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Palliative Care of Respiratory Symptoms James S. Botts, MD, FACP Southwest Area Medical Director VistaCare.

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1 Palliative Care of Respiratory Symptoms James S. Botts, MD, FACP Southwest Area Medical Director VistaCare

2 2 Outline of Topics… Identification of the Patient with Endstage Pulmonary Disease Dyspnea Cough Pulmonary Infections Hemoptysis Pulmonary Hypertension and Cor pulmonale Primary Pulmonary Hypertension Pulmonary Fibrosis Pulmonary Emboli Stridor Neuromuscular Disorders & Restrictive Pulmonary Disease Bronchiectasis and Cystic Fibrosis α- 1 Antitrypsin Deficiency α- 1 Antitrypsin Deficiency List of Links

3 3 Identification of Endstage Pulmonary Disease No single event or parameter signals end stage  Persistent dyspnea despite optimal medical treatment  Dyspnea impairing efforts to leave home  Increasing number of hospital admissions  Limited improvement after hospitalization  Increasing number of physician visits  Onset of fear, anxiety or panic attacks  Expression of concerns about dying  No reference to oxygen saturation or other parameter of pulmonary function It is difficult to accurately identify those with a prognosis of six months or less 1. Derek, D. et al. (2004). Oxford Textbook of Palliative Medicine, pp. 903

4 4 Identification of Endstage Pulmonary Disease Using CMS LCD pulmonary guidelines  50% of patients qualifying for pulmonary disease will live six months or less (n = 94)*  Pulse rate > 100 has the best correlation with a prognosis of six months or less in patients with endstage pulmonary disease  65.38% of patients meeting the CMS LCD guidelines for pulmonary disease with a pulse rate > 100 will live less than six months (n = 29)* * Hospice Eligibility Evaluation Database (HEED) ; J.S. Botts

5 Palliative Care of Dyspnea Main Menu…

6 6 Palliative Care of Dyspnea Definition of Dyspnea (American Thoracic Society) “A subjective experience of breathing discomfort consisting of qualitatively distinct sensations that vary in intensity. Physiologic, psychologic and environmental factors all may play a role. The severity varies widely among patients.” (2) 2. American Journal of Respiratory and Critical Care Medicine - Jan 1999American Journal of Respiratory and Critical Care Medicine - Jan 1999 ARS-1

7 7 Palliative Care of Dyspnea Correlation of the complaint with the pathology of the underlying disease.  Little correlation in general  Some correlation of the following: “I am drowning.” – Pulmonary edema with CHF “I can’t get enough air in.” – Interstitial disease or pulmonary emboli. (2,3) “Tight”, “Constricted” – a sensation used by those with airways obstruction such as asthma and cystic fibrosis but not COPD 2. Chest. 2005;127: Chest. 2005;127: Excerpt: Chest. 2005;127: Chest. 2005;127:

8 8 The Language of Dyspnea Other studies in the literature have attempted to judge whether or not there are diagnostic clues in the language patients choose to describe their dyspnea or the discomfort they associate with breathing. Mahler et al5 have explored the language that patients with seven different disease states (e.g., asthma, congestive heart failure, interstitial lung disease) use to describe their dyspnea. These authors presented their subjects with a list of 15 descriptors. The investigators then asked each patient to walk along a hospital corridor until he felt an intensity of dyspnea equal to a grade of 3, or moderate, on the Borg scale. Patients were then asked to select those descriptors that best characterized their discomfort after the walk. Of interest, only patients with diagnoses associated with airway obstruction (egg, asthma and cystic fibrosis but not COPD) chose terms that imply tightness, such as "tight" or "constricted," to describe their discomfort. Other terms, such as "work" or "inhalation" were not specific for any diagnostic category. This may make sense from the point of view of the pathophysiology in that asthma and cystic fibrosis, unlike any of the other diagnostic categories, are associated with edema, inflammation, and muscular constriction of the larger airways. The feeling of tightness may be a feeling generated by the stimulation of airway afferents, a physiologic event shared by, and specific to, these two disease entities. A criticism of the work of Mahler et al is, however, that their subjects were asked to choose their words from a list of descriptors that were given to them. In this author’s experience, when patients with asthma are asked to describe their dyspnea using their own words, very few will volunteer a descriptor similar to those given by Mahler et al. Invariably, however, the few patients who do volunteer the word "tight" will have asthma, and the few who volunteer "I can’t breathe in" will have interstitial lung disease or pulmonary emboli. It appears, then, that there is some link between the pathophysiology of a disease and the words that patients choose to describe their discomfort. The fact that very few subjects will use these words, however, should send us another message: that is, it is not reasonable to expect all people, even if they speak the same language, to link the same word or descriptor to a given sensation.5 Chest. 2005;127: << Back

9 9 Midbrain Respiratory Center Respiratory Muscles of Breathing Peripheral Chemoreceptors Aorta and Carotid Arteries Central Chemoreceptors Medulla Mechanoreceptors Lungs and Chest Wall Sensory Cortex Dyspnea Pathophysiology of Dyspnea Emotions Personality Sense levels of oxygen, carbon dioxide and pH of the blood. Sense levels of oxygen, carbon dioxide and pH of the blood. Motor Cortex Sense stretching of structures in lungs and chest wall Corollary Discharge Adapted From: Derek, D. et al. (2004). Oxford Textbook of Palliative Medicine, pp. 898

10 10 Palliative Care of Dyspnea Assessment of Dyspnea Five etiologic categories  Cardiac  Pulmonary  Neuromuscular  Psychiatric / Social / Spiritual  Any combination of the above

11 11 Palliative Care of Dyspnea Assessment of Dyspnea History and Physical Examination  Frequently identifies the specific system responsible for the dyspnea  Indicated diagnostic testing follows

12 12 Palliative Care of Dyspnea Assessment of Dyspnea - Testing Pulmonary Testing  ABG  Chest X-ray  Pulmonary Functions  Bronchial Challenge  High resolution CT  Lung scan  PET  Diaphragmatic Fluoroscopy Cardiac Testing  EKG  Echocardiography  Coronary angiography  Myocardial perfusion scan Other  Sleep studies  Esophageal pH monitoring  Laryngoscopy Often hospice and palliative care patients choose not to be tested, placing more reliance on the history and physical examination.

