1

Asthma Management:
Optimizing Patient Outcomes
Stanley B. Fiel, MD
Vice Chairman of Medicine
Professor and Chief
Division of Pulmonary/Critical Care Medicine
MCP Hahnemann University School of Medicine
and
Chief of Medicine, MCP Hospital
Philadelphia, Pennsylvania, USA
2
Asthma in USA:
Morbidity and Mortality
15 million asthmatic patients
6% prevalence
75% increase in last 15 yr
466,000 hospitalizations
2 million emergency department visits
5000 deaths
$11.3 billion healthcare costs
Mannino DM et al. Mor Mortal Wkly Rep. 1998;47(suppl 1):1; US Department of Health and Human Services/HHS Fact
Sheet. Available at: http://www.os.dhhs.gov/news/press/2001pres/01fsasthma.html. Accessed February 21, 2001

3
Asthma Death Rates
5
Japan


White 1.5
Black 3.8
USA

Death Rates* Country
Mannino DM et al. Mor Mortal Wkly Rep. 1998;47(suppl 1):1
Nakazawa T et al. [in japanese] Nihon Kyobu Shikkan Gakkai Zasshi. 1996;34:157
*Per 100,000 population
4
Rickard KA, Stempel DA. J Allergy Clin Immunol. 1999;103(1 pt 2):S171
Impact of Asthma on Quality of Life
Patients (%)
Sleep disruption
> once/wk
Missed school
in past yr

Limited
sports/recreation
Unscheduled ED
visits in past yr
0 10 20 30 40 50 60
Missed work
in past yr

23
48
49
25
30
N=2509
5
0
5
10
15
20
25
30
35
40
Severe Moderate Mild
Robertson CF et al. Pediatr Pulmonol. 1992;13:95
Patient Assessment
Pediatric Asthma Deaths
Not Limited to Severe Disease
Findings from cohort study reviewing all pediatric asthma-related
deaths (n = 51) in Australian state of Victoria
6
Solutions to Enhance
Asthma Management
7
Stepwise Approach to Asthma Management

Daytime
Symptoms
Nighttime
Symptoms
Step 4
Severe persistent
Continuous; limited
physical activity
Frequent
Step 3
Moderate persistent
Daily; use |
2
-agonist daily,
attacks affect activity

> once/wk
Step 2
Mild persistent
> once/wk but s once/d
> twice/mo
Step 1
Intermittent
< once/wk; asymptomatic
and normal PEF between
attacks
s twice/mo
NIH/NHLBI. Global Initiative for Asthma. Bethesda, Md: 1998, NIH Publication No. 96-3659B
Classify Severity of Clinical Features Before Treatment
8
R
a
t
e

R
a
t
i
o

f
o
r

D
e
a
t
h

F
r
o
m

A
s
t
h
m
a

Canisters of Inhaled Glucocorticoids/yr
Adapted with permission from Suissa S et al. N Engl J Med. 2000;343:332
Low-Dose Inhaled Glucocorticoids

2.5
2.0
1.5
1.0
0.5
0.0
0 1 2 3 4 5 6 7 8 9 10 11 12
Preventing Death From Asthma
9
Inhaled Glucocorticoids Reduce
Asthma-Related Hospitalizations
Donahue JG et al. JAMA.1997;277:887
Prescriptions/Person-yr
8
7
6
5
4
3
2
1
0
R
e
l
a
t
i
v
e

R
i
s
k

None 12 23 35 58 8+ 01
|
2
-agonists
Total
Age 017
Total
Age 017
Inhaled Glucocorticoids
10
Definition of Asthma
Episodic attacks of wheezing, breathlessness,
chest tightness, and cough
Chronic airway inflammation
Hyperresponsive airways react to various
stimuli or triggers
Obstructed airways and limited airflow
(bronchoconstriction, mucus plugs)
NIH/NHLBI. Global Initiative for Asthma. Bethesda, Md: 1998, NIH Publication No. 96-3659B; NIH/NHLBI. Guidelines for
the Diagnosis and Management of Asthma, Expert Panel Report 2. Bethesda, Md: 1997, NIH Publication No. 97-4051;
NIH/NHLBI. International Consensus Report on Diagnosis and Treatment of Asthma. Bethesda, Md: 1992, NIH
Publication No. 92-3091
11
Definition of Asthma
Many cells and cellular elements play role,
including mast cells, eosinophils, neutrophils,
T-lymphocytes, and epithelial cells
Airflow obstruction reversible
Requires long-term management
NIH/NHLBI. Guidelines for the Diagnosis and Management of Asthma, Expert Panel Report 2. Bethesda, Md: 1997, NIH
Publication No. 974051; NIH/NHLBI. International Consensus Report on Diagnosis and Treatment of Asthma. Bethesda,
Md: 1992, NIH Publication No. 92-3091

