DR. ESAU ESPAÑA MORALES NEUMÓLOGO GUATEMALA, 04-08-2016 Exacerbación de EPOC DR. ESAU ESPAÑA MORALES NEUMÓLOGO GUATEMALA, 04-08-2016

Enfermedad Pulmonar Obstructiva Crónica La Enfermedad Pulmonar Obstructiva Crónica afecta a 210 millones de personas en el mundo y se prevé que será la tercera causa de muerte en 2020

Contenido Definición y síntomas Epidemiologia e impacto Etiología Inflamación antes y durante la exacerbación Prevención Tratamiento. 4

Definición "Un evento en el curso natural de la enfermedad que se caracteriza por un cambio de la disnea basal del paciente, tos y / o esputo que está más allá de las variaciones normales día a día, es de inicio agudo, y puede provocar un cambio en los medicamentos ordinarios en un paciente con EPOC . " Speaker Notes An exacerbation of COPD is defined as an event in the natural course of the disease characterised by a change in the “An event in the natural course of the disease characterised by a change in the patient’s baseline dyspnoea, cough, and/or sputum that is beyond normal day-to-day variations, is acute in onset, and may warrant a change in regular medication in a patient with underlying COPD.” Reference Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2009. Available from: http://www.goldcopd.org. From the Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2009. Available from: http://www.goldcopd.org. 5

Síntomas y Diagnostico de Exacerbación de EPOC Síntomas Primarios Síntomas secundarios Incremento de la disnea Incremento de la tos y esputo Cambio en el color y/o consistencia del esputo Deterioro de sus capacidades diarias. Sibilancias Opresión de pecho Dolor torácico Taquicardia Taquipnea Cefalea Insomnio Sueño Fatiga Depresión Confusión Speaker Notes The primary symptoms of an exacerbation of COPD are increased dyspnoea, increased cough and sputum, a change in the colour and/or tenacity of sputum and fever. Secondary symptoms may include wheezing, tightening of the chest, tachycardia, tachypnoea, malaise, insomnia, sleepiness, fatigue, depression, and confusion. Diagnostic tests that may be employed in assessing a patient with a suspected exacerbation include a targeted history and physical exam, spirometry, arterial blood gases or pulse oximetry, chest x-ray, and other laboratory tests as indicated. Reference Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2009. Available from: http://www.goldcopd.org. Adapted from the Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2009. Available from: http://www.goldcopd.org. 6

Diagnostico Diferencial. No hay ninguna prueba de confirmación diagnóstica para exacerbación de EPOC. La evaluación del paciente con una posible exacerbación debe centrarse en la gravedad del episodio y excluir otras causas potenciales del deterioro clínico. Estas condiciones, que pueden agravar y / o imitar una exacerbación pueden incluir: Neumonía Neumotórax Cáncer Pulmonar Derrame Pleural Embolia Pulmonar Falla Cardiaca Arritmia Cardiaca Fractura Costal Obstrucción de vía aérea superior. Speaker Notes There is no confirmatory diagnostic test for an exacerbation of COPD. Evaluation of the patient with a possible exacerbation should focus on the severity of the episode and exclude other potential causes for the deterioration in symptoms. These may include: Pneumonia Pneumothorax Lung carcinoma Pleural effusion Pulmonary embolism Cardiac failure Cardiac arrhythmia Rib fracture Upper airway obstruction Reference Hurst JR, Wedzicha JA. Chronic obstructive pulmonary disease: the clinical management of an acute exacerbation. Postgrad Med J. 2004;80:497-505. Hurst JR, Wedzicha JA. Postgrad Med J. 2004;80:497-505. 7

Factores asociados con un incremento del riesgo de las exacerbaciones. Incremento de la edad1,2 Severidad de la obstrucción ( Caída delFEV1 )1,2 Hipersecreción mucosa cronica2 Larga duración del EPOC1 Tos productiva y sibilancias.1 Tos incrementada y esputo3 Uso de Antibióticos y esteroides sistémicos en el ultimo año.1 Colonización bacteriana4 Comorbiliaddes.5 (ej. Enfermedad cardiovascular.) Problemas de salud relacionados con su calidad de vida.6 Speaker Notes A large number of factors have been associated with increased risk for exacerbations. These include older age, increased severity of airway obstruction, chronic mucous hypersecretion, longer duration of COPD, elevated cough and sputum, history of recent systemic corticosteroid, antibiotic, or COPD medication use, bacterial colonisation, comorbid conditions (e.g., cardiovascular disease), and poor health-related quality of life.1-6 References 1. Niewoehner DE, Lokhnygina Y, Rice K, et al. Risk indexes for exacerbations and hospitalizations due to COPD. Chest. 2007;131:20-28. 2. Miravitlles M, Guerrero T, Mayordomo C, Sánchez-Agudo L, Nicolau F, Segú JL. Factors associated with increased risk of exacerbation and hospital admission in a cohort of ambulatory COPD patients: a multiple logistic regression analysis. The EOLO Study Group. Respiration. 2000;67:495-501. 3. Burgel P-R, Nesme-Meyer P, Chganez P, et al. Cough and sputum production are associated with frequent exacerbations and hospitalizations in COPD subjects. Chest. 2009;135:975-982. 4. Rosell A, Monsó E, Soler N, et al. Microbiologic determinants of exacerbation in chronic obstructive pulmonary disease. Arch Intern Med. 2005;165:891-897. 5. Vitacca M. Exacerbations of COPD: predictive factors, treatment and outcome. Monaldi Arch Chest Dis. 2001;56:137-143. 6. Seemungal TA, Donaldson GC, Paul EA, Bestall JC, Jeffries DJ, Wedzicha JA. Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1998;157:1418-1422. 4. Rosell A, et al. Arch Intern Med. 2005;165:891-897. 5. Vitacca M. Monaldi Arch Chest Dis. 2001;56:137-143. 6. Seemungal TA, et al. Am J Respir Crit Care Med. 1998;157:1418-1422. 1. Niewoehner DE, et al. Chest. 2007;131:20-28. 2. Miravitlles M, et al. Respiration. 2000;67:495-501. 3. Burgel P-R, et al. Chest. 2009;135:975-982. 8

Exacerbaciones NO reportadas Las exacerbaciones de la EPOC no reportadas son comunes Se desconoce a corto o mediano plazo el impacto de estas en la calidad de vida El objetivo del estudio fue examinar el impacto de las exacerbaciones NO reportadas en la calidad de vida siguiendo por mas de 1 año a 491 pacientes con EPOC. Los pacientes fueron monitoreados mensualmente por 12 meses documentando síntomas-signos de exacerbación (al menos un síntoma en 48 hrs) Los pacientes se dividieron en 6 grupos: sin exacerbación, solo una exacerbación no reportada, mas de una exacerbación no reportada, solo una exacerbación reportada, mas de una exacerbación reportada y ambas: exacerbaciones reportadas y no reportadas Adapted from Xu W, et al. Eur Respir J. 2010;35:1022-1030

