Exacerbaciones de EPOC

1. Exacerbación de EPOC en la era de los nuevos fármacos. pablo.rubinstein@separ.es

3. Epidemiologia e Impacto.

4. Etiología.

5. Mecanismos Patogénicos.

6. Prevención.

8. MC: aumento su disnea habitual, de inicio súbito. No fiebre ni expectoración. Saturando al 90%. Roncus y subcrepitantes.

9. Se inicia tto corticoideo y broncodilatador.

11. Caso Clínico 1

13. Tto corticoideo y broncodilatador, sin mejoría.

16. Disnea progresiva de 4 meses. Ingresa por aumento brusco de su disnea, con fiebre.

17. Rx con infiltrado en LM.

18. TAC

19. FBC

21. EXACERBACIÓN DE EPOC

22. Definición de Exacerbación de EPOC “An event in the natural course of the disease characterized by a change in the patient’s baseline dyspnea, 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.” GOLD 2011 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.

24. Cambios en el color, cantidad o purulencia del esputo.

25. Aumento de la tos.

26. Otros: cansancio, astenia, anorexia, dificultad para dormir o sentirse adormilado, fiebre, o cuadro confusional.

27. Causas: infección de las vías aéreas e irritantes atmosféricos (tabaco).

28. Diagnóstico: anamnesis, exploración.

29. Test dependerán de los síntomas, de la posibilidad de diagnósticos diferenciales y gravedad: analítica, PCR, cultivo de esputo, hemocultivos, antigenuria, RX de tórax o TAC, espirometría, pulsioximetría, gasometría arterial, etc. 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.

30. GOLD 2011 FENOTIPOS DE LA EPOC

31. Ipratropio Salbutamol c/4-6 hs ¿De dónde venimos? Indacaterol Tiotropio ICS+LABA Roflumilast

32. ICS+LABA+M3 ¿Omalizumab?

33. Epidemiología e Impacto

35. Caída acelerada FEV1 Aumento mortalidad

36. Menor actividad física Aumento en los costos

37. Deterioro calidad de vida

38. Prevenir las exacerbaciones es la clave en el manejo de la EPOC a largo plazo.

39. La exacerbaciones son más frecuentes cuanto más grave es el paciente.

41. Estos conceptos han dado origen a la teoría del: FENOTIPO EXACERBADOR un grupo de pacientes con exacerbaciones frecuentes, independientes de la gravedad, con una peor evolución y que ameritarían un tratamiento más enérgico. ‘ Tashkin D., Frequent Exacerbations of Chronic Obstructive Pulmonary Disease — A Distinct Phenotype? NEJM 363;12 ‘ Wedzicha J., Choice of Bronchodilator Therapy for Patients with COPD NEJM 364;12 ‘ POET-COPD Investigators, Tiotropium versus Salmeterol for the Prevention of Exacerbations of COPD NEJM 364;12

42. Impacto de las Exacerbaciones en EPOC. Pacientes con Exacerbaciones Frecuentes Caída FEV1 Mayor inflamación Mayor Mortalidad Peor calidad de vida Wedzicha JA, Seemungal TA. Lancet. 2007;370:786-796. 19

44. Severidad de la obstrucción (FEV1).

45. Hipersecreción o broncorrea crónica.

46. Exacerbaciones previas frecuentes

47. Tos y disnea diarias

48. Síntomas persistentes de bronquitis crónica.

49. Hipercapnia

50. Hipoxia

51. Comorbilidad

52. Cor pulmonale

53. HipoalbuminemiaVitacca M. Monaldi Arch Chest Dis. 2001;56:137-143. Anzueto A, et al. Proc Am Thorac Soc. 2007;4:554-564. Takabatake N, et al. Am J Respir Crit Care Med. 2006;174:875-885.

54. La Frecuencia de lasExacerbaciones se Relaciona con el FEV1. 3.0 2.5 2.0 Exacerbaciones por año 1.5 1.0 0.5 0 < 1.25 1.25 – 1.54 > 1.54 2.40 2.50 FEV1 (1) Donaldson GC, Wedzicha JA. Thorax. 2006;61:164-168.