12
Asthma and Airway Remodeling
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
20 40 60 80
Airway inflammation

Remodeling

Chronic persistent
airway obstruction and
hyperresponsiveness
Normal
Asthma
Age (yr)
F
E
V
1

(
L
)

Kumar RK. Pharmacol Ther. 2001;91:93

13
Asthma Inflammatory Process
Allergen Exposure




Glucocorticoids
Block activation of this pathway


Arachidonic acid
Cyclooxygenase Lipoxygenase
Chemotactic Platelet-activating
factors factor (PAF) Histamine Prostaglandins Leukotrienes



Broncho- Increased Decreased Chemotaxis Increased
constriction mucus mucus vascular
secretion clearance permeability


Symptoms of Asthma
Schleimer RP. American Review of Respiratory Disease. 1990;141(2 pt 2):S59

Inflammatory mediators released
14
Smooth Muscle
Dysfunction
Airway
Inflammation
Inflammatory cell infiltration/
activation
Mucosal edema
Cellular proliferation
Epithelial damage
Basement membrane thickening
Bronchoconstriction
Bronchial hyperreactivity
Hypertrophy/hyperplasia
Inflammatory mediator release
Symptoms/Exacerbations
Asthma Pathophysiology
15
Effects of Inhaled Glucocorticoids
on Inflammation
Posttreatment (3 mo)
600 g budesonide bid
Reprinted with permission from Laitinen LA et al. J Allergy Clin Immunol. 1992;90:32
Pretreatment
E=epithelium; BM=basement membrane
16
Progression of Pharmacologic Therapy
in Asthma
Mild
Intermittent
Mild
Persistent
Moderate
Persistent
Severe
PRN |
2
-agonists
Antiinflammatory therapy
Inhaled glucocorticoids
Cromolyn/nedocromil (for patients <12 yr)
High-dose inhaled
glucocorticoids
Long-acting
bronchodilator
Oral glucocorticoids
Other experimental therapies
NIH/NHLBI. Guidelines for the Diagnosis and Management of Asthma, Expert Panel Report 2. Bethesda, Md: 1997,
NIH Publication No. 97-4051
17
Acute Care


Why do we still have a problem?
Morbidity and mortality
Lack of compliance
Underaccess to care

18
Effectiveness of Systemic Steroids
for Acute Treatment of Asthma
How soon?
How soon do they work?
Are they useful in ED setting?
How much?
How long?
Which route?
Which steroids?

19
How Soon Do Steroids Work?
20 asthmatics, 3132 yr
Hydrocortisone 2 mg/kg
bolus, then 0.5 mg/kg/hr
24 hr vs placebo
Results
Initial 6 hr lag, followed by
progressive improvement
No A in PaO
2
response
20
0
20
40
60
80
100
120
140
5 0 5 20
Time (hr)
F
E
V
1

C
h
a
n
g
e

(
%
)

Placebo
Hydrocortisone
Adapted with permission from Fanta CH et al. Am J Med. 1983;74:845
*
*
*
10 15 25
*P<0.025 vs placebo
20
How Soon?
How soon should systemic steroids be given?
Within 1 hr of presentation at emergency department
Not all studies show benefit

How soon do they work?
Improvement in pulmonary function may
occur in 26 hr
Can delay admission decision 46 hr post glucocorticoid
treatment
21
Methylprednisolone in Emergency
Treatment of Asthma
97 asthmatics
Mean age 3233 yr
Methylprednisolone
(125 mg IV) vs placebo
Followed through ED
discharge (112.5 hr)
Conclusions
Decreased hospitalizations
Improved symptom scores
(0.68 steroid vs 1.02 control
on 03 scale)
0
10
20
30
40
50
60
70
FEV
1
(Mean Predicted)
Hospital
Admission Rate
Control
Steroid
P=0.07
P<0.003
Adapted with permission from Littenberg B, Gluck EH.
N Engl J Med. 1986;314:150
%

