1. Management of acute exacerbations of COPD Pharm D student: Noha Alaa El Dine Supervised by: Prof. Seham Hafez

2. Definition of Acute COPD Exacerbation An exacerbation of chronic obstructive pulmonary disease (COPD) is an acute increase in symptoms beyond normal day-to-day variation. This generally includes an acute increase in one or more of the following cardinal symptoms: Cough increases in frequency and severity Sputum production increases in volume and/or changes character (more purulent) Dyspnea increases Defined by: The Global Initiative for Chronic Obstructive Lung Disease (GOLD)

3. Definition of Acute COPD Exacerbation Constitutional symptoms, an unchanged chest radiograph, a variable decrease in pulmonary function, and tachypnea are typical in acute exacerbations. However, severe cases can lead to respiratory failure and death. Defined by: The Global Initiative for Chronic Obstructive Lung Disease (GOLD)

4. Classification Type III (mild) has one symptom plus at least one of the following: Upper respiratory infection in the past 5 days Fever without another apparent cause Increased wheezing Increased cough Increase in respiratory rate or heart rate by 20% above baseline. Type II (moderate) has two Type I (severe) has all of the three symptoms

5. Based on health-care utilization, an exacerbation can be further classified as: Mild When the patient has an increased need for medication, which he can manage in his own normal environment Moderate When the patient has an increased need for medication and feels the need to seek additional medical assistance Severe When the patient/caregive r recognizes obvious and/or rapid deterioration in condition, requiring hospitalization

6. PRECIPITANTS It is estimated that: 50 to 60 percent of exacerbations are due to respiratory infections (mostly bacterial and viral) 10 percent are due to environmental pollution 30 percent are of unknown etiology Non compliance with medication use & physician orders: Smoking Lack of a pulmonary rehabilitation program Improper use of an inhaler Poor adherence to a drug therapy program

7. RISK FACTORS According to observational studies, the risk of developing an exacerbation of COPD correlates with: Advanced age Productive cough Duration of COPD Antibiotic therapy COPD-related hospitalization within the previous year Chronic mucous hypersecretion Theophylline therapy Having one or more comorbidities (eg, ischemic heart disease, chronic heart failure, or diabetes mellitus). Gastroesophageal reflux disease (GERD) may be an additional risk factor for COPD exacerbations. Additional studies are needed to confirm this observation.

8. TREATMENT GOALS Successful management of acute exacerbations of COPD in either the inpatient or outpatient setting requires attention to a number of key issues: Identifying and ameliorating the cause of the acute exacerbation, if possible Optimizing lung function by administering bronchodilators and other pharmacologic agents Assuring adequate oxygenation and secretion clearance Averting the need for intubation, if possible Preventing complications of immobility, such as thromboemboli and deconditioning Addressing nutritional needs

10. OXYGEN THERAPY Supplemental oxygen is a critical component of acute therapy.oxygen Arterial oxygen tension (PaO 2 ) of 60 to 70 mmHg Oxyhemoglobin saturation of 90 to 94 percent Target

11. PHARMACOLOGIC TREATMENT The major components of managing an acute exacerbation of COPD: Inhaled short-acting bronchodilators (beta adrenergic agonists and anticholinergic agents) Glucocorticoids Antibiotics

12. Beta adrenergic agonists Inhaled short-acting beta adrenergic agonists (eg, albuterol) are the mainstay of therapy for an acute exacerbation of COPD because of their rapid onset of action and efficacy in producing bronchodilation. albuterol Nebulizer Metered dose inhaler (MDI) with a spacer device Administration may be via

13. Many clinicians prefer nebulized therapy on the presumption of more reliable delivery of drug to the airway. We favor nebulized therapy because we find that many patients have difficulty using proper MDI technique in this setting (during acute exacerbations). Beta adrenergic agonists Nebulizer Metered dose inhaler (MDI) with a spacer device Vs Equal efficacy

14. Typical doses of albuterol for this indication are:albuterol Beta adrenergic agonists By Nebulizer: 2.5 mg (diluted to a total of 3 mL) every one to four hours as needed By Metered dose inhaler (MDI) with a spacer device: 4 to 8 puffs (90 mcg per puff) every one to four hours as needed.