55. La Función Pulmonar se Recupera Lentamente después de una Exacerbación 101 Exacerbación 100 99 98 Daily Median PEFR as % Baseline 97 96 95 -14 -9 -4 1 6 11 16 21 26 31 Días Seemungal TA, et al. Am J Respir Crit Care Med. 2000;161:1608–1613.

56. Caída Más Rápida del FEV1 en Exacerbadores Frecuentes 0.95 Exacerbadores no-Frecuentes Exacerbadores Frecuentes 0.90 Percent Change from Baseline in FEV1 0.85 0.80 0.75 0 1 2 3 4 Años Donaldson GC, et al. Thorax. 2002;57:847-852.

57. Las Exacerbaciones Frecuentes se Asocian Con una Caída más Rápida del FEV1. FEV1 (mL) PEF (L/minute) ** Annual Change * P<0.05 versus infrequent exacerbators * Donaldson GC, et al. Thorax. 2002;57:847-852.

58. Mortalidad Luego de una Agudización de EPOC. Kim S, et al. COPD. 2006;3:75-81.

59. Frecuencia Y Severidad Incrementan La Mortalidad. 1.0 1.0 0.8 0.8 (1) A p<0.0002 NS 0.6 0.6 (2) p<0.0001 Probability of surviving Probability of surviving p=0.005 p<0.0 B p=0.069 0.4 0.4 p<0.0001 (3) NS C 0.2 0.2 (4) 0.0 0.0 0 10 20 30 40 50 60 0 10 20 30 40 50 60 Time (months) Time (months) 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 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 Soler-Cataluña JJ, et al. Thorax. 2005;60:925-931.

60. Las Exacerbaciones Afectan Negativamente la Calidad de Vida. * * * * * P<0.05 versus lower exacerbation rate Seemungal TA, et al. Am J Respir Crit Care Med. 2000;161:1608–1613.

61. Depresión y Frecuencia de Exacerbación de EPOC p = 0.03 Quint et al ERJ 2008

62. ¿Quién es el cuidador principal?

63. Aspectos económicos

64. Costo del Tratamiento de una Exacerbación de EPOC O'Reilly JF, et al. Int J Clin Pract. 2007;61:1112-1120.

65. ETIOPATOGENIA

66. Inflamación Pulmonar y Sistémica. Exacerbation symptoms TRIGGERS Virus Bacteria Pollutants Inflamed COPD airways EFFECTS Greater airway inflammation Bronchoconstriction oedema, mucus Systemic inflammation Expiratory flow limitation Cardiovascular comorbidity Dynamic hyperinflation Wedzicha JA, Seemungal TA. Lancet. 2007;370:786-796.

67. Patógenos Bacterias (50%) Haemophilus influenzae Moraxella catarrhalis Streptococcus pneumoniae Pseudomonas aeruginosa Gram-negative bacilli Chlamydia pneumoniae Mycoplasma pneumoniae Legionella spp Virus (39%) Influenza Parainfluenza Respiratory syncytial virus (RSV) Human metapneuomia virus Picornaviruses Sykes A, et al. Proc Am Thorac Soc. 2007;4:642-646. Martinez FJ. Proc Am Thorac Soc. 2007;4:647-658.

68. Acquisition of new bacterial strain Pathogen virulenceHost lung defense Change in airway inflammation Level of symptoms Colonization Exacerbation Strain Specific immune response+/– Antibiotics Tissue InvasionAntigenic alteration Modelo de InfecciónBacteriana en Exacerbaciones Elimination ofInfecting Strain Persistent infection

69. Infección Viral + Bacteriana Tiene Sintomas Más Severos Y Peor Función Pulmonar. * *+ * + * * 1 Cold & Bacterial Pathogen No PPM & No Cold No PPM & No Cold PPM Alone Cold Alone Cold & Bacterial Pathogen PPM Alone Cold Alone PPM = potentially pathogenic microorganisms * P<0.05 versus cold and bacterial pathogen +,* P<0.05 versus correspondingly labeled categories Wilkinson TM, et al. Chest. 2006;129:317-324.