13 13 Palliative Care of Dyspnea Assessment of Dyspnea Reporting Intensity of Dyspnea  Verbal numerical scales (0-10)  VAS (Visual Analog Scale)  Modified Borg Dyspnea Scale Link to Modified Borg Dyspnea ScaleModified Borg Dyspnea Scale

14 14 Palliative Care of Dyspnea Assessment of Dyspnea Modified Borg Dyspnea Scale Intensity of Sensation Rating Nothing at all 0 Very, very, slight 0.5 Very Slight 1 Slight 2 Moderate 3 Somewhat severe 4 Severe 5 Very Severe 7-8 Very, Very Severe 9 Maximal 10 Derek, D. et al. (2004). Oxford Textbook of Palliative Medicine, pp. 899 << BACKBACK

15 15 Palliative Care of Dyspnea Assessment of Dyspnea Common Physiological Measurements of Respiratory Disease  Spirometry FEV 1 is a POOR predictor of dyspnea and improvements in dyspnea after bronchodilators do not match improvements of FEV 1 (4,5)  Oxygen saturation – with its limitations (6) NOT a good predictor of the subjective feeling of dyspnea 4. Derek, D. et al. (2004). Oxford Textbook of Palliative Medicine, pp Lareau, S.C. et al. (1999).Dyspnea in patients with chronic obstructive pulmonary disease: doesLareau, S.C. et al. (1999).Dyspnea in patients with chronic obstructive pulmonary disease: does dyspnea worsen longitudinally in the presence of declining lung function? Heart & Lung eMedicine - Pulmonary Function Testing : Article by Raed A Dweik, MD, FACP, FCCP, FRCPCeMedicine - Pulmonary Function Testing : Article by Raed A Dweik, MD, FACP, FCCP, FRCPC

16 16 Palliative Care of Dyspnea Treatment – Non-Pharmacologic Influenza and pneumonia vaccines Cold facial stimulation (i.e. fan) (6) Nutrition (7)  Weight gain for malnourished COPD (“pink puffer”) Weight reduction is accompanied by respiratory muscle weakness. Non-fluid weight gain will help correct this Weight gain is difficult to achieve – poor response to nutritional supplements  Weight loss for hypercapnic COPD (“blue bloater”) 6. Am Rev Respir Dis Jul;136(1):58-61Am Rev Respir Dis Jul;136(1): Am Rev Respir Dis Aug;142(2):283-8.Am Rev Respir Dis Aug;142(2):283-8

17 17 Palliative Care of Dyspnea Treatment – Non-Pharmacologic Controlled cough  Deep breath followed by coughing  For clearing secretions Forced expiration – incentive spirometry  Good for prevention and treatment of atelectasis  Follow with controlled cough to clear secretions Emotional, spiritual and social counselling  These issues are important just as they are in the control of pain  Addressing these factors may improve the sensation of dyspnea 8. Derek, D. et al. (2004). Oxford Textbook of Palliative Medicine, pp. 904

18 18 Palliative Care of Dyspnea Treatment – Non-Pharmacologic Exercise (8)  Exercise is the best way to strengthen the respiratory muscles  Methods Walking; stair climbing; Upper extremity and shoulder girdle strengthening  These are accessory muscles of breathing Pulmonary rehabilitation Inspiratory resistance breathing  No better than general reconditioning exercise alone in COPD patients 8. Derek, D. et al. (2004). Oxford Textbook of Palliative Medicine, pp. 904

19 19 Palliative Care of Dyspnea Treatment – Non-Pharmacologic Controlled Breathing (8)  Purse lipped breathing Improves alveolar ventilation and gas exchange  Slow expiration Useful in overcoming associated panic attacks  Bending forward position Improves diaphragmatic function through increasing intraabdominal pressure Helps relieve dyspnea 8. Derek, D. et al. (2004). Oxford Textbook of Palliative Medicine, pp. 904

20 20 Palliative Care of Dyspnea Treatment – Non-Pharmacologic BiPAP (Bilevel Positive Airways Pressure)  Reduces time in ICU  Reduces need for intubation  Reduces mortality in COPD exacerbations  Improves quality of life in ALS patients (64)  Value of BiPAP in a skilled care setting to “rest” the respiratory muscles is uncertain 8. Derek, D. et al. (2004). Oxford Textbook of Palliative Medicine, pp Neurology Jul 22;61(2):171-7Neurology Jul 22;61(2):171-7

21 21 Palliative Care of Dyspnea Treatment – Non-Pharmacologic Summary…  Immediate treatment Cold facial stimulation with a fan Controlled cough Forced expiration Pursed lip breathing Slow expiration Bend forward posture  Non-immediate treatment Vaccinations – influenza & pneumococcal Nutritional assessment and treatment Addressing emotional, social and spiritual issues Exercise – walking; stair climbing; shoulder girdle strengthening

22 22 Palliative Care of Dyspnea Treatment – Pharmacologic Bronchodilators Antiinflammatories Oxygen Anxiolytics Mucolytics Antidepressants Antibiotics ARS-2

23 23 Palliative Care of Dyspnea Treatment – Pharmacologic - Bronchodilators β 2 agonists – in COPD  Do not necessarily improve FEV 1 or FVC  Do improve dyspnea Anticholinergics  Improve FEV 1  Reduce dyspnea Phosphodiesterase Inhibitors  Theophylline Leukotriene Antagonists

24 24 Palliative Care of Dyspnea Treatment – Pharmacologic - Bronchodilators β 2 agonists  In stable COPD Short acting levalbuterol (Xopenex ® ) – In stable COPD patients, no advantage over racemic mixture (albuterol) in prn doses (9) Long acting β 2 agonists salmeterol (Serevent ® ), formoterol (Foradil ® ), arformoterol (Brovana®) 9. Chest Sep;124(3):844-9Chest Sep;124(3):844-9

25 25 Palliative Care of Dyspnea Treatment – Pharmacologic - Bronchodilators Anticholinergics  Short acting – Ipratropium (Atrovent ® )  Long acting Tiotropium (Spiriva ® )  Tiotropium (Spiriva ® ) alone is more effective than long acting β 2 agonists alone in COPD patients (10)  Tiotropium (Spiriva ® ) added to a regimen of a long acting β 2 agonist and a corticosteroid significantly improved dyspnea, FEV 1 and FVC in COPD patients (11)  Comparing tiotropium alone to fluticasone/salmeterol/tiotropium therapy showed no difference in rates of COPD exacerbation but the combination therapy did improve lung function, quality of life, and hospitalization rates in patients with moderate to severe COPD. (11a) 10. Thorax May;58(5): Thorax May;58(5): Respirology Sep;11(5): Respirology Sep;11(5): a. Annals of Internal Medicine April 17; 146( 8): Annals of Internal Medicine April 17; 146( 8):

