronchitis)
Bronchiectasis
Associated conditions
Infection- responsible for most cases of bronchiectasis Bronchial obstruction
Primary ciliary dyskinesia Cystic fibrosis
Allergic bronchopulmonary aspergillosis Immunodeficiency
a1-antitrypsin inhibitor deficiency Unilateral hyperlucent lung
Bronchopulmonary sequestration Tracheobronchomegaly
Yellow-nails syndrome
Problems in COPD
• Increased resistance to airflow due to narrowing of airways and increased collapsibility of airways
• Increased work of breathing (normally 1 mL 02/liter) that is increased 10-20x in COPDTreatment of COPD
• Indices of clinical improvement
Improvement in spirometric indices
FEV1 or VC improve 0.20 L
Improvement in gas exchange indices
Sympathomimetic Agents
• Most recommended doses may result in less-than-maximal bronchodilation• Potential for inducing hypokalemia must be recognized
• Anticholinergic agents
• Ipatroprium and nebulized atropine have been reported to produce greater bronchodilation than conventional doses of -agonists
• Maximal doses of -agonists probably produce the same degree of bronchodilation
• Ipratropium and a -agonists are equally effective in the treatment of acute exacerbations of COPD
• Neither medication potentiates the action of the other
• Because of its slower onset and longer duration of action it is more suitable for use on a regular basis rather than PRN
Theophylline
• Administration at night decreases overnight decline in FEV1 and morning respiratory symptoms
• May improve respiratory muscle function, mucociliary clearance, central ventilatory drive, and possibly airway inflammation
• Maintain serum concentration of 5-15 ug/mL
Corticosteroids
• Some patients may benefit- it is not possible to predict who a priori
• A closely monitored trial of therapy should be considered in patients who have continuing
symptoms or severe airflow limitation despite maximal therapy with other agents
• Long-term treatment should be prescribed only for patients with documented improvement in airflow or exercise performance and in the lowest possible dose
• Inhaled steroid therapy may be beneficial in patients with COPD
Lung reduction surgery
• Cooper et al, J Thorac Cardiovasc Surg, 199520 patients, avg FEV] 0.77 L (25% predicted), 3 with PaCO2 > 50 mm Hg Median stemotomy, removal of 20-30% of each lung (poorly emptying after anesthesia bag inflation)
No early (6 months) morbidity and mortality 82% improvement in FEV1 39% reduction in RV
Improvement in 6 minute walk, quality of life questionnaire scores
• Sciurba et al, N Engl J Med, 1996
20 patients, avg FEV1 0.87 L (32% predicted)
3-6 months after surgery (thoracoscopy with YAG laser or sternotomy):
FEV1 increases 28%
RV decreases 16%
TLC decreases 6%
Elastic recoil at TLC increases 14%
Lung Transplantation
Living-donor lobar lung transplantation
• Starnes et al, J Thorac Cardiovasc Surg 1996; 112:1284-1291
USC experience, 38 living donor double-lower lobe transplants in 27 adult and 10 pediatric patients (mostly cystic fibrosis)
2000 patients on transplant list- most die waiting transplant
End-stage patients, 6 on ventilators, mean PaCO2 = 69 mm Hg, mean FEV1 = 19% One-year survival 68% (national survival = 73%), good functional status in survivors
In 76 donors, 3 with re-ops, 3 with post-pericardiotomy syndrome
Asthma
"...a disease characterized by an increased responsiveness of the trachea and bronchi to various stimuli manifested by widespread narrowing of the airways that changes in severity either spontaneously or as the result of therapy."
