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Asthma and COPD: A Comprehensive Review and Implications for Anesthesia

Asthma and COPD: A Comprehensive Review and Implications for Anesthesia. Warner W. Carr, MD Allergy and Asthma Associates of Southern California 949-364-2900 wcarr @allergee.com www.socalallergy.com. Disclosures. CONSULTANCY AstraZeneca Teva MEDA Mylan

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Asthma and COPD: A Comprehensive Review and Implications for Anesthesia

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  1. Asthma and COPD: A Comprehensive Review and Implications for Anesthesia Warner W. Carr, MD Allergy and Asthma Associates of Southern California 949-364-2900 wcarr@allergee.com www.socalallergy.com

  2. Disclosures CONSULTANCY AstraZeneca Teva MEDA Mylan Glenmark Pharmaceutical Sanofi DBV Technologies Optinose Glenmark SPEAKER Regeneron/SanofiGenzyme BoehringerIngelheim TEVA Genzyme Mylan AstraZeneca Research Stallergenes Merck Aimmune 3M TEVA Vectura Watson Menlo Chronic Cough   DBV AstraZeneca Genentech Regeneron Novartis Glenmark

  3. Learning Objectives • Discuss current insights into asthma and COPD pathophysiology. • Review current treatment strategies for Asthma and COPD. • Understand the implications of anesthesia in patients with asthma and COPD. • Discuss tools for assessing control • Discuss strategies for perioperative management

  4. Introduction Asthma is a chronic inflammatory disease. Its clinical hallmarks include Partially or completely reversible airway obstruction Bronchial hyperresponsiveness (BHR) Multiple inflammatory and immune-modulated mechanisms contribute to asthma Persistent inflammation may result in cellular damage and worsening lung function Targeting acute and chronic inflammation is essential to successful asthma management

  5. Pathophysiology of Asthma CD4 + Lymphocyte Asthmatic Airway Inflammation Eosinophils Airway thickening Significant reversibility

  6. Early onset asthma is an allergic disease

  7. Allergy is more than IgE

  8. Asthma involves complex immunologic processes.

  9. Multiple Mechanisms Contribute to Asthma: Inflammatory Mediators Mast Cells Macrophages Eosinophils T-Lymphocytes Epithelial Cells Platelets Neutrophils Myofibroblasts Basophils Bronchoconstriction Mediator Soup Microvascular Leakage Mucus Hypersecretion AirwayHyperresponsiveness Histamine Lipid Mediators* Peptides† Cytokines‡ Growth Factors *For example, prostaglandins and leukotrienes.†For example, bradykinin and tachykinin.‡For example, tumor necrosis factor (TNF). Adapted with permission from Barnes PJ. In: Barnes PJ et al, eds. Asthma: Basic Mechanisms and Clinical Management. 3rd ed. Academic Press; 1998:487-506.

  10. Asthma Is a Chronic Inflammatory Disease: Pathophysiologic Changes Normal Architecture Disrupted Architecture Bronchial Mucosa From a Subject Without Asthma Bronchial Mucosa From a Subject With Mild Asthma Hematoxylin and eosin stain. Photographs courtesy of Nizar N. Jarjour, MD, University of Wisconsin.

  11. Consequences of Persistent Asthma: Progressive Decline in FEV1 120 100 80 FEV1 % Predicted 60 40 n = 89 r = -0.47 20 P<.001 0 10 20 30 40 50 Duration of Asthma (years) FEV1 = forced expiratory volume in 1 second. Adapted with permission from Brown PJ et al. Thorax. 1984;39:131-136.

  12. Asthma Is Prevalent:Significant Morbidity and Mortality 32.6 Million People Have Had an Asthma Diagnosis in Their Lifetime 22.2 Million People Are CurrentlyDiagnosed With Asthma 12.2 Million People Suffer From Asthma Attacks Annually Approximately 4000 Asthma-Related Deaths Occur Annually Approximately 11 People Die From Asthma Each Day Available at: http://www.cdc.gov/nchs/products/pubs/pubd/hestats/asthma03-05/asthma03-05.htm. Accessed February 28, 2007.

  13. How Many of Your Adult Patients Have Inadequately Controlled Eosinophilic Asthma?1-4 24 million people in the US have asthma1 17.7 million of asthma sufferers are adults1 8.9 million are inadequately controlled2 4.5 to 5.9 million adults with severe asthma have persistent large airway tissue eosinophils3 600,000 to 900,000 adults have uncontrolled severe eosinophilic asthma4 1. Centers for Disease Control and Prevention. Asthma fast stats. http://www.cdc.gov/nchs/fastats/asthma.htm. Accessed September 8, 2016. 2. Centers for Disease Control and Prevention. Uncontrolled asthma among persons living with asthma. http://www.cdc.gov/asthma/asthma_stats/uncontrolled_asthma.htm. Accessed September 8, 2016. 3. Wenzel S. Am J Respir Crit Care Med. 2005;172:149-160. 4. McGrath KW, et al. A Am J RespirCrit Care Med. 2012;185(6):612-619.