26 26 Palliative Care of Dyspnea Treatment – Pharmacologic - Bronchodilators Theophylline (12)  A non-selective phosphodiesterase (PDE) inhibitor with antiinflammatory and bronchodilatory effects  Improves dyspnea  Improves FEV 1  24 hour sustained release preparation may be given once before bedtime without disturbing sleep (13)  Is now used less because of narrow therapeutic range and risks of toxicity. ? Resurgence due to antiinflammatory effects and lower serum levels (<10mg/L). (35a)  On the horizon, “Cilomilast and roflumilast are selective PDE4 inhibitors that are currently in pre-registration and phase III clinical trials, respectively, for the treatment of COPD (cilomilast and roflumilast) and for treatment of asthma (roflumilast).” (35) 12. Derek, D. et al. (2004). Oxford Textbook of Palliative Medicine, pp Chest, Vol 110, Chest, Vol 110, Curr Opin Investig Drugs May;7(5):412-7Curr Opin Investig Drugs May;7(5): a. American Journal of Respiratory and Critical Care Medicine Vol pp , (2003)American Journal of Respiratory and Critical Care Medicine Vol pp , (2003)

27 27 Palliative Care of Dyspnea Treatment – Pharmacologic - Bronchodilators Leukotriene Receptor Antagonists  Zafirlukast (Accolade®)– Has bronchodilation effect in COPD and asthma There is no additive effect when added to inhaled steroids (34) May reduce pulmonary hypertension in COPD (35)  Montelukast (Singulair ® ) There is long term benefit in elderly COPD patients with moderate to severe disease (36) 34. Pulm Pharmacol Ther. 2000;13(6):301-5Pulm Pharmacol Ther. 2000;13(6): Chin Med J (Engl) Mar;116(3):459-61Chin Med J (Engl) Mar;116(3): Respir Med Feb;98(2):134-8Respir Med Feb;98(2):134-8

28 28 Palliative Care of Dyspnea Treatment – Pharmacologic - Antiinflammatories Corticosteroids in the treatment of COPD / Dyspnea  Short term oral corticosteroids: Acute exacerbation of COPD  Long term inhaled corticosteroids: Reduces all cause mortality in moderate to severe COPD (14) Not a first line drug in mild COPD (15) Long term oral corticosteroids:  Only in those not responding to inhaled corticosteroids  Sometimes beneficial in hospice patients with malnutrition Identification of those who will benefit from long term use:  Remains controversial  One method:  Check FEV 1 then give a trial of mg prednisone per day for 14 days, then repeat the FEV 1. A ≥ 20% increase indicates the patient will benefit from inhaled steroids (16) 14. Thorax Dec;60(12): Epub 2005 Oct 14Thorax Dec;60(12): Epub 2005 Oct Curr Opin Pulm Med Mar;10(2):113-9Curr Opin Pulm Med Mar;10(2): Derek, D. et al. (2004). Oxford Textbook of Palliative Medicine, pp. 903

29 29 Palliative Care of Dyspnea Treatment – Pharmacologic - Antiinflammatories Nebulized Indomethacin  May be of value in reduction of mucus secretions in bronchiectasis and chronic bronchitis (52,53) Inhibits production of a proteolytic enzyme, neutrophil elastase  May have long term beneficial effect on progression of bronchiectasis  Dyspnea was improved (52) 52. Am Rev Respir Dis Mar;145(3):548-52Am Rev Respir Dis Mar;145(3): Eur Respir J Sep;8(9): Eur Respir J Sep;8(9):

30 30 Palliative Care of Dyspnea Treatment – Pharmacologic - Oxygen Indications  Resting O 2 saturation ≤ 89% with or without dyspnea  Those with dyspnea relieved by O 2 despite the resting oxygen saturation. Studies have shown ↑ survival with use of long term oxygen, as well as improvement in health related quality of life measures including dyspnea (17,18) The level of O 2 saturation does not correlate with the degree of dyspnea (17) 17. Derek, D. et al. (2004). Oxford Textbook of Palliative Medicine, pp Curr Opin Pulm Med Mar;10(2):120-7Curr Opin Pulm Med Mar;10(2):120-7

31 31 Palliative Care of Dyspnea Treatment – Pharmacologic - Oxygen Beware!  Patients on oxygen with high oxygen saturation and confusion or lethargy may have C0 2 retention Treat with discontinuation or reduction in oxygen flow and close observation Titrate to the flow of oxygen that does not cause the confusion or lethargy

32 32 Palliative Care of Dyspnea Treatment – Pharmacologic - Opioids Meta-analysis concludes that opioids in modest doses are effective in treating dyspnea (28) Dose – as little as 2.5 mg of MS q4h (29) Sustained release morphine reduces dyspnea (27) (Don’t start on the sustained release forms.) 27. BMJ Sep 6;327(7414):523-8BMJ Sep 6;327(7414): Thorax Nov;57(11):939-44Thorax Nov;57(11): Derek, D. et al. (2004). Oxford Textbook of Palliative Medicine, pp. 904

33 33 Palliative Care of Dyspnea Treatment – Pharmacologic - Opioids No clear evidence that inhaled morphine is effective in the relief of dyspnea (30) 30. Eur Respir J May;10(5): Eur Respir J May;10(5):

34 34 Palliative Care of Dyspnea Treatment – Pharmacologic - Anxiolytics Benzodiazepines  Scant literature on the use of benzodiazepines in the treatment of dyspnea but they are commonly used (19, 20)  Opioids are first line anxiolytic drugs for dyspnea secondary to advanced disease of any cause (21) 19. Q J Med Winter;49(193):9-20Q J Med Winter;49(193): Am J Hosp Palliat Care Nov-Dec;15(6):322-30Am J Hosp Palliat Care Nov-Dec;15(6): Can Fam Physician Dec;49: Can Fam Physician Dec;49:

35 35 Palliative Care of Dyspnea Treatment – Pharmacologic - Anxiolytics Buspirone (BuSpar ® )  Conflicting reports of its effect on dyspnea (22,23) Concerns about respiratory depression in COPD patients receiving anxiolytics is unfounded. (24) Anxiolytics can be beneficial in some patients with dyspnea, even those without appreciable anxiety. (24) 22. Respiration. 1993;60(4):216-20Respiration. 1993;60(4): Chest Mar;103(3):800-4Chest Mar;103(3): Derek, D. et al. (2004). Oxford Textbook of Palliative Medicine, pp. 904