70. Las Concentraciones Bacterianas Aumentan Ligeramente Durante Una Exacerbacíón. P=0.02 H influenzae S pneumoniae H heamolyticus M catarrhalis Sethi S, et al. Am J Respir Crit Care Med. 2007;176:356-361.

71. _ _ 1 Odds Ratio Predictores De Exacerbaciones Fan VS, et al. J COPD. 2007;4:29-39.

72. Elevación De Mediadores Inflamatorios En Exacerbaciones C-reactive peptide Copeptin IL-8 IL-6 Tumor necrosis factor-α Leptin Eosinophillic cationic protein Myeloperoxidase α1-antitrypsin Leukotrienes E4 and B4 Fibrinogen Myeloid progenitor inhibitory factor-1 (MPIF-1) Pulmonary and activation–regulated chemokine (PARC) Soluble intercellular adhesion molecule-1 (sICAM-1) Adiponectin (ACRP-30) Wouters EF, et al. Proc Am Thorac Soc. 2007;4:626-634.

73. Marcadores Inflamatorios Están Elevados Antes de la Agudización y Son Más Elevados en Exacerbadores Frecuentes. 20,000 N=23 10,000 IL-8 (pg/mL) N=21 0 ≤2 ≥3 Number of Exacerbations in Previous Year IL-8 Is Elevated in Frequent Exacerbators1 Fibrinogen Levels Are Elevated Prior to Exacerbations2 100 <3.45 g/L 90 ≥3.45 g/L 80 No Severe Exacerbation (%) 70 60 50 0 3 6 9 12 Months 1. Bhowmik et al. Thorax. 2000;55:114-120. 2. Groenewegen et al. Chest. 2008;133:350-357.

74. Aumento de Neutrófilos Durante Agudización This study shows that the numbers of neutrophils was significantly increased during exacerbations (P<0.01). 300 * P<0.01 versus stable disease * 250 200 Neutrophils/mm2 150 100 50 Acute Exacerbation, Neutrophil 0 Exacerbations Stable Disease Saetta M, et al. Am J Respir Crit Care Med. 1994;150:1646-1652.

75. Marcadores de Inflamación Sistémica en Exacerbaciones. Persistent, low-grade systemic inflammation is thought to play a key role in the pathogenesis of atherothrombosis. 41 exacerbaciones * P<0.001 versus baseline * Serum Concentration * Acute Exacerbation, CRP, IL-8 Hurst JR, et al. Am J Crit Care Med. 2006;71-78.

76. Aumento Inflamación Esputo Durante Exacerbación y al Mes Esputo inducido 800 500 IL-8 TNF- 400 600 300 400 200 [TNF] % Change from Baseline [IL-8] % Change from Baseline 100 200 0 0 -100 -200 -200 Baseline Exacerbation Convalescent Baseline Exacerbation Convalescent Patient Status (n = 14) Patient Status (n = 14) Aaron SD, et al. Am J Respir Crit Care Med. 2001;163:349-355.

77. La Inflamación Sistémica se Relaciona con Deterioro Función Pulmonar en Exacerbaciones. 8000 6000 4000 Increase in peripheral blood neutrophilsat exacerbation (cells/dL) 2000 r=0.5518P<0.001 0 -2000 -4000 -5 0 5 10 15 20 25 30 Percent decrease FEV1 at exacerbation Papi A, et al. 2006, “Infections and Airway Inflammation in Chronic Obstructive Pulmonary Disease Severe Exacerbations ,”American Journal of Respiratory and Critical Care Medicine, Vol 173:1114-1121. Official Journal of the American Thoracic Society © American Thoracic Society, Christina Shepherd, Managing Editor, 12/18/08.