15. Beta adrenergic agonists Increasing the dose of nebulized albuterol to 5 mg does not have a significant impact on spirometry or clinical outcomes. Similarly, continuously nebulized beta agonists have not been shown to confer an advantage. Subcutaneous injection of short-acting beta adrenergic agonists is reserved for situations in which inhaled administration is not possible. Parenteral use of these agents results in greater inotropic and chronotropic effects, which may cause arrhythmias or myocardial ischemia in susceptible individuals.

16. Anticholinergic agents Inhaled short-acting anticholinergic agents (eg, ipratropium bromide) are used with inhaled short- acting beta adrenergic agonists to treat exacerbations of COPD. ipratropium This is based on several studies that found that combination therapy produces synergistic bronchodilation in patients with a COPD exacerbation, an asthma exacerbation, or stable COPD. However, this finding has not been universal in patients having an exacerbation of COPD.

17. Typical doses of ipratropium for this indication are:ipratropium Anticholinergic agents By Metered dose inhaler (MDI) with a spacer device: 2 puffs (18 mcg per puff) every four hours as needed. By Nebulizer: 500 mcg every four hours as needed

18. Anticholinergic agents The choice between the two might depend on potential undesirable side effects based on the comorbidity of the patient. Beta adrenergic agonists Choice Anticholinergic agents have a safer and more tolerable side effect profile (tremors, dry mouth, and urinary retention) β 2 -agonists (tremors, headache, nausea, vomiting, palpitations, heart rate, and blood pressure variations). This may be an important point to consider, when deciding which bronchodilator agent to use during an acute exacerbation.

19. Glucocorticoids Systemic glucocorticoid therapy improves: Lung function Treatment success Reducing the length of hospital stay

20. Glucocorticoids Oral — Prednisone (40 to 60 mg orally, once daily) High doses of systemic glucocorticoids increase the risk of side effects. Lower doses (eg, equivalent of 30 to 40 mg of Prednisone) may be equally effective and safe glucocorticoids The duration of systemic glucocorticoid therapy varies from patient to patient and exacerbation to exacerbation. As a rough guide, most exacerbations should be treated with full dose therapy for 7 to 14 days After this time, many pulmonologists taper over about seven days as a trial to see if continued glucocorticoid therapy is required. Tapering solely because of concerns about adrenal suppression is not necessary if the duration of therapy is less than three weeks (a duration too brief to cause adrenal atrophy).

21. Glucocorticoids The efficacy of inhaled glucocorticoids on the course of a COPD exacerbation has not been studied in randomized trials. glucocorticoids Thus, they should not be used as a substitute for systemic glucocorticoid therapy.  Intravenous glucocorticoids should be given to patients who present with a severe exacerbation, whoglucocorticoids respond poorly to oral glucocorticoids, who are vomiting, or who may have impaired absorption due to decreased splanchnic perfusion (eg, patients in shock).  The optimal dose of systemic glucocorticoids for treating a COPD exacerbation is unknown.glucocorticoids  Frequently used regimens include: IV Methylprednisolone (60 to 125 mg, two to four times daily)Methylprednisolone Oral administration is used in most other patients. Oral glucocorticoids are rapidly absorbed (peak serum levels achieved at one hour after ingestion) with virtually complete bioavailability and their efficacy is comparable to that with intravenous therapy.glucocorticoids

22. Most Common Infectious Causes of COPD Exacerbations Mild to moderate exacerbations Streptococcus pneumoniae Haemophilus influenzae Moraxella catarrhalis Chlamydia pneumoniae Mycoplasma pneumoniae Viruses Severe exacerbations Pseudomonas species Other gram-negative enteric bacilli

23. Antibiotics Commonly Used in Patients with COPD Exacerbations Mild to moderate exacerbations* First-line antibiotics Doxycycline (Vibramycin), 100 mg twice daily Trimethoprim-sulfamethoxazole (Septrin DS), one tablet twice daily Amoxicillin-clavulanate potassium(Augmentin), one 500 mg/125 mg tablet three times daily or one 875 mg/125 mg tablet twice daily Macrolides Clarithromycin (Klacid), 500 mg twice daily Azithromycin (Zithromax), 500 mg initially, then 250 mg daily Fluoroquinolones Levofloxacin (Tavanic), 500 mg daily Gatifloxacin (Tequin), 400 mg daily Moxifloxacin (Avalox), 400 mg daily *--For orally administered antibiotics, the usual duration of therapy is five to 10 days.