Exacerbaciones NO reportadas Se registraron 466 exacerbaciones reportadas y 410 no reportadas Al comparar los pacientes sin exacerbaciones frente a los pacientes con 1 sola exacerbación , el cambio en el en el cuestionario de calidad de vida de San Jorge (SGRQ) fue similar (significancia ajustada de 1.22 puntos), pero significativamente peor en los pacientes con mas de una exacerbación no reportada (4.61 puntos de significancia ajustada) Adapted from Xu W, et al. Eur Respir J. 2010;35:1022- 1030

Exacerbaciones no reportadas. Change from Baseline in SGRQ Versus Patients with No Exacerbations Worsening Speaker Notes Unreported COPD exacerbations are common, but their intermediate-to-long-term impacts on health-related quality of life are unknown. The aim of the present study was to examine the impact of unreported exacerbations on health-related quality of life over 1 year of follow-up in 491 COPD patients. Patients were monitored monthly for 12 months to document exacerbations (at least one symptom worsening for ≥48 hours). Patients were categorised into six groups: no exacerbation, one unreported exacerbation only, more than one unreported exacerbation only, one reported exacerbation only, more than one reported exacerbation only, and both unreported and reported exacerbations. A total of 466 unreported and 410 reported exacerbations were recorded. Compared with patients with no exacerbations, the change in SGRQ total score was similar amongst patients with one unreported exacerbation (adjusted mean change 1.22 points [95% CI -4.05-6.48]), but significantly worse among patients with more than one unreported exacerbation (4.61 [95% CI 0.09-9.13]). Reference Xu W, Collet JP, Shapiro Set al. Negative impacts of unreported COPD exacerbations on health-related quality of life at 1 year. Eur Respir J. 2010;35:1022-1030. 95% CI = -4.05-6.48 Adapted from Xu W, et al. Eur Respir J. 2010;35:1022-1030. 11

Tos crónica y producción de esputo en E-EPOC Este estudio se realizo para identificar las características asociadas a tos crónica y producción de esputo en pacientes con EPOC Se encontró que el tener tos crónica y esputo se asociaba con aumento de exacerbaciones totales en promedio por paciente al año Exacerbaciones moderadas y Exacerbaciones Severas que requerían hospitalización Exacerbaciones frecuentes (2 o mas ) ocurrieron en 55% de los pacientes con tos y expectoración frente a 22% en pacientes sin estos síntomas Adapted from Burgel P-R, et al. Chest. 2009;135:975-982.

Percent With ≥2 Exacerbations per Patient per Year Elevado riesgo de exacerbación asociado con tos y producción de esputo. * * P<0.0001 Percent With ≥2 Exacerbations per Patient per Year Speaker Notes This study was undertaken to identify features associated with chronic cough and sputum production in COPD subjects. Cross-sectional analysis of data were obtained in 433 COPD subjects with (n=321) and without (n=112) chronic cough and sputum production. Subjects with chronic cough and sputum production had increased total mean numbers of exacerbations per patient per year (2.20 versus 0.97, P<0.0001), moderate exacerbations (1.80 versus 0.66, P<0.0001), and severe exacerbations requiring hospitalisations (0.43 versus 0.22, P<0.02). Frequent exacerbations (two or more per patient per year) occurred in 55% versus 22% of subjects, respectively, with and without chronic cough and sputum production (P<0.0001). Reference Burgel P-R, Nesme-Meyer P, Chganez P, et al. Cough and spiutum production are associated with frequent exacerbatgions and hospitalizations in COPD subjects. Chest. 2009;135:975-982. Adapted from Burgel P-R, et al. Chest. 2009;135:975-982. 13

Factores de Riesgo para exacerbaciones Frecuentes Estudio observacional-transversal en pacientes ambulatorios con EPOC realizado en 201 centros de medicina general a lo largo de toda España En el modelo predictor de exacerbaciones frecuentes se incluyo información de 896 pacientes (627 muestra y 269 en modelo de validación) Las variables del modelo incluían edad, sexo, índice de masa corporal, VEF1, tabaquismo activo, hipersecreción de moco crónicamente y una comorbilidad significativa Adapted from Miravitlles M, et al. Respiration. 2000;67:495-501

Factores de Riesgo para exacerbaciones Frecuentes. 2 * P<0.05 based on 95% CIs * 1.54 1.5 * 1.21 * Odds Ratio for Exacerbation 1 0.82 0.5 Speaker Notes Information was obtained in a cross-sectional observational study on ambulatory COPD patients performed in 201 general practices located throughout Spain. A prediction model for frequent exacerbations included information from 896 patients, 627 in the developmental sample and 269 in the validation model. Candidate variables assessed in the model included age, sex, BMI, FEV1 (percent predicted) active smoking, chronic mucous hypersecretion, and significant comorbidity. The model for frequent exacerbations included three variables: Age (OR = 1. 21, 95% CI = 1.01-1.44; for every 10 years of increasing age) FEV1 % predicted (OR = 0.82, 95% CI = 0.70-0.96, for every 10 units) Chronic mucous hypersecretion (OR = 1.54, 95% CI = 1.11-2.14) Reference Miravitlles M, Guerrero T, Mayordomo C, Sánchez-Agudo L, Nicolau F, Segú JL. Factors associated with increased risk of exacerbation and hospital admission in a cohort of ambulatory COPD patients: a multiple logistic regression analysis. The EOLO Study Group. Respiration. 2000;67:495-501. Age FEV Chronic Mucous 1 Hypersecretion Adapted from Miravitlles M, et al. Respiration. 2000;67:495-501. 15

Efecto de la frecuencia de las exacerbaciones sobre la función Pulmonar El estudio incluyo 102 pacientes con EPOC (44 fumadores, 58 ex-fumadores) Se evaluó el efecto de las exacerbaciones frecuentes y la caída de VEF1 Tasa de exacerbación media fue de 2.85 con IC de 95% La tasa media anual de VEF1 se redujo significativamente en fumadores y no fumadores con exacerbaciones frecuentes, pero principalmente en fumadores activos. Makris D, et al. Respir Med. 2007;101:1305-1312

Efecto de la frecuencia de las exacerbaciones sobre la función Pulmonar. Disminución anual del FEV1 % Predicho Speaker Notes Results from 102 COPD patients (44 smokers, 58 ex-smokers) to assess the effect of frequent exacerbations on decline in FEV1. The median annual exacerbation rate was 2.85 (95% CI = 2.7-3.6). The average annual rate of FEV1 % predicted, adjusted for smoking decline was significantly increased in frequent compared to infrequent exacerbators (P=0.017). Reference Makris D, Moschandreas J, Damianaki A, et al. Exacerbations and lung function decline in COPD: new insights in current and ex-smokers. Respir Med. 2007;101:1305-1312. P=0.017 * 2.85 per year Adapted from Makris D, et al. Respir Med. 2007;101:1305-1312. 17

