Prof.Dr.Hakan GÜNEN
     İnönü Üniversitesi Tıp Fakültesi
    Göğüs Hastalıkları Ana Bilim Dalı
 To learn about the treatment of
  exacerbations of chronic obstructive
  pulmonary disease (COPD)
  (outpatients, hospital, intensive care unit)
       Overview of Presentation
   Introduction
   Definition of COPD exacerbation
   Epidemiology of COPD exacerbation
   Patient evaluation
   Treatment at home
   Treatment at hospital and intensive care unit
   Other treatments
   Discharge criteria and follow-up
 COPD is the 4th leading cause of death worldwide
 It is the 3rd. leading cause of death in Turkey.
 Mortality in COPD is significant.
 Mortality during exacerbations is approximately 5-
 Cost of treatment in COPD is high (8500 USD per
 Cost of treatment in COPD exacerbations is much
  higher (5400 USD per exacerbation)
    Definitions of Exacerbations of
 Previous definitions:
a)Antonisen’s definition (1987): This definition
  is based upon the hypothesis that
  exacerbations are are caused by bacterial
  ―defined as worsening of at least one of the
  cardinal COPD symptoms, dyspnea,
  ,increased sputum volume or sputum
  purulence; Type 1, Type 2, Type 3‖
   Definitions of Exacerbations of
 ACCP Working Group definition (2000)

“a sustained worsening of the patient’s
condition, from the stable state and beyond
normal day-to-day variations, that is acute in
onset and necessitates a change in regular
medication in a patient with underlying COPD”
   Definitions of Exacerbations of
 c)Definition of ATS-ERS (2004):