24. Antibiotics Commonly Used in Patients with COPD Exacerbations Moderate to severe exacerbations (Ý) Cephalosporins Ceftriaxone (Rocephin), 1 to 2 g IV daily Cefotaxime (Claforan), 1 g IV every 8 to 12 hours Ceftazidime (Fortum), 1 to 2 g IV every 8 to 12 hours Antipseudomonal penicillins Piperacillin-tazobactam (Tazocin), 3.375 g IV every 6 hours Ticarcillin-clavulanate potassium (Timentin), 3.1 g IV every 4 to 6 hours Fluoroquinolones Levofloxacin(Tavanic), 500 mg IV daily Gatifloxacin(Tequin), 400 mg IV daily Aminoglycoside Tobramycin (Tobracin), 1 mg per kg IV every 8 to 12 hours, or 5 mg per kg IV daily Ý--Drugs are often used in combination for synergy; IV therapy is usually employed.

25. Mucoactive agents There is little evidence supporting the use of mucoactive agents (eg, N-acetylcysteine) in acute exacerbations of COPD. Some mucoactive agents may worsen bronchospasm.

26. Methylxanthines Aminophylline and theophylline are NOT recommended for the treatment of acute exacerbations of COPD. Aminophyllinetheophylline In addition to lack of efficacy, methylxanthines caused significantly more nausea and vomiting than placebo and trended toward more frequent tremor, palpitations, and arrhythmias.

27. CHEST PHYSIOTHERAPY Mechanical techniques to augment sputum clearance, such as: Directed coughing, Chest physiotherapy with percussion and vibration, Intermittent positive pressure breathing, and postural drainage, have not been shown to be beneficial in COPD and may provoke bronchoconstriction.

28. CHEST PHYSIOTHERAPY Mechanical techniques to augment sputum clearance, such as: Directed coughing, Chest physiotherapy with percussion and vibration, Intermittent positive pressure breathing, and postural drainage, have not been shown to be beneficial in COPD and may provoke bronchoconstriction. Their use in acute exacerbations of COPD is not supported by clinical trials.

29. MECHANICAL VENTILATION Noninvasive ventilation Noninvasive positive pressure ventilation (NPPV) refers to mechanical ventilation delivered through a noninvasive interface, such as a face mask, nasal mask, or nasal prongs. It improves numerous clinical outcomes and is the preferred method of ventilatory support in many patients with an acute exacerbation of COPD. Invasive ventilation Invasive mechanical ventilation should be administered: when patients fail NPPV, do not tolerate NPPV, or have contraindications to NPPV.

30. Management of acute COPD Controlled O 2 therapy Nebulized bronchodilators Steroids Antibiotics Physiotherapy to aid sputum expectoration If no response Repeat nebulizers & consider IV aminophylline If no response Consider NIPPV if RR >30 or pH<7.35 Consider intubation & ventillation if pH <7.26 & Pa CO 2 is rising Consider a respiratory stimulant (doxapram) [Only for patient who are not suitable for mechanical ventillation]

31. PROGNOSIS It is estimated that 14 % of patients admitted for an exacerbation of COPD will die within three months of admission. Even if the acute exacerbation resolves, many patients never return to their baseline level of health.

32. PREVENTION of COPD exacerbation Vaccination, pneumonia and annual flu vaccine (a flu shot can decrease serious illness and death by as much as 50% for patients with COPD).flu vaccine Handwashing Balanced diet Sufficient amount of exercise/activity Adequate sleep Avoiding exposure to environmental irritants such as air pollution (pay attention to air quality alerts) Extreme temperatures Cigarette smoke (including secondhand smoke) Avoid crowds, especially during cold and flu season Pulmonary rehabilitation Proper use of medications (including metered dose inhaler technique)

33. References American Family Physician 2001: “COPD: Management of Acute Exacerbations and Chronic Stable Disease” Clinical Pharmacy & Therapeutics (fourth edition) Curr Opin Pulm Med 9(2):117-124, 2003. “Evidence-Based Approach to Acute Exacerbations of COPD” D. Trendel RN, 2009: “Learn How to Manage and Prevent COPD Exacerbations” Oxford handbook of clinical medicine (seventh edition) Uptodate 2009