  14. Diagnosis of asthma • The diagnosis of asthma should be based on: • A history of characteristic symptom patterns • Evidence of variable airflow limitation, from bronchodilator reversibility testing or other tests • Eosinophil count and Total IgE should be checked in all patients • Asthma is usually characterized by airway inflammation and airway hyperresponsiveness.

  15. Diagnosis of asthma – variable airflow limitation • Confirm presence of airflow limitation • Document that FEV1/FVC is reduced (at least once, when FEV1 is low) • FEV1/ FVC ratio is normally >0.75 – 0.80 in healthy adults, and >0.90 in children • Confirm variation in lung function is greater than in healthy individuals • The greater the variation, or the more times variation is seen, the greater probability that the diagnosis is asthma • Excessive bronchodilator reversibility (adults: increase in FEV1 >12% and >200mL; children: increase >12% predicted) • Excessive diurnal variability from 1-2 weeks’ twice-daily PEF monitoring (daily amplitude x 100/daily mean, averaged) • Significant increase in FEV1 or PEF after 4 weeks of controller treatment • If initial testing is negative: • Repeat when patient is symptomatic, or after withholding bronchodilators • Refer for additional tests (especially children ≤5 years, or the elderly)

  16. Typical Spirometric Tracings Normal Volume Flow FEV1 Asthma (after BD) Normal Asthma (before BD) Asthma (after BD) Asthma (before BD) 1 2 3 4 5 6 Volume Time (seconds) Note: Each FEV1 represents the highest of three reproducible measurements

  17. Classifying Asthma Severity and Assessing Asthma Control • In patients not on long-term controller medications • Severity based upon domains of impairment and risk • Level of severity based upon most severe category in which any feature appears • In patients on long-term controller medications • Severity based upon lowest step required to maintain clinical control • Control of asthma based upon domains of impairment and risk • Level of control based upon most severe impairment or risk category • Validated questionnaires may be used in patients aged ≥12 years National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma (EPR-3 2007). U.S. Department of Health and Human Services. Available at: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf. Accessed August 29, 2007.

  18. Persistent Intermittent Components of Severity Mild Moderate Severe Symptoms 2 days/week >2 days/week but not daily Daily Throughout the day Nighttime awakenings 2x/month 3-4x/month >1x/week butnot nightly Often 7x/week SABA use for symptom control (not prevention of EIB) 2 days/week >2 days/weekbut not daily and not more than 1x on any day Daily Several timesper day Impairment Normal FEV1/FVC: 8-19 yr 85% 20-39 yr 80% 40-59 yr 75% 60-80 yr 70% Interference withnormal activity None Minor limitation Some limitation Extremely limited • Normal FEV1 between exacerbations • FEV1 >80% predicted • FEV1/FVC normal • FEV1 >80% predicted • FEV1/FVC normal • FEV1 >60% but <80% predicted • FEV1/FVCreduced 5% • FEV1 <60% predicted • FEV1/FVC reduced >5% Lung Function 0-1/year ≥2/year Exacerbations requiring oral systemic corticosteroids Consider severity and interval since last exacerbationFrequency and severity may fluctuate over time for patients in any severity category Risk Relative annual risk of exacerbations may be related to FEV1 Step 1 Step 2 Step 3 Step 4 or 5 Recommended Stepfor Initiating Treatment and consider short course of oral systemic corticosteroids In 2 to 6 weeks, evaluate level of asthma control that is achieved and adjust therapy accordingly Classifying Asthma Severity and Initiating Treatment in Youths ≥12 Years of Age and Adults EIB = exercise-induced bronchospasm; FEV1 = forced expiratory volume in one second; FVC = forced vital capacity. Adapted from National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma (EPR-3 2007). U.S. Department of Health and Human Services. Available at: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf. Accessed August 29, 2007.

