Pulmonary Function Studies

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Pulmonary Function Studies

• The Role of the Therapist in COPD Diagnosis
• S. Lande Lambert, CRT

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SPIROMETRY FOR HEALTH CARE PROVIDERSGlobal
Initiative for Chronic Obstructive Lung Disease
(GOLD)
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CONTENTS

• I. INTRODUCTION
• II. BACKGROUND INFORMATION
• A. What Is Spirometry?
• B. Why Perform Spirometry?
• C. Spirometry in Primary Care
• D. Screening for Airway Obstruction in Primary
  Care
• E. Recognizing COPD
• III. USING SPIROMETRY IN CLINCIAL PRACTICE
• A. Types of Spirometers
• B. Information Provided by the Spirometer
• C. Diagnosis of Airway Obstruction
• Figure 1. GOLD Spirometric Criteria for COPD
  Severity

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CONTENTS (contd)

• IV. SPIROGRAM INTERPRETATION
• A. Normal Lung Function
• Figure 2. Normal Spirogram Volume-Time
  Curve
• B. Bronchodilator Reversibility Testing in COPD
• C. Patterns of Spirometric Curves
• Figure 3. Volume-Time Curves (before and
  after bronchodilator)
• Figure 4. Features of Ventilatory Abnormality
  in Spirometry
• Figure 5. Patterns of Ventilatory
  abnormalities
• D. Flow-Volume Measurement

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CONTENTS (contd)

• V. PERFORMING SPIROMETRY
• A. Preparing the Patient
• Figure 6A. Normal Flow-Volume Curve
• Figures 6B, 6C, 6D. Patterns of Flow-Volume
  Curves Showing Ventilatory Abnormalities
• B. Measuring FEV1, FVC, and Flow-Volume
  Curves
• C. Differential Diagnosis

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CONTENTS (contd)

• VI. TROUBLESHOOTING
• A. Accuracy and Quality of Readings
• Figure 7. Examples Poorly Performed Curves
• B. Equipment Maintenance and Calibration
• C. Infection Control
• D. When to Refer for Further Respiratory
  Function Testing
• REFERENCES

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I.INTRODUCTION
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I. Introduction

• Chronic Obstructive Pulmonary disease (COPD) is a
  clinical diagnosis that should be based on
  carefully history taking, the presence of
  symptoms and assessment of airway obstruction
  (also called airflow limitation). The GOLD
  international COPD guidelines1, as well as
  national guidelines2, advise spirometry as the
  gold standard for accurate and repeatable
  measurement of lung function. Evidence is
  emerging that when spirometry confirms a COPD
  diagnosis, doctors initiate more appropriate
  treatment. Spirometry is also helpful in making a
  diagnosis in patients with breathlessness and
  other respiratory symptoms and for screening in
  occupational environments.

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I. Introduction (Contd)

• Although the use of spirometers in primary care
  is increasing, in some countries uptake is still
  low. In those countries where spirometry is in
  more common usage, there are major concerns
  regarding the technical ability of operators to
  perform the test and interpret its results. Many
  primary care physicians, nurses, and other health
  care providers have had little formal training in
  spirometry. More accredited courses are appearing
  but these are often time consuming and fairly
  expensive. Many clinicians feel apprehensive
  about purchasing a spirometer because of
  uncertainties about performing and interpreting
  spirometry. Epidemiologic studies confirm that
  both late diagnosis and under-diagnosis of COPD
  are commonproblems that wider use of spirometry
  could help to address.

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I. Introduction (Contd)

• There is therefore a considerable need to
• Encourage the use of spirometers in primary
  care
• Explain the importance of spirometry in the
  management of COPD
• Provide information on how to perform
  spirometry correctly
• Explain interpretation of spirometry results

Most guidelines recommend the use of spirometers
that provide a real-time trace to help assess the
quality and repeatability of blows. Such
spirometers tend to be quite expensive and
expectations that these could be used widely in
poorer countries are unrealistic. Cheaper
substitutes are available at relatively low cost
these can provide the basic indices accurately
but give little indication as to how well
patients perform the test.
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II.BACKGROUND INFORMATION
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A. What Is Spirometry?

• Spirometry is a method of assessing lung function
  by measuring the volume of air that the patient
  can expel from the lungs after a maximal
  inspiration.
• The indices derived from this forced exhaled
  maneuver have become the most accurate and
  reliable way of supporting a diagnosis of COPD.
  When these values are compared with predicted
  normal values determined on the basis of age,
  height, sex, and ethnicity, a measure of the
  severity of airway obstruction can be determined.
  It is on these values that COPD guidelines around
  the world base the assessment of mild, moderate,
  and severe disease levels.

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A. What Is Spirometry? (contd)

• Spirometry is however only one way of
  interpreting COPD disease severity. Other
  measures, such as the MRC dyspnea scale for
  measuring breathlessness, exacerbation
  frequency, body mass index, quality of life
  assessment, and exercise capacity all help to
  build a more complete picture2.

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B. Why Perform Spirometry?

• Spirometry is the best way of detecting the
  presence of airway obstruction and making a
  definitive diagnosis of asthma and COPD. Its
  major uses in COPD are to
• Confirm the presence of airway obstruction
• Confirm an FEV1/FVC ratio lt 0.7 after
  bronchodilator
• Provide an index of disease severity
• Help differentiate asthma from COPD
• Detect COPD in subjects exposed to risk
  factors, predominantly tobacco smoke,
  independently of the presence of respiratory
  symptoms
• Enable monitoring of disease progression
• Help assess response to therapy

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B. Why Perform Spirometry? (contd)

• Aid in predicting prognosis and long-term
  survival
• Exclude COPD and prevent inappropriate
  treatment if spirometry is normal

Spirometry has many other applications in
assessing and managing respiratory disease. These
include measuring the presence and severity of
restrictive lung defects, screening of the
workforce in hazardous occupational environments,
pre-employment screening for certain occupations,
and assessing fitness to dive. Some believe it
may be useful as a motivating tool to help
smokers to quit, but solid scientific evidence on
this point is lacking at present, and research
findings have been equivocal.
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C. Spirometry in Primary Care