 “an exacerbation of COPD is an event in
 the natural course of the disease
 characterised by a change in the patient’s
 baseline dyspnoea, cough and/or sputum
 beyond day-to-day variability sufficient to
 warrant a change in management”
    Definitions of Exacerbations of
d) Definition of GOLD: GOLD avoided making
  a specific definition until 2006. Their
  definition resembels ATS-ERS definition.
  Definition of GOLD 2007;
“An exacerbation of COPD is defined as an event
in the natural course of the disease characterized
by a change in the patientes 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.”
    Definitions of Exacerbations of
 Conclusion:
 There is no consensus regarding the
 Even investigators set study specific their
  own definitions (ISOLDE – ―worsening of
  COPD symptoms which necessitates oral
  steroid and/or antibiotic utilization‖).
 Conflicts (acute exacerbation, attack, acute
  attack etc.)
Causes of COPD Exacerbations
 Bacterial and viral infections are assumed to
  be responsible from 70-80% of the
  -Primary causes: Infections, inhalation of
  environmental irritants, cold air,
  uncompliance with the treatment
  -Sekondary causes: Pneumoniae,
  pulmonary emboli, pneumothorax, cardiac
Causes of COPD Exacerbations
Causes of COPD Exacerbations
 Bacterial causes:
  S. Pneumoniae, H. İnfluenza, M.
  Catarrhalis, (less frequently, Mycoplasma
  P. , Chylamidia P., P. aeuroginosa).
 Viral causes:
  Rhinoviruses, RSV,
  (less frequently Influenza A-B,
  Parainfluenza, Coronavirus, Adenovirus).
        Epidemiology of COPD
 Until recently, attack rates were not
  evaluated and analyzed as a primary result
  in the studies. There are few studies
  addressing this issue.
 However, attack rates have been utilized in
  comparing the different primary results in
  COPD studies.
        Epidemiology of COPD
 So far it is not possible to give a certain
  figure on exacerbation rates in COPD
 Patient statements, hospitalization rates,
  medical records, PEF values, complicated
  device utlizations, drug dozimeters, phone
  calls, home visits etc.
 Studies bare many pitfalls, perfect method
  could not be reached yet.
        Epidemiology of COPD
 Exacerbation rates from major COPD
    TORCH: 1 exacerbation/year
    MISTRAL: 1,5 exacerbation/year
    GLAXO world data: 1exacerbation/year
    ISOLDE: 1,5 exacerbation/year
            Epidemiology of COPD
   What is the reality??
   Haughney et al.; 4.6 exacerbation/year (ERJ 2005)
   PERCEIVE study; 5.1 exacerbation/year
   Conclusions:
      According to the results of all studies
    1) COPD patients do not report at least half of their
    exacerbations when asked.
    2) One of every 2 exacerbation ends with hospitalization
      (8 times more exacerbation and hospitalization rates than
        Epidemiology of COPD
 FEV1; Most significant factor on COPD
  exacerbation rates (Burge et al. ERJ 2003)
           Determining Severity of
 There is no consensus in determining the severity of an
 However, it is important in determining how to treat and
  where to treat the patient
   -home, hospital, intensive care unit
   -non-invasive, invasive mechanical ventilation
   -bronchodilator dosages
   -corticosteroid durations
   -antibiotic choice
   -additional treatments (diuretics, cardiac support destek)
       Determining Severity of
 Anthonisen’s (1987) classification
 The classification based upon symptom
  severity and symptom duration with
  spirometric alterations
  (Seemungal ve ark. AJRCCM 2000)
        Determining Severity of
 Classification based upon the increased
  need for bronchodilators and antibiotic use,
  corticosteroid administration and
  (Burge et al. ERJ 2003)
           Determining Severity of
 GOLD’s recommendations are quite
― Assessment    of the severity of an exacerbation is based
on the patientes medical history before the exacerbation,
preexisting comorbidities, symptoms, physical examination,
arterial blood gas measurements, and other laboratory
tests. Specific information is required on
the frequency and severity of attacks of breathlessness
and cough, sputum volume and color, and limitation of
daily activities. When available, prior arterial blood gas
measurements are extremely useful for comparison with
those made during the acute episode, as an acute change
in these tests is more important than their absolute values―.
          Determining Severity of
 GOLD’s recommendations for assessment of COPD
  exacerbations: medical history and signs of severity
        • Severity of FEV1            • Use of accessory
        • Duration of worsening or      respiratory muscles
          new symptoms                • Paradoxical chest wall
        • Number of previous            movements
          episodes (exacerbations/    • Worsening or new onset
          hospitalizations)             central cyanosis
        • Comordibities               • Development of peripheral
        • Present treatment regimen     edema
                                      • Hemodynamic instability
                                      • Signs of right heart failure
                                      • Reduced alertness
         Determining Severity of
 GOLD’s other recommendations;
 - Spirometry and PEF measurements
 - Arterial blood gas analysis (PaO2<60 mmHg,
  PaCO2>50 mmHg, pH<7.35)
 - Chest films and ECG
 - Blood tests (leucocyte, hemoglobin, electrolytes,
  blood glucose)
 - Sputum Gram staining and culture antibiogram
           Determining Severity of
 Home or hospital?
  There is no strict criteria about which
  patients should be treated at home.
  However there are some criteria which
  patients should not be treated at home
    Respiratory rate higher than 25/min
    Pulse rate higher than110/min
    PaO2 less than 60 mm Hg
    Abnormal chest radiograph
    Serious concomitant disease
    Altered mental state
    Living alone
     At Home Treatment Plan
 ABC plan
     At Home Treatment Plan
 GOLD’s recommendation
 Although there is no consensus, antibiotics
  are recommended when there is an
  increase in one of the cardinal COPD
  symptoms in addition to increased sputum
  purulence in patients who will be treated
  outpatients settings (GOLD 2007).
 Oral route should be preferred
  Treatment duration 3-10 days
    Bronchodilators; how and how
- If the patient can use, inhalers or spacers should
   be preferred. There is no additional efficacy
   administrating the drugs by nebulizers except
 - Short acting Beta-2 mimetics should be preferred.
   Initial doses can be given more frequently. The
   total dose should not exceed 12 times a day by
   inhaled or nebulized routes.
 - Side effects??
 Maximum dose of anticholinergics should
  not exceed 6 times a day (inhaled or
 Even at the initial period, it should not be
  given more frequently than 2 hrs.
 Intermittent combination with Beta-2
  agonists is justified
 Side effects??
 Theophyllin??
- If the expected result from frequent initial
   bronchodilator treatment can not be obtained
   specifically in patients with FEV1<%50; 7-10 days
   perdnisolone 30-40 mgr/gün (GOLD 2007)
 - Oral route should be preferred
 - It is assumed to shorten the recovery period and
   accelarates the normalization of FEV1 and PaO2
 - High dose nebulized budesonide may be an
   alternative (GOLD 2007 ref.419)
    Hospital Treatment of COPD
 Mortality in hospitalized patients is higher
  than the mortality in patients treated at
  home (1-2% versus 10%)