36 36 Palliative Care of Dyspnea Treatment – Pharmacologic - Mucolytics N-Acetylcysteine (Mucomyst ® ) by mouth or inhalation will help patients with excessive or viscous mucous clear these secretions  Effect on dyspnea has not been studied  Evidence is conflicting as to its reduction of COPD exacerbations (31,32) 31. Lancet Apr 30-May 6;365(9470): Lancet Apr 30-May 6;365(9470): Eur Respir J May;21(5):795-8Eur Respir J May;21(5):795-8

37 37 Palliative Care of Dyspnea Treatment – Pharmacologic - Mucolytics Additional agents that may assist in mucolysis and expectoration of thick sputum:  Normal or hypertonic saline nebulizations  Inhaled mannitol powder (66)  Inhaled atropine  Corticosteroids  β 2 agonists  Indomethacin  Theophylline Glycerol guaiacolate  Of limited value 33. Derek, D. et al. (2004). Oxford Textbook of Palliative Medicine, pp Respirology Jan;10(1):46-56 Respirology Jan;10(1):46-56

38 38 Palliative Care of Dyspnea Treatment – Pharmacologic - Antidepressants SSRIs; Tricyclics – In depressed patients with endstage lung disease  Beneficial for anxiety  Benefit for dyspnea is not conclusive (25,26) 25. Psychosomatics Jan-Feb;39(1):24-9.Psychosomatics Jan-Feb;39(1): Derek, D. et al. (2004). Oxford Textbook of Palliative Medicine, pp. 904

39 39 Palliative Care of Dyspnea Treatment – Pharmacologic - Antibiotics Treatment of Exacerbations  Antibiotics Fluoroquinolones (37,38) Amoxicillin almost as effective and cheaper (39)  Short acting β 2 agonists → long acting  Short acting anticholinergics → long acting  Oral prednisone → Inhaled corticosteroid 37. Clin Microbiol Infect May;12 Suppl 3:42-54Clin Microbiol Infect May;12 Suppl 3: Chest Mar;125(3):953-64Chest Mar;125(3): American Family Physician Vol. 70/No. 4 (August 15, 2004)American Family Physician Vol. 70/No. 4 (August 15, 2004)

40 Palliative Treatment of Cough Main Menu…

41 41 Palliative Care of Cough Assessment Many patients will not want the usual diagnostic tests A thorough history and physical examination is often our best and only tool for assessing the cause of the cough ARS-3

42 42 Palliative Care of Cough Assessment Causes  Acute infections  Chronic Infections  Airways Disease  Cardiovascular  Parenchymal Disease  Irritant  Recurrent Aspiration  Drug Induced  Pleural Disease  Vocal Cord Disease Examples  Pneumonia; Acute Bronchitis  Chronic bronchitis; Bronchiectasis  COPD; Asthma  LV failure; pulmonary edema  Interstitial Fibrosis  GERD; Foreign body  Stroke; Motor neuron disease  ACE Inhibitors; inhaled drugs  Pneumothorax; pleural effusion  Paralysis; nodules on cords 40. Derek, D. et al. (2004). Oxford Textbook of Palliative Medicine, pp. 899

43 43 Palliative Care of Cough Treatment of the Underlying Cause Acute and chronic infections  Antibiotics Asthma and COPD  Bronchodilators and anti- inflammatories Left ventricular failure  Diuretics, ACE inhibitors, ± β- blockers Recurrent aspiration  Postioning of patient; swallowing evaluation → alter food consistency Drug induced (ACE inhibitors)  Discontinue drug Pleural disease  Correct pneumothorax; drain pleural effusion Vocal cord dysfunction  ENT evaluation and treatment GERD  PPIs; metoclopramide; positioning of patient Post-nasal drip  Decongestants; antihistamines 40. Derek, D. et al. (2004). Oxford Textbook of Palliative Medicine, pp. 899

44 44 Palliative Care of Cough Treatment – Protussive and Antitussive Protussive Treatments  Measures to improve cough effectiveness and secretion clearance Antitussive Treatments  Measures to prevent or eliminate cough 40. Derek, D. et al. (2004). Oxford Textbook of Palliative Medicine, pp. 899

45 45 Palliative Care of Cough Treatment – Protussive Treatments Measures to make cough more effective (40)  Adequate hydration – po fluids; steam inhalations; saline nebulizations  Physiotherapy – only in select patients with COPD and bronchiectasis (41) Forced exhalations Airways vibrations Postural drainage Assisted cough techniques 40. Derek, D. et al. (2004). Oxford Textbook of Palliative Medicine, pp Chron Respir Dis. 2006;3(2):83-91Chron Respir Dis. 2006;3(2):83-91

46 46 Palliative Care of Cough Treatment – Protussive Treatments Measures to make cough more effective (40)  Pharyngeal suctioning  Mini-tracheostomy  For thick, excessive, infected sputum Steroids Antibiotics Inhaled mannitol powder or hypertonic saline (42,43) 40. Derek, D. et al. (2004). Oxford Textbook of Palliative Medicine, pp Cochrane Database Syst Rev Jul 20;(3):CD001506Cochrane Database Syst Rev Jul 20;(3):CD J Aerosol Med Fall;15(3):331-41J Aerosol Med Fall;15(3):331-41

47 47 Palliative Care of Cough Treatment – Protussive Treatments Increase of secretion clearance (40,44)  Liquification of secretions N-acetylcysteine Recombinant human DNAse Arginine – not as effective as N-acetylcysteine Uridine-5'-triphosphate – useful for getting sputum samples from mild chronic bronchitics (67)  Bronchodilators β 2 – agonists (albuterol) 40. Derek, D. et al. (2004). Oxford Textbook of Palliative Medicine, pp Expert Opin Pharmacother Feb;5(2):369-77Expert Opin Pharmacother Feb;5(2): Chest Dec;122(6): Chest Dec;122(6):2021-9

48 48 Palliative Care of Cough Treatment – Antitussive Treatments Antitussive Treatment  Used when cough is not reversible  Used primarily for dry non-productive cough Opioids Oral local anesthetics Nebulized local anesthetics Other antitussive agents Antimuscarinics 40. Derek, D. et al. (2004). Oxford Textbook of Palliative Medicine, pp. 900

