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COPD Exacerbation

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					  COPD Exacerbation:
Practical Evidence-based
       Strategies

Daniel D. Dressler, MD, MSc
          Director of Education
      Section of Hospital Medicine
    IM Associate Residency Director
     Assistant Professor of Medicine
   Emory University School of Medicine
      Daniel.Dressler@emory.edu

Society of Hospital Medicine Annual Meeting
            San Diego, California
                April 4, 2008
     What will NOT be discussed during
                this session…


•   Knock-out mice      • Pathophysiology
                        • Disease Burden
                        • Precipitants
                        • Differential
                        • Adm criteria
                   Objectives
• By the end of this session, participants
  will be able to:
• Locate, Evaluate and Interpret the highest
  level of medical evidence for management
  of COPD Exacerbations
   Summary of RCT data
   RCT data
   Observational Data
             Definition of COPD
   Progressive Pulmonary airflow limitation that is not
    completely reversible
   Abnormal inflammatory response of the lung to
    noxious particles or gases
   Preventable and Treatable
   Extrapulmonary effects may contribute to
    disease severity
     Weight loss
     Nutritional abnormalities

     Skeletal muscle dysfunction
       Classification of COPD Severity
                 by Spirometry
Stage I: Mild           FEV1/FVC < 0.70
                        FEV1 > 80% predicted

Stage II: Moderate      FEV1/FVC < 0.70
                        50% < FEV1 < 80% predicted

Stage III: Severe       FEV1/FVC < 0.70
                        30% < FEV1 < 50% predicted

Stage IV: Very Severe   FEV1/FVC < 0.70
                        FEV1 < 30% predicted or
                          FEV1 < 50% predicted plus
                          chronic respiratory failure
 Exacerbation of COPD: Definition
 Acute change in baseline dyspnea, cough,
  and/or sputum beyond normal day-to-day
  variations
 May warrant a change in regular
  medication(s)
          Exacerbations: Mortality
• Hospitalized
   – Inpatient mortality (non-ICU): 2.5%* (1 in 40)
   – 3-month mortality after hospitalization for exacerbation: 14%
     (1 in 7)
   – If pCO2>50:
        • 6 month mortality = 33%
        • 12 month mortality = 43%

• ICU
   – 17% in-hospital (1 in 6)
   – 26% in-hospital if intubated* (1 in 4)
   – 45% 1-year mortality (1 in 2)

                                         *Patil SP, et al. Arch Intern Med. 2003.
                   DIAGNOSIS
• Exacerbations: CLINICAL Diagnosis


• Spirometry (PFTs and/or Peak Flows)
   – No demonstrated value in setting of COPD exacerbation
   – Useful only in the outpatient diagnosis of stable COPD
   – DIFFERENT for Asthma patients, where spirometry is
     useful in the setting of stable asthma and asthma
     exacerbation


• Assess Severity!!
              The Evidence: Pharmacologic
             Therapies for COPD Exacerbation
             BRONCHODILATOR THERAPIES
Inhaled Bronchodilators
•    Short-acting inhaled ß2 agonist BDs recommended by guidelines
     (Evidence A)*
       – Outcomes: Main benefit on symptoms and FEV1
•    5 RCTs suggest ß2 agonists similar efficacy to anticholinergic BDs on
     FEV1**
       – Fewer side effects with anticholinergics agents alone
•    Some patients benefit from adding a 2nd bronchodilator after
     maximum dose** of the initial bronchodilator has been reached
•    Oral and injected bronchodilators NOT as effective**
•    No clinical studies of long-acting inhaled BDs during exacerbation


*American Thoracic Society (ATS), European Respiratory Society (ERS), National Institute for Clinical
Excellence (NICE/Thorax), GOLD (Global Initiative for Chronic Obstructive Lung Disease)
** Bach PB, et al. Ann Intern Med 2001. 134: 600-620.
    The Evidence: Pharmacologic
   Therapies for COPD Exacerbation
   BRONCHODILATOR THERAPIES