Exacerbaciones frecuentes son asociadas con reducción en la Calidad de Vida. no exacerbations 1 exacerbation ≥2 exacerbations N=421 56 52 48 44 SGRQ total score Improvement 40 36 Speaker Notes This study assessed the impact of exacerbations on health status in 421 patients with 421 who were being treated with budesonide/formoterol (200 µg/6 µg, two puffs twice daily) and were followed for 6 months. An exacerbation was defined as a change in respiratory symptoms lasting >24 hours. Study results showed that patients with 0 or 1 exacerbation had improvements in SGRQ over the course of the study. Those with ≥2 exacerbations had no improvement. Reference Bourbeau J, Ford G, Zackon H, Pinsky N, Lee J, Ruberto G. Impact on patients' health status following early identification of a COPD exacerbation. Eur Respir J. 2007;30:907-913. 32 28 Baseline 1 month 3 months 6 months Study period Reproduced with the permission of European Respiratory Society Journal Ltd. Bourbeau J, et al. Eur Respir J. 2007;30:907-913. 18

Impacto de las exacerbaciones en EPOC. Paciente con exacerbaciones Frecuentes Mayor Mortalidad. Más Rápida caída de la función Pulmonar. Pobre Calidad de Vida Mayor Inflamación de la Vía Aérea Speaker Notes Patients with frequent exacerbations of COPD result in higher mortality, poorer QOL, increased airway inflammation, and a more rapid decline in lung function versus those with less frequent exacerbations. COPD exacerbations are associated with increased airway and systemic inflammation and physiological changes, especially the development of hyperinflation. They are triggered mainly by respiratory viruses and bacteria, which infect the lower airway and increase airway inflammation. Some patients are particularly susceptible to exacerbations, and show worse health status and faster disease progression than those who have infrequent exacerbations. Reference Wedzicha JA, Seemungal TA. COPD exacerbations: defining their cause and prevention. Lancet. 2007;370:786-796. Adapted from Wedzicha JA, Seemungal TA. Lancet. 2007;370:786-796. 19

La función Pulmonar Puede Recuperarse Lentamente después de una exacerbación En un estudio se encontró que antes de la aparición de la exacerbación hubo deterioro de los síntomas de disnea, dolor de garganta, tos y síntomas de resfriado común y luego ocurrió deterioro función pulmonar La media del tiempo de recuperación para la tasa de flujo espiratorio máximo (FEM) fue de 6 días y 7 días para los síntomas La recuperación del FEM a los valores basales se completó en los 75.2% de las exacerbaciones a los 35 días y solo 7.1% de las exacerbaciones la recuperación del FEM no había ocurrido a los 91 días En 404 exacerbaciones que no recuperaron el FEM a valores basales a los 91 días, se encontró que la disnea y el resfriado al inicio de la exacerbación se asoció con aumento del tiempo de recuperación de la función pulmonar (P 0.001) Seemungal TA, et al. Am J Respir Crit Care Med. 2000;161:1608–1613.

Daily Median PEFR as % Baseline La función Pulmonar Puede Recuperarse Lentamente después de una exacerbación. 101 N=91 Exacerbation 100 99 Daily Median PEFR as % Baseline 98 97 Speaker Notes Before onset of exacerbation there was deterioration in the symptoms of dyspnoea, sore throat, cough, and symptoms of a common cold (all P<0.05), but not lung function. Median recovery times were 6 days for peak expiratory flow rate (PEFR) and 7 days for daily total symptom score. Recovery of PEFR to baseline values was complete in only 75.2% of exacerbations at 35 days; whereas in 7.1% of exacerbations at 91 days PEFR recovery had not occurred. In the 404 exacerbations where recovery of PEFR to baseline values was complete at 91 days, increased dyspnoea and colds at onset of exacerbation were associated with prolonged recovery times (P<0.001). The declines in lung function, whether measured by PEFR, FEV1, or FVC, were all highly significant (P<0.001). Reference Seemungal TA, Donaldson GC, Bhowmik A, Jeffries DJ, Wedzicha JA. Time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2000;161:1608-1613. 96 95 -14 -9 -4 1 6 11 16 21 26 31 Days Adapted from Seemungal TA, et al. Am J Respir Crit Care Med. 2000;161:1608–1613. 21

Percent Change from Baseline in FEV1 Más Rápida disminución del VEF1, con mayor Frecuencia de exacerbaciones. FEV1 (mL) 0.95 Infrequent Exacerbators Frequent Exacerbators -5 0.90 -10 -15 Percent Change from Baseline in FEV1 0.85 -20 Annual Change -25 0.80 -30 Speaker Notes Frequent exacerbations have been shown to be associated with a slightly higher rate of decline in FEV1. Results from frequent exacerbators indicated a decline in FEV1 of 40.1 mL/year (95% CI = 38-42) versus 32.1 mL/year (95% CI = 31-33) for infrequent exacerbators (P<0.05). Reference Donaldson GC, Seemungal TA, Bhowmik A, Wedzicha JA. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax. 2002;57:847-852. -32.1 -35 0.75 -40 Frequent -40.1 Exacerbators 1 2 3 4 * Infrequent -45 Exacerbators Years *P<0.05 versus infrequent exacerbators Adapted from Donaldson GC, et al. Thorax. 2002;57:847-852. Permission requested. 22

Mortalidad seguida de una visita a urgencias por exacerbación de EPOC. 5% 9% 11% 16% 23% 32% 39% 0% 10% 15% 20% 25% 30% 35% 40% 45% 30 Days 60 Days 90 Days 180 Days 1 Year 2 Years 3 Years Time Following Admission Percent Mortality Speaker Notes This retrospective cohort study of emergency department patients who presented with an acute exacerbation indicated that mortality increased over time after the index event. Mortality was 5% at 30 days, 9% at 60 days, 11% at 90 days, 16% at 180 days, 23% at 1 year, 32% at 2 years, and 39% at 3 years. At the end of follow-up, 220 (46%) patients had died. On multivariate analysis, independent predictors of mortality were increasing age, having congestive heart failure, having a metastatic solid tumor, and hospital utilisation for COPD exacerbation during past year. Reference Kim S, Clark S, Camargo CA Jr. Mortality after an emergency department visit for exacerbation of chronic obstructive pulmonary disease. COPD. 2006;3:75-81. Adapted from Kim S, et al. COPD. 2006;3:75-81. 23

Exacerbaciones incrementan mortalidad: Estudio investigó si las exacerbaciones de EPOC ejercen una acción directa sobre la mortalidad. Cohorte prospectiva de 304 pacientes varones seguidos por 5 años. Diseño de multivariables para analizar las exacerbaciones agudas de la EPOC tratados en el hospital (visitas a emergencia e ingresos hospitalarios), edad , tabaquismo, IMC, comorbilidad, terapia con oxigeno a largo plazo, parámetros espirométricos forzados y gases arteriales Las variables independientes para un pobre pronostico fueron: edad mayor, presión de bióxido de carbono y exacerbaciones agudas. Los pacientes con mayor riesgo de mortalidad fueron aquellos con tres o mas exacerbaciones agudas de EPOC Soler-Cataluña JJ, et al. Thorax. 2005;60:925-931.

