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					    CHRONIC OBSTRUCTIVE PULMONARY DISEASE
                                         (COPD)
DEFINITION
     Unifying feature = chronic airway obstruction
     A disorder defined by abnormal tests of expiratory flow that do not change markedly over
      periods of several months
     Excludes other causes of airflow obstruction such as UAW obstruction, bronchiectasis, TB,
      sarcoidosis, localized bronchial tumors, and CF
     Synthesis concept: each patient has a unique composition of the three components of
      COPD
     Three components which may occur in isolation but usually occur in combination; clinical
      features and presentation depends on which component(s) predominate
                    Reactive airway component: bronchospasm
                    Emphysema component: airway collapse
                    Chronic bronchitis component: airway inflammation
     COPD exacerbations
                    Definition is problematic
                    Studies are heterogenous
                    Some look at only acute exacerbations of chronic bronchitis and exclude
                     those with chronic airflow obstruction
                    Others include all with chronic airflow obsturction
                    Some studies exclude those with significant bronchodilator response, others
                     don’t
                    Canadian Guidelines: 85% of COPD patients have element of chronic
                     bronchitis; minority of chronic bronchitis patients have COPD


EPIDEMIOLOGY
     Prevelence: 14% in men, 8% in women
     4th leading cause of death in men, 7th in women
     Accounts for 13% of all hospital admissions
     Mechanical ventilation: mortality rate is 20-60%
    Natural history: 2 year survival rates correlates with post bronchodilator FEV1
            FEV1 20-30%:           65% 2yr survival
            FEV1 30-40%:           83% 2 yr survival
    Mortality with COPD exacerbation and pC02 > 50
                   6 month mortality: 33%
                   12 month mortality: 43%
    Severity
                   FEV1 is the most important predictor
                   Asymptomatic until FEV1 < 50-70% predicted
                   Variable definitions of severity (see table 1 NEJM review article)
                   Literature does not support strict definitions of severity based on fev1
                   CHR guideline: mild FEV1 60-80%, mod 40-60%, severe < 40% (all
                    measurement post BD therapy)
ETIOLOGY OF COPD
    Smoking, smoking, smoking, smoking, ......
    Alpha1 antitrypsan deficiency (young, lower lobe, nonsmoker)
    Environmental exposure
    Infections
REACTIVE AIRWAY COMPONENT
    Reactive airway component more appropriate than terming “asthma”
    Pathophysiology
                   Airway obstruction from bronchospasm and mucous plugging
                   Mucous plugging is the more important part of airway obstruction in critically
                    ill patients
                   Mucous plugging is from edema, mucus, and cellular debris
                   Variable small AWO, air trapping, hyperinflation, right to left shunting,
                    hypoxemia
    Clinical Features
                   Wheezing in absence of prior dx of asthma
                   Wheezing is most common, cough, dyspnea, chest pain may predominate
                   May have silent chest with markedly decreased AE
                   Look for degree of respiratory distress
EMPHYSEMA COMPONENT
    Airway collapse component
    Permanent enlargement of airspaces distal to the terminal bronchi accompanied by the
     destruction of their walls and without obvious fibrosis (microscopic definition)
    “Pink Puffers” – cachectic
    May have emphysema w/o COPD and may have COPD without emphysema
    Three types (CPP) ....
                    Centriacinar
                              -      proximal acinar emphysema
                              -      upper lung fields
                              -      cigarette smokers
                    Panacinar
                              -      entire acinus
                              -      lower lung fields
                              -      alpha 1 antitrypsin def
                    Paraseptal
                              -      distal acinus
                              -      adjacent to pleura and septa


    Pathophysiology
                    Obstruction from alveoli and bronchial collapse
                    Gradual destruction of alveolar septi and obliteration of pulm capillary bed
                    Alveolar septal destruction leads to collapse of bronchi and significant obstrn
                    Chronic wbc infiltration leads to release of elastase which destroy alveolar
                     septa and destruction of airspaces
                    Pulmonary cachexia re hyperventilation
                    Pulmonary HTN and cor pulmonale do not occur with normal ABGs
    NHI Staging
                    See Figure
                    Asymptomatic, dyspnea on exertion, SOB at rest, chronic decompensation,
                     acute respiratory failure
    Clinical Features
                      Pure emphysema is a pink puffer (PP) in full dz state
                      Thin, anxious, alert, SOB: dyspnea is hallmark
                      Pursed lips to increase end expiratory pressure to keep alveoli open (they
                       want to collapse because of alveolar destruction)
                      Chronically sits with elbows on knees to brace thorax to help with breathing
                       and often have pressure marks on knees
                      PE: hyperresonant chest, thin, decreