Exacerbación de EPOC en la era de los nuevos fármacos.
Índice
Definición de Exacerbación.
Epidemiologia e Impacto.
Etiología.
Mecanismos Patogénicos.
Prevención.
Actitud Terapéutica.
Caso Clínico 1
JML, 72 años, EPOC colonizado Pseudomona,
Aspergillus.
MC: aumento su disnea habitual, de inicio súbito.
No fiebre ni expectoración. Saturando al 90%.
Roncus y subcrepitantes.
Se inicia tto corticoideo y broncodilatador.
Analítica y Rx.
Caso Clínico 1
Caso Clínico 1
Caso Clínico 2
TF, mujer, 81años, asma + EPOC, 4 meses de
ingresos repetidos y síntomas broncoespasmo.
Ingreso por tos y disnea no controlados.
Saturación 92%, roncus y sibilancias con
espiración muy alargada.
Tto corticoideo y broncodilatador, sin mejoría.
TAC inspiración espiración.
Caso Clínico 2
Caso Clínico 3Paciente 73 años, EPOC, lobectomía LID por
escamoso hace 5 años.Disnea progresiva de 4 meses. Ingresa por
aumento brusco de su disnea, con fiebre.Rx con infiltrado en LM.TACFBCMTS escamoso de pulmón, endoluminal- Láser
Caso Clínico 3
EXACERBACIÓN DE EPOC
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.”
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.
GOLD 2011
Síntomas y Diagnóstico de la Exacerbación de EPOC.
Disnea, acompañado de ruidos respiratorios y opresión torácica. Cambios en el color, cantidad o purulencia del esputo. Aumento de la tos. Otros: cansancio, astenia, anorexia, dificultad para dormir o sentirse
adormilado, fiebre, o cuadro confusional. Causas: infección de las vías aéreas e irritantes atmosféricos
(tabaco). Diagnóstico: anamnesis, exploración. 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.
FENOTIPOS DE LA EPOC
GOLD 2011
¿De dónde venimos?IpratropioSalbutamolc/4-6 hs
IndacaterolTiotropioICS+LABARoflumilast
¿Omalizumab?
ICS+LABA+M3
EPIDEMIOLOGÍA E IMPACTO
Exacerbaciones La evolución de la EPOC está marcada por las exacerbaciones,
ellas determinanCaída acelerada FEV1 Aumento mortalidadMenor actividad física Aumento en los costosDeterioro calidad de vida
Prevenir las exacerbaciones es la clave en el manejo de la EPOC a largo plazo.
La exacerbaciones son más frecuentes cuanto más grave es el paciente.
El principal factor de riesgo para una exacerbación es haber tenido otra previa independientemente del estadío GOLD.
Exacerbaciones
Las exacerbaciones frecuentes se relacionan con una mayor inflamación en estado estable.
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
Impacto de las Exacerbaciones en EPOC.
Wedzicha JA, Seemungal TA. Lancet. 2007;370:786-796.
Pacientes con Exacerbaciones Frecuentes
Mayor Mortalidad
Caída FEV1
Peor calidad de vida
Mayor inflamación
19
Factores Asociados con Aumento del Riesgo de Exacerbaciones.
Edad avanzada.
Severidad de la obstrucción
(FEV1).
Hipersecreción o broncorrea
crónica.
Exacerbaciones previas
frecuentes
Tos y disnea diarias
Síntomas persistentes de
bronquitis crónica.
Hipercapnia
Hipoxia
Comorbilidad
Cor pulmonale
Hipoalbuminemia
Vitacca 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.
La Frecuencia de las Exacerbaciones se Relaciona con el FEV1.
Donaldson GC, Wedzicha JA. Thorax. 2006;61:164-168.
FEV1 (1)
2.5
2.0
0.5
0< 1.25 1.25 – 1.54 > 1.54 2.40
3.0
1.5
Exa
cerb
acio
nes
po
r añ
o
2.50
1.0
Dai
ly M
edia
n P
EF
R a
s %
Bas
elin
e
La Función Pulmonar se Recupera Lentamente después de una
Exacerbación
Seemungal TA, et al. Am J Respir Crit Care Med. 2000;161:1608–1613.
Días
100
99
96
95
-14
101
98
97
-9 -4 1 6 11 16 21 26 31
Exacerbación
Caída Más Rápida del FEV1 en Exacerbadores Frecuentes
Donaldson GC, et al. Thorax. 2002;57:847-852.