La frecuencia y la severidad de la exacerbación ambos incrementan el Riesgo de Mortalidad. 1.0 1.0 0.8 0.8 A P<0.0002 (1) NS 0.6 0.6 (2) Probability of surviving Probability of surviving P<0.0001 B P=0.069 P<0.0001 P=0.005 0.4 0.4 P<0.0001 (3) C NS 0.2 0.2 (4) 0.0 0.0 10 20 30 40 50 60 10 20 30 40 50 60 Time (months) Time (months) Speaker Notes A study was undertaken to investigate whether severe acute exacerbations of COPD exert a direct effect on mortality. Multivariate techniques were used to analyse the prognostic influence of acute exacerbations of COPD treated in hospital (visits to the emergency service and admissions), patient age, smoking, body mass index, comorbidity, long term oxygen therapy, forced spirometric parameters, and arterial blood gas tensions in a prospective cohort of 304 men with COPD followed up for 5 years. Only older age, arterial carbon dioxide tension, and acute exacerbations of COPD were found to be independent indicators of a poor prognosis. The patients with the greatest mortality risk were those with three or more acute COPD exacerbations. Reference Soler-Cataluña JJ, Martínez-García MA, Román Sánchez P, Salcedo E, Navarro M, Ochando R. Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease. Thorax. 2005;60:925-931. Group A patients with no acute exacerbations Group B patients with 1–2 acute exacerbations requiring hospital management Group C patients with ≥3 acute exacerbations Group (1) no acute exacerbations Group (2) acute exacerbations requiring emergency service visits without admission Group (3) patients with acute exacerbations requiring one hospital admission Group (4) patients with acute exacerbations requiring readmissions Soler-Cataluña JJ, et al. Thorax. 2005;60:925-931. Permission requested. 25

Costos de Tratamiento Para Una Exacerbación de EPOC. £110 £1,536 £484 £0 £200 £400 £600 £800 £1,000 £1,200 £1,400 £1,600 £1,800 Medication Ward (bed) Costs Other Services and Investigations Mean Cost of an Admission for Exacerbation Speaker Notes Exacerbations of COPD have serious health consequences for patients and are strongly associated with unscheduled healthcare resource use. This study evaluated the impact of exacerbations on healthcare resource utilisation. In total, 149 patients consented to take part in the study representing 222 admissions to hospital. The mean cost of an admission was £2130.34 with a cost of £110.37 for medication. Reference O'Reilly JF, Williams AE, Rice L. Health status impairment and costs associated with COPD exacerbation managed in hospital. Int J Clin Pract. 2007;61:1112-1120. Adapted from O'Reilly JF, et al. Int J Clin Pract. 2007;61:1112-1120. 26

Inflamación Pulmonar y sistémica en la exacerbación TRIGGERS Viruses Bacteria Pollutants EFFECTS Inflamed COPD airway Greater airway inflammation Speaker Notes COPD exacerbations are associated with increased upper and lower airway and systemic inflammation. The airway inflammatory responses cause oedema, bronchospasm, and increased sputum production, leading to worsening airflow limitation and development of dynamic hyperinflation, which is a main cause of dyspnoea, the most common symptom of an exacerbation. Systemic inflammation increases at exacerbation and, although the causes of this response in COPD are not clear, there is probably a spill-over of inflammatory markers from the lungs. Reference Wedzicha JA, Seemungal TA. COPD exacerbations: defining their cause and prevention. Lancet. 2007;370:786-796. Bronchoconstriction oedema, mucus Systemic inflammation Expiratory flow limitation Cardiovascular comorbidity Exacerbation symptoms Dynamic hyperinflation Reprinted from The Lancet, Vol 370, Wedzicha JA, Seemungal TA, COPD exacerbations: defining their cause and prevention, 786-796, Copyright 2007, with permission from Elsevier. 27 27 27

Causas potenciales de exacerbación. Infección Bacteriana o viral (1, 2) Contaminantes: (2) dióxido de nitrógeno Partículas (PM10) dióxido de azufre ozono Época de frio (1) La interrupción del tratamiento habitual (1) Speaker Notes The principal identified causes of COPD exacerbations include bacterial and viral infections, pollution, cold weather, and interruption of regular treatment. References Burge S, Wedzicha JA. COPD exacerbations: definitions and classifications. Eur Respir J Suppl. 2003;41:46s-53s. Burge S, Wedzicha JA. Eur Respir J Suppl. 2003;41:46s-53s. Sapey E, Stockley RA. Thorax. 2006;61:250-258. 28

Patógenos Bacterias (50 %) Virus (20-40%) Influenza1,2 Common1 Haemophilus influenzae Moraxella catarrhalis Streptococcus pneumoniae Staphylococcus aureus Común en Exacerbaciones Severas1 Pseudomonas aeruginosa Gram-negative bacilli Atípicas Chlamydia pneumoniae Mycoplasma pneumoniae Legionella spp Virus (20-40%) Influenza1,2 Parainfluenza1,3 Respiratory syncytial virus (RSV)1,2 Human metapneumovirus1 Picornaviruses1,3 Coronavirus3 Speaker Notes Many viruses are implicated in acute exacerbations of COPD, including influenza, parainfluenza, respiratory syncytial virus (RSV), coronavirus, and rhinovirus. Human rhinovirus is the dominant viral pathogen. Newly emerging viruses, such as human metapneumoviruses, may also be important, because in 10 to 15% of acute respiratory illness no pathogen can be detected despite PCR.1 Traditional virological techniques have reported rates of viral detection up to 20%. More recently, studies using polymerase chain reaction (PCR) of nasal aspirates during acute exacerbation identified infection rates of 39%. 1 The predominant bacteria isolated from sputum samples in COPD exacerbations are noncapsulated Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae. 1 In patients with more severe exacerbations who required mechanical ventilation, Pseudomonas aeruginosa and gram-negative bacilli are also recognised. 1 Bacteria are associated with 50% of exacerbations and have been shown to enhance pulmonary inflammation, induce mucus hypersecretion, and reduce ciliary beat frequency in vitro. 1 References 1. Sykes A, Mallia P, Johnston SL. Diagnosis of pathogens in exacerbations of chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2007;4:642-646. 2. Rohde G, Wiethege A, Borg I, et al. Respiratory viruses in exacerbations of chronic obstructive pulmonary disease requiring hospitalisation: a case-control study. Thorax. 2003;58:37-42. 3. Martinez FJ. Pathogen-directed therapy in acute exacerbations of chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2007;4:647-58. 1. Sykes A, et al. Proc Am Thorac Soc. 2007;4:642-646. 3. Martinez FJ. Proc Am Thorac Soc. 2007;4:647-658. 2. Rohde G, et al. Thorax. 2003;58:37-42 29