• The development of COPD is slow and insidious and
  symptoms tend to be noted by patients only after
  there has been a significant loss of lung
  function, often to 50-60 of predicted value.
  People with COPD often present far too late to
  their doctor because they accept cough or mild
  breathlessness as a normal result of years of
  smoking or because they do not wish to be told
  that they have to stop smoking. However, stopping
  smoking is key. It is the most important way of
  slowing disease progression, and it is most
  beneficial in the early stages of COPD.
• COPD is markedly under-diagnosed, with recent
  estimates of between 25 and 50 of patients with
  clinically important disease being undetected or
  misdiagnosed. (contd)

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C. Spirometry in Primary Care (contd)

• Although awareness has increased in the last 10
  years, the management and diagnosis of COPD in
  primary care is still poor. The wrong diagnosis
  is commonsome patients who have a clinical
  diagnosis of COPD are found to have normal lung
  function, many patients with COPD are
  undiagnosed, and there is much confusion
  regarding labeling patients with COPD or asthma.
• Primary care physicians are in an ideal position
  to be able to detect COPD in its early stages and
  perform spirometry to confirm the diagnosis3,4.
  Management of COPD is largely carried out in
  primary care and much can now be done to improve
  symptoms and quality of life, and to reduce the
  frequency and impact of exacerbations. Such
  information is clearly set out in most national
  and international guidelines.

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D. Screening for Airway Obstruction in Primary
Care

• The role of screening at-risk populations in
  primary care is more controversial. When
  assessing the efficacy of screening programs, a
  number of important factors need to be
  considered. These include the criteria for the
  population to be screened, the percentage of
  positive results, and the cost effectiveness of
  screening. It is crucial to assess the clinical
  outcomes of screening. Although we have some
  answers to these questions, the main issue of
  whether detecting early disease in relatively
  asymptomatic smokers significantly increases quit
  rates has still to be resolved.
• The most cost-effective method would appear to be
  a case-finding technique, performing spirometry
  in those atrisk of COPD. In a Dutch study5, 27
  of smokers or exsmokers over 35 years of age
  who also had a persistent cough were found to
  have airway obstruction.

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E. Recognizing COPD
The GOLD guidelines1 define COPD as A
preventable and treatable disease with some
significant extrapulmonary effects that may
contribute to the severity in the individual
patient. Its pulmonary component is characterized
by airflow limitation that is not fully
reversible. The airflow limitation is usually
progressive and associated with an abnormal
inflammatory response of the lung to noxious
particles or gases.

• The main clinical features of COPD are
• Chronic cough, which may be daily and
  productive, but can also be intermittent and
  unproductive
• Breathlessness on exertion, initially
  intermittent and becoming persistent

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E. Recognizing COPD (contd)

• Sputum production any pattern of sputum
  production may indicate COPD
• Frequent exacerbations of bronchitis
• A history of exposure to risk factors,
  especially tobacco smoke, occupational dusts,
  home cooking and biomass fuels.

The GOLD guidelines recommend that clinicians
should suspect COPD and perform spirometry
whenever any of these indicators are present in
an individual aged over 40 years. When these
features are present it is crucial to ask, COULD
IT BE COPD?
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III.USING SPIROMTERYIN CLINICAL PRACTICE
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A. Types of Spirometers

• There are many different types of spirometer with
  costs varying from 1003,000 Euros/502,000 USD.
• Bellows or rolling seal spirometers are large
  and not very portable, and are used predominantly
  in lung function laboratories. They require
  regular calibration with a 3-liter syringe and
  are very accurate.
• Electronic desktop spirometers are compact,
  portable, and usually quick and easy to use. They
  have a real-time visual display and paper or
  computer printout. Some require calibration with
  the 3-liter syringe others can be checked for
  accuracy with the syringe but require any changes
  to be performed by the manufacturer. (contd)

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A. Types of Spirometers (contd)

• Generally they need little attention other than
  cleaning. They maintain accuracy over years and
  are ideal for primary care.
• Small, inexpensive hand-held spirometers
  provide a numerical record of blows but no
  printout. It may be necessary to look up
  predicted values in tables, but some include
  these in their built-in software. Recent models
  allow pre-programming of patient details so that
  the spirometer also gives percent predicted
  values. These are good for simple screening and
  are accurate for diagnosis if the more expensive
  desktop form is impractical or too expensive.5

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A. Types of Spirometers (contd)

• Many spirometers provide two forms of traces. One
  is the standard plot of volume exhaled against
  time. The other is a plot of flow (L/sec) on the
  vertical axis versus volume expired (L) on the
  horizontal axis. This is a flowvolume trace and
  is most helpful in diagnosing airway obstruction.
• In some countries a printed record of spirometry
  is essential for claiming insurance/practitioner
  reimbursement. The type of spirometer to be used
  may need to be considered in the light of this,
  as some automatically produce a printout, others
  can store data to be printed later from a PC, and
  others do not have printing capacity at all.

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B. Information Provided by the Spirometer
The standard spirometry maneuver is a maximal
forced exhalation (greatest effort possible)
after a maximum deep inspiration (completely full
lungs). Several indices can be derived from this
blow.

• FVC Forced Vital Capacity the total volume
  of air that the patient can forcibly exhale in
  one breath.
• FEV1 Forced Expiratory Volume in One Second
  the volume of air that the patient is able to
  exhale in the first second of forced expiration.
• FEV1 /FVC the ratio of FEV1 to FVC expressed
  as a fraction (previously this was expressed as a
  percentage).

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B. Information Provided by the Spirometer
(contd)

• Values of FEV1 and FVC are measured in liters and
  are also expressed as a percentage of the
  predicted values for that individual.
• The ratio of FEV1/FVC is normally between 0.7 and
  0.8. Values below 0.7 are a marker of airway
  obstruction, except in older adults where values
  0.650.7 may be normal. Caution particularly
  needs to be taken in patients over 70 years,
  where the use of predicted values extrapolated
  from the younger population may result in
  over-diagnosing COPD. In people over 70 years
  old, the FEV1/FVC ratio may need to be lowered to
  0.65 as a lower limit of normal. Conversely, in
  people under 45, using a ratio of 0.7 may result
  in under-diagnosis of airway obstruction. To
  avoid both of these problems, many experts
  recommend use of the lower limit of normal for
  each population.

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B. Information Provided by the Spirometer
(contd)

• Predicted values are calculated from thousands of
  normal people and vary with sex, height, age and
  ethnicity. The standard predicted values in most
  of Europe are those established by the European
  Respiratory Society or the European Community
  Health and Respiratory Survey (ECHRS), but other
  values may be used in different countries. Those
  values most appropriate for the local population
  should be used.
• FlowVolume Measurement - Many electronic desktop
  spirometers and spirometers used in lung function
  laboratories utilize a pneumotachograph measuring
  gauge, which measures airflow and integrates the
  signal to derive volume. This allows the
  spirometer to plot traces of flow rate against
  the volume of air exhaled, producing a
  flowvolume curve. On many spirometers such
  curves provide the main initial visual realtime
  display when patients are performing their blows.