Methylxanthine Systemic Bronchodilators
• Meta-analysis summary
• 4 RCTs, 169 total patients
• Evaluation in patients treated in EDs or
  inpatient for exacerbations of COPD
• Relevant Outcomes:
  – Return to ED, Symptoms, Arrhythmias
       The Evidence: Pharmacologic
      Therapies for COPD Exacerbation
      BRONCHODILATOR THERAPIES
Methylxanthine Bronchodilators: Efficacy

ED Return Visits within 1 wk               Symptom Scores




  Barr RG, et al. BMJ 2003. 327: 643-48.
           The Evidence: Pharmacologic
          Therapies for COPD Exacerbation
          BRONCHODILATOR THERAPIES
 Methylxanthine Bronchodilators: Adverse Effects

              Arrhythmias/Palpitations




Barr RG, et al. BMJ 2003. 327: 643-48.
    The Evidence: Pharmacologic
   Therapies for COPD Exacerbation
               OXYGEN
• ―Controlled oxygen therapy‖ recommended by
  GOLD Guidelines (no evidence level provided)
   – Flow-controlled systems (e.g. Venturi mask) preferred

• Indicated for hypoxemic patients (PaO2 < 60)
   – Give just enough to relieve hypoxemia

• Monitor closely for signs of hypercarbia and
  respiratory failure (i.e. ABG 30 – 60 min after
  initiation of new O2 rx)
What about Steroids…
          The Evidence: Pharmacologic
         Therapies for COPD Exacerbation
          SYSTEMIC CORTICOSTEROIDS
  • Oral or IV glucocorticosteroids recommended in
    hospital management of COPD exacerbations
    (Evidence A)*
         – Improve symptoms and FEV1* (based on 6 RCTs**)

  • 30-40 mg prednisolone daily x 7-10 days is
    effective and safe (Evidence C)*
         – No more than 2 weeks of systemic rx necessary***

  • No role for inhaled corticosteroids in acute
    exacerbation of COPD (no studies to date*)
*Global Initiative for Chronic Obstructive Lung Disease (“GOLD”). NIH/NHLBI; April 2001,
updated May 2007. NIH Publication 2701. Available at: www.goldcopd.com
** Bach PB, et al. Ann Intern Med 2001. 134: 600-620.
***Niewoehner DE, et al. N Engl J Med 1999. 340: 1941-47.
COPD: Systemic Steroids on Rx Failure




Figure: Kaplan-Meier Estimates of the Rate of First Treatment Failure at Six Months,
According to Treatment Group (271 patients)

Niewoehner DE, et al. N Engl J Med 1999. 340: 1941-47.
ACP Journal Club 2000. 132(1): 14.
 COPD Exac: Systemic Steroids effects on
     A. FEV1 after BD, and B. LOS
A. FEV1 after BD
                                             B. LOS (p = 0.039)
(p<0.0001)




RCT data, 56 patients
Davies L, et al. Lancet 1999; 354: 456-60.
The Evidence for Mucolytics…
          The Evidence: Pharmacologic
         Therapies for COPD Exacerbation
              MUCOLYTIC AGENTS

  • 5 RCTs of Mucolytic/Mucokinetic agents
    in the setting of COPD Exacerbations did
    NOT demonstrate shortening of disease
    course, but may improve symptoms*


  • However, outpatient use of mucolytics in
    COPD patients may reduce number of
    exacerbations…

*Bach PB, et al. Ann Intern Med 2001. 134: 600-620.
                    Mucolytic Agents in Chronic COPD:
                         Effect on Exacerbations




Reduces mean number of exacerbations per subject per month (weighted mean
difference, and 95% confidence intervals)
*No effect on lung function
Poole, P. et al. BMJ 2001;322:1271
What about Pulmonary Toilet?
  The Evidence: Therapies for COPD
            Exacerbation
      CHEST PHYSIOTHERAPY

• Mechanical percussion of the chest by
  PTs or RTs is ineffective (or detrimental)
• No change or decrease in FEV1
• Therefore: NO Pulmonary Toilet!