22
Effect of Steroids on Peak Flow
in Acute Asthma
1997 study in 45 asthmatics
PF higher at 1 hr with placebo
55% predicted PF with placebo vs 45% with
steroid (P<0.061)
1999 study in 56 asthmatics
PF significantly higher with steroid (P=0.002)
Increases of 79 and 96 L/m at 1 and 2 hr with
steroid vs 54 and 68 L/m with placebo (P=0.005)
No difference in hospitalization rates
Lin RY et al. Am J Emerg Med. 1997;15:621
Lin RY et al. Ann Emerg Med. 1999;33:487
23
More Is Better
25 patients with asthma
unresponsive to
standard R
x

Methylprednisolone
Low: 15 mg q6hr
Medium: 40 mg q6hr
High: 125 mg q6hr
Treatment 3 days
Adapted with permission from Haskell RJ et al. Arch Intern Med. 1983;143:1324
20
30
40
50
60
70
0 1 2 3
High
Medium
Low
Days of Treatment
F
E
V
1

(
%
)

*
*
*
*
*
*
*
*
*
*P<0.01 compared with time 0
24
Meta-analysis: Methylprednisolone
Dosing in Acute Asthma
9 trials with 344 patients
Low dose: equivalent of <80 mg/d methylprednisolone
Medium dose: equivalent of 80160 mg/d
methylprednisolone
High dose: equivalent of >360 mg/d methylprednisolone
Manser R et al. In: The Cochrane Database of Systematic Reviews. Oxford: Update Software; 2001 (4):1

25
How Much?
No differences in hospital admissions between
doses
No significant differences in side effect rates or
respiratory failure between doses
No apparent therapeutic advantage with higher
doses

Manser R et al. In: The Cochrane Database of Systematic Reviews. Oxford: Update Software; 2001 (4):1

26
How Long Should Systemic Steroids
Be Given After Acute Exacerbation?
Studies limited in number and power
Meta-analysis shows significantly fewer patients
relapse after 710 days of systemic steroids
Patients given IV glucocorticoids should continue
oral systemic glucocorticoids for 310 days
Taper not needed with inhaled steroids
NIH/NHLBI. Guidelines for the Diagnosis and Management of Asthma, Expert Panel Report 2. Bethesda, Md: 1997,
NIH Publication No. 97-4051
27
76 asthmatics (1545 yr) discharged from
emergency department
Methylprednisolone (4 mg/kg IV bolus), followed
by 8-day taper starting at 32 mg bid vs placebo
Outcome variables
Relapse
Symptoms
Fiel SB et al. Am J Med. 1983;75:259
Short-Term Glucocorticoid Therapy
in Patients With Acute Bronchial Asthma
28
Treatment Outcomes in Patients
With Acute Bronchial Asthma
Adapted with permission from Fiel SB et al. Am J Med. 1983;75:259

P=0.05
P=0.05
P
a
t
i
e
n
t
s

(
%
)

50
25
0
Relapse Symptomatic
Methylprednisolone Placebo
29
Short-Term Glucocorticoid Therapy
for Preventing Asthma Relapse
93 asthmatic patients (2331 yr) discharged
from emergency department
Randomized at discharge to prednisone, tapered
400 mg over 8 days
Relapse rate primary outcome variable
Chapman KR et al. N Engl J Med. 1991;324:788
30
Relapse Outcomes in Patients
With Acute Asthma
Reprinted with permission from Chapman KR et al. N Engl J Med. 1991;324:788

50
60
70
80
90
100
0 2 4 6 8 10
12
14 16 18 20
Days After ED Treatment
P
r
o
b
a
b
i
l
i
t
y

o
f

R
e
m
a
i
n
i
n
g

R
e
l
a
p
s
e
-
f
r
e
e

(
%
)

0
Prednisone
Placebo
48
47
46
45
44
43
42
40
39
38
45
43
42 40
39
38
37
35
34
32
31
30
27
26
25
P<0.05
Values shown are numbers of patients remaining relapse-free at beginning of days which relapse occurred
31
Which Route?
Oral
Intravenous
Intramuscular
After acute exacerbation
Chronic steroid-dependent asthma
32
Which Steroid?
33
5 10 15
B
A
L
F