  19. Persistent Asthma: Daily Medication IntermittentAsthma Consult with asthma specialist if Step 4 care or higher is required. Consider consultation at Step 3. Step 6 Preferred:High-dose ICS + LABA + Oral Corticosteroid AND Consider Omalizumab for Patients WhoHave Allergies Step Up If Needed (first, check adherence, environmental control, and comorbid conditions) Step 5 Preferred:High-dose ICS + LABA (B) AND Consider Omalizumabfor PatientsWho HaveAllergies (B) Step 4 Preferred:Medium-dose ICS + LABA (B) Alternative:Medium-dose ICS + eitherLTRA (B), Theophylline (B),or Zileuton (D) Step 3 Preferred: Low-dose ICS + LABA (A)OR Medium-dose ICS (A) Alternative:Low-dose ICS + either LTRA (A), Theophylline (B),or Zileuton (D) Step 2 Preferred:Low-dose ICS (A) Alternative: Cromolyn (A), LTRA (A), Nedocromil (A),orTheophylline (B) Step 1 Preferred:SABA PRN Assess Control Step Down If Possible (and asthma is well controlled at least 3 months) Each Step: Patient education, environmental control, and management of comorbidities Steps 2-4: Consider subcutaneous allergen immunotherapy for patients who have allergic asthma • Quick-Relief Medication for All Patients • SABA as needed for symptoms. Intensity of treatment depends on severity of symptoms: up to 3 treatments at 20-minute intervals as needed. Short course of systemic oral corticosteroids may be needed • Use of SABA >2 days a week for symptom relief (not prevention of EIB) generally indicates inadequate control and the need to step up treatment Stepwise Approach for Managing Asthma in Patients Aged ≥12 Years ICS = inhaled corticosteroids; LABA = long-acting β2-agonist; LTRA = leukotriene receptor antagonist. Adapted from National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma (EPR-3 2007). U.S. Department of Health and Human Services. Available at: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf. Accessed August 29, 2007.

  20. Well Controlled Not Well Controlled Very Poorly Controlled Components of Control Symptoms ≤2 days/week >2 days/week Throughout the day Impairment Nighttime awakenings ≤2x/month 1-3x/week ≥4x/week Interference with normal activity None Some limitation Extremely limited SABA use for symptom control (not prevention of EIB) ≤2 days/week >2 days/week Several times per day FEV1 or peak flow >80% predicted/personal best 60%-80% predicted/personal best <60% predicted/personal best Validated questionnairesATAQACQACT 0≤0.75≥20 1-2≥1.516-19 3-4N/A≤15 0-1/year ≥2/year Exacerbations requiring oral systemic corticosteroids Consider severity and interval since last exacerbation Risk Progressive loss of lung function Evaluation requires long-term follow-up Treatment-related adverse effects Medication side effects can vary in intensity from none to very troublesome and worrisome. The level of intensity does not correlate to specific levels of control but should be considered in the overall assessment of risk • Maintain current step • Regular follow-ups every 1-6 months to maintain control • Consider step down if well controlled for at least 3 months • Step up 1 step and • Reevaluate in 2 to 6 weeks • For side effects, consider alternative treatment options • Consider short course of oral systemic corticosteroids • Step up 1-2 steps, and • Reevaluate in 2 weeks • For side effects, consider alternative treatment options Recommended Actionfor Treatment Assessing Asthma Control and Adjusting Therapy in Youths ≥12 Years of Age and Adults Adapted from National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma (EPR-3 2007). U.S. Department of Health and Human Services. Available at: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf. Accessed August 29, 2007.

  21. Management of severe asthma • Optimize dose of ICS/LABA • Complete resistance to ICS is rare • Consider therapeutic trial of higher dose • Consider low dose maintenance oral corticosteroids • Monitor for and manage side-effects, including osteoporosis • Add-on treatments without phenotyping • Tiotropium - reduces exacerbations (history of exacerbations, age ≥12 years) • Theophylline, LTRA – limited benefit • Phenotype-guided treatment • Severe allergic asthma: add-on omalizumab (anti-IgE) • Severe eosinophilic asthma: add-on anti-IL5 therapy • Sputum-guided treatment to reduce exacerbations and/or steroid dose • Aspirin-exacerbated respiratory disease: consider add-on LTRA • Non-pharmacological interventions • Consider bronchial thermoplasty for selected patients • Comprehensive adherence-promoting program

  22. The “unresponsive” patient with asthma Biologics and Personalized Care • Targets • IGE • Eosinophils and Anti-IL5 • IL-4 and IL-13 • TSLP • Others • Bronchial Thermoplasty

  23. Pathobiology of asthma: complex inflammatory process The Journal of Allergy and Clinical Immunology: In Practice 2015 3, 152-160DOI: (10.1016/j.jaip.2014.09.014)

  24. Asthma Phenotypes

  25. Biologics in Asthma • Omalizumab – Xolair • Anti-IgE • Approved for asthma and urticaria • Eosinophils and anti-IL5 • Mepolizumab- approved • Reslizumab- approved • Benralizumab- approved

  26. Biologics in Asthma • Anti-IL13- failed to reach primary endpoints in phase 3 • Anti IL-4 / IL-13 • Phase 3 for asthma • Approved for atopic dermatitis • Dupilumab

  27. Bronchial Thermoplasty • A radiofrequency controller and a specialized catheter are used to administer thermal energy (target tissue temperature 65 ̊C) to the airway; • reduces the increased mass of airway smooth muscle associated with asthma • Three separate bronchoscopies (moderate sedation), 3 weeks apart.