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B. Information Provided by the Spirometer
(contd)

• FEV6 - This is a more recently derived value
  which measures the volume of air that can
  forcibly be expired in 6 seconds. It approximates
  the FVC and in normal people the two values would
  be identical. Using FEV6 instead of FVC may be
  helpful in patients with more severe airflow
  obstruction who make take up to 15 seconds to
  fully exhale. As they find this difficult and
  often stop before full exhalation, the FVC, and
  hence the severity of airway obstruction, may be
  underestimated. Some new hand-held spirometers
  from Vitalograph use the FEV6 instead of FVC and
  have predicted tables to match. The FEV1/FEV6 is
  well validated and is an acceptable alternative
  to FEV1/FVC6,7.

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B. Information Provided by the Spirometer
(contd)

• Slow VC Slow Vital Capacity the patient takes
  a full breath in as before but exhales slowly in
  their own time. In patients with COPD with more
  marked airway obstruction and dynamic
  compression, the slow vital capacity may exceed
  the FVC by gt 0.5 liters. This index is not used
  routinely in primary care. However, ATS /ERS
  guidelines are increasingly suggesting FEV1/ Slow
  VC as the preferred ratio6.

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C. Diagnosis of Airway Obstruction

• The spirometric criterion required for a
  diagnosis of COPD is an FEV1/FVC ratio below 0.7
  after bronchodilator.
• Go to Figure 1.

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IV.SPIROGRAM INTERPRETATION
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A. Normal Lung Function

• Interpretation of spirometry involves looking at
  the absolute values of FEV1, FVC, and FEV1/FVC,
  comparing them with predicted values, and
  examining the shape of the spirograms. Patients
  should complete three blows that are consistent
  and within 5 of each othermany electronic
  spirometers automatically provide this
  information.
• In a patient with normal lung function, the
  volumetime curve should rise rapidly and
  smoothly and plateau within 3-4 seconds. With
  increasing degrees of airway obstruction it takes
  longer to blow out the airup to 15 secondsand
  the upward slope of the spirogram is much less
  steep.
• Go to Figure 2.

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B. Bronchodilator Reversibility Testing in COPD

• Assessing bronchodilator reversibility is
  important to determine whether fixed airway
  narrowing is present8. In patients with COPD,
  post-bronchodilator FEV1/FVC remains lt 0.7.
  However, the FEV1 may improve significantly after
  bronchodilator, and a change of gt 12 AND gt 200
  mL in FEV1 can occur in COPD1. In addition, the
  degree of bronchodilator reversibility can vary
  from day to day. Larger changes in FEV1 do not
  negate a diagnosis of COPD, although the greater
  these changes are the greater the likelihood that
  the patient has asthma, either instead of or in
  addition to COPD.

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B. Bronchodilator Reversibility Testing in COPD
(contd)

• Bronchodilator reversibility testing is best done
  as a planned procedure, as it is time consuming.
  If the patient is undiagnosed and on no therapy,
  acute reversibility can be assessed on the first
  visit. Short-acting bronchodilators need to be
  withheld for at least 4 hours prior to testing,
  and long-acting bronchodilators for 12 hours.
  Recent treatment with inhaled glucocorticosteroids
  can also reduce bronchodilator reversibility
  because the pre-bronchodilator FEV1 may improve
  significantly with inhaled glucocorticosteroid
  therapy, especially if asthma is present.

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B. Bronchodilator Reversibility Testing in COPD
(contd)
Reversibility testing needs to be interpreted in
the light of the patients clinical history and
examination. Some patients with COPD can have
greater reversibility and some, especially those
with late-onset or longstanding asthma,
demonstrate very little FEV1 change in response
to bronchodilators.

• Spirometry should be undertaken when the
  patient is clinically stable and free from a
  respiratory tract infection.
• Short-acting bronchodilators should be
  withheld for the previous 6 hours, long-acting
  bronchodilators for 12 hours, and sustained
  release theophylline for 24 hours.

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B. Bronchodilator Reversibility Testing in COPD
(contd)

• FEV1/FVC should be measured before and 15-20
  minutes after bronchodilator is given.
• The bronchodilator should be given by metered
  dose inhaler, ideally through a spacer. A
  nebulizer may be used but generally larger doses
  are delivered by this route.
• The dose administered should be high on the
  dose-response curve.
• Possible dose protocols include 400 µg
  salbutamol, up to 160 µg ipratropium, or the two
  combined.

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B. Bronchodilator Reversibility Testing in COPD
(contd)

• Calculating bronchodilator reversibility
• FEV1 Reversibility Post-bronchodilator
  FEV1
• Pre-bronchodilator FEV1 x 100
• Pre-bronchodilator FEV1
• In the example shown in Figure 3
• FEV1 reversibility 2.2 2.0
  x 100 10
• 
  2.0
• As a general rule spirometry that becomes normal
  after bronchodilator is not COPD!

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C. Patterns of Spirometric Curves

• There are 3 basic patterns to recognize
• NORMAL FEV1 and FVC above 80 predicted
  FEV1/FVC ratio above 0.7
• OBSTRUCTIVE FEV1 below 80 predicted
• FVC can be normal or reduced usually to a
  lesser degree than FEV1
• FEV1/FVC ratio below 0.7
• RESTRICTIVE FEV1 below 80 predicted
• FVC below 80 predicted
• FEV1/FVC ratio normal - above 0.7.
• Spirometry may show a restrictive pattern,
  suggesting the patient's dyspnea is due to a
  restrictive lung disease, and not COPD. In this
  case, the patient should be referred for further
  lung function testing and investigations.