 Mortality is much higher in patients treated
  at intensive care unit than the patients
  treated at ward (3% versus 27 %) (GOLD
  2007, 316. ref.)
  Hospitalization Criteria in COPD
 Marked increase in intensity of symptoms, such as sudden
  development of resting dyspnea
 Severe underlying COPD
 Onset of new physical signs (e.g., cyanosis, peripheral edema)
 Failure of exacerbation to respond to initial medical
 Significant comorbidities
 Frequent exacerbations
 Newly occurring arrhythmias
 Diagnostic uncertainty
 Older age
 Insufficient home support
                Treatment Algorhytm
   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 2-agonists and anticholinergics
       – Use spacers or air-driven nebulizers
       – Consider adding intravenous mehylxanthines, if needed
   Add oral or intravenous glucocorticosteroids
   Consider antibiotics (oral or occasionally intravenous) when signs of bacterial
   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 Ward or Intensive Care
 Severe dyspnea that responds inadequately to initial
  emergency therapy
 Changes in mental status (confusion, lethargy, coma)
 Persistent or worsening hypoxemia (PaO2<40 mmHg),
  and/or severe/worsening hypercapnia
  (PaCO2>60 mmHg), and/or severe/worsening
  respiratory acidosis (pH<7.25) despite supplemental
  oxygen and noninvasive ventilation
 Need for invasive mechanical ventilation
 Hemodynamic instability — need for vasopressors

These patients should be transferred to the intensive care unit
           Oxygen Treatment

1. Oxygen treatment should be given in a controlled
   manner (PaO2>60 mm Hg or Saturation >90)
2. CO2 retention and development of acidosis
   should be monitored
3. Arterial blood gas analysis should be repeated
   every 30-60 minutes. After the stability, pulse
   oximetry could be applied.
4. The route of oxygen delivery depends upon
   patient comfort or physician’s experience
      Bronchodilator Treatment

1. Inhaled or nebulized short acting Beta-2 agonists
   should be preferred
2. In cases with limited response, combination with
   anticholinergics can be tried
3. Same principles for bronchodilator treatment at
   home are applicable (the routes and dosages)
4. Theophylline infusion can be tried in cases with
   unresolving symptoms (efficacy?, side effects?,
   narrow therapeutic range?, close monitorization?).
       Corticosteroid Treatment

1. It should be initiated to every hospitalized patient
   without any contraindication
2. It shortens the hospitalization period, and
   accelarates the recovery of hypoxemia and
3. 30-40 mg prednizolone/day, 7-15 days
4. Oral or intravenous
5. Side effects???
6. Alternative: high dose nebulized budesonide?
   (GOLD 2007)
Antibiotic treatment; to whom, when
         and which antibiotic

1) Worsening of 3 cardinal COPD symptoms
2) Worsening of at least 1 cardinal COPD
   symptom in addition to increased sputum
3) In conditions where invasive or non-
   invasive mechanical ventilation indicated
    Hospitalized patients are Grup B and C
   any more
         Antibiotic Treatment

 Group B: In addition to Group A; beta
  lactamase producing penicillinase resistant
  S.pneumoniae and Enterobacteriacea (K.
  Pneumoniae, E. coli, Proteus, Enterobacter
  vs.). No risk for P. aeruginosa.
 Group C: In adition to Group B, there is risk
  for P. aeruginosa
         Antibiotic Treatment