C
o
n
c
e
n
t
r
a
t
i
o
n


(
n
g

G
l
u
c
o
c
o
r
t
i
c
o
i
d
/

g

U
r
e
a
)


0
25
50
75
Methylprednisolone
r=0.95 (P<0.001)
Prednisolone
r=0.54 (P<0.05)
Plasma Concentration
(ng Glucocorticoid/gUrea)
Methylprednisolone vs Prednisolone:
Lung Penetration
Adapted with permission from Vichyanond P et al. J Allergy Clin Immunol. 1989;84;867

34
Methylprednisolone vs Prednisolone:
Pharmacokinetics
Single and multiple oral doses for 3 days in 24 men
Methylprednisolone 180 mg
Prednisolone 1.25100 mg
Methylprednisolone (pharmacokinetics more predictable)
Linear pharmacokinetics
No apparent dose or time dependency
Concentrations proportional to dose
Plasma protein determination not necessary
Prednisolone
No linear pharmacokinetics
Dose and time dependency
Rohatagi S et al. J Clin Pharmacol. 1997;37:916

35
Methylprednisolone vs Prednisolone:
Peripheral Blood Mononuclear Cell Sensitivities
0
5
10
15
20
25
30
Healthy Asthmatic
Prednisolone
Methylprednisolone
M
e
d
i
a
n

I
C
5
0

IC
50
=concentration that produces 50% inhibition of PBMCs
Adapted with permission from Hirano T et al. Immunopharmacology. 1998;40:57
n=100
n=91
n=40
n=39
36
Acute Exacerbation of Asthma
Glucocorticoids: Recommended minimum dose
of methylprednisolone 120180 mg/d divided
q68hr 48 hr, then 6080 mg/d until PF >70%
of predicted personal best
Epinephrine: 0.3 mg of 1:1000 dilution SC
q20min 3 doses

NIH/NHLBI. Guidelines for the Diagnosis and Management of Asthma, Expert Panel Report 2. Bethesda, Md: 1997,
NIH Publication No. 97-4051; NIH/NHLBI. International Consensus Report on Diagnosis and Treatment of Asthma.
Bethesda, Md: 1992, NIH Publication No. 92-3091; Manthous CA. Am J Med. 1995;99:298
37
Initial Assessment
Initial Treatment
Assess Response
Good Response Moderate Exacerbation Severe Exacerbation
|
2
-agonist
Double inhaled steroid dose 10
days or begin medium to high dose
inhaled steroid
Consider oral steroid taper
Consider home PF meter
Physician follow-up
Repeat Assessment in 13 hr
Good Response Incomplete Response Poor Response
Admit to Hospital
Reassessment: PF, clinical exam
Continue |
2
-agonist,
Glucocorticoids until improved
Patient education
Admit to Intensive Care Unit
Consider intubation and
mechanical ventilation for
Continued deterioration
Clinical signs of fatigue
Rising PCO
2
despite therapy
pH <7.25; respirations >35
Acute Exacerbation of Asthma
Good Response
Poor Response
NIH/NHLBI. Guidelines for the Diagnosis and Management of Asthma, Expert Panel Report 2. Bethesda, Md: 1997, NIH Publication
No. 97-4051; NIH/NHLBI. International Consensus Report on Diagnosis and Treatment of Asthma. Bethesda, Md: 1992, NIH Publication
No. 92-3091; Manthous CA. Am J Med. 1995;99:298
38
Asthma Facts
Worldwide prevalence of asthma: 37 million
USA: 15 million; Europe: 16 million
Severe asthma: 20%30% of asthma patients or 7
15 million patients
Between 19801994, prevalence of asthma in USA
increased 75% overall and 74% in children 514 yr
In 1995, 2 million asthma-related visits to ED in USA
Estimated healthcare costs for asthma care in USA
$11.3 billion/yr
Mannino DM et al. Mor Mortal Wkly Rep. 1998; 47(suppl 1):1.
US Department of Health and Human Services/HHS Fact Sheet. Available at
http://www.os.dhhs.gov/news/press/2001pres/01fsasthma.html. Accessed February 21, 2001.
Asthma in America Survey. Available at: http://www.asthma.com/htm. Accessed: January 2002

39
Management of Acute
Exacerbation of COPD
Sidney Braman, MD
Division Director
Pulmonary & Critical Care Medicine
Brown University School of Medicine
Rhode Island Hospital
Providence, Rhode Island, USA