78. Prevención de Exacerbaciones

79. Subtotal (95% CI) 46 51 58.2% 1.06 [0.48, 2.33] Subtotal (95% CI) 62 63 41.8% 0.46 [0.22, 1.42] Total events: 49 (Treatment), 55 (Placebo) Heterogeneity: not applicable Test for overall effect: Z = 1.23 (P = 0.22) Total (95% CI) 108 114 100.0% 0.81 [0.44, 1.48] Total events: 74 (Treatment), 82 (Placebo) Heterogeneity: Chi2 = 13.74, df = 2 (P = 0.001); 12 = 8% Test for overall effect: Z = 0.69 (P = 0.49) Test for subgroup differences: Chi2 = 1.06, df = 1 (P = 0.30), 12 = 6% Influenza Vaccination: Risk for Any Exacerbation Weight(%) Placebo n/N Peto Odds RatioPeto, Fixed, 95% CI Treatmentn/N Peto Odds RatioPeto, Fixed, 95% CI Study or subgroup 1 Clinical exacerbations Fell 1977 5.42 [1.64, 17.96] 15/20 7/22 25.4% Howells 1961 32.8% 10/26 20/29 0.30 [0.10, 0.86] Total events: 25 (Treatment), 27 (Placebo) Heterogeneity: Chi2 = 12.68, df = 1 (P = 0.00037); 12 =92% Test for overall effect: Z = 0.14 (P = 0.89) 2 Any acute respiratory illness Wongsurakiat 2004 49/62 55/63 41.8% 0.56 [0.22, 1.42] META-ANALISIS: Vacunar disminuye exacerbaciones 0.2 0.5 2 5 1 Favors Placebo Favors Antibiotic Poole PJ, et al. Cochrane Database Syst Rev. 2006;CD002733.

80. Vacunación Neumococo. ¿? Acute Exacerbation Pneumococcal Vaccinen/N Study or subgroup Controln/N Odds RatioM-H, Fixed, 95% CI Odds RatioM-H, Fixed, 95% CI 1 Vaccine > 14 serotypesSteentoft 2006 30/37 9/12 1.43 [0.31, 6.69] 2 Vaccine 14 or less serotypes 0.1 1 10 Favors control Favors treatment Hospitalization for Acute Exacerbation log [Rate Ratio] n/N Study or subgroup Rate RatioIV, Fixed, 95% CI Rate RatioIV, Fixed, 95% CI 1 Vaccine > 14 serotypes 2 Vaccine 14 or less serotypesLeech, 1987 -0.185 (0.2178) 0.83 [0.54, 1.27] 0.0 1 10 0.1 100 Favors control Favors treatment Granger R, et al. Cochrane Database Syst Rev. 2006;CD001390. Permission requested.

82. Corticoides Inhalados ICS no previenen la caída del FEV1. Disminuyen la frecuencia de exacerbaciones. Dados de manera aislada, podrían aumentar la frecuencia de NAC. Mejoran la calidad de vida relacionada con la salud en pacientes con FEV1 <50%. Guía GOLD 2011.

83. 0.85/yr 0.73/yr; P<0.001 (14% reduction) Tiotropio- Estudio UPLIFT: Efecto en Exacerbaciones. 80 Control 60 Tiotropium Probability of exacerbation (%) Hazard ratio = 0.86, (95% CI, 0.81, 0.91) P< 0.0001 (log-rank test) 40 20 0 0 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.