 While the severity of exacerbation is
  increasing, infecting microorganism profile
  shifts from S.pneumoniae to Gram (-)
  enteric bacilli and P.aeruginosa
  Antibiotic Treatment
Shifting Microorganisms
Antibiotic Algorhytm
         Antibiotic Treatment
 Oral or intravenous.
 3-10 days
  Additional Therapeutic Options

1. Respiratory stimulants;
   Not recommenden in general termsç.
   Only doxapram may be tried in cases where
   noninvasive ventilation is indicared but can not
   be available
2. Ventilatory support:
   Noninvasive and invasive mechanical
       Noninvasive Mechanical
 It helps in avoiding ICU admissions and
 Its indications have increased for the last 10
 Indicated in 40% of hospitalized patients
  with COPD exacerbations.
 Success rate 70-80%
     Indications of Noninvasive
       Mechanical Ventilation
 Moderate to severe dyspnea with use of
  accessory muscles and paradoxical
  abdominal motion
 Moderate to severe acidosis (pH less than
  7.35 ) and/ or hypercapnia (PaCO2 > 45
  mm Hg)
 Respiratory frequency > 25 breaths per
   Contraindications of Noninvasive
        Mechanical Ventilation
 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.
       How to Apply Noninvasive
        Mechanical Ventilation
 CPAP mode is not recommended in COPD
  patients except in cases where BIPAP is not
 BIPAP mode is recommended to be adjusted from
  low pressures to high pressures
 Initial pressures approximately İ:8 mm Hg, E:4 cm
 Arterial blood gas analyses and SpO2 will help in
  titrating the pressures
   Expectations from Noninvasive
      Mechanical Ventilation

1) Recovery of acidosis (pH rises, PaCO2
2) Respiratory rate and load decreases
3) Dyspnea perception decreases
4) Shortens the hospitalization period
5) Helps in avoiding intubation
6) Mortality decreases
 Invasive Mechanical Ventilation
 It is indicated in the patients with intolerable
  respiratory load
 Used in approximately 20% of hospitalized
  COPD patients due to an exacerbation
  (Quinnell et al. Chest 2006)
 Used in intensive care units
  Indications of Invasive Mechanical
 Unable to tolerate NIV or NIV failure (for exclusion criteria)
 Severe dyspnea with use of accessory muscles and paradoxical
  abdominal motion.
 Respiratory frequency > 35 breaths per minute
 Life-threatening hypoxemia
 Severe acidosis (pH < 7.25) and/or hypercapnia (PaCO2 > 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)
       Expectations from Invasive
         Mechanical Ventilation
 Mortality is high in patients intubated due to COPD
  exacerbation (20-50%)

 Mortality; increases while FEV1 and PaO2
  decreasing and PaCO2 and ve co-morbid
  conditions are increasing
 Extubation is much more difficult than intubation
  (extubation failure 5-45%)
 Routine NIMV during extubation is contraversial in
  favour of its use
         Additional Treatments

 Cardiac support (positive inotrpic support,
  diuretics, digitalisations, Ca++ channel blockers)
 Deep vein thromboprophylaxis
 Treatment of additional pathologies (pulmonary
  emboli, pneumoniae, MI etc.)
 Metabolic disorders, nutrition and electrolyte
                Discharge Criteria
 Inhaled Beta-2 agonist therapy is required no more frequently than
  every 4 hrs.
 Patient, if previously ambulatory, is able to walk across room.
 Patient is able to eat and sleep without frequent awakening by
 Patient has been clinically stable for 12-24 hrs.
 Arterial blood gases have been stable for 12-24 hrs.
 Patient (or home caregiver) fully understands correct use of
 Follow-up and home care arrangements have been completed (e.g.,
  visiting nurse, oxygen delivery, meal provisions).
 Patient, family, and physician are confident patient can manage
  successfully at home.
 Treatment without follow-up does not help
 Written action plan should be prepared
 First follow-up visit is 4-6 weeks after discharge;
  -ability to cope in usual environment
  -measurement of FEV1, arterial blood gases if necessary
  -reassessment of inhaler technique, medication, smoking,
  -understanding of recommended treatment regimen
              should be evaluated
There after follow-up visits to be repeated every 4-6 weeks

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