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D. FlowVolume Measurement

• Many electronic desktop spirometers and
  spirometers used in lung function laboratories
  utilize a pneumotachograph measuring gauge, which
  measures airflow and integrates the signal to
  derive volume. This allows the spirometer to plot
  traces of flow rate against the volume of air
  exhaled, producing a flowvolume curve. On many
  spirometers such curves provide the main initial
  visual realtime display when patients are
  performing their blows.
• The interpretation of flowvolume curves is less
  well understood in primary care as it may not be
  taught in basic spirometry courses. Nevertheless
  the curve is a most helpful addition when
  interpreting lung function results, and provides
  a quick and simple check on whether or not airway
  (contd)

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D. FlowVolume Measurement (contd)
obstruction is present. It is also a tool for
identifying the early stages of airway
obstruction and provides additional help in the
interpretation of a mixed pattern of obstruction
and restriction. In the simplest terms it is
adequate to look at the shape of the curve and
compare it with the shape of the predicted
curveusually a dotted lineconstructed by the
spirometer.

• A normal trace (Figure 6A) will have a rapid
  rise to maximal expiratory flow and then an
  almost linear, uniform decline in flow until all
  the air is expelledthe point of intersection
  with the x axis is the FVC.

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D. FlowVolume Measurement (contd)

• In airflow obstruction (Figure 6B) there is a
  concave dip in the second part of the curve which
  will become more marked with increasing
  obstruction. This will be seen in COPD and asthma
  and any other disease causing airflow
  obstruction.
• In more severe emphysema (Figure 6C) where
  loss of airway elasticity causes the airways to
  collapse when forced exhalation occurs (dynamic
  compression), there will be a characteristic
  sudden fall in flow after maximal expiratory flow
  is reachedthe steeple pattern.
• In restrictive lung abnormalities (Figure 6D)
  the shape of the flowvolume curve is normal but
  there is a reduction in lung volume which moves
  the FVC point to the left compared with the
  predicted curve.

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V.PERFORMING SPIROMETRY
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A. Preparing The Patient

• It is important to explain the purpose of the
  test and describe clearly what the patient will
  be asked to do. It is often helpful to
  demonstrate or mimic the procedure yourself and
  emphasize the importance of taking a full breath
  and blowing out as fast and hard as possible.
• Before starting the patients age, sex, and
  height need to be recorded and entered into the
  spirometer so that predicted curves and values
  can be calculated by the spirometer. If the
  patient is of Asian or Afro-Caribbean origin you
  may need to adjust the normal values as these
  tend to be about 10 less in these groups than in
  Caucasians. Many spirometers do this adjustment
  for you.

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A. Preparing The Patient (contd)

• Inquire and record the time of last
  bronchodilator inhaler use, particularly if
  performing a reversibility test. The patient
  should be comfortable and preferably have
  recently emptied their bladder the procedure
  can cause urinary incontinence. Ideally, they
  should be seated for the procedure as there is a
  small risk of syncope, which is greater if
  standing.
• Go to Figure 6A.
• Go to Figure 6B.

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B. Measuring FEV1, FVC, and FlowVolume Curves

• Attach a clean, disposable, one-way mouthpiece
  to the spirometer.
• Instruct the patient to breathe in fully until
  the lungs feel full.
• The patient should hold their breath long
  enough to seal their lips tightly around the
  mouthpiece.
• Blast the air out as forcibly and fast as
  possible until there is no more air left to
  expel. The operator should verbally encourage the
  patient to keep blowing and keep blowing during
  this phase. Watch the patient to make sure a good
  mouth seal around the mouthpiece is achieved.

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B. Measuring FEV1, FVC, and FlowVolume Curves
(contd)

• Check that an adequate trace has been
  achieved. Sometimes with electronic spirometers
  the patient may leak a small volume of air into
  the mouthpiece while sealing the lips which will
  register as the blow.
• Repeat the procedure at least twice until
  three acceptable and reproducible blows are
  obtained. Maximum of 8 efforts.
• There should be three readings, of which the
  best two are within 100 mL or 5 of each other
  and best.
• Depending on the model of spirometer, the
  numbers appear as a table of actual and predicted
  figures together with volumetime and flowvolume
  traces. The best readings of FEV1 and FVC are
  usually recorded.

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B. Measuring FEV1, FVC, and FlowVolume Curves
(contd)

• The use of a nose clip is uncommon in primary
  care but it can be helpful alternatively, ask
  the patient to pinch their nose if they are
  having difficulties with blowing correctly.
• Spirometers with real-time traces and printouts
  are preferred as they provide helpful information
  about the quality and acceptability of the blows.

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C. Differential Diagnosis

• If spirometry confirms airway obstruction, the
  main differential diagnoses are COPD and asthma.
  These two conditions can often be differentiated
  through a careful clinical history and smoking or
  other exposure patterns. However, at times
  certainty is not possible. Although FEV1
  reversibility of more than 12 favors a diagnosis
  of asthma, reversibility of this magnitude and
  higher is seen in COPD, even if less frequently.

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C. Differential Diagnosis (contd)

• A history of childhood wheezing, atopic symptoms,
  and diurnal variation in peak flow gt 20 (as
  established by monitoring at home twice daily for
  2 weeks) may all favor a diagnosis of asthma.
  Similarly, a therapeutic trial of prednisolone 30
  mg daily for 2 weeks, or of inhaled
  corticosteroids for 2-4 weeks, that leads to
  marked improvement in FEV1 may help to identify
  asthma as the more likely diagnosis. The British
  NICE COPD Guidelines2 suggest a greater than 400
  mL increase in FEV1 after treatment trial
  indicates asthma. A reduced diffusing capacity in
  addition to airflow limitation is characteristic
  of emphysema.

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VI.TROUBLESHOOTING
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A. Accuracy and Quality of Readings

• The most common reason for inconsistent readings
  is patient technique. Errors may be detected by
  observing the patient throughout the maneuver and
  by examining the resultant traces.
• Spirometry becomes much easier to perform and
  interpret with practice. Despite this, some
  patients find it a difficult test, and will not
  be able to perform repeatable curves. Do not be
  discouraged this can occur even for
  professionals in respiratory function
  laboratories. However, familiarity with the
  spirometer is important, and adopting the same
  careful approach each time will help you gain
  confidence. Common problems are shown below but
  do not be discouraged by the long list it is
  simply to alert you to points you need to watch
  closely.