Patógenos y no Patógenos LatinEPOC-2014 / Abril 2015

Relación entre FEV1 y la Etiología de las Exacerbaciones. 500 1000 1500 2000 2500 3000 3500 FEV1 (mL) H influenzae S pneumoniae P aeruginosa M catarrhalis Others Non-PPMs Speaker Notes This study assessed the relationship between FEV1 and the etiology of exacerbations. The study included 91 patients with exacerbations, quantitative sputum culture was performed, and bacterial growth was considered significant only when the organism was isolated at concentrations >106 cfu/mL (>105 cfu/mL for Streptococcus pneumoniae) in samples with <10 epithelial cells and >25 leukocytes per low magnification field (x 100). Bacteria isolated included Haemophilus influenzae (22%), Pseudomonas aeruginosa (15%), S pneumoniae (10%), Moraxella catarrhalis (9%), other Gram-negative bacteria (7%), and non-potentially pathogenic microorganisms (non-PPMs, 36%). P aeruginosa and H influenzae were isolated more frequently among the patients with FEV1 <50% than among those with FEV1 >50% (P<0.05). All patients with P aeruginosa in sputum had FEV1 <1,700 mL. FEV1 <50% was associated with a very high risk of P aeruginosa or H influenzae isolation (odds ratios = 6.62, 95% CI = 1.2 to 123.6; and 6.85, 95% CI = 1.6 to 52.6; respectively). Reference Miravitlles M, Espinosa C, Fernández-Laso E, Martos JA, Maldonado JA, Gallego M. Relationship between bacterial flora in sputum and functional impairment in patients with acute exacerbations of COPD. Study Group of Bacterial Infection in COPD. Chest. 1999;116:40-46. Miravitlles M, et al. Chest. 1999;116:40-46. Permission requested. 31

Etiología de las Exacerbaciones para Diferentes estadios de EPOC. P=0.016 for differences in distributions S pneumoniae and Gram positive cocci 70 63 H influenzae/M catarrhalis 60 Enterobacteriaceae/Pseudomonas spp 50 47 40 40 Percent 33 30 30 27 23 23 Speaker Notes This study evaluated clinical data and sputum culture results from 211 unselected COPD patients admitted to the hospital with an infective exacerbation. Lung function tests revealed an FEV1 of ≥50% of the predicted value in 30 patients (stage I), an FEV1 of 35% to <50% of the predicted value in 30 patients (stage II), and an FEV1 of ≤35% of the predicted value in 34 patients (stage III). Bacteria were classified into three groups: group 1 contained S pneumoniae and other Gram-positive cocci; group 2, H influenzae and M catarrhalis; and group 3, Enterobacteriaceae and Pseudomonas spp. For all patients together, the most frequently isolated bacteria were group 3 organisms (48.2%), followed by group 1 organisms (30.4%), and group 2 organisms (21.4%). In stage I patients, 14 of 30 had bacteria from group 1, seven of 30 had group 2, and nine of 30 had group 3. In stage II patients, eight of 30 had group 1 bacteria, 10 of 30 had group 2, and 12 of 30 had group 3. In stage III patients, 12 of 52 had group 1 bacteria, seven of 52 had group 2, and 22 of 52 had group 3. The three groups of bacteria causing infective exacerbations were unevenly distributed among the three severity stages of lung function (P=0.016). Reference Eller J, Ede A, Schaberg T, Niederman MS, Mauch H, Lode H. Infective exacerbations of chronic bronchitis: relation between bacteriologic etiology and lung function. Chest. 1998;1131542-1548. 20 13 10 Stage I Stage II Stage III Eller J, et al. Chest. 1998;113:1542-1548. Permission requested. 32

Como Prevenir las E-EPOC?

Vacunación de Influenza : Riesgo para Cualquier Exacerbación. Los resultados de los ensayos clínicos aleatorios indican que la vacuna antigripal inactivada disminuye las exacerbaciones en pacientes con EPOC. La reducción en las exacerbaciones ocurren tres o más semanas después de la vacunación. Hay un leve aumento de efectos adversos locales transitorios con la vacunación, pero no hay evidencia de un aumento de las exacerbaciones a corto plazo. Speaker Notes Influenza vaccinations are currently recommended in the care of people with COPD, but these recommendations are based largely on evidence from observational studies with very few randomised controlled trials (RCTs) reported. Eleven trials were included but only six of these were specifically performed in COPD patients. The others were conducted on elderly and high-risk individuals, some of whom had chronic lung disease. Inactivated vaccine in COPD patients resulted in a significant reduction in the total number of exacerbations per vaccinated subject compared with those who received placebo (P=0.006). This was due to the reduction in "late" exacerbations occurring after 3 or 4 weeks (P=0.0004). Meta-analysis indicates that inactivated vaccine reduces exacerbations in COPD patients. The size of effect was similar to that seen in large observational studies, and was due to a reduction in exacerbations occurring three or more weeks after vaccination, and due to influenza. There is a mild increase in transient local adverse effects with vaccination, but no evidence of an increase in early exacerbations. Reference Poole PJ, Chacko E, Wood-Baker RW, Cates CJ. Influenza vaccine for patients with chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2006;1:CD002733. Poole PJ, et al. Cochrane Database Syst Rev. 2006;CD002733. 35

Vacunación de Influenza : Riesgo para Cualquier Exacerbación Para la EPOC leve, moderada o grave, la efectividad de la vacuna fue del 84%, 45% y 85% respectivamente. No existen diferencias entre el grupo vacunado y el grupo placebo en cuanto a hospitalizaciones por infecciones respiratorias agudas relacionadas a influenza y la necesidad de ventilación mecánica Si la vacuna es trivalente, virus fragmentado e inactivado la probabilidad de no enfermarse es de 76% Guía LatinEPOC-2014

Vacunación de Neumococo 1.00 1.00 Vaccinated = 132 Control = 114 0.95 0.95 0.90 0.90 0.85 0.85 Cumulative Proportion of Patients Without Pneumonia Cumulative Proportion of Patients Without Pneumonia 0.80 0.80 Vaccinated = 91 Control = 116 0.75 0.75 Speaker Notes A study was undertaken to evaluate the clinical efficacy of the 23-valent pneumococcal polysaccharide vaccine (PPV) in immunocompetent patients with COPD. Kaplan-Meier survival curves for CAP did not show significant differences between the intervention and non-intervention arms (log rank test = 1.15, P=0.28) in the whole group of patients. The efficacy of PPV in all patients was 24% (95% CI = -24 to 54; P=0.333). In the subgroup aged <65 years the efficacy of PPV was 76% (95% CI = 20 to 93; P=0.013), while in those with severe functional obstruction (FEV1 <40%) it was 48% (95% CI = -7 to 80; P=0.076). In younger patients with severe airflow obstruction the efficacy was 91% (95% CI = 35 to 99; P=0.002). Reference Alfageme I, Vazquez R, Reyes N, et al. Clinical efficacy of anti-pneumococcal vaccination in patients with COPD. Thorax. 2006;61:189-195. Log rank = 6.68 P=0.0097 Log rank = 3.85 P=0.0498 (NS) 0.70 0.70 250 500 750 1000 1250 300 600 900 1200 1500 Time (days) Time (days) Alfageme I, et al. Thorax. 2006;61:189-195. Permission requested. 37