  *Based on 3 RCTs and 1 observational study
  *Bach PB, et al. Ann Intern Med 2001. 134: 600-620.
          The Evidence: Pharmacologic
         Therapies for COPD Exacerbation
                  ANTIBIOTICS
   • Antibiotics indicated for exacerbation…
        – COPD Exacerbation with 3/3 ‗cardinal
          symptoms‘: increased dyspnea, increased
          sputum volume, increased sputum purulence
          (Evidence B)*
        – COPD Exacerbation with 2/3 ‗cardinal
          symptoms‘ that includes increased sputum
          purulence (Evidence C)*

   • Antibiotics indicated for hospitalized
     exacerbation…?
*GOLD Initiative Guidelines
        The Evidence: Antibiotic vs Placebo—
                 Outcome: Mortality




RR = 0.23 (0.10, 0.52), NNT = 8
Ram FSF, et al. Cochrane Database of Systematic Reviews 2006, Issue 2. Art. No.: CD004403. DOI:
10.1002/14651858.DC004403.pub2.
                       Antibiotic vs Placebo—
                      Outcome: Length of Stay




Ram FSF, et al. Cochrane Database of Systematic Reviews 2006, Issue 2. Art. No.: CD004403. DOI:
10.1002/14651858.DC004403.pub2.
                             New Evidence
                          Procalcitonin Levels
Decision Support for Antibiotic Use in COPD Exacerbation
   •   Background
         – Serum procalcitonin may be useful for detecting bacterial
           infections
   •   Design
         – RCT, blinded, COPD exacerbation presenting to ED
   •   Randomized to:
         – Rx guided by Procalcitonin level
                 •   <0.1  abx discouraged
                 •   >0.25  abx recommended
         – Control
                 •   Clinician abx rx based on guidelines (attending discretion)

   Stolz D, et al. Chest 2007; 131: 9-19.
                      New Evidence
                   Procalcitonin Levels
•   Results
    – No difference b/w groups with respect to mortality,
      symptoms, re-exacerbation rate, LOS, ICU LOS, FEV1
    – +Reduction in ABX use
           •   RR = 0.64 in procalcitonin-guided group
           •   NNT = 4

•   Availability
    – Not currently broadly available
•   Cost
    – Lab Charge: approximately $170
Which Antibiotic?...not great evidence




                                Martinez FJ, et al. Expert
                                Rev Anti Infect Ther. 2006;
                                4: 101-124.
      Bottom Line: Pharmacologic Therapies for
        Hospitalized with COPD Exacerbation

YES!                                 NO!
•   Inhaled Bronchodilators          •   Methylxanthine
    – Duh! (Evidence A)                  – Unless you like that
                                           ‗speed‘ feeling and
•   Oxygen                                 arrhythmias
    – Duh! (No Evidence)             •   Mucolytic Agents
•   Systemic Steroids (Evidence A)       – Little valuable evidence
                                           for exacerbations
    – Improves BD response
                                         – Some evidence in
    – Reduces Hospital LOS                 chronic COPD for
    – Improves time to next                decreasing exacerbations
      exacerbation or rx failure     •   Chest PT
•   Antibiotics                      •   Heliox
                          NPPV

Indications                    Contraindications
•   COPD exacerbations         •   Cardiac/Respiratory arrest

•   Hypoxemic or ventilatory   •   Malignant arrhythmias
    Respiratory Failure
                               •   Refractory hypoxemia
•   CHF
                               •   Hemodynamic instability
•   Extubation Management
                               •   Severe encephalopathy
                               •   Unable to tolerate mask
                               •   High risk of aspiration
                               •   Anatomic abnormalities
              NPPV vs Usual Care
• Meta-Analysis of RCTs (14)           Averages for Studies
   – Concealed allocation, unblinded   Age: 63-76
• Patients                             Adm pH: 7.26-7.34
   – COPD with Respiratory Failure
                                       FEV1: 0.68-1.03
   – Total of 758 patients studied

• Outcomes
   – Mortality (n = 622)
   – Treatment Failure (n = 541)
   – Intubation (n = 758)
   – LOS (n = 546)
   – Other Surrogate Outcomes (RR, pCO2, pH)
                             NPPV vs Usual Care—
                              Outcome: Mortality