40
Global Initiative for Obstructive Lung
Disease (GOLD)

Recommend effective COPD management and
prevention strategies for all countries
Increase awareness in medical and public health
community and general public that COPD is public
health problem
Decrease morbidity and mortality from COPD through
implementation and evaluation of effective programs
Promote studies to explain increasing COPD
prevalence and COPDs relationship to environment

NIH/NHLBI. Global Initiative for Chronic Obstructive Lung Disease. NHLBI/WHO Workshop Report 2001.
Available at: http://www.goldcopd.com/workshop.html. Accessed February 12, 2002
41
Projected Global Mortality From COPD
0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.5
1990 2000 2010 2020
Adapted with permission from Murray CJL, Lopez AD. Lancet. 1997;349:1498
4.0
M
o
r
t
a
l
i
t
y

(

1
0
6
)

Year
42
COPD and Asthma: Different Diseases
Adapted with permission from Barnes PJ. Chest 2000;117(suppl):10S
COPD
Affects elderly,
especially smokers
Slowly progressive
inflammatory cells
Neutrophils
Macrophages
CD8+ cells
Partially reversible

~10%
Asthma
Affects all ages,
including children
Episodic course
Inflammatory cells
Eosinophils
Mast cells
CD4+
Macrophages
Fully reversible
Wheezy bronchitis
43
Mechanisms Underlying
Airflow Limitation in COPD
Inflammation
Small Airway Disease Parenchymal Destruction
Airflow Limitation
NIH/NHLBI. Global Initiative for Chronic Obstructive Lung Disease. NHLBI/WHO Workshop Report 2001.
Available at: http://www.goldcopd.com/workshop.html. Accessed February 12, 2002
44
Pathogenesis of COPD
Noxious Particles and Gases
Lung Inflammation
COPD Pathology
Antioxidants Antiproteinases
Host Factors
Oxidative Stress
Proteinases
NIH/NHLBI. Global Initiative for Chronic Obstructive Lung Disease. NHLBI/WHO Workshop Report 2001.
Available at: http://www.goldcopd.com/workshop.html. Accessed February 12, 2002
45
Proteinases
Neutrophil elastase
Cathepsin
Proteinase-3
MMPs
Cells and Mediators Involved
in Pathogenesis of COPD
Adapted with permission from Barnes PJ. Chest. 2000;117(suppl);10S
Mediators
LTBI
IL-8, GRO-1 o
MCP-1, MIP-1 o
GM-CSF
Endothelin
Substance P
Cells
Macrophages
Neutrophils
CD8
+
lymphocytes
Eosinophils
Epithelial cells
Fibroblasts
Effects
Mucus hypersecretion
Fibrosis
Alveolar wall
destruction
46
Causes of Airflow Limitation in COPD
Fibrosis and narrowing of airways
Loss of elastic recoil due to alveolar
destruction
Destruction of alveolar support that
maintains potency of small airways
Irreversible
Accumulation of inflammatory cells,
mucus, and plasma exudate in bronchi
Smooth muscle contraction in peripheral
and central airways
Dynamic hyperinflation during exercise
Reversible
NIH/NHLBI. Global Initiative for Chronic Obstructive Lung Disease. NHLBI/WHO Workshop Report 2001.
Available at: http://www.goldcopd.com/workshop.html. Accessed February 12, 2002
47
Risk Factors for COPD

Genes (eg, o-1-antitrypsin
deficiency)
Airway hyperresponsiveness
Lung growth
Tobacco smoke
Occupational dusts and chemicals
Outdoor and indoor air pollution
Infections
Socioeconomic status
Host factors
Exposures
NIH/NHLBI. Global Initiative for Chronic Obstructive Lung Disease. NHLBI/WHO Workshop Report 2001.
Available at: http://www.goldcopd.com/workshop.html. Accessed February 12, 2002
48
Normal Spirogram and Spirogram Typical
of Patients With Mild to Moderate COPD
1 2 3 4 5 6
Seconds
FVC
COPD
FEV
1

FEV
1

Normal
FVC
0
1
2
3
4
5
L
i
t
e
r
s

FEV
1
FVC FEV
1
/FVC
Normal 4.15 5.2 80%
COPD 2.35 3.9 60%
NIH/NHLBI. Global Initiative for Chronic Obstructive Lung Disease. NHLBI/WHO Workshop Report 2001.
Available at: http://www.goldcopd.com/workshop.html. Accessed February 12, 2002