Vacunación de Neumococo Revisión sistemática que incluye estudios con vacunas contra el neumococo: polisacáridos purificados de 14 y 23 serotipos en pacientes con EPOC, no mostró reducción de la probabilidad de desarrollar neumonía neumocócica y mortalidad cardiovascular o por cualquier causa En el estudio de sub-grupos de pacientes se encontró que la prevención de neumonías (neumocócica y de etiología desconocida) en los pacientes con EPOC menores de 65 años fue de 76% y con VEF1 menor de 40% fue de 48% Otro autor encontró que en pacientes jóvenes con obstrucción severa de la vía aérea la eficacia es de 91% Guía LatinEPOC-2014

Salmeterol e Ipratropium Disminuye el riesgo para exacerbaciones. 1.00 0.95 0.90 0.85 Probability of Being Free from Exacerbations (Kaplan-Meier Analysis) 0.80 0.75 0.70 0.65 Placebo Salmeterol Ipratropium Risk for exacerbation was significantly lower with salmeterol versus ipratropium- (P<0.0411) or placebo-treated patients (P<0.0052) Speaker Notes This study assessed the effects of salmeterol and ipratropium on risk for exacerbations in 411 patients with COPD. Analyses of time to first COPD exacerbation revealed salmeterol to be superior to placebo and ipratropium (P<0.05). Kaplan-Meier survival analysis of time to first exacerbation demonstrated that a significantly higher percentage of salmeterol-treated patients completed the study without experiencing a COPD exacerbation than did either ipratropium-treated (P<0.0411) or placebo-treated (P<0.0052) patients. Reference Mahler DA, Donohue JF, Barbee RA, et al. Efficacy of salmeterol xinafoate in the treatment of COPD. Chest. 1999;115:957-965. 0.60 0.55 0.50 1 2 3 4 5 6 7 8 9 10 11 12 Weeks of Treatment Adapted from Mahler DA, et al. Chest. 1999;115:957-965. Permission requested.

Tiotropium Disminuye la frecuencia de exacerbaciones. * P=0.045 versus placebo * 0.76 0.95 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Exacerbations per Patient-Year Tiotropium Placebo Speaker Notes This study assessed the long-term efficacy of tiotropium in 911 patients with COPD. Study results demonstrated that tiotropium significantly decreased the risk for exacerbations versus placebo (P=0.045). Reference Casaburi R, Mahler DA, Jones PW, et al. A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease. Eur Respir J. 2002;19:217-224. Adapted from Casaburi R, et al. Eur Respir J. 2002;19:217-224. 40

ICS disminuye el porcentaje de exacerbaciones.* * P=0.026 versus placebo 1.4 1.32 1.2 * 0.99 1.0 0.8 Annual Exacerbation Rate 0.6 Speaker Notes This study assessed the long-term effects of ICS (fluticasone) on exacerbations in 751 patients with COPD. The median exacerbation rate was reduced by 25% from 1.32 a year on placebo to 0.99 a year on with fluticasone propionate (P=0.026). Reference Burge PS, Calverley PM, Jones PW, Spencer S, Anderson JA, Maslen TK. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ. 2000;320:1297-1303. 0.4 0.2 Fluticasone Placebo ** per patient, per year Adapted from Burge PS, et al. BMJ. 2000;320:1297-1303. 41

TORCH: Disminución del porcentaje de las exacerbaciones con LABA más ICS * P<0.05 versus placebo 1.2 1.13 * Placebo (N=1524) Salmeterol (N=1521) Fluticasone (N=1534) Combination Therapy (N=1533) * 0.97 1 * 0.93 0.85 0.8 0.8 * 0.64 * Annual Rate 0.6 * 0.52 0.46 0.4 * * Speaker Notes Results from the TORCH showed that all active treatments were significantly superior to placebo in decreasing the risk for moderate-to-severe exacerbations and exacerbations requiring systemic steroids (all P<0.05). Combination treatment and salmeterol were also significantly superior to placebo in decreasing the risk for exacerbations requiring hospitalisation (both P<0.05). Reference Calverley PM, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356:775-789. 0.19 0.2 0.16 0.17 0.16 Moderate or Severe Requiring Systemic Requiring Corticosteroids Hospitalisation Adapted from Calverley PM, et al. N Engl J Med. 2007;356:775-789. 42

UPLIFT Estudio – Efecto sobre las Exacerbaciones Estudio UPLIFT demostró que tiotropium se asoció con una reducción en el número de exacerbaciones del 14% (P menor 0.001) Un total de 5993 pacientes fueron incluidos en el estudio UPLIFT; 2987 en el grupo de tiotropium y 3006 en el grupo placebo El promedio del número de exacerbaciones que conducen a la hospitalización fueron infrecuentes y no difieren significativamente entre los dos grupos estudiados Tashkin DP, et al. N Engl J Med. 2008;359:1543-1554. Copyright © 2008 Massachusetts Medical Society.

UPLIFT Estudio – Efecto sobre las Exacerbaciones. 0.85/yr 0.73/yr; P<0.001 (14% reduction) 80 Control 60 Tiotropium Probability of exacerbation (%) 40 Hazard ratio = 0.86, (95% CI = 0.81, 0.91) P<0.0001 (log-rank test) 20 Speaker Notes Results from UPLIFT indicated that tiotropium was associated with a reduction in the mean number of exacerbations of 14% (P<0.001) . The mean numbers of exacerbations leading to hospitalisations were infrequent and did not differ significantly between the two study groups. A total of 5993 patients were included in the UPLIFT study; 2987 in the tiotropium group and 3006 in the placebo group. Reference Tashkin DP, Celli B, Senn S, et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008;359:1543-1554. 6 12 18 24 30 36 42 48 Months Tashkin DP, et al. N Engl J Med. 2008;359:1543-1554. Copyright © 2008 Massachusetts Medical Society. All rights reserved. 44

Exacerbaciones de EPOC La tasa de exacerbaciones fue un 26,6% más baja con BUD/FORM vs. FLU/SAL RR = 0,74 (IC: 0,69, 0,79) p<.0001 RR, cociente de tasa Journal of Internal Medicine, 2013, 273; 584–594