Años
0.90
0.75
0
0.95
0.85
Per
cen
t C
han
ge
fro
m B
ase
lin
e in
FE
V1
0.80
1 2 3 4
Exacerbadores no-Frecuentes
Exacerbadores Frecuentes
Las Exacerbaciones Frecuentes se Asocian Con una Caída más Rápida del FEV1.
*
FEV1 (mL) PEF (L/minute)
An
nu
al C
ha
ng
e **
* P<0.05 versus infrequent exacerbators
Donaldson GC, et al. Thorax. 2002;57:847-852.
Mortalidad Luego de una Agudización de EPOC.
Kim S, et al. COPD. 2006;3:75-81.
Frecuencia Y Severidad Incrementan La Mortalidad.
Soler-Cataluña JJ, et al. Thorax. 2005;60:925-931.
Group A patients with no acute exacerbations Group B patients with 1–2 acute exacerbations
requiring hospital managementGroup C patients with >3 acute exacerbations
Group (1) no acute exacerbations Group (2) acute exacerbations requiring emergency
service visits without admissionGroup (3) patients with acute exacerbations requiring
one hospital admissionGroup (4) patients with acute exacerbations requiring
readmissions
1.0
0.8
0.6
0.4
0.2
0.00 10 20 30 40 50 60
Time (months)
A
p<0.0002
B
p=0.069
C
p<0.0
Pro
ba
bil
ity
of
su
rviv
ing
1.0
0.8
0.6
0.4
0.2
0.00 10 20 30 40 50 60
Time (months)
(1)
(3)
(4)
Pro
ba
bil
ity
of
su
rviv
ing
p<0.0001
(2)
NS
NS
p=0.005p<0.0001
Las Exacerbaciones Afectan Negativamente la Calidad de Vida.
Seemungal TA, et al. Am J Respir Crit Care Med. 2000;161:1608–1613.
* P<0.05 versus lower exacerbation rate
*
**
*
Depresión y Frecuencia de Exacerbación de EPOC
p = 0.03
Quint et al ERJ 2008
¿Quién es el cuidador principal?
Aspectos económicos
Costo del Tratamiento de una Exacerbación de EPOC
O'Reilly JF, et al. Int J Clin Pract. 2007;61:1112-1120.
ETIOPATOGENIA
Inflamación Pulmonar y Sistémica.
Wedzicha JA, Seemungal TA. Lancet. 2007;370:786-796.
Systemicinflammation
Bronchoconstrictionoedema, mucus
Expiratory flowlimitation
Cardiovascularcomorbidity
Exacerbationsymptoms
Dynamichyperinflation
InflamedCOPD airways
Greater airwayinflammation
VirusBacteria Pollutants
EFFECTS
TRIGGERS
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.
Modelo de Infección Bacteriana en Exacerbaciones
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
Persistent infection
Elimination ofInfecting Strain
Infección Viral + Bacteriana Tiene Sintomas Más Severos Y Peor Función Pulmonar.
Wilkinson TM, et al. Chest. 2006;129:317-324.
PPM = potentially pathogenic microorganisms
* P<0.05 versus cold and bacterial pathogen
+,* P<0.05 versus correspondingly labeled categories
1
No PPM & No Cold
No PPM & No Cold
PPM Alone
PPM Alone
Cold Alone
Cold Alone
Cold & Bacterial Pathogen
Cold & Bacterial Pathogen
*
** * +
*+
Las Concentraciones Bacterianas Aumentan Ligeramente Durante Una Exacerbacíón.
7.51 7.79
8.81
6.09
8.08 7.898.5
6.38
0
1
2
3
4
5
6
7
8
9
10
Lo
g S
pu
tum
Ba
cte
ria
l C
on
ce
ntr
ati
on
Stable
Exacerbation
H influenzae S pneumoniae H heamolyticusM catarrhalis
P=0.02
Sethi S, et al. Am J Respir Crit Care Med. 2007;176:356-361.
Predictores De Exacerbaciones
Fan VS, et al. J COPD. 2007;4:29-39.
1,16
1,67
1,08
2,07
2,05
1,69
0,0 0,5 1,0 1,5 2,0 2,5
FEV
PAO <55 mm Hg
SOBQ Total Score
>1 Prior COPD Hospitalization
>1 Prior COPD ED Visit
Comorbidity (Charlson-Deyo …
Odds Ratio
1
_
_
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.