49
COPD Classification by Severity
FEV
1
=forced expiratory volume in 1 sec; FVC=forced vital capacity; respiratory failure arterial partial pressure of
oxygen (PaO
2
) <8.0 kPa (60 mm Hg) with or without arterial partial pressure of CO
2
(PaCO
2
) >6.7 kPa (50 mm Hg)
while breathing air at sea level
Normal spirometry
Chronic symptoms (cough, sputum production)
0: At Risk
FEV
1
/FVC <70%
FEV
1
>80% predicted
With or without chronic symptoms (cough, sputum production)
I: Mild
FEV
1
/FVC <70%
30% sFEV
1
<80% predicted (IIA: 50% sFEV
1
<80% predicted)
(IIB: 30% sFEV
1
<80% predicted)
With or without chronic symptoms (cough, sputum production, dyspnea)
II: Moderate
FEV
1
/FVC <70%
FEV
1
<30% predicted or FEV
1
<50% predicted plus respiratory failure
or clinical signs of right heart failure
III: Severe
Stage Characteristics
NIH/NHLBI. Global Initiative for Chronic Obstructive Lung Disease. NHLBI/WHO Workshop Report 2001. Available at:
http://www.goldcopd.com/workshop.html. Accessed February 12, 2002

50
Natural History of COPD

0
1
2
3
4
5
10 20 30 40 50 60 70 80
Dyspnea
Oxygen
Home bound
Bed bound
Death
F
E
V
1

(
L
)

Age
Adapted with permission from Fletcher C, Peto R. BMJ. 1977;1:1645
Normal
Smoker
COPD
51
Clinical Features of COPD
Chronic productive cough commonly presents
in 5th decade often with acute chest disorder
Usually, 1 pack per day smoker for >20 yr
Dyspnea on effort usually in 6th or 7th decade
Mucoid sputum production primarily in morning
Wheezing and dyspnea may lead to erroneous
diagnosis of asthma
Prognosis poor in late disease; FEV
1
<.75 L;
mortality 30% at 1 yr, 95% at 10 yr
American Thoracic Society. Am J Respir Crit Care Med. 1995;152:S77
52
Adapted with permission from Anthonisen NR et al. JAMA. 1994;272:1497
The Lung Health Study:
Benefits of Smoking Cessation
1 2 3 4 5
2.9
2.8
2.7
2.6
2.5
2.4
F
E
V
1

(
L
)


Quitter
Smoker
Follow-up (yr)
53
Smoking and Lung Function Decline
0
25
50
75
100
Smoked regularly
and susceptible to
smoke
Disability
Death
Stopped at 45 yr
Stopped at 65 yr
25 50
75
Age (yr)
Never smoked or not
susceptible to smoke
F
E
V
1


(
%

o
f

V
a
l
u
e


a
t

A
g
e

2
5
)

Adapted with permission from Fletcher C, Peto R. BMJ. 1977;1:1645
54
Therapy at Each Stage of COPD
Stage Recommended Treatment
ALL Avoidance of risk factor(s)
Influenza vaccination
0: At Risk
I: Mild Short-acting bronchodilator when needed
II: Moderate

Regular treatment with one
or more bronchodilators
Rehabilitation

III: Severe
NIH/NHLBI. Global Initiative for Chronic Obstructive Lung Disease. NHLBI/WHO Workshop Report 2001.
Available at: http://www.goldcopd.com/workshop.html. Accessed February 12, 2002



Regular treatment with one or more bronchodilators
Inhaled glucocorticoids if significant symptoms and lung
function response or if repeated exacerbations
Treatment of complications
Rehabilitation
Long-term oxygen therapy if respiratory failure
Inhaled glucocorticoids
if significant symptoms
and lung function response
55

Acute Exacerbation
Definition

Unexpected event characterized by increase in
dyspnea, cough, and sputum production or change
in color of sputum requiring need for increase
in therapy
56
Pathophysiology of Severe Acute
Exacerbations
Worsening of gas exchange, primary physiologic
change
Airway inflammation, edema, mucus hypersecretion,
and bronchoconstriction contribute to changes in
ventilation
Hypoxic constriction of pulmonary arterioles may
modify perfusion
Abnormal breathing patterns and fatigue of respiratory
muscles contribute to increased respiratory acidosis,
leading to respiratory failure and death
NIH/NHLBI. Global Initiative for Chronic Obstructive Lung Disease. NHLBI/WHO Workshop Report 2001.
Available at: http://www.goldcopd.com/workshop.html. Accessed February 12, 2002