Exacerbaciones de EPOC Eventos por cada 100 pacientes por años para exacerbaciones en pacientes con EPOC pareados por propensión y tratados con BUD/FORM o con FLU/SAL NNT = 3,4 Comparado con FLU/SAL Diskus, BUD/FOR Turbuhaler estuvo asociado con una reducción en el riesgo: de todo tipo de exacerbaciones del 26 % (26,6%), presentado aquí como evento/100 pacientes/año; 80/100 vs, 109/100: NNT = 3,4 La budesonida/formoterol tuvo 26,0% menos ciclos bajo esteroides orales y 29,0% menos ciclos con antibióticos reducción en el riesgo de hospitalizaciones por causa de EPOC del 29% y un riesgo 21,0% más bajo con respecto a visitas a sala de emergencias en el grupo de tratamiento bajo budesonida/formoterol Todas fueron altamente significativas La media de la dosis de budesonida retirada fue de 568µg/día para pacientes pareados a los que se les prescribió budesonida/formoterol, mientras que la media de la dosis de fluticasona fue de 783 µg/día para pacientes a los que se les prescribió fluticasona/salmeterol, correspondiendo a 89% vs. 78% de la dosis recomendada en etiqueta para EPOC; budesonida 640 µg/día y fluticasona 1000 µg/d (dosis entregada). NNT = 16 Las tasas anuales ajustadas de eventos de utilización de atención médica fueron comparadas usando el análisis de regresión de Poisson . **P<0,0001; *P=0,0003 para la diferencia. IC, intervalos de confianza Journal of Internal Medicine, 2013, 273; 584–594

Exacerbaciones por edad BUD/FORM fue más efectiva que FLU/SAL en pacientes < o > 60 años de edad iniciando terapia con CCI/ABAP, con una mayor eficacia en el subgrupo >60 D 31% RR = 0,69 (IC: 0,65, 0,75) D 27% RR = 0,74 (IC: 0,69, 0,79) D 25% RR = 0,75 (IC: 0,66, 0,85) (n=2734) (n=2734) (n=600) (n=600) (n=2134) (n=2134)

Uso de prescripciones triples/tiotropio Los pacientes tratados con BUD/FORM necesitaron 16% menos prescripciones de tiotropio por año que los pacientes tratados con FLU/SAL (los gráficos representan los promedios en todos los pacientes y en todos los años del estudio) D 16% RR = 0,84 (IC: 0,79, 0,89) p<.0001 (n=2734) (n=2734)

Uso de agonistas β2 de acción corta Los pacientes tratados con BUD/FORM tuvieron 22% menos prescripciones de ABAC por año que los que usaban FLU/SAL (los gráficos representan los promedios en todos los pacientes y en todos los años del estudio) D 22% RR = 0,78 (IC: 0,72, 0,84) p<.0001 (n=2734) (n=2734)

Mean rate exacerbations (moderate or severe) per patient per year Roflumilast disminuye significativamente las exacerbaciones cuando se asocia con LABA Pre-specified analysis of exacerbation rate in LABA subgroup -21% (CI -31;-9) P=0.0011 Mean rate exacerbations (moderate or severe) per patient per year Speaker Notes In response to observations from the early clinical studies, the pivotal 12-month studies were designed to investigate the effects of roflumilast in patients with severe COPD, symptoms of chronic cough and sputum, and a history of exacerbations.1 Patient inclusion criteria included diagnosed COPD, severe airflow limitation, age ≥40 years, bronchitic symptoms, and a history of exacerbations.1 Patients were randomly assigned to receive roflumilast (500μg once daily) (n=1537) or placebo (n=1554) for 52 weeks.1 Primary endpoints were change in pre-bronchodilator FEV1 and the rate of exacerbations that were moderate (glucocorticosteroid-treated) or severe.1 Analysis was by intention to treat. Patients were stratified according to smoking status and treatment with LABAs. Treatment with ICS was stopped at the beginning of the study. Data from the two studies were analysed separately and in a pooled analysis.1 Approximately 50% of patients in the two 12-month studies continued to use LABAs throughout the roflumilast treatment period.1 Roflumilast reduced the rate of exacerbations irrespective of whether patients were taking concomitant COPD maintenance therapy.1 A pre-specified analysis of the effects of roflumilast in the LABA subgroup, revealed approximately 21% lower exacerbation rate in patients receiving roflumilast relative to placebo (P=0.0011).2 References 1. Calverley PMA, Rabe KF, Goehring UM, et al. Roflumilast in symptomatic chronic obstructive disease: two randomised clinical trials. Lancet 2009;374:685–694. 2. Hanania NA, Brose M, Larsson T, et al. Efficacy of roflumilast in patients receiving concomitant treatments for chronic obstructive pulmonary disease over 12 months. American Thoracic Society International Conference, May 14-19, 2010, New Orleans, LA. Hanania NA, Brose M, Larsson T, et al. Am J Respir Crit Care Med 2010;181:A4435. Abstract. 50

Indacaterol/Glycopyrronium en la prevención de E-EPOC

Indacaterol/Glycopyrronium en la prevención de E-EPOC Wedzicha JA et al. N Engl J Med 2016;374:2222-2234

Indacaterol/Glycopyrronium en la prevención de E-EPOC Wedzicha JA et al. N Engl J Med 2016;374:2222-2234

Estudio FLAME Indacaterol/Glycopyrronium en la prevención de E-EPOC

Manejo de las Exacerbaciones. Manejo Ambulatorio Terapia Broncodilatadora Glucocorticoides Antibióticos Manejo Hospitalario Terapia broncodilatadora Antibióticos Esteroides orales o IV Ventilación Mecánica No Invasiva. Vigilancia estrecha del estado general del paciente, incluyendo comorbilidades Speaker Notes Home management of exacerbations may more intensive bronochodilatory therapy and administration of glucocorticosteroids and/or antibiotics. If the patient is referred to the hospital, treatment may include all of the above interventions plus oral or intravenous glucocorticosteroids, and noninvasive mechanical ventilation. Reference From the Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2010. Available from: http://www.goldcopd.org. From the Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2010. Available from: http://www.goldcopd.org. 55

Terapia Broncodilatadora para el tratamiento de le E-EPOC Guía LatinEPOC-2014

Terapia antibiótica en pacientes ambulatorios con E-EPOC Guía LatinEPOC-2014

Indicaciones para considerar manejo intrahospitalario. Marcado aumento en la intensidad de los síntomas, como el desarrollo repentina Disnea de reposo EPOC subyacente grave La aparición de nuevos signos físicos (por ejemplo, cianosis, edema periférico) falla en responder al tratamiento médico inicial comorbilidades significativas exacerbaciones frecuentes Nuevos eventos de arritmias Incertidumbre diagnóstica La edad avanzada Insuficiente apoyo en el hogar Speaker Notes Any of the following should prompt consideration of hospital management of exacerbations: Marked increase in intensity of symptoms, such as sudden development of resting dyspnoea Severe underlying COPD Onset of new physical signs (e.g., cyanosis, peripheral oedema) Failure of exacerbation to respond to initial medical management Significant comorbidities Frequent exacerbations Newly occurring arrhythmias Diagnostic uncertainty Older age Insufficient home support Reference Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2009. Available from: http://www.goldcopd.org. From the Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2009. Available from: http://www.goldcopd.org. 58