Marcadores Inflamatorios Están Elevados Antes de la Agudización y Son Más Elevados en
Exacerbadores Frecuentes.
IL-8 Is Elevated in Frequent Exacerbators1
Fibrinogen Levels Are Elevated Prior to Exacerbations2
1. Bhowmik et al. Thorax. 2000;55:114-120.2. Groenewegen et al. Chest. 2008;133:350-357.
N=23
N=21
≤2 ≥30
10,000
20,000
Number of Exacerbations in Previous Year
IL-8
(pg
/mL)
<3.45 g/L
0 350
100
Months
No
Sev
ere
Exa
cerb
atio
n (%
)
90
80
70
60
6 9 12
≥3.45 g/L
Aumento de Neutrófilos Durante Agudización
Saetta M, et al. Am J Respir Crit Care Med. 1994;150:1646-1652.
* P<0.01 versus stable disease *
300
0
Ne u
tro
ph
il s/m
m2
250
200
100
150
50
Stable Disease Exacerbations
Marcadores de Inflamación Sistémica en Exacerbaciones.
Hurst JR, et al. Am J Crit Care Med. 2006;71-78.
* P<0.001 versus baseline
*
*
Ser
um
Co
nce
ntr
atio
n
41 exacerbaciones
Aumento Inflamación Esputo Durante Exacerbación y al Mes
Aaron SD, et al. Am J Respir Crit Care Med. 2001;163:349-355.
800
600
400
0
-200[I
L-8
] %
Ch
ang
e fr
om
Bas
elin
e
200
Baseline Exacerbation Convalescent
500
400
300
200
100
0
-100
-200
Baseline Exacerbation Convalescent
[TN
F]
% C
han
ge
fro
m B
asel
ine
Patient Status (n = 14) Patient Status (n = 14)
TNF- IL-8Esputo inducido
La Inflamación Sistémica se Relaciona con Deterioro Función Pulmonar en
Exacerbaciones.
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.
Incr
ease
in p
erip
her
al b
loo
d n
eutr
op
hils
at e
xace
rbat
ion
(ce
lls/d
L)
Percent decrease FEV1 at exacerbation
6000
4000
2000
0
-4000-5 0 5 10 15 20 25 30
r=0.5518
P<0.001
-2000
8000
Prevención de Exacerbaciones
Influenza Vaccination: Risk for Any Exacerbation
Poole PJ, et al. Cochrane Database Syst Rev. 2006;CD002733.
Weight(%)
0.2 0.5 2 51
Favors PlaceboFavors Antibiotic
Placebo n/N
Peto Odds RatioPeto, Fixed, 95% CI
Treatmentn/N
Peto Odds RatioPeto, Fixed, 95% CI
Subtotal (95% CI) 46 51 58.2% 1.06 [0.48, 2.33]
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]
Subtotal (95% CI) 62 63 41.8% 0.46 [0.22, 1.42]
Total events: 49 (Treatment), 55 (Placebo)Heterogeneity: not applicableTest 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%
1 Clinical exacerbations
Howells 1961 32.8%10/26 20/29 0.30 [0.10, 0.86]Fell 1977 5.42 [1.64, 17.96]15/20 7/22 25.4%
Study or subgroup
META-ANALISIS: Vacunar disminuye exacerbaciones
Vacunación Neumococo.
Granger R, et al. Cochrane Database Syst Rev. 2006;CD001390. Permission requested.
0.1 1 10
Favors controlFavors treatment
Pneumococcal Vaccinen/N
Study or subgroup Controln/N
Odds RatioM-H, Fixed, 95% CI
Odds RatioM-H, Fixed, 95% CI
Acute Exacerbation
1 Vaccine > 14 serotypesSteentoft 2006 30/37 9/12 1.43 [0.31, 6.69]
2 Vaccine 14 or less serotypes
0.0 1 10
Favors controlFavors treatment
log [Rate Ratio] n/N
Study or subgroup Rate RatioIV, Fixed, 95% CI
Rate RatioIV, Fixed, 95% CI
Hospitalization for Acute Exacerbation
1 Vaccine > 14 serotypes
-0.185 (0.2178) 0.83 [0.54, 1.27]2 Vaccine 14 or less serotypes
Leech, 1987
0.1 100
¿?
Brusasco V, et al. Thorax. 2003;58:399-404.