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A. Accuracy and Quality of Readings (contd)
Common problems (and examples of traces where
appropriate) include

• Inadequate or incomplete inhalation (Figure
  7C, 7E)
• Lack of blast effort during exhalation
  sub-maximal effort (Figure 7E)
• Delayed onset of maximal effort
  under-estimates FEV1 (Figure 7D)
• Incomplete emptying of lungs common in COPD
  where this can take up to 15 seconds, and in more
  elderly and infirm patients (Figure 7E)
• Additional breath during maneuver
• Lips not tight around mouthpiece (leaks
  under-estimate FEV1 and FVC)

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A. Accuracy and Quality of Readings (contd)
Common problems (and examples of traces where
appropriate) include (Contd)

• A slow start to the blow - under-estimates FEV1
  (Figure 7D)
• Exhaling in part through the nose
• Coughing (Figure 7A)
• Glottic closure
• Obstruction of mouthpiece by teeth or tongue
• Poor posturee.g., leaning forward or
  slouching
• Poor operator knowledge and training
• Poorly maintained and calibrated spirometer
• Go to Figure 7A, B, C, D, E.

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B. Equipment Maintenance and Calibration

• In order to provide accurate and repeatable
  results, spirometers must be regularly cleaned
  and maintained as directed in the manufacturers
  instructions. The correct functioning must be
  frequently checked with some form of calibration.
  
• Ideally, calibration should be performed with a
  3-liter syringe which will allow validation of
  spirometer accuracy. Some electronic spirometers
  can be recalibrated by the user but others only
  by returning them to the manufacturer. Most
  modern electronic spirometers, however, drift
  very little from the set calibration levels so
  use of the 3-liter syringe helps to check that
  levels are unchanged.

64
B. Equipment Maintenanceand Calibration (contd)

• An alternative is to assess overall performance
  of the spirometer by regularly testing of a
  healthy individual every weeka biological
  control. Generally a variation of more than 5
  in FEV1 or FVC should alert you to a problem
  which may necessitate further testing and
  possible return to the manufacturer.

65
C. Infection Control

• Precautions must be taken to minimize any cross
  infection via the spirometer. The use of
  low-resistance barrier filters and disposable
  mouthpieces significantly reduces the risk of
  infection and also helps to protect the equipment
  from exhaled secretions. A new filter must be
  used for each patient.

66
D. When To Refer For Further Respiratory
Function Testing

• Many physicians do not have the time to perform
  their own spirometry, and their practice nurse or
  assistant physician may undertake spirometry.
  Some studies suggest that superior results
  (reliability and validity) are obtained this way.
  When spirometry is abnormal but not diagnostic,
  or if the test cannot be performed reproducibly,
  it is preferable for patients to be referred to a
  lung function laboratory or a specialist, for
  optimal performance and interpretation of
  spirometry. In addition, further lung function
  testing that includes more comprehensive tests
  will assist in making a definitive diagnosis.
  These tests may include full lung volumes,
  diffusing capacity, bronchial provocation
  testing, skin-prick testing, exhaled breath
  testing, and arterial blood gas measurements. A
  restrictive or mixed obstructive-restrictive
  spirometric pattern almost always requires more
  complete lung function testing before a final
  diagnosis can be made.

67
REFERENCES
68

• 1. Global Initiative for Chronic Obstructive
  Lung Disease. Global strategy for the diagnosis,
  management, and prevention of chronic obstructive
  pulmonary disease. (Updated 2007).
  http//www.goldcopd.org.
• 2. National Collaborating Centre for Chronic
  Conditions. Chronic obstructive pulmonary
  disease national clinical guideline on
  management of chronic obstructive pulmonary
  disease in adults in primary and secondary care.
  Thorax 2003, 59 (Suppl 1) 1-232.
• 3. Dales RE, Vandemheen KL, Clinch J, et al.
  Spirometry in the primary care setting. Influence
  on clinical diagnosis and management of airflow
  obstruction. Chest 2005, 128 2443 7.
• 4. Enright P. Does screening for COPD by Primary
  Care Physicians have the potential to cause more
  harm than good? Chest 2006, 129 833-4.
• 5. van Schayck CP,Loozen JM, Wagena et al.
  Detecting patients at high risk of developing
  chronic obstructive pulmonary disease in general
  practice cross-sectional case-finding study. BMJ
  2002, 324 1370-4.
• 6. Miller MR, Hankinson J, Brusasco V, et al.
  ATS-ERS taskforce Standardisation of Lung
  Function Testing. Standardisation of spirometry.
  Eur Respir J 20052631938
• 7. Vandevoorde J, Verbanck S, Schuermans D,
  Kartounian J, Vincken W. FEV1/FEV6 and FEV6 as
  alternative for FEV1/FTC and FVC in the
  spirometric detection of airway obstruction and
  restriction. Chest 20051271560-64.
• 8. Johannsen A, Lehmann S, Omenaas E R, et al.
  Post bronchodilator spirometry reference values
  in adults and implications for disease
  management. Am J Respir Crit Care Med 2006, 73
  1316 -257.

69
lobal Initiative for Chronicbstructiveungisease
G OLD
70
GOLD Structure

• GOLD Executive Committee
• Roberto Rodriguez-Roisin, MD Chair
• Klaus Rabe, MD, PhD Co-Chair

Dissemination/Implementation Task Group
Christine Jenkins, MD - Chair
Science Committee Peter Calverley - Chair
71
GOLD Executive Committee
Y. Fukuchi, Japan, APSR C. Jenkins, Australia A.
Kocabas, Turkey E. Nizankowska, Poland T. van der
Molen, Netherlands C. Van Weel, Netherlands ,WONCA

• R. Rodriguez-Roisin, Chair, Spain
• K. Rabe, Co-Chair, Netherlands
• A. Anzueto, US, ATS
• P. Calverley, UK
• A. Casas, Columbia, ALAT
• A. Cruz, Switzerland, WHO
• T. DeGuia, Philippines

72
GOLD Science Committee
P. Jones K. Rabe R. Rodriguez-Roisin J.
Vestbo J. Zielinski

• P. Calverley, Chair
• A. Agusti
• A. Anzueto
• P. Barnes
• M. Decramer
• Y. Fukuchi

73
Description of Levels of Evidence
74
Bangladesh
Saudi Arabia
Slovenia
Germany
Ireland
Brazil
Yugoslavia
Croatia
United States
Australia
Canada
Austria
Taiwan ROC
Portugal
Philippines
Thailand
Malta
Norway
Greece
Moldova
China
Syria
South Africa
United Kingdom
Hong Kong ROC
Italy
New Zealand
Israel
Chile
Nepal
Argentina
Mexico
Russia
Pakistan
United Arab Emirates
Japan
Peru
GOLD National Leaders
Korea
Poland
Netherlands
Egypt
Venezuela
Switzerland
India
Georgia
France
Macedonia
Iceland
Denmark
Czech Republic
Turkey
Belgium
Slovakia
Singapore
Spain
Ukraine
Columbia
Romania
Uruguay
Sweden
Vietnam
Kyrgyzstan
Albania
75
GOLD Structure

• GOLD Executive Committee
• Roberto Rodriguez-Roisin, MD Chair
• Klaus Rabe, MD, PhD Co-Chair

Dissemination/Implementation Task Group
Christine Jenkins, MD - Chair
Science Committee P. Calverley - Chair
76
GOLD Website Address
http//www.goldcopd.org
77
lobal Initiative for Chronicbstructiveungisease
G OLD
78
GOLD Objectives

• Increase awareness of COPD among health
  professionals, health authorities, and the
  general public.
• Improve diagnosis, management and prevention of
  COPD.
• Stimulate research in COPD.