57
Recognizing Exacerbations of COPD
Sputum volume
and purulence
Dyspnea
Wheeze
Fluid retention
NIH/NHLBI. Global Initiative for Chronic Obstructive Lung Disease. NHLBI/WHO Workshop Report. 2001.
Available at: http://www.goldcopd.com/workshop.html. Accessed: February 12, 2002.

58
Time Course and Recovery
From Exacerbations in COPD Patients
Study
101 patients (mean age 67.5 yr) with moderate to
severe COPD (FEV
1
<42% predicted)
Symptoms and lung function changes studied at 2.5 yr
Results
Symptom changes do not closely reflect lung function
Increase in symptoms may predict exacerbations
Recovery incomplete in significant percent of
exacerbations

Seemungal TAR et al. Am J Respir Crit Care Med. 2000;161:1608
59
Symptoms Associated With
Acute Exacerbation


Dyspnea 64%
Sputum purulence 42%
Colds 35%
Wheeze 35%
Sputum volume 26%
Cough 20%
Sore throat 12%

Seemungal TAR et al. Am J Respir Crit Care Med. 2000;161:1608
60
0
20
30
40
50
60
70
1 6 11 16 21 26 31 14 9 4


E
x
a
c
e
r
b
a
t
i
o
n
s

W
i
t
h

I
n
c
r
e
a
s
e
d

D
y
s
p
n
e
a


(
%
)


10
1 11 31 14 9 4
5
36
0
10
15
25
30
35
40
6 16 21 26
20
41
E
x
a
c
e
r
b
a
t
i
o
n
s


W
i
t
h

C
o
l
d
s


(
%
)


0
10
15
20
25
6 16 21 26 41
5
36 31 11 14 9 4 1
E
x
a
c
e
r
b
a
t
i
o
n
s

W
i
t
h

I
n
c
r
e
a
s
e
d

C
o
u
g
h

(
%
)


Time Course of Symptoms
Adapted with permission from Seemungal TAR et al. Am J Respir Crit Care Med. 2000;161:1608
Days Days
Days
61
Common Causes
of Acute Exacerbations of COPD
Primary
Tracheobronchial infection
Air pollution
Secondary
Pneumonia
Pulmonary embolism
Pneumothorax
Rib fractures/chest trauma
Inappropriate use of sedatives, narcotics, |-blocking agents
Right and/or left heart failure or arrhythmias

NIH/NHLBI. Global Initiative for Chronic Obstructive Lung Disease. NHLBI/WHO Workshop Report 2001.
Available at: http://www.goldcopd.com/workshop.html. Accessed February 12, 2002



62
Infectious Agents
in COPD Exacerbations
Viruses 30%
Influenza
Parainfluenza
Rhinovirus
Bacteria 40%50%
H. influenzae
S. pneumoniae
M. catarrhalis
Other 10%25%
Air pollution, eg
Atypical bacteria 5%10%
C. pneumoniae
63
Management of Acute Exacerbations
of COPD: Risk Stratification
Outpatients at high risk for relapse have low
FEV
1
, pH, and PaO
2
; high PaCO
2
; and receive
more bronchodilator treatments in emergency
departmentno predictive model is satisfactory
for clinical use
No reliable method to identify high-risk (>90%)
in-hospital or 6-mo mortality to help with end of
life decisions
64
Management of Acute Exacerbations
of COPD: Glucocorticoids
Randomized placebo-controlled studies show that
short course of systemic Glucocorticoid therapy
improves symptoms, spirometry, and treatment
failure rates and shortens length of stay
Dose and duration of treatment variable
High doses and prolonged treatment increase
risk of side effects
65
Effect of Systemic Glucocorticoids
on Exacerbations of COPD
Standard therapy: antibiotics, albuterol and ipratropium
MDI/aerosol qid, O
2
, and inhaled glucocorticoid
Primary end point: treatment failure, death, mechanical
ventilation, readmittance, | therapy
Secondary end points: | FEV
1
, length of hospital stay, death
during 6-mo follow-up
Complications assessed: hyperglycemia, upper
gastrointestinal bleed, acute psychiatric illness, infection
Niewoehner DE et al. N Engl J Med. 1999;340:1941
Study Design
66
Results on
271 Veterans/1840 Screened
Treatment failure higher with placebo
At 30 days 33% vs 23% (P=0.04)
At 90 days 48% vs 37% (P=0.04)
Hospital stay shorter with steroids
8.5 vs 9.7 days (P=0.03)
FEV
1
higher with steroids by day 1 (100 mL);
no difference at 2 wk
8-wk not superior to 2-wk regimen
Niewoehner DE et al. N Engl J Med. 1999;340:1941
67
Mean FEV
1
at Selected Times
According to Treatment Group
The numbers at each time point are the numbers of patients in each group for whom data were available
Adapted with permission from Niewoehner DE et al. N Engl J Med. 1999;340:1941
101
127
120
130
137
140
92
86
77
82
145
95
1.2
1.1
1.0
0.9
0.8
0.7
*
*
*
67
103
F
E
V
1