• Prevalence- 5% of population
• Basic characteristics
Airway obstruction that is at least partially reversible either spontaneously or with treatment
Airway hyperresponsiveness to a variety of stimuli
Airway inflammation
Risk factors for asthma
Allergens and atopy
House dust mites
Respiratory infections
Diet
Genetic factors, including race and gender
Passive smoking
• Functional consequences of airway inflammation
Airway hyperresponsiveness
Peak flow variability
Airflow limitation
• Drugs used to treat asthma
Aerosolized corticosteroids (beclomethasone, triamcinolone, flunisolide, budesonide, fluticasone)
First-line drugs for chronic asthma
Proper technique in using MDIs essential- ? need for spacers
Side effects: oral candidiasis, dysphonia
Suppression of hypothalamic-pituitary-adrenal axis with high doses
Can substitute for systemic steroids when high doses (1500-2000 ug/day) are given
Problems with compliance and expense
Systemic corticosteroids Cromolyn and nedocromil
Theophyline Anticholinergic agents Zafirlukast, zileuton, montelukast
Other drugs (methotrexate, troleandomycin, Au salts)
Therapy guidelines
National Asthma Education Program Expert Panel Report 2
National Asthma Education Program - NHLBI, 1997
Mild intermittent:
wheeze/cough/dyspnea up to BIW, brief Sx with activity, nocturnal Sx <2 times/month Rx: agonist via MDI pre exposure or q3-4 hr PRN
Mild persistent:
Sx >2/week but < I/day, nocturnal Sx >2/month
Rx: Inhaled corticosteroids or cromolyn or nedocromil, b2 agonist via MDI PRN to QID. If necessary add theophylline, zafirlukast, zileuton, or montelukast
Moderate persistent:
Daily Sx, daily use of b2 agonist, nocturnal Sx >1/week
Rx: Inhaled corticosteroids (medium doses), b2 agonist via MDI PRN to QID, salmeterol, sustained release theophylline, long acting oral b2 agonist
Severe persistent:
Continuous Sx, limited activity level, frequent exacerbations, frequent nocturnal Sx
Rx: Inhaled corticosteroids (high doses), salmeterol, sustained release theophylline, long acting oral [32 agonist, b2 agonist via MDI [32 agonist via MDI PRN to QID. Systemic corticosteroids (up to 60 mg prednisone daily)
Inhaled steroids and the risk of hospitalization for asthma
(Donahue et al, JAMA 1997; 277: 887-891)
Retrospective cohort study of HMO members in eastern Massachusetts
16,941 people with Dx of asthma
742 hospitalizations for asthma (4.4% of sample)
Relative risk of hospitalization 0.5 in patients prescribed inhaled steroids Increasing 15 agonist use associated with increase risk of hospitalization (RR = 4.3 c/w no b2 agonis0
Inhaled steroids reduced risk in all age groups
Effect of Long-Term Treatment with Salmeterol on Asthma Control
(Wilding et al, BMJ 1997; 314: 1441-1446)
Determine the effect of adding salmeterol 50 ug BID to current Rx in pts with mild to moderate asthma requiring > 400 gg beclomethasone daily
Double blind, randomized crossover study, 101 patients, 6 months per crossover period
Very tight control, vary inhaled steroids depending on PEFR
Salmeterol use associated with:
17% reduction in steroid use
Improved PEFR, FEV1 symptom score
Decreased bronchial hyper-responsiveness to methacholine
No tachyphylaxis to acute administration of albuterol
Oral Montelukast, Inhaled Beclomethasone, and Placebo for Chronic Asthma
(Malmstrom et al, Ann Int Med 1999; 130: 487-495
895 patients with FEV1 50-85% predicted, mild intermittent or mild to moderate persistent asthma Rx'ed with theophylline or PRN b2 agonists
12 week treatment period: montelukast 10 mg OD, beclomethasone MDI 200 ug BID, or placebo
FEV1 change from baseline: 13% beclomethasone, 7% montelukast, 1% placebo Montelukast had faster onset (1 day vs 1 week) and greater initial effect
No Churg-Strauss syndrome seen, small decrease in eosinophilia noted
Acute asthma
Pathophysiology• Lung mechanics
Reduction in expiratory flow due to narrowing of airway caliber in large and small airways
Increase in lung volumes (RV, FRC, TLC) due to closure of small airways in expiration and "breath stacking"
• Gas exchange
Hypoxemia secondary to development of low V/Q regions
Increased Vd/vt (wasted ventilation) due to development of high regions (overventilation
of regions of lung with less severe obstruction to airflow)
Arterial PCO2 initially <40 mm Hg, then "pseudo-normalization," then >40 mm Hg as severity of airflow obstruction increases and respiratory muscle fatigue develops
• Hemodynamics
Development of pulsus paradoxus
Occasionally RV strain and p-pulmonale on EKG