79
Global Strategy for Diagnosis, Management and
Prevention of COPD

• Definition, Classification
• Burden of COPD
• Risk Factors
• Pathogenesis, Pathology, Pathophysiology
• Management
• Practical Considerations

80
Definition of COPD

• COPD is a preventable and treatable disease with
  some significant extrapulmonary effects that may
  contribute to the severity in individual
  patients.
• Its pulmonary component is characterized by
  airflow limitation that is not fully reversible.
• The airflow limitation is usually progressive and
  associated with an abnormal inflammatory response
  of the lung to noxious particles or gases.

81
Classification of COPD Severity by Spirometry
Stage I Mild FEV1/FVC lt 0.70
FEV1 gt 80 predicted Stage II Moderate
FEV1/FVC lt 0.70
50 lt FEV1 lt 80 predicted Stage III Severe
FEV1/FVC lt 0.70
30 lt FEV1 lt 50 predicted Stage IV Very
Severe FEV1/FVC lt 0.70 FEV1
lt 30 predicted or FEV1 lt 50 predicted
plus chronic respiratory failure
82
At Risk for COPD

• COPD includes four stages of severity classified
  by spirometry.
• A fifth category--Stage 0 At Risk--that appeared
  in the 2001 report is no longer included as a
  stage of COPD, as there is incomplete evidence
  that the individuals who meet the definition of
  At Risk (chronic cough and sputum production,
  normal spirometry) necessarily progress on to
  Stage I Mild COPD.
• The public health message is that chronic cough
  and sputum are not normal remains important -
  their presence should trigger a search for
  underlying cause(s).

83
Global Strategy for Diagnosis, Management and
Prevention of COPD

• Definition, Classification
• Burden of COPD
• Risk Factors
• Pathogenesis, Pathology, Pathophysiology
• Management
• Practical Considerations

84
Burden of COPD Key Points

• COPD is a leading cause of morbidity and
  mortality worldwide and results in an economic
  and social burden that is both substantial and
  increasing.
• COPD prevalence, morbidity, and mortality vary
  across countries and across different groups
  within countries.
• The burden of COPD is projected to increase in
  the coming decades due to continued exposure to
  COPD risk factors and the changing age structure
  of the worlds population.

85
Burden of COPD Prevalence

• Many sources of variation can affect estimates of
  COPD prevalence, including e.g., sampling
  methods, response rates and quality of
  spirometry.
• Data are emerging to provide evidence that
  prevalence of Stage I Mild COPD and higher is
  appreciably higher in
• - smokers and ex-smokers
• - people over 40 years of age
• - males

86
COPD Prevalence Study in Latin America
The prevalence of post-bronchodilator FEV1/FVC lt
0.70 increases steeply with age in 5 Latin
American Cities
Source Menezes AM et al. Lancet 2005
87
Burden of COPD Mortality

• COPD is a leading cause of mortality worldwide
  and projected to increase in the next several
  decades.
• COPD mortality trends generally track several
  decades behind smoking trends.
• In the US and Canada, COPD mortality for both men
  and women have been increasing.
• In the US in 2000, the number of COPD deaths was
  greater among women than men.

88
Percent Change in Age-Adjusted Death Rates, U.S.,
1965-1998
Proportion of 1965 Rate
3.0
Coronary Heart Disease
Stroke
Other CVD
COPD
All Other Causes
2.5
2.0
1.5
1.0
0.5
59
64
35
163
7
0
1965 - 1998
1965 - 1998
1965 - 1998
1965 - 1998
1965 - 1998
Source NHLBI/NIH/DHHS
89
Of the six leading causes of death in the United
States, only COPD has been increasing steadily
since 1970
Source Jemal A. et al. JAMA 2005
90
COPD Mortality by Gender,U.S., 1980-2000
Number Deaths x 1000
Source US Centers for Disease Control and
Prevention, 2002
91
Global Strategy for Diagnosis, Management and
Prevention of COPD

• Definition, Classification
• Burden of COPD
• Risk Factors
• Pathogenesis, Pathology, Pathophysiology
• Management
• Practical Considerations

92
Risk Factors for COPD

• Genes
• Exposure to particles
• Tobacco smoke
• Occupational dusts, organic and inorganic
• Indoor air pollution from heating and cooking
  with biomass in poorly ventilated dwellings
• Outdoor air pollution

Lung growth and development Oxidative
stress Gender Age Respiratory infections Socioecon
omic status Nutrition Comorbidities
93
Risk Factors for COPD
Nutrition
Infections
Socio-economic status
Aging Populations
94
Global Strategy for Diagnosis, Management and
Prevention of COPD

• Definition, Classification
• Burden of COPD
• Risk Factors
• Pathogenesis, Pathology, Pathophysiology
• Management
• Practical Considerations

95
(No Transcript)
96
Pathogenesis of COPD
Cigarette smoke Biomass particles Particulates
Host factors Amplifying mechanisms
LUNG INFLAMMATION
Anti-oxidants
Anti-proteinases
Oxidative stress
Proteinases
Repair mechanisms
COPD PATHOLOGY
Source Peter J. Barnes, MD
97
Changes in Lung Parenchyma in COPD
Alveolar wall destruction
Loss of elasticity
Destruction of pulmonary capillary bed
? Inflammatory cells macrophages, CD8
lymphocytes
Source Peter J. Barnes, MD
98
Pulmonary Hypertension in COPD
Chronic hypoxia
Pulmonary vasoconstriction
Muscularization Intimal hyperplasia Fibrosis Obli
teration
Pulmonary hypertension
Cor pulmonale
Edema
Death
Source Peter J. Barnes, MD
99
ASTHMA
Allergens
Mast cell
Ep cells
CD4 cell (Th2)
Eosinophil
Bronchoconstriction AHR
Airflow Limitation
Reversible
Irreversible
Source Peter J. Barnes, MD
100
Global Strategy for Diagnosis, Management and
Prevention of COPD