RR = 0.52 (95%CI: 0.35, 0.76), NNT = 10
Ram FS, et al. Non-invasive positive pressure ventilation for treatment of respiratory failure due to
exacerbations of chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews.
(3):CD004104, 2004.
                      NPPV vs Usual Care—
                       Outcome: Mortality

                                            pH 7.3-7.35
                                            Summary
                                            pH < 7.3
                                            Summary



                                            ICU
                                            Summary
Ram FS, et al.
Cochrane Database
of Systematic
Reviews.(3):CD00410
                                            Ward
4, 2004.                                    Summary
                    NPPV vs Usual Care—
                  Outcome: Treatment Failure




RR 0.48 (95%CI: 0.37, 0.63), NNT = 5
Ram FS, et al. Cochrane Database of Systematic Reviews. (3):CD004104, 2004.
                         NPPV vs Usual Care—
                         Outcome: Intubation




RR 0.41 (95%CI: 0.33, 0.53), NNT = 4
Ram FS, et al. Cochrane Database of Systematic Reviews. (3):CD004104, 2004.
                          NPPV vs Usual Care—
                            Outcome: LOS




LOS Reduction 3.2 days (95%CI: 2.1 - 4.4 days)
Ram FS, et al. Cochrane Database of Systematic Reviews. (3):CD004104, 2004.
What about less severe exacerbations?
                  NPPV for pH > 7.30?
                     Systematic Review, Annals of IM
                     “Non-Severe Exacerbations”: pH>7.30
                     )
•   Hospital
    Mortality




•   Intubations




                                     Keenan SP, et al. Ann Intern Med. 2003.
                      NPPV for pH > 7.35?
•   RCT 2007                                                      *pCO2
    – NPPV + Usual Care vs.
    – Usual Care
•   Hospital Admissions for COPD      *
    Exacerbation
•   pH>7.35 in all patients
•   Results                                                   **
    – No mortality or intubation
                                                              LOS
      reduction
    – More rapid reduction in pCO2*
    – +LOS Reduction (5.5 vs. 10.2
      days, p = 0.0004)**


                                      Pastaka C, et al. Eur J Intern Med 2007; 18: 524-530.
             Bottom Line: NPPV in
              COPD Exacerbation
• Improves respiratory status
   – Rapidly improved physiologic variables (pH, PCO2, RR,
     breathlessness)
• Reduces Hospital LOS
   – >3 days on average!
   – Even for less severe exacerbations (pH>7.35)
• Reduced Intubation Rate
   – NNT 4
• Reduced complications (e.g. VAP)
• Improves mortality!!
   – NNT 10
                                       Evidence Level A
             Bottom Line: NPPV in
              COPD Exacerbation
• Maintain a low threshold to utilize!
• Apply in the ED!!
   – Early intervention likely improves outcomes
• Monitor closely with ABGs (30-60 min after
  initiation or change in NPPV settings)
• Adjust with assistance from RT
   – Mask type, pressure levels (usual start 10/5)
• Recommendations/Guidelines: pH 7.25-7.35
   – But likely benefit in COPD exacerbation with
        • pH < 7.25 (use cautiously, monitor closely)
        • pH > 7.35 (LOS benefit)
                  The Evidence and Bottom Line:
                  ß-block in COPD Exacerbation
        • NO Studies in inpatient or outpatient
          exacerbations!
        • Outpatient studies summarized in 2007
          Meta-Analysis (Cochrane Collaboration)
              – 20 RCTS in patients with COPD, including
                severe COPD
              – No significant effects of single dose or longer-
                term treatment with ß-block on outcomes of
                symptoms or FEV1


Salpeter S, et al. Cardioselective beta-blockers for chronic obstructive pulmonary disease. Cochrane Database
of Systematic Reviews 2005, Issue 4. Art. No.: CD003566. DOI: 10.1002/14651858.CD003566pub2.
      Prevention for COPD:
   Smoking Cessation Counseling
 Smoking Cessation Counseling
      Single counseling event, tob cessation 1 yr
             Meta-analysis RCTs*
             ARR 2% (NNT 50)
             P<0.001