  28. Bronchial Thermoplasty • All accessible airways distal to the mainstem bronchus (3-10 mm) are treated once • except those in the RML; difficult to access • FDA approved in ≥18 years old, severe asthma, not well-controlled with ICS and LABA

  29. Bronchial Thermoplasty • Criteria: • require intermittent or continuous OCS, • FEV1 ≥50 percent of predicted, • no h/o of life-threatening exacerbation • Risk of immediate increase in exacerbations and hospitalizations • Decrease in asthma exacerbations and utilization over 1-5 years

  30. COPD

  31. Chronic Obstructive Pulmonary Disease (COPD) • COPD is currently the fourth leading cause of death in the world.1 • COPD is projected to be the 3rd leading cause of death by 2020.2 • More than 20 million Americans have COPD1 • COPD prevalence is 6% (females > males) • 12.7 million diagnosed and 12 million undiagnosed • Asthma prevalence is 8% (28 million) - NHANES • More than 3 million people died of COPD in 2012 accounting for 6% of all deaths globally. • Globally, the COPD burden is projected to increase in coming decades because of continued exposure to COPD risk factors and aging of the population. • 1. Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380(9859): 2095-128. • 2. Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med 2006; 3(11): e442.

  32. Impact of COPD • Affects 16 to 30 million in US 1,2– Approximately 1 in 10 Americans over age 65 3 • 110,000 deaths annually • 14 million have primarily chronic bronchitis • Fourth leading cause of death 2 • Annual cost about $32 billion– 75% of direct costs related to exacerbations • Impact of COPD rising while others falling 1. Petty TL. J Respir Dis. 1997;18:365. 2. NHLBI. Morbidity & mortality: chartbook on cardiovascular, lung, and blood diseases. 1998. 3. Mannino DM, et al. Arch Intern Med. 2000;160:1683.

  33. The GOLD Definition of COPD • COPD is a disease state characterized by airflow limitation that is not fully reversible • The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases

  34. Pathophysiology of Asthma CD4 + Lymphocyte Asthmatic Airway Inflammation Eosinophils Airway thickening Significant reversibility

  35. COPD Pathogenesis: Chronic Bronchitis Environmental and Occupational Exposure Childhood Respiratory Infections Genetic Susceptibility (CD8 Lymphocyte) (Macrophage) (Neutrophil) Chronic inflammation / Airflow limitation

  36. Airway Changes of COPD Normal Airway Chronic Bronchitis With permission from Rubin Tuder, MD, Johns Hopkins Medical Institute and Carlyne Cool, MD, National Jewish Medical and Research Center

  37. COPD Pathogenesis: Emphysema Genetic Susceptibility (Neutrophil) (Macrophage) x Protease Inhibitors (Liver) Proteases Tissue Destruction Emphysema

  38. Parenchymal Changes of COPD Normal Lung Parenchymal Changes of Emphysema With permission from Rubin Tuder, MD, Johns Hopkins Medical Institute and Carlyne Cool, MD, National Jewish Medical and Research Center

  39. Assess for COPD Symptoms Cough Sputum Dyspnea Exposure to Risk Factors Tobacco Occupation Indoor/outdoor pollution Spirometry 50% of Lung Function can be lost BEFORE symptoms appear!

  40. Spirometry: A Key to EarlyDetection of COPD • Spirometryis crucial 1,2 • Simple, inexpensive, office-based • Consider every smoker (past and present) • Decline in lung function often not recognized by patient 3 • Patients may be asymptomatic or may unconsciously modify activity to compensate • Early identification and aggressive intervention can improve prognosis 4-6 1. Ferguson GT et al. Chest. 2000;117:1146-1161 2. NLHEP. Chest. 1998;113(suppl):123S-163S. 3. NCAP. J Respir Dis. 2000; 21 (suppl):S5-S21. 4. CDC. MMWR. 1990;39(RR-12):2-10. 5. Anthonisen NR et al. JAMA. 1994;272:1497-1505. 6. Kanner RE. Med Clin North Am. 1996;80:523-547.