89. †† *** INVOLVE Estudio INVOLVE: Indacaterol Disminuye Medicación de Rescate vs Placebo y Formoterol Placebo (n=364) Formoterol 12 μg b.i.d. (n=373) Indacaterol 300 μg o.d. (n=383) 70 60 50 40 30 20 10 0 58.3% *** 52.1% 68% Mejora 34.8% Dias libres de medicación de rescate (%) Durante 52 semanas ***p<0.001 vs placebo; ††p=0.007 vs formoterol. Nonikov, et al. ERS 2009

90. INLIGHT 2 Estudio INLIGHT: IndacaterolDisminuyeMedicación de Rescatevs Placebo y Salmeterol. Indacaterol 150 µg o.d. (n=320) Salmeterol 50 µg b.i.d. (n=317) Placebo (n=321) †† 70 ** *** 60 60 55 30% Mejora 50 42 40 Dias libres de medicación de rescate (%) 30 20 10 0 Durante 26 semanas **p<0.01, ***p<0.001 vs placebo; ††p<0.01 vs salmeterol. Kornmann, et al. ACCP 2009

91. Prevención de exacerbaciones.Nuevas líneas. Macrólidos Seemungal TAR et al, AMRCCM 2008 Estatinas Soyseth V et al, ERJ 2007 Blamoun AI et al, Int J Clin Pract 2008 Mucolíticos (Carbocisteina) Zheng JP et al Lancet 2008

93. Tiempo hasta 1ª Exacerbac Tiempo a 1ª IOT

94. Reducción de Volumen The effect of lung volume reduction surgery on chronic obstructive pulmonary disease exacerbations. Washko GR et al, Am J Respri Crit Care Med 2008;177(2):164-9. Conclusiones: LVRS reduce la frecuencia de exacerbaciones.

95. El nº de exacerbaciones a un año fue 325 en el grupo carbocisteina y 439 en el grupo placebo (p=0.004) Zheng JP. Et al. Lancet 2008;371:2013-18

96. Tratamiento de las Exacerbaciones

97. Severidad de la Exacerbación Acidosis: pH <7.36 y pCO2 > 45 mmHg. Rx tórax (PA y perfil): diagn. diferencial. ECG: descartar arritmias, isquemia, hipetrofia ventricular. Esputo. Hemograma: leucocitosis. Poliglobulia. Anemia.

98. Treatment Algorithm for Mild-toModerate Exacerbations Initiate or increase short acting bronchodilator therapyConsider antibiotics Reassess within hours No improvement Improvement ofsigns/ symptoms Add oral corticosteroids Continue managementStep down when possible Reassess within hours,exclude complications Review long term management Worsening of signs/symptoms or failure Refer to hospital Rodríguez-Roisin R. Thorax. 2006;61:535-544.

99. Indications for Hospital Management of Acute 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 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.

100. Indications for Intensive Care Unit Admission for Acute Exacerbations 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 mmHg), 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 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.

101. Management of Severe, but Not Life-threatening Exacerbations* Assess severity of symptoms, blood gases, chest X-ray Administer controlled oxygen therapy and repeat arterial blood gas measurement after 30-60 minutes Bronchodilators: Increase doses and/or frequency Combine β2-agonists and anticholinergics Use spacers or air-driven nebulizers Consider adding intravenous methylxanthines, if needed Add oral or intravenous glucocorticosteroids Consider antibiotics (oral or occasionally intravenous) when signs of bacterial infection Consider noninvasive mechanical ventilation At all times: Monitor fluid balance and nutrition Consider subcutaneous heparin Identify and treat associated conditions (e.g., heart failure, arrhythmias) Closely monitor condition of the patient * In the Emergency department or hospital 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.

102. Meta-analysis of Efficacy: Systemic Corticosteroids and Risk for Treatment Failure Favors Placebo Favors Steroid Bullard et al, 1996 Thompson et al, 1996 Davies et al, 1999 Niewoehner et al, 1999 Maltais et al, 2002 Aaron et al, 2003 Pooled summary(RR, 0.54; 95% CI, 0.41-0.71) 10 0.1 0.2 0.5 2 5 1 Relative Risk (95% Confidence Interval) Reproduced with permission of Chest, from “Contemporary Management of Acute Exacerbations of COPD”, Quon BS et al, Vol 133, Copyright © 2008; permission conveyed through Copyright Clearance Center, Inc.