      Pneumonia Outcomes Research Team
       (PORT)**
             15% of counseled quit
             93% of those who quit did so at the time they
              developed PNA
*Law M, Tang JL. Arch Intern Med. 1995; 155: 1933-41.
**Rhew DC. Ann Intern Med. 2001; 135: 736-43.
        Smoking Cessation Slows Lung
        Function Decline in Mild COPD:
                    The Lung Health Study at 11 Years
     2.9
     2.8
     2.7
     2.6
     2.5
     2.4            Sustained quitters

     2.3            Intermittent quitters
     2.2
     2.1            Continuous
                    smokers
       2
              0     1      2      3      4     5      6      7   8   9   10   11


Anthonisen NR et al. Am J Respir Crit Care Med 2002:166:675-9.
Calverley PMA and Walker P. Lancet 2003;362:1053-1061.
                          Prevention for COPD:
                              Vaccination
 Pneumococcal                                             Influenza Vaccination in
  Vaccination*                                              Chronic Lung Disease**
        Chronic Lung                                          Reduced mortality
         Disease                                                         RRR >50%
                 Reduced Mortality                            Reduced hospitalization
                         RRR 30%                                        RRR 20-30%
                 Reduced Pneumonia
                                                               Reduced PNA
                         RRR 43%
                                                               Cost-effective
                                                               Annual Revaccination
                                                                necessary


*Nichol KL, et al. Arch Intern Med. 1999; 159: 2437-42.     **Multiple studies
*Large Retrospective Cohort                                 Summary: Seymann GB. J of Hosp Med. 2006; 1: 344-53.
Jackson LA, et al. N Engl J Med. 2003; 348: 1747-55.
                              Prevention for COPD:
                                VTE Prophylaxis
     • Prevalence of VTE in COPD Exacerbation
            – Up to 30% based on Autopsy Studies*
            – Approx 10% based on retrospective assessments*
            – Risk of VTE in COPD: Adjusted HR 1.33 (1.17-1.51)**
                     • >92,000 patients inpatient COPD
                     • Comparison HRs
                              – ICU Adm: HR 1.35
                              – Paralysis/paresis: HR 1.35


*Ambrosetti M, et al. Prevalence and prevention of venous thromboembolism in patients with acute
exacerbations of COPD. Thrombosis Research 2003. 112: 203-207. [systematic review]
**Edelsberg J, et al. Risk of venous thromboembolism among hospitalized medically ill patients. Am J
Health-Syst Pharm 2006. 63 (S6): S16-S22.
                       Prevention for COPD:
                         VTE Prophylaxis
• Pharmacologic prophylaxis*
     – Reduces risk of VTE with use of pharmacologic
       prophylaxis (LMWH or UFH) in medical patients
              • RRR 55%

• ACCP Guidelines for VTE Prophylaxis (Grade 1A,
  RCT):
     – ―Acutely ill medical patients admitted...with severe
       respiratory disease…‖ should receive pharmacologic
       VTE prophylaxis


*Mismetti P, et al. Prevention of venous thromboembolism in internal medicine with unfractionated or low-
molecular-weight heparins: a meta analysis of randomised clinical trials. Thromb Haemost 2000; 83: 14-19.
Geerts WH, et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and
Thrombolytic Therapy. Chest 2004. 126(3 Suppl):338S-400S.
            Prevention:
  Augmentation of Home Medication
    Regimen—Newest Evidence




• Systematic Review of RCTs and Meta-Analyses
• Published November 2007
• Outcomes:
    Mortality Reduction
    Exacerbation Reduction
                Prevention:
Augmentation of Home Medication Regimen—
           OUTCOME: Mortality
     • Outpatient Interventions that Reduce Mortality
       (statistically significant…and clinically relevant!)
     • Severity @ baseline: Mod to Very Severe
             Combined LABA and Corticosteroid therapy vs.
              Placebo*
                    >4600 patients
                    Mortality reduction: RR = 0.83, NNT = 53
             Combined LABA and corticosteroid therapy vs.
              Corticosteroid therapy alone*
                    Mortality reduction: RR = 0.79, NNT = 44
             Combined LABA and corticosteroid vs. Tiotropium**
                    Mortality reduction: RR = 0.56, NNT = 55 (p = 0.032)
 *Wilt TJ, et al. Ann Intern Med 2007; 147: 639-653.
 **Wedzicha JA, et al. Am J Respir Crit Care Med 2008; 177: 19-26.
                Prevention:
Augmentation of Home Medication Regimen—
           OUTCOME: Mortality