Criterios de Hospitalización en pacientes con E-EPOC Guía LatinEpoc-2014

Factores de riesgo para infecciones por Pseudomonas aeruginosa Guía LatinEPOC-2014

Resultados de la terapia antibiótica en pacientes hospitalizados con exacerbaciones: Estudio de cohorte retrospectivo. P<0.001 P<0.001 Percent of Patients P<0.001 Speaker Notes This retrospective cohort study included patients ≥40 years old who were hospitalised from January 1, 2006, through December 31, 2007, for exacerbations of COPD at 413 acute care facilities throughout the United States. Of 84,621 patients, 79% received at least 2 consecutive days of antibiotic treatment. Study results indicated that patients who received early antibiotic treatment (on day 1 or 2 of hospitalisation) were significantly less likely than those who received late (after day 2 of hospitalisation) or no antibiotic treatment to experience in-hospital mortality, treatment failure (defined as defined as the initiation of mechanical ventilation after the second hospital day, inpatient mortality, or readmission for acute exacerbations of COPD within 30 days of discharge), or readmission within 30 days for COPD (all P<0.001). Reference Rothberg MB, Pekow PS, Lahti M, Brody O, Skiest DJ, Lindenauer PK. Antibiotic therapy and treatment failure in patients hospitalized for acute exacerbations of chronic obstructive pulmonary disease. JAMA. 2010;303:2035-2042. Adapted from Rothberg MB, et al. JAMA. 2010;303:2035-2042. 61

Indicaciones para Posible admisión a terapia Intensiva. Disnea severa que responde inadecuadamente a la terapia inicial de emergencia. Cambios en el estado mental (confusión, letargia, coma) Hipoxemia persistente o que empeora (PaO2 <5,3 kPa, 40 mmHg), y / o graves / peores episodios de hipercapnia (PaCO2> 8,0 kPa, 60 mmHg), y / o graves / peores episodios de acidosis respiratoria (pH <7,25) a pesar de oxígeno suplementario y ventilación no invasiva Necesidad de ventilación mecánica invasiva Inestabilidad hemodinámica, necesidad de vasopresores Speaker Notes Management of the patient with an exacerbation in the intensive care unit might be considered for any of the following reasons: Severe dyspnoea that responds inadequately to initial emergency therapy Changes in mental status (confusion, lethargy, coma) Persistent or worsening hypoxaemia (PaO2 <5.3 kPa, 40 mm Hg), and/or severe/worsening hypercapnia (PaCO2 >8.0 kPa, 60 mm Hg), and/or severe/worsening respiratory acidosis (pH <7.25) despite supplemental oxygen and noninvasive ventilation Need for invasive mechanical ventilation Haemodynamic instability—need for vasopressors Reference Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2009. Available from: http://www.goldcopd.org. From the Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2009. Available from: http://www.goldcopd.org. 62

Ventilación Mecánica No Invasiva (NIV) Criterios de selección Disnea moderada a severa con uso de músculos accesorios Acidosis moderada a grave (PH > 7,25 y ≤ 7.35 y / o hipercapnia (PaCO2> 50 mm Hg) Pa02 < 60 o Pa02/FI02 < 200 Frecuencia respiratoria> 30 respiraciones por minuto Sin neumotórax en Rx tórax Glasgow > 11 APACHE II <29 Contraindicaciones -paro respiratorio -Inestabilidad cardiovascular (hipotensión, arritmias, infarto de miocardio) -Cambios en el estado mental, paciente que no coopera -Alto riesgo de aspiración -Secreciones viscosas o copiosas -Cirugía reciente o facial gastroesofágico -trauma craneofacial -anormalidades nasofaríngeas -Quemaduras - obesidad extrema -Glasgow < 11 pts. APACHE II > 29 > Speaker Notes Selection criteria for NIV include: Moderate to severe dyspnoea with use of accessory muscles Moderate to severe acidosis (pH ≤7.35) and/or hypercapnia (PaCO2 >6.0 kPa, 45 mm Hg) Respiratory frequency >25 breaths per minute Contraindications for NIV include: Respiratory arrest Cardiovascular instability (hypotension, arrhythmias, myocardial infarction) Change in mental status; uncooperative patient High aspiration risk Viscous or copious secretions Recent facial or gastroesophageal surgery Craniofacial trauma Fixed nasopharyngeal abnormalities Burns Extreme obesity Reference Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2009. Available from: http://www.goldcopd.org. From the Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2009. Available from: http://www.goldcopd.org and Guia LatinEPOC-2014 63

Indicaciones para ventilación Mecánica Invasiva. Incapaz de tolerar o fracaso de la VNI. -Disnea grave con uso de músculos accesorios y movimiento paradójico abdominal -Frecuencia respiratoria> 35 respiraciones por minuto -Hipoxemia que amenaza la vida -Acidosis grave (pH <7,25) y / o hipercapnia (PaCO2> 8,0 kPa, 60 mm Hg) -paro respiratorio -Somnolencia, alteración del estado mental -complicaciones cardiovasculares (hipotensión, shock) -Otras complicaciones (alteraciones metabólicas, sepsis, neumonía, embolia pulmonar, barotrauma, derrame pleural masivo) -Signos progresivos de fatiga respiratoria Speaker Notes Indications for mechanical ventilation include: Unable to tolerate NIV or NIV failure Severe dyspnoea with use of accessory muscles and paradoxical abdominal motion Respiratory frequency >35 breaths per minute Life-threatening hypoxaemia Severe acidosis (pH <7.25) and/or hypercapnia (PaCO2 >8.0 kPa, 60 mm Hg) Respiratory arrest Somnolence, impaired mental status Cardiovascular complications (hypotension, shock) Other complications (metabolic abnormalities, sepsis, pneumonia, pulmonary embolism, barotrauma, massive pleural effusion) Ventilate patients to normal pH Reference Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2009. Available from: http://www.goldcopd.org. From the Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2009. Available from: http://www.goldcopd.org. 64

La Espiral Descendente en EPOC COPD Lung inflammation Mucous hypersecretion Airway obstruction Exacerbation Continued smoking Impaired mucous clearance Exacerbation Submucousal gland hypertrophy Alveolar destruction Speaker Notes COPD is a progressive disease in which patients experience pulmonary inflammation, mucus hypersecretion, airway obstruction, and exacerbations. This cycle continues ultimately leading to disability and death. Reference From the Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2008. Available from: http://www.goldcopd.org. Exacerbation Hypoxaemia DEATH From the Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2008. Available from: http://www.goldcopd.org. 65

Gracias.