49 49 ACP Medicine 2006 Antitussive Treatment of Cough ARS-4

50 50 Palliative Care of Cough Treatment – Antitussive Treatments Opioids  Morphine is the strongest antitussive (47) Useful especially in the terminal patient  Codeine is used widely In its OTC form codeine has no more antitussive effect than the demulcent vehicle (47)  Dextromethorphan – an opioid derivative No analgesic effect in antitussive doses As effective as codeine for cough suppression 45. Chest Jan;129(1 Suppl):284S-286SChest Jan;129(1 Suppl):284S-286S 46. Pulm Pharmacol Ther. 2004;17(6):459-62Pulm Pharmacol Ther. 2004;17(6): Thorax May;59(5):438-40Thorax May;59(5): Chest Jan;129(1 Suppl):284S-286SChest Jan;129(1 Suppl):284S-286S 46. Pulm Pharmacol Ther. 2004;17(6):459-62Pulm Pharmacol Ther. 2004;17(6): Thorax May;59(5):438-40Thorax May;59(5):438-40

51 51 Palliative Care of Cough Treatment – Antitussive Treatments Oral Local Anesthetics  Benzonatate (Tessalon Perles ® ) Peripheral acting / opiates largely central acting Often effective in opiate resistant cough (47)  Levodropropizine – not available in USA Widely used in Europe Peripheral acting and useful in cancer related cough (47) 45. Chest Jan;129(1 Suppl):284S-286SChest Jan;129(1 Suppl):284S-286S 46. Pulm Pharmacol Ther. 2004;17(6):459-62Pulm Pharmacol Ther. 2004;17(6): Thorax May;59(5):438-40Thorax May;59(5):438-40

52 52 Palliative Care of Cough Treatment – Antitussive Treatments Nebulized Local Anesthetics  Risk is aspiration 2-4 hours after a treatment Patient should not eat or drink for 1 hour after Rx  Nebulized lidocaine is effective in reduction of cough (48, 49) (5mg/kg in normal saline)  Bupivacaine and Lidocaine have been associated with bronchoconstriction in patients with reactive airways. Consider giving with salmeterol (50) 48. Am J Emerg Med May;19(3):206-7Am J Emerg Med May;19(3): Emerg Med J Jun;22(6):429-32Emerg Med J Jun;22(6): Canadian Family Physician. May 2002Canadian Family Physician. May 2002

53 53 Palliative Care of Cough Treatment – Antitussive Treatments Other Antitussive Agents  If cause is bronchospasm, inflammation, or tumor… Theophylline β 2 –agonists Anti-inflammatories  Steroids  Sodium cromoglycate 40. Derek, D. et al. (2004). Oxford Textbook of Palliative Medicine, pp. 901

54 54 Palliative Care of Cough Treatment – Antitussive Treatments Other Antitussive Agents  OTC Marketed as Antitussive but Not Proven Effective Pseudoephedrine Dexbrompheniramine Guaifenesin 40. Derek, D. et al. (2004). Oxford Textbook of Palliative Medicine, pp. 901

55 55 Palliative Care of Cough Treatment – Antitussive Treatments Antimuscarinics  Ipratropium bromide Good in chronic bronchitis  Reduces secretions without reduction in mucus viscosity  Hyoscine.2-.4mg sc prn or Glycopyrronium bromide.2-.4 mg IM prn Good for the death rattle and associated cough May cause ataxia and hallucinations in the elderly 40. Derek, D. et al. (2004). Oxford Textbook of Palliative Medicine, pp. 901

56 56 Palliative Care of Cough Treatment – Antitussive Treatments Antimuscarinics (68)  Ophthalmic Atropine 1% drops Give sublingually or po  Scopolamine Patch ® Hyoscine in a patch Not effective for about 12 hours 68. AAHPC Fast Fact and Concept #109: Death rattle and oral secretionsAAHPC Fast Fact and Concept #109: Death rattle and oral secretions

57 Palliative Care of Respiratory Infections Main Menu…

58 58 Palliative Care of Respiratory Infections Treatment – Establishing Goals Above all - goals must be discussed and formulated with the patient and family  The patient or POA may ultimately decide against antibiotic therapy If antibiotics are not chosen as a treatment, symptomatic treatment of fever, dyspnea and cough should be the plan

59 59 Palliative Care of Respiratory Infections Treatment – Antibiotic Selection COPD with FEV 1 < 50% (Most hospice patients with end stage lung disease) exacerbations should be treated with a quinolone COPD with FEV 1 > 50% use ampicillin, tetracycline or trimethoprim/sulfa 51. ACP Medicine Chapter 14:Respiratory Medicine: III Chronic Obstructive Disease of the Lung

60 60 Palliative Care of Respiratory Infections Treatment – Antibiotic Selection Bronchiectasis and Cystic Fibrosis  Coverage of anaerobic bacteria and pseudomonas are important  Antibiotics should be given in high doses, sometimes rotated and for 3-4 week courses Ciprofloxacin Metronidazole Augmentin 40. Derek, D. et al. (2004). Oxford Textbook of Palliative Medicine, pp. 901

61 61 Palliative Care of Respiratory Infections Treatment – Antibiotic Selection Bronchiectasis and Cystic Fibrosis  Nebulized antibiotics Gentamicin (300 mg bid) Tobramycin (300 mg bid) 40. Derek, D. et al. (2004). Oxford Textbook of Palliative Medicine, pp. 901

62 Palliative Care of Hemoptysis Main Menu…

63 63 Palliative Treatment of Hemoptysis Assessment Majority of cases are mild to moderate 500 cc per day) Most common causes  Infection ~ 80% TB Abscesses Bronchiectasis  Malignancy ~ 20% 40. Derek, D. et al. (2004). Oxford Textbook of Palliative Medicine, pp. 901

64 64 Palliative Treatment of Hemoptysis Assessment History and Physical Examination Examination of the sputum  Presence of food particles Hematemesis T/E fistula  Purulent sputum Infection Laboratory and X-Ray Studies  Chest x-ray  CT with contrast  Bronchial artery or pulmonary artery arteriogram 40. Derek, D. et al. (2004). Oxford Textbook of Palliative Medicine, pp. 901

65 65 Palliative Treatment of Hemoptysis Treatment - Anticipatory Anticipation - If resuscitation is or is not the goal  Education of patient, family and caregivers  Goals must be established  Dark colored towels  Morphine  Anxiolytics Lorazepam Diazepam Midazolam 40. Derek, D. et al. (2004). Oxford Textbook of Palliative Medicine, pp. 901

66 66 Palliative Treatment of Hemoptysis Treatment of Massive Hemoptysis If resuscitation is the goal…  Patent airway + oxygen Intubation and ventilation if needed  Position Lateral decubitus  Head down  Bleeding lung down  Determine the site of bleeding  Avoid excessive manipulation  Cough suppression (codeine mg po q6h) 40. Derek, D. et al. (2004). Oxford Textbook of Palliative Medicine, pp. 901