  41. Global Obstructive Lung Disease (GOLD)Classification by Severity Stage 0At risk Stage IMild Stage IIModerate Normal spirometryChronicsymptoms (cough, sputum)  FEV1/FVC < 70%; FEV1 ≥ 80% predictedWith or withoutsymptoms (cough, sputum) FEV1/FVC < 70%; 50% ≤ FEV1 < 80% predictedIncreasedshortness of breath and repeated exacerbations which have an impact on patient’squality of life

  42. Global Obstructive Lung Disease (GOLD)Classification by Severity Stage III Severe FEV1/FVC < 70%; 30%< FEV1 < 50% predicted Increased shortness of breath, and repeated exacerbations which have an impact on patients’ quality of life. FEV1/FVC < 70%; FEV1 < 30% predicted Severe airflow limitation or the presence of chronic repiratory failure. Patients may have very severe COPD even if the FEV1 is > 30% if they have appreciably impaired quality of life and life threatening exacerbations. Stage IV Very severe

  43. GOLD Guidelines: Model of Symptom/Risk Evaluation of COPD1 (C) High Risk Less Symptoms ≥2 1 0 4 3 2 1 (D) High Risk More Symptoms Risk GOLD Classification of Airflow Limitation Risk Exacerbation History (A) Low Risk Less Symptoms (B) Low Risk More Symptoms Budesonide/formoterol combination therapy is not indicated for reduction of exacerbations in COPD. 1. Adapted from Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of COPD. Revised 2011. http://www.goldcopd.org/uploads/users/files/GOLD_Report_2011_Feb21.pdf. Accessed June 11, 2012. mMRC ≥2 CAT ≥10 mMRC 0-1 CAT <10 Symptoms mMRC or CAT Score

  44. GOLD Guidelines: Nonpharmacologic Therapy to Manage COPD1 1. Adapted from Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of COPD. Revised 2011. http://www.goldcopd.org/uploads/users/files/GOLD_Report_2011_Feb21.pdf. Accessed June 11, 2012.

  45. GOLD Guidelines: Initial Pharmacologic Therapy to Manage COPD1,a 1. Adapted from Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of COPD. Revised 2011. http://www.goldcopd.org/uploads/users/files/GOLD_Report_2011_Feb21.pdf. Accessed June 11, 2012.

  46. Treatment of Stable COPD

  47. Long-Term Oxygen Therapy Indicated for PaO2 < 55 mm Hg or SaO2 < 88%1 Improves1-4 • Only therapy that improves survival in hypoxemic patients • Cognitive function, affect • Exercise performance • Sleep quality • Activities of daily living 1. NCAP. J Respir Dis. 2000;21(suppl):S5-S21. 2. Report of the Medical Research Council Working Party. Lancet. 1981;681-686. 3. Nocturnal Oxygen Therapy Trial Group. Ann Intern Med. 1980;93:391-398. 4. Bye et al. Am Rev Respir Dis. 1985;132:236-240.

  48. Risk Factors for COPD Smoking is the predominant risk factor1,2 • Implicated in >90% of US patients with COPD Others proposed risk factors include1: • Air pollution • Poor nutrition • Childhood respiratory infections • Preexisting bronchial hyperreactivity • 1-Antitrypsin deficiency (genetic, rare) • Occupational and environmental exposure (eg, coal dust, silica)

  49. Smoking Cessation • Smoking cessation with continued abstinence is the single most effective way to improve clinical outcomes in patients at all stages of COPD, from asymptomatic to severe1-4 • With early smoking cessation, rate of FEV1 decline can return to that seen in nonsmokers 5,6 • 3 or 4 quitting attempts may be necessary for success1 • Decreased smoking slows the decline in FEV16 1. NCAP. J Respir Dis. 2000;21(suppl):S5-S21. 2. CDC. MMWR. 1990;39(RR-12):2-10. 3. Anthonisen NR et al. JAMA. 1994;272:1497-1505. 4. Kanner RE et al. Med Clin North Am. 1996;80:523-547. 5. Fletcher C et al. BMJ. 1977;1:1645-1648. 6. Higgins MW et al. JAMA. 1993;269:2741-2748.

  50. Never smoked or not susceptible to smoke Stopped at 45 y Stopped at 65 y Smoked regularly and susceptible to its effects 100 75 50 25 0 25 50 75 Age-Related Decline in FEV1 isAccelerated in Susceptible Smokers FEV1 (% of value at age 25 y) Disability Death Age (y) Adapted with permission from Fletcher C, Peto R. BMJ. 1977;1:1645-1648.

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