• Definition, Classification
• Burden of COPD
• Risk Factors
• Pathogenesis, Pathology, Pathophysiology
• Management
• Practical Considerations

101
Four Components of COPD Management

• Assess and monitor disease
• Reduce risk factors
• Manage stable COPD
• Education
• Pharmacologic
• Non-pharmacologic
• Manage exacerbations

102
GOALS of COPD MANAGEMENT VARYING EMPHASIS WITH
DIFFERING SEVERITY

• Relieve symptoms
• Prevent disease progression
• Improve exercise tolerance
• Improve health status
• Prevent and treat complications
• Prevent and treat exacerbations
• Reduce mortality

103
Four Components of COPD Management

• Assess and monitor disease
• Reduce risk factors
• Manage stable COPD
• Education
• Pharmacologic
• Non-pharmacologic
• Manage exacerbations

104
Management of Stable COPD Assess and Monitor
COPD Key Points

• A clinical diagnosis of COPD should be considered
  in any patient who has dyspnea, chronic cough
  or sputum production, and/or a history of
  exposure to risk factors for the disease.
• The diagnosis should be confirmed by spirometry.
  A post-bronchodilator FEV1/FVC lt 0.70 confirms
  the presence of airflow limitation that is not
  fully reversible.
• Comorbidities are common in COPD and should be
  actively identified.

105
Diagnosis of COPD
EXPOSURE TO RISK FACTORS
SYMPTOMS
cough
tobacco
sputum
occupation
shortness of breath
indoor/outdoor pollution
è
è
è
SPIROMETRY
106
Management of Stable COPD Assess and Monitor
COPD Spirometry

• Spirometry should be performed after the
  administration of an adequate dose of a
  short- acting inhaled bronchodilator to minimize
  variability.
• A post-bronchodilator FEV1/FVC lt 0.70 confirms
  the presence of airflow limitation that is not
  fully reversible.
• Where possible, values should be compared to
  age-related normal values to avoid overdiagnosis
  of COPD in the elderly.

107
Spirometry Normal and Patients with COPD
108
Differential Diagnosis COPD and Asthma
COPD
ASTHMA

• Onset early in life (often childhood)
• Symptoms vary from day to day
• Symptoms at night/early morning
• Allergy, rhinitis, and/or eczema also present
• Family history of asthma
• Largely reversible airflow limitation

• Onset in mid-life
• Symptoms slowly progressive
• Long smoking history
• Dyspnea during exercise
• Largely irreversible airflow
• limitation

109
COPD and Co-Morbidities

• COPD patients are at increased risk for
• Myocardial infarction, angina
• Osteoporosis
• Respiratory infection
• Depression
• Diabetes
• Lung cancer

110
COPD and Co-Morbidities

• COPD has significant extrapulmonary
• (systemic) effects including
• Weight loss
• Nutritional abnormalities
• Skeletal muscle dysfunction

111
Four Components of COPD Management

• Assess and monitor disease
• Reduce risk factors
• Manage stable COPD
• Education
• Pharmacologic
• Non-pharmacologic
• Manage exacerbations

112
Management of Stable COPD Reduce Risk Factors
Key Points

• Reduction of total personal exposure to tobacco
  smoke, occupational dusts and chemicals, and
  indoor and outdoor air pollutants are important
  goals to prevent the onset and progression of
  COPD.
• Smoking cessation is the single most effective
  and cost effective intervention in most people
  to reduce the risk of developing COPD and stop
  its progression (Evidence A).

113
Brief Strategies to Help the Patient Willing to
Quit Smoking

• ASK Systematically identify all tobacco
  users at every visit.
• ADVISE Strongly urge all tobacco users to
  quit.
• ASSESS Determine willingness to make a
  quit attempt.
• ASSIST Aid the patient in quitting.
• ARRANGE Schedule follow-up contact.

114
Management of Stable COPD Reduce Risk Factors
Smoking Cessation

• Counseling delivered by physicians and other
  health professionals significantly increases quit
  rates over self-initiated strategies. Even a
  brief
• (3-minute) period of counseling to urge a
  smoker to quit results in smoking cessation rates
  of 5-10.
• Numerous effective pharmacotherapies for smoking
  cessation are available and pharmacotherapy is
  recommended when counseling is not sufficient to
  help patients quit smoking.

115
Management of Stable COPD Reduce Risk Factors
Indoor/Outdoor Air Pollution

• Reducing the risk from indoor and outdoor air
  pollution is feasible and requires a combination
  of public policy and protective steps taken by
  individual patients.
• Reduction of exposure to smoke from biomass fuel,
  particularly among women and children, is a
  crucial goal to reduce the prevalence of COPD
  worldwide.

116
Four Components of COPD Management

• Assess and monitor disease
• Reduce risk factors
• Manage stable COPD
• Education
• Pharmacologic
• Non-pharmacologic
• Manage exacerbations

117
Management of Stable COPD Manage Stable COPD
Key Points

• The overall approach to managing stable COPD
  should be individualized to address symptoms and
  improve quality of life.
• For patients with COPD, health education plays an
  important role in smoking cessation (Evidence A)
  and can also play a role in improving skills,
  ability to cope with illness and health status.
• None of the existing medications for COPD have
  been shown to modify the long-term decline in
  lung function that is the hallmark of this
  disease (Evidence A). Therefore, pharmacotherapy
  for COPD is used to decrease symptoms and/or
  complications.

118
Management of Stable COPD Pharmacotherapy
Bronchodilators

• Bronchodilator medications are central to the
  symptomatic management of COPD (Evidence A).
  They are given on an as-needed basis or on a
  regular basis to prevent or reduce symptoms and
  exacerbations.
• The principal bronchodilator treatments are
  ß2- agonists, anticholinergics, and
  methylxanthines used singly or in combination
  (Evidence A).
• Regular treatment with long-acting
  bronchodilators is more effective and convenient
  than treatment with short-acting bronchodilators
  (Evidence A).