67 67 Palliative Treatment of Hemoptysis Treatment of Massive Hemoptysis – Goal Resuscitation If resuscitation is the goal…(continued)  Immediate bronchoscopy If source identified, lavage with iced saline and adrenalin (10cc of 1:10,000 dilution) Topical thrombin Balloon catheter tamponade Vasopressin Bronchial stent placement  If source not found CT with contrast Bronchial or pulmonary angiography 40. Derek, D. et al. (2004). Oxford Textbook of Palliative Medicine, pp. 901

68 68 Palliative Treatment of Hemoptysis Treatment of Massive Hemoptysis – Goal Resuscitation If resuscitation is the goal…(continued)  Bronchial arterial embolization Successful in % of cases Especially good in those with dilated bronchial arteries (bronchiectasis) Complications  Rebleeding - common  Anterior spinal artery infarction and paraplegia – 5%  Ischemic necrosis of the bronchus  Arterial dissection  Surgical resection of the bleeding tissue 40. Derek, D. et al. (2004). Oxford Textbook of Palliative Medicine, pp. 901

69 Palliative Care of Pulmonary Hypertension and Cor Pulmonale Main Menu…

70 70 Palliative Care of Pulmonary Hypertension and Cor Pulmonale Clinical Manifestations  Dependent edema  Right ventricular hypertrophy  Right ventricular dilatation ARS-5

71 71 Palliative Care of Pulmonary Hypertension and Cor Pulmonale Etiology and Pathophysiology Most chronic pulmonary diseases can ultimately cause pulmonary hypertension and cor pulmonale Pathophysiology (56)  COPD – severe pulmonary hypertension only in a small percentage of COPD patients Hypoxia → constriction of pulmonary arterial vasculature – However…  Poor correlation between arterial p0 2 and pulmonary artery pressure in COPD Chronic inflammation Repeated hyperinflation of the lungs Cigarette smoking  Pulmonary Emboli and Pulmonary Fibrosis Obstruction of the pulmonary vasculature  Primary Pulmonary Hypertension Etiology unknown 40. Derek, D. et al. (2004). Oxford Textbook of Palliative Medicine, pp The Proceedings of the American Thoracic Society 2:20-22 (2005)The Proceedings of the American Thoracic Society 2:20-22 (2005)

72 72 Palliative Care of Pulmonary Hypertension and Cor Pulmonale Pathophysiology Pathophysiology of Edema in COPD  Exercise →  ↑ right ventricular end diastolic pressure →  ↑ stretching of the right atrium →  ↑ sympathetic tone →  ↑ renin angiotensin aldosterone production →  ↑ renal distal tubular retention of water and sodium →  ↑ edema (56)  C0 2 retention →  ↑ renal proximal tubular sodium retention →  ↑ edema 56. The Proceedings of the American Thoracic Society 2:20-22 (2005)The Proceedings of the American Thoracic Society 2:20-22 (2005)

73 73 Palliative Care of Pulmonary Hypertension and Cor Pulmonale Treatment Treat the underlying pulmonary disease Oxygen  Long term oxygen therapy in COPD Only produces a small decrease in pulmonary artery pressure  In acute exacerbations of COPD Delivered with BiPAP, reduces pulmonary artery pressure 40. Derek, D. et al. (2004). Oxford Textbook of Palliative Medicine, pp. 909

74 74 Palliative Care of Pulmonary Hypertension and Cor Pulmonale Treatment β 2 – agonists  Reduce pulmonary artery pressure  Increase right ventricular ejection fraction Diuretics – the primary treatment of edema  Edema is secondary to – Hypoxic renal dysfunction Excessive release of pituitary hormones Not caused by right heart failure Caution: hypochloremic alkalosis → ↓ ventilation and C0 2 retention Calcium Channel Blockers  Only short term effect on pulmonary hypertension  May produce ventilation-perfusion mismatch and worsen oxygen saturation  May produce systemic hypotension 40. Derek, D. et al. (2004). Oxford Textbook of Palliative Medicine, pp. 909

75 75 Palliative Care of Pulmonary Hypertension and Cor Pulmonale Treatment ACE Inhibitors  Cause systemic hypotension  No improvement in pulmonary vascular resistance, gas exchange or ventilatory parameters 40. Derek, D. et al. (2004). Oxford Textbook of Palliative Medicine, pp. 909

76 Palliative Care of Primary Pulmonary Hypertension Main Menu…

77 77 Palliative Care of Primary Pulmonary Hypertension Treatment Endothelin antagonists  Bosentan (Tracleer ® ) (57) – Oral endothelin receptor blocker Mild improvement in dyspnea 36 meter increase in 6 minute walking distance  Approved for use in pulmonary arterial hypertension May be used in patients with COPD and severe pulmonary hypertension, but these patients are difficult to identify in an end of life setting. Clinical trials are ongoing. (58) Caution – Numerous drug interactions 57. U.S. Pharmacist Vol. No: 30:05 Posted: 5/16/05U.S. Pharmacist Vol. No: 30:05 Posted: 5/16/ Curr Opin Pulm Med Mar;9(2):139-43Curr Opin Pulm Med Mar;9(2):139-43

78 78 Palliative Care of Primary Pulmonary Hypertension Treatment Prostacyclin Analogs  Epoprostenol (Flolan ® ) and Treprostinil (Remodulin ® ) Improves exercise tolerance Must be given as a continuous infusion  Iloprost (Ventavis ® ) Inhaled Improves exercise tolerance  Beraprost – Not available in USA Inhaled Improvement in symptoms 57. U.S. Pharmacist Vol. No: 30:05 Posted: 5/16/05U.S. Pharmacist Vol. No: 30:05 Posted: 5/16/05

79 79 Palliative Care of Primary Pulmonary Hypertension Treatment Phosphodiesterase V Inhibitors  Sildenafil (Viagra ® ) Improves exercise tolerance Other phosphodiesterase V inhibitors are being evaluated  Tadalafil (Cialis ® ) – only once daily dosing Anticoagulants  Warfarin – To prevent microthrombi formation in pulmonary circulation To prevent thrombophlebitis in the lower extremities Keep INR at Reduces progression of the disease and those symptoms that will worsen with progression of the disease 57. U.S. Pharmacist Vol. No: 30:05 Posted: 5/16/05U.S. Pharmacist Vol. No: 30:05 Posted: 5/16/05