     Inhaled Combined LABA and Corticosteroid therapy
        vs. Placebo
      RR = 0.83, NNT = 53

 Wilt TJ, et al. Ann Intern Med 2007; 147: 639-653.
                Prevention:
Augmentation of Home Medication Regimen—
           OUTCOME: Mortality

   • No Mortality Reduction with the following
     inhaled therapies (vs. placebo):
          – Short-Acting Anticholinergic (Ipratropium)
          – Long-Acting Anticholinergic (Tiotropium)
          – LABA alone
          – Corticosteroids alone
          – D2/ß2-Agonist (Sibenadet)

 Wilt TJ, et al. Ann Intern Med 2007; 147: 639-653.
                Prevention:
Augmentation of Home Medication Regimen—
       OUTCOME: Exacerbations
 Outpatient Inhaled Therapies that Reduce Exacerbations vs.
               Placebo (statistically significant)
 YES!!
 • Tiotropium (p<0.001)                                RR = 0.84, NNT = 15
 • LABA (p<0.001)                                      RR = 0.76, NNT = 13
 • Corticosteroids (p=0.01)                            RR = 0.87, NNT = 22
 • Combined LABA and                                   RR = 0.83, NNT = 16
   corticosteroid (p=0.06)
 No!!
 • Ipratropium
  Wilt TJ, et al. Ann Intern Med 2007; 147: 639-653.
        Bottom Line: Hospitalist Prevention
          Efforts for COPD Exacerbation
•   Tobacco Cessation
    Counseling
•   Pneumonia Vaccine
    and Influenza Vaccine
•   VTE Prophylaxis during
    hospital stay
•   Augment Home
    Medication Regimen
        LABA + Corticosteroid
         inhalers
         Who Benefits from and qualifies
          for Home Oxygen Therapy?

   •      Evidence for Benefit
         – Supplemental O2 for >15 hours/day to
           maintain pO2 > 60*
         – Reduced death** in patients with
                 •    Mean FEV1 < 30% &
                 •    PaO2 < 55

   •      Medicare Criteria

*Report of the Medical Research Council Working Party. Lancet 1981; 1: 681-686.
**Gorecka D, et al. Thorax 1997; 52: 674-679.
             Medicare Coverage Criteria:
               Home Oxygen Therapy
Group I Coverage                       Group II Coverage
•   PaO2 < 55 or SaO2 < 88%            •   PaO2 56-59mmHg or SaO2
                                           89% +
    – At Rest
    – During Sleep                     •   Any of the following*:
         •   OR ↓ PaO2 > 10mmHg or ↓       – Dependent Edema
             SaO2 5% associated with
             symptoms or signs of          – Pulmonary HTN or Cor
             hypoxemia*                      Pulmonale

    – During Activity                      – Erythrocythemia
                                                 •   Hct > 56%

                                       •   Requires re-testing between
                                           61 and 90 days
Final Summary
                              Final Summary
•   Pharmacologic Therapies                   •   Prevention (Inpatient)
     Bronchodilators                               Smoking Cessation Counseling—
                                                     YES!!
           Inhaled—YES!
          o   Oral/IV—No!                           Vaccines

     Steroids—YES!                                      Pneumovax—YES!
                                                         Influenza Vaccine—YES!
     Antibiotics—YES!!!
                                                    VTE Prophylaxis—YES!!
           Procalcitonin levels to decide?

•   Other Therapies                           •   Prevention (Home Regimen)

     Oxygen—YES!                                   Augmentation with combined
                                                     LABA/steroid inhaled—YES!!
     NPPV—ABSOLUTELY YES!!!                             Mortality Reduction!!
     Mucolytics—Maybe!                             Most others for exacerbation and
    o   Chest PT—NO!!                                symptom reduction
                                              •   Home O2: Medicare Criteria

				
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