(
L
)

Glucocorticoid
Placebo
*P<0.05 vs placebo
0 1 2 3
14 56 182
Time (day)
68
Complications of Treatment
Complication Placebo Steroid 2 wk Steroid 8 wk P

Hyperglycemia* 4 (4) 14 (18) 10 (12) 0.002
GI bleed 5 (5) 0 3 (4) NS
2 infection 19 (17) 12 (15) 18 (22) NS
Hypertension 4 (4) 6 (8) 4 (5) NS
Psychiatric 3 (3) 5 (6) 2 (2) NS
Other

16 (14) 18 (22) 21 (26) 0.04

*Comparison of placebo vs combined steroid groups

Includes 41 different symptoms or conditions

Adapted with permission from Niewoehner DE et al. N Engl J Med. 1999;340:1941
69
Effect of Systemic Glucocorticoids
on Exacerbations of COPD
Systemic glucocorticoids improve clinical outcomes
in patients hospitalized for exacerbations of COPD
2-wk regimen as effective as 8-wk regimen
Recommended therapy: methylprednisolone 125 mg
q6hr 72 hr then oral prednisone for 14 days
Initial hospitalization decreased by ~1.2 days
with glucocorticoids
Hyperglycemia most frequently reported side effect
requiring treatment
Conclusions
Niewoehner DE et al. N Engl J Med. 1999;340:1941
70
Management of Acute Exacerbations
of COPD: Therapy
NIPPV improves ventilation and lowers PaCO
2
This therapy avoids intubation and shortens ICU
and hospital stay, lowers complication rates, and
improves overall survival
Selection criteria for this treatment not uniform

NIH/NHLBI. Global Initiative for Chronic Obstructive Lung Disease. NHLBI/WHO Workshop Report. 2001.
Available at: http://www.goldcopd.com/workshop.html. Accessed: February 12, 2002
NIH/NHLBI. Global Initiative for Chronic Obstructive Lung Disease. NHLBI/WHO Executive Report
71
Management of Acute Exacerbations
of COPD: Therapy
Following therapeutic options are not beneficial
(and may be harmful)



Mucolytic agents
Chest physiotherapy
Theophylline
72
Exacerbation Rate and Health Status
St. Georges Respiratory Questionnaire

0
20
40
60
80
Low Rate
(0.38/yr)
High Rate
(1.97/yr)
T
o
t
a
l

S
c
o
r
e

Baseline Health Status
0
3
6
9
12
15
Low Rate
(0.38/yr)
High Rate
(1.97/yr)
A
n
n
u
a
l

I
n
c
r
e
a
s
e

i
n


T
o
t
a
l

S
c
o
r
e

Decline in Health Status
P=0.002
P=0.0001
Burge PS et al. BMJ. 2000;320:1297
Spencer S et al. Am J Respir Crit Care Med. 2001;163:122
73
Healthcare Utilization and
Mortality Due to Exacerbations
0
10
20
30
40
50
60
Hospital
stay
60 days 180 days 1 yr 2 yr
Time After Hospitalization
M
o
r
t
a
l
i
t
y

(
%
)

Connors AF et al. Am J Respir Crit Care Med. 1996;154:959
Median length of hospital stay 9 days
Median cost of hospitalization $7400
Readmission rate (6 mo) 44%