103. Recommended Antimicrobial Therapy Group A: Mild exacerbation, no risk factors for poor outcome Group B: Moderate exacerbation with risk factor(s) for poor outcome Group C: Severe exacerbation with risk factors for P aeruginosa infection 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.

104. Meta-analysis of Efficacy: Antibiotic Therapy and Risk for Treatment Failure Favors Placebo Favors Antibiotics Elmes et al, 1965 Pines et al, 1968 Anthonisen et al, 1987 Jorgensen et al, 1992 Nouira et al, 2001 Pooled summary(RR, 0.54; 95% CI, 0.32-0.92) 10 0.1 0.2 0.5 2 5 1 Relative Risk (95% Confidence Interval) Reproduced with permission of Chest, from “Contemporary Management of Acute Exacerbations of COPD”, Quon BS et al, Vol 133, Copyright © 2008; permission conveyed through Copyright Clearance Center, Inc.

105. Meta-analysis of Efficacy: Antibiotic Therapy and Risk for Mortality Weight(%) Placebo Groupn/N Relative Risk (Forced)95% CI Relative Risk (Forced) 95% CI Study Antibiotic Groupn/N 0.33 [0.07, 1.52] Alonso 1992 2/29 6/29 3.5 0.70 [0.45, 1.11] Anthonisen 1987 19/57 28/59 16.2 Elmes 1965a 6/29 19/29 11.2 0.32 [0.15, 0.68] Jorgenson 1992 49/132 49/136 28.4 1.03 [0.75, 1.41] Pines 1968 6/15 15/15 8.8 0.40 [0.22, 0.74] Pines 1972 31/89 53/86 31.8 0.57 [0.41, 0.79] Total (95% CI) 351 354 100.0 0.67 [0.56, 0.80] Total events: 113 (Antibiotic Group), 170 (Placebo Group)Test for heterogeneity dri-square = 15.46 df = 5 p = 0.009 F = 67.7% Test for overall effect z=4.27 p=0.00002 10 0.1 0.2 0.5 2 5 1 Favors Placebo Favors Antibiotic Ram FS, et al. Cochrane Database Syst Rev. 2006;CD004403. Permission requested.

106. Noninvasive Mechanical Ventilation (NIV) Selection Criteria Moderate to severe dyspnoea with use of accessory muscles and paradoxical abdominal motion Moderate to severe acidosis (pH ≤7.35) and/or hypercapnia (PaCO2 > 6.0 kPa, 45 mm Hg) Respiratory frequency >25 breaths per minute Contraindications 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 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.

107. Meta-analysis of Efficacy: NIV Risk for Intubation Risk for In-hospital Mortality Favors NPPV Favors NPPV Favors StandardTherapy Favors StandardTherapy Bolt et al, 1993 Desinkpoulou et al, 1993 Servillo et al, 1994 Brochard et al, 1995 Kramer et al, 1995 Angus et al, 1996 Cellical et al, 1998 Plant et al, 2000 Olkensoy et al, 2002 CRC et al, 2005 Dharnja et al, 2005 Keenan et al, 2005 Pooled summary(RR.036: 96% CL 0.26-0.47) Bolt et al, 1993 Servillo et al, 1994 Brochard et al, 1995 Kramer et al, 1995 Angus et al, 1996 Cellical et al, 1998 Plant et al, 2000 Olkensoy et al, 2002 CRC et al, 2005 Dharnja et al, 2005 Keenan et al, 2005 Pooled summary(RR.045: 95% CL 0.30-0.66) 0.01 0.1 10 100 1 0.01 0.1 10 100 1 Relative Risk (95% Confidence Interval) Relative Risk (95% Confidence Interval) Reproduced with permission of Chest, from “Contemporary Management of Acute Exacerbations of COPD”, Quon BS et al, Vol 133, Copyright © 2008; permission conveyed through Copyright Clearance Center, Inc.

108. Indications for Invasive Mechanical Ventilation 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) 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.

109. Gracias pablo.rubinstein@separ.es