80 Palliative Care of Pulmonary Fibrosis Main Menu…

81 81 Palliative Care of Pulmonary Fibrosis Treatment Pneumoconioses – Most Common Cause Idiopathic Pulmonary Fibrosis  Treatment with interferon gamma-1b Conflicting evidence of effectiveness (59,60) Metaanalysis suggests it does prolong life ( 61) In general pulmonary fibrosis patients do not retain CO 2  High flows of oxygen may be used 59. Mayo Clin Proc Sep;78(9):1082-7Mayo Clin Proc Sep;78(9): Ann Pharmacother Oct;39(10): Epub 2005 Sep 13Ann Pharmacother Oct;39(10): Epub 2005 Sep Chest Jul;128(1):203-6Chest Jul;128(1):203-6

82 Palliative Care of Pulmonary Emboli Main Menu…

83 83 Palliative Care of Pulmonary Emboli Most deaths from PE are a result of inadequate prophylaxis Which end of life patients should receive prophylaxis?  End stage cardiopulmonary patients  Cancer patients with prothrombotic tumors  Minimal data on prophylactic treatment VTE in end of life outpatients

84 84 Palliative Care of Pulmonary Emboli Current VTE Prophylaxis  Hydration  Not crossing legs  Traditional stockings probably not effective  Encouraging mobility  Drug therapy Low molecular weight heparin is preferred  No prothrombin time needed  Once daily injection Warfarin  INR should be 2-3  Difficult to regulate in the end of life patient because of other drug therapies and fluctuating liver functions

85 85 Palliative Care of Pulmonary Emboli On the horizon…  Ximelagatran Oral medication As effective as low dose warfarin with enoxaparin Not yet approved because of potential hepatotoxicity and ↑ incidence of coronary events  Idraparinux Once weekly injection In phase III trials 62. Semin Vasc Med Aug;5(3):276-84Semin Vasc Med Aug;5(3):276-84

86 Palliative Care of Stridor Main Menu…

87 87 Palliative Treatment of Stridor Causes  Infection – epiglottitis, diphtheria  Tumor  Aspirated objects Thick sputum Blood clots Foreign bodies Dislodged tumor particles  Crohn's Disease – rare – resistant to dexamethasone (54)  Diffuse Idiopathic Skeletal Hyperostosis (DISH) Forestier’s Disease – from large cervical spine osteophytes compressing the trachea (55)  Achalasia – megaesophagus compression of trachea (56)  Myasthenia gravis – presenting with exertional stridor (57)  Psychogenic stridor (58)  Drug hypersensitivity – amphotericin (60) 40. Derek, D. et al. (2004). Oxford Textbook of Palliative Medicine, pp Chest Aug;130(2):579-81Chest Aug;130(2): J Laryngol Otol Jan;113(1):65-7J Laryngol Otol Jan;113(1): Eur J Gastroenterol Hepatol Nov;9(11):1125-8Eur J Gastroenterol Hepatol Nov;9(11): Thorax Jan;51(1):108-9Thorax Jan;51(1): Gen Hosp Psychiatry May;16(3):213-23Gen Hosp Psychiatry May;16(3): Ann Allergy Asthma Immunol Nov;91(5):460-6Ann Allergy Asthma Immunol Nov;91(5):460-6

88 88 Palliative Treatment of Stridor Treatment – Non-pharmacologic and Pharmacologic Treatment  Postural manipulation  Heimlich maneuver – for acute onset stridor  Physiotherapy  Bronchoscopy or laryngoscopy  Tracheostomy  Stents  Medications Dexamethasone 16 mg po qd for edema or inflammation Oxygen / Helium 4:1 Mixture Infliximab – for Crohn’s Disease (54) 40. Derek, D. et al. (2004). Oxford Textbook of Palliative Medicine, pp Chest Aug;130(2):579-81Chest Aug;130(2):579-81

89 Palliative Care of Neuromuscular and Restrictive Pulmonary Disorders Main Menu…

90 90 Palliative Care of Neuromuscular Disorders and Restrictive Pulmonary Disease Hypercapnia and sleep disorders are very common in neuromuscular disorders MS and ALS – bulbar disorders result in dysphagia and frequent aspiration and pneumonia Long term anticoagulation is often prescribed for thromboembolic prophylaxis Glossopharyngeal breathing is a good technique to improve ventilation in patients with high cervical injuries

91 91 Palliative Care of Neuromuscular Disorders and Restrictive Pulmonary Disease Non-invasive mechanical ventilation  Rocking beds  Abdominal pneumatic belts  Negative pressure ventilators  Nasal CPAP

92 Palliative Care of Bronchiectasis and Cystic Fibrosis Main Menu…

93 93 Palliative Care of Bronchiectasis and Pulmonary Fibrosis Nebulized Deoxyribonuclease (DNAse)  Hydrolysis of extranuclear DNA that accumulates with neutrophil degradation in infected airways Useful in cystic fibrosis and to a lesser extent in bronchiectasis 40. Derek, D. et al. (2004). Oxford Textbook of Palliative Medicine, pp. 908

94 Palliative Care of α -1 Antitrypsin Deficiency Main Menu…

95 95 Palliative Care of α -1 Antitrypsin Deficiency “AAT replacement therapy is for enzyme deficient patients with impaired FEV-1 (35- 65% of predicted value), who have quit smoking and are on optimal medical therapy but continue to show a rapid decline in FEV-1 after a period of observation of at least 18 months.” (63) 63. Treat Respir Med. 2005;4(1):1-8Treat Respir Med. 2005;4(1):1-8

96 96 Happy Trails from Lea County, NM

97 97 Links - 1 Spiriva Cost Spiriva vs. Serevent Respiratory Sep;11(5): Respiratory Sep;11(5): Is a long-acting inhaled bronchodilator the first agent to use in stable chronic obstructive pulmonary disease? Emerging drugs for the treatment of chronic obstructive pulmonary disease. Pharmacologic treatment of chronic obstructive pulmonary disease: past, present, and future. Names of leukotriene related drugs Effect of Intravenous Magnesium Sulfate on Chronic Obstructive Pulmonary Disease Addition of anticholinergic solution prolongs bronchodilator effect of beta 2 agonists Comparison of the bronchodilating effect of salmeterol and zafirlukast in combination Retrospective evaluation of systemic corticosteroids for the management of acute exacerbations Efficacy and safety of inhaled corticosteroids in patients with COPD Roflumilast for the treatment of chronic obstructive pulmonary disease Corticosteroids and Chronic Obstructive Pulmonary Disease Theophylline in chronic obstructive pulmonary disease: new horizons. Corticosteroid resistance in chronic obstructive pulmonary disease: inactivation of histone deacetylase. Inhaled corticosteroids and mortality in chronic obstructive pulmonary disease. Inhaled corticosteroids in chronic obstructive pulmonary disease: is there a long-term benefit? Health-related quality of life in individuals with chronic obstructive pulmonary disease. Improving health-related quality of life in chronic obstructive pulmonary disease.

98 98 Links - 2 Diazepam in the treatment of dyspnea in the 'Pink Puffer' syndrome. The palliation of dyspnea in terminal disease More research needed The palliation of dyspnea in terminal disease An approach to dyspnea in advanced disease. Opioids are first line drugs An approach to dyspnea in advanced disease. Buspirone effect on breathlessness and exercise performance in patients with chronic obstructive pulmonary disease. Buspirone effect on breathlessness and exercise performance in patients with chronic obstructive pulmonary disease. Effects of buspirone on anxiety levels and exercise tolerance in patients with chronic airflow obstruction and mild anxiety. Effects of buspirone on anxiety levels and exercise tolerance in patients with chronic airflow obstruction and mild anxiety. Sertraline effects on dyspnea in patients with obstructive airways disease Randomized, double blind, placebo controlled crossover trial of sustained release morphine for the management of refractory dyspnea Randomized, double blind, placebo controlled crossover trial of sustained release morphine for the management of refractory dyspnea A systematic review of the use of opioids in the management of dyspnea Disabling dyspnea in patients with advanced disease: lack of effect of nebulized morphine Roflumilast for the treatment of chronic obstructive pulmonary disease Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomized placebo-controlled trial Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomized placebo-controlled trial N-acetylcysteine reduces the risk of re-hospitalization among patients with chronic obstructive pulmonary disease Short-term effects of montelukast in stable patients with moderate to severe COPD Therapeutic responses in asthma and COPD. Bronchodilators Review of effects of PDE4 Inhibitors and LRAs Therapeutic responses in asthma and COPD. Bronchodilators Long-term montelukast therapy in moderate to severe COPD--a preliminary observation Current and future pharmacologic therapy of exacerbations in chronic obstructive pulmonary disease and asthma. Should patients with acute exacerbation of chronic bronchitis be treated with antibiotics? Advantages of the use of fluoroquinolones. Should patients with acute exacerbation of chronic bronchitis be treated with antibiotics? Advantages of the use of fluoroquinolones.

99 99 Links - 3 Short-term and long-term outcomes of moxifloxacin compared to standard antibiotic treatment in acute exacerbations of chronic bronchitis Short-term and long-term outcomes of moxifloxacin compared to standard antibiotic treatment in acute exacerbations of chronic bronchitis Moxifloxacin vs. Alternatives for Chronic Bronchitis Palliative Home Care for Advanced Lung Disease Is there a role for airway clearance techniques in chronic obstructive pulmonary disease? Nebulized hypertonic saline for cystic fibrosis Osmotic stimuli increase clearance of mucus in patients with mucociliary dysfunction Potential future therapies for the management of cough: ACCP evidence-based clinical practice guidelines Potential new cough therapies. Potential new cough therapies Current and future drugs for the treatment of chronic cough Comparison of lidocaine and bronchodilator inhalation treatments for cough suppression in patients with chronic obstructive pulmonary disease. Comparison of lidocaine and bronchodilator inhalation treatments for cough suppression in patients with chronic obstructive pulmonary disease. Lidocaine inhalation for cough suppression Effect of indomethacin on bronchorrhea in patients with chronic bronchitis, diffuse panbronchiolitis, or bronchiectasis Effect of indomethacin on bronchorrhea in patients with chronic bronchitis, diffuse panbronchiolitis, or bronchiectasis In vivo study of indomethacin in bronchiectasis: effect on neutrophil function and lung secretion Stridor in Crohn disease and the use of infliximab

100 100 Links - 4 An unusual case of stridor due to osteophytes of the cervical spine: (Forestier's disease). Myasthenia gravis presenting with stridor Achalasia presenting as acute stridor Psychogenic stridor Amphotericin-induced stridor: a review of stridor, amphotericin preparations, and their immunoregulatory effects Use of the Dumon Y-stent in the management of malignant disease involving the carina: a retrospective review of 86 patients Use of the Dumon Y-stent in the management of malignant disease involving the carina: a retrospective review of 86 patients Thoracic embolotherapy for life-threatening hemoptysis: a pulmonologists perspective Bronchial and non bronchial systemic artery embolization for life-threatening hemoptysis: a comprehensive review Pulmonary hypertension and right heart failure in chronic obstructive pulmonary disease Advances in the treatment of secondary pulmonary hypertension Overview of treprostinil sodium for the treatment of pulmonary arterial hypertension Sildenafil for pulmonary hypertension Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide Treatment of Pulmonary Hypertension Interferon gamma-1b as therapy for idiopathic pulmonary fibrosis. An intra-patient analysis. Interferon gamma-1b therapy for advanced idiopathic pulmonary fibrosis Interferon gamma-1b in the treatment of idiopathic pulmonary fibrosis Interferon-gamma1b therapy in idiopathic pulmonary fibrosis: a metaanalysis Emphysema in alpha1-antitrypsin deficiency: does replacement therapy affect outcome? Ximelagatran vs low-molecular-weight heparin and warfarin for the treatment of deep vein thrombosis: a randomized trial. Ximelagatran vs low-molecular-weight heparin and warfarin for the treatment of deep vein thrombosis: a randomized trial.

101 101 Links - 5 Is long-term low-molecular-weight heparin acceptable to palliative care patients in the treatment of cancer related venous thromboembolism? A qualitative study. Is long-term low-molecular-weight heparin acceptable to palliative care patients in the treatment of cancer related venous thromboembolism? A qualitative study. Acceptability of low molecular weight heparin thromboprophylaxis for inpatients receiving palliative care: qualitative study. Acceptability of low molecular weight heparin thromboprophylaxis for inpatients receiving palliative care: qualitative study. Treating patients with venous thromboembolism: initial strategies and long-term secondary prevention. Inhaled mannitol for the treatment of mucociliary dysfunction in patients with bronchiectasis: effect on lung function, health status and sputum. Inhaled mannitol for the treatment of mucociliary dysfunction in patients with bronchiectasis: effect on lung function, health status and sputum. Improved sputum expectoration following a single dose of INS316 in patients with chronic bronchitis.


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