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
TiotropiumSalmeterolPlacebo
P=0.025N
um
ber
of
Exa
cerb
atio
ns
per
P
atie
nt
Yea
r1.49
1.07
1.23
· 3.48
Efecto de los Broncodilatadores en Frecuencia Exacerbaciones.
NS
Estudio TORCH: Menos Exacerbaciones conLABA + ICS
Calverley PM, et al. N Engl J Med. 2007;356:775-789.
*
*
* *
*
**
*
* P<0.05 versus placebo
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.
Hazard ratio = 0.86, (95% CI, 0.81, 0.91)P< 0.0001 (log-rank test)
Months
Tiotropium
Control
0
20
40
60
80
0 6 12 18 24 30 36 42 48
Pro
bab
ility
of e
xace
rba
tion
(%) 0.85/yr
0.73/yr; P<0.001(14% reduction)
Tiotropio- Estudio UPLIFT: Efecto en Exacerbaciones.
Tashkin DP, et al. N Engl J Med. 2008;359:1543-1554. Copyright © 2008 Massachusetts Medical Society. All rights reserved.
Nuevas Moléculas
Roflumilast
Indacaterol
Mea
n N
um
ber
of
Exa
cerb
atio
ns
per
Pat
ien
t
Placebo Roflumilast 250 µg
Roflumilast 500 µg
0.4
0.6
0.8
1.0
1.2
0.2
0
1.4
1.131.03
0.75
p=0.0029 Roflumilast vs Placebo
Roflumilast Disminuye las Exacerbaciones vs Placebo
Rabe et al. Lancet. 2005;366:563-571.
34% menos exacerbac.
Efecto del Roflumilast en las Exacerbaciones (estudio OPUS)*
* Exacerbaciones moderadas o severas† Analysis Post-hoc
RoflumilastPlacebo
0.92 0.86
Exa
cerb
atio
ns
/ pat
ien
t / y
ear
P=0.451
Todos los pacientes (n=1513)
0
0.4
1.2
0.8
Exa
cerb
atio
ns
/ pat
ien
t / y
ear
Pacientes con EPOC muy severo†P=0.024
1.61.59
1.01
RoflumilastPlacebo
D 36%
0
0.4
1.2
0.8
1.6
Calverley et al. Am J Respir Crit Care Med. 2007;176:154-161.
Nuevas Moléculas
Roflumilast
Indacaterol
Estudio Inhance: Indacaterol Disminuye Medicación de Rescate vs Placebo y
Tiotropio
***p<0.001 vs placebo; †††p<0.001 vs tiotropioLötvall, et al. ERS 2009
36% Mejora
INHANCE
80
60
40
20
0Dia
s lib
res
de
med
icac
ión
de
resc
ate
(%)
Durante 26 semanas
*** †††
*** †††
41.846.1
56.7 57.8
Placebo (n=351) Tiotropio 18 µg o.d. (n=383)
Indacaterol 150 µg o.d. (n=380) Indacaterol 300 µg o.d. (n=377)
Estudio INVOLVE: Indacaterol Disminuye Medicación de Rescate vs Placebo y Formoterol
***p<0.001 vs placebo; ††p=0.007 vs formoterol.
***
68% Mejora
Nonikov, et al. ERS 2009
Durante 52 semanas
Dia
s lib
res
de
med
icac
ión
de
resc
ate
(%)
70
60
50
40
30
20
10
0
34.8%
52.1%58.3%
Placebo (n=364) Formoterol 12 μg b.i.d. (n=373)
Indacaterol 300 μg o.d. (n=383)
*** ††
INVOLVE
Estudio INLIGHT: Indacaterol Disminuye Medicación de Rescate vs Placebo y
Salmeterol.
Kornmann, et al. ACCP 2009
Indacaterol 150 µg o.d. (n=320) Salmeterol 50 µg b.i.d. (n=317)Placebo (n=321)
††
*****
**p<0.01, ***p<0.001 vs placebo; ††p<0.01 vs salmeterol.
30% Mejora
INLIGHT 2
Durante 26 semanas
Dia
s lib
res
de
med
icac
ión
de
resc
ate
(%) 42
5560
0
10
20
30
40
50
60
70
Prevención de exacerbaciones.Nuevas líneas.
• Macrólidos Seemungal TAR et al, AMRCCM 2008
• EstatinasSoyseth V et al, ERJ 2007
Blamoun AI et al, Int J Clin Pract 2008
• Mucolíticos (Carbocisteina)Zheng JP et al Lancet 2008
Tiempo hasta 1ª Exacerbac
Tiempo a 1ª IOT
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.