119
Management of Stable COPD Pharmacotherapy
Glucocorticosteroids

• The addition of regular treatment with inhaled
• glucocorticosteroids to bronchodilator
  treatment is appropriate for symptomatic COPD
  patients with an FEV1 lt 50 predicted (Stage III
  Severe COPD and Stage IV Very Severe COPD) and
  repeated exacerbations (Evidence A).
• An inhaled glucocorticosteroid combined with a
  long-acting ß2-agonist is more effective than the
  individual components (Evidence A).

120
Management of Stable COPD Pharmacotherapy
Glucocorticosteroids

• The dose-response relationships and long-term
  safety of inhaled glucocorticosteroids in COPD
  are not known.
• Chronic treatment with systemic
  glucocorticosteroids should be avoided because of
  an unfavorable benefit-to-risk ratio (Evidence A).

121
Management of Stable COPD Pharmacotherapy
Vaccines

• In COPD patients influenza vaccines can reduce
  serious illness (Evidence A).
• Pneumococcal polysaccharide vaccine is
  recommended for COPD patients 65 years and older
  and for COPD patients younger than age 65 with an
  FEV1 lt 40 predicted (Evidence B).

122
Management of Stable COPDAll Stages of Disease
Severity

• Avoidance of risk factors
• - smoking cessation
• - reduction of indoor pollution
• - reduction of occupational exposure
• Influenza vaccination

123
IV Very Severe
III Severe
II Moderate
I Mild
Add regular treatment with one or more
long-acting bronchodilators (when needed) Add
rehabilitation
Add inhaled glucocorticosteroids if repeated
exacerbations
Add long term oxygen if chronic respiratory
failure. Consider surgical treatments
124
Management of Stable COPD Other Pharmacologic
Treatments

• Antibiotics Only used to treat infectious
  exacerbations of COPD
• Antioxidant agents No effect of
  n-acetylcysteine on frequency of exacerbations,
  except in patients not treated with inhaled
  glucocorticosteroids
• Mucolytic agents, Antitussives, Vasodilators
  Not recommended in stable COPD

125
Management of Stable COPD Non-Pharmacologic
Treatments

• Rehabilitation All COPD patients benefit from
  exercise training programs, improving with
  respect to both exercise tolerance and symptoms
  of dyspnea and fatigue (Evidence A).
• Oxygen Therapy The long-term administration of
  oxygen (gt 15 hours per day) to patients with
  chronic respiratory failure has been shown to
  increase survival (Evidence A).

126
Four Components of COPD Management

• Assess and monitor disease
• Reduce risk factors
• Manage stable COPD
• Education
• Pharmacologic
• Non-pharmacologic
• Manage exacerbations

127
Management COPD Exacerbations Key Points
An exacerbation of COPD is defined as An
event in the natural course of the disease
characterized by a change in the patients
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.
128
Management COPD Exacerbations Key Points

• The most common causes of an exacerbation are
  infection of the tracheobronchial tree and air
  pollution, but the cause of about one-third of
  severe exacerbations cannot be identified
  (Evidence B).
• Patients experiencing COPD exacerbations with
  clinical signs of airway infection (e.g.,
  increased sputum purulence) may benefit from
  antibiotic treatment (Evidence B).

129
Manage COPD Exacerbations Key Points

• Inhaled bronchodilators (particularly inhaled
  ß2-agonists with or without anticholinergics)
  and oral glucocortico- steroids are effective
  treatments for exacerbations of COPD (Evidence
  A).

130
Management COPD Exacerbations Key Points

• Noninvasive mechanical ventilation in
  exacerbations improves respiratory acidosis,
  increases pH, decreases the need for endotracheal
  intubation, and reduces PaCO2, respiratory rate,
  severity of breathlessness, the length of
  hospital stay, and mortality (Evidence A).
• Medications and education to help prevent future
  exacerbations should be considered as part of
  follow-up, as exacerbations affect the quality of
  life and prognosis of patients with COPD.

131
Global Strategy for Diagnosis, Management and
Prevention of COPD

• Definition, Classification
• Burden of COPD
• Risk Factors
• Pathogenesis, Pathology, Pathophysiology
• Management
• Practical Considerations

132
Translating COPD Guidelines into Primary CareKEY
POINTS

• Better dissemination of COPD guidelines and their
  effective implementation in a variety of health
  care settings is urgently required.
• In many countries, primary care practitioners
  treat the vast majority of patients with COPD and
  may be actively involved in public health
  campaigns and in bringing messages about reducing
  exposure to risk factors to both patients and the
  public.

133
Global Strategy for Diagnosis, Management and
Prevention of COPDSUMMARY

• Definition, Classification
• Burden of COPD
• Risk Factors
• Pathogenesis, Pathology, Pathophysiology
• Management
• Practical Considerations

134
Global Strategy for Diagnosis, Management and
Prevention of COPD Summary

• COPD is increasing in prevalence in many
  countries of the world.
• COPD is treatable and preventable.
• The GOLD program offers a strategy to identify
  patients and to treat them according to the best
  medications available.

135
Global Strategy for Diagnosis, Management and
Prevention of COPD Summary

• COPD can be prevented by avoidance of risk
  factors, the most notable being tobacco smoke.
• Patients with COPD have multiple other conditions
  (comorbidities) that must be taken into
  consideration.
• GOLD has developed a global network to raise
  awareness of COPD and disseminate information on
  diagnosis and treatment.

136
Bangladesh
Saudi Arabia
Slovenia
Germany
Ireland
Brazil
Yugoslavia
Croatia
United States
Australia
Canada
Austria
Taiwan ROC
Portugal
Philippines
Thailand
Malta
Norway
Greece
Moldova
China
Syria
South Africa
United Kingdom
Hong Kong ROC
Italy
New Zealand
Israel
Chile
Nepal
Argentina
Mexico
Russia
Pakistan
United Arab Emirates
Japan
Peru
GOLD National Leaders
Korea
Poland
Netherlands
Egypt
Venezuela
Switzerland
India
Georgia
France
Macedonia
Iceland
Denmark
Czech Republic
Turkey
Belgium
Slovakia
Singapore
Spain
Ukraine
Columbia
Romania
Uruguay
Sweden
Vietnam
Kyrgyzstan
Albania
137
GOLD Website Address
http//www.goldcopd.org
138
ADDITIONAL SLIDES WITH NOTES PREPARED
BY PROFESSOR PETER J. BARNES, MD NATIONAL HEART
AND LUNG INSTITUTE LONDON, ENGLAND
139
Changes in Large Airways of COPD Patients
Mucus hypersecretion
Neutrophils in sputum