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
Tratamiento de las Exacerbaciones
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.
Treatment Algorithm for Mild-toModerate Exacerbations
Rodríguez-Roisin R. Thorax. 2006;61:535-544.
Reassess within hours
Initiate or increase short acting bronchodilator therapyConsider antibiotics
No improvement
Add oral corticosteroids
Reassess within hours,exclude complications
Worsening of signs/symptoms or failure
Refer to hospital
Improvement ofsigns/ symptoms
Continue managementStep down when
possible
Review long term management
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.
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.
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 hospitalFrom 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.
Meta-analysis of Efficacy: Systemic Corticosteroids and Risk for Treatment Failure
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.
100.1 0.2 0.5
Relative Risk (95% Confidence Interval)
2 51
Favors PlaceboFavors Steroid
Pooled summary(RR, 0.54; 95% CI, 0.41-0.71)
Bullard et al, 1996
Thompson et al, 1996
Davies et al, 1999
Niewoehner et al, 1999
Maltais et al, 2002
Aaron et al, 2003
Recommended Antimicrobial Therapy
Oral Treatment(No particular order)
Alternative OralTreatment
(No particular order)
ParenteralTreatment
(No particular order)
Group A Patients with only one cardinal symptom should notReceive antibiotics
If indication then: β-lactam (penicillin, ampicillin/amoxicillin), tetracycline, trimethoprim/sulfamethoxazole
β-lactam/β-lactamase inhibitor (Co-amoxiclav)Macrolides (azithromycin, clarithromycin,roxithromycin)Cephalosporins (2nd or 3rd generation)Ketolides (telithromycin)
Group B β-lactam/β-lactamase inhibitor (Co-amoxiclav)
Fluoroquinolones (gemifloxacin, levofloxacin, moxifloxacin)
β-lactam/β-lactamase inhibitor (Co-amoxiclav, ampicillin/sulbactam)Cephalosporins (2nd or 3rd generation)Fluoroquinolones (levofloxacin, moxifloxacin)
Group C In patients at risk for pseudomonasinfections:Fluoroquinolones (ciprofloxacin, levofloxacin - high dose)
Fluoroquinolones (ciprofloxacin, levofloxacin - high dose) or β-lactam with P aeruginosa activity
Group A: Mild exacerbation, no risk factors for poor outcomeGroup B: Moderate exacerbation with risk factor(s) for poor outcomeGroup 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.
Meta-analysis of Efficacy: Antibiotic Therapy and Risk for Treatment Failure
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.
100.1 0.2 0.5
Relative Risk (95% Confidence Interval)
2 51
Favors PlaceboFavors Antibiotics
Pooled summary(RR, 0.54; 95% CI, 0.32-0.92)
Elmes et al, 1965
Pines et al, 1968
Anthonisen et al, 1987
Jorgensen et al, 1992
Nouira et al, 2001
Meta-analysis of Efficacy: Antibiotic Therapy and Risk for Mortality
Ram FS, et al. Cochrane Database Syst Rev. 2006;CD004403. Permission requested.
Weight(%)
0.67 [0.56, 0.80]
0.33 [0.07, 1.52]
0.70 [0.45, 1.11]
0.32 [0.15, 0.68]
1.03 [0.75, 1.41]
0.40 [0.22, 0.74]
0.57 [0.41, 0.79]
100.1 0.2 0.5 2 51
Favors PlaceboFavors Antibiotic
Placebo Group
n/N
Relative Risk (Forced)95% CI
Relative Risk (Forced)
95% CI
Study Antibiotic Group
n/N
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
Total (95% CI)
Alonso 1992
Anthonisen 1987
Elmes 1965a
Jorgenson 1992
Pines 1968
Pines 1972
351
2/29
19/57
6/29
49/132
6/15
31/89
354
6/29
28/59
19/29
49/136
15/15
53/86
100.0
3.5
16.2
11.2
28.4
8.8
31.8
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.
Meta-analysis of Efficacy: NIV
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.
Risk for Intubation Risk for In-hospital Mortality
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
Relative Risk (95% Confidence Interval)
1
Favors NPPV Favors StandardTherapy
0.01 0.1 10 100
Relative Risk (95% Confidence Interval)
1
Favors NPPV Favors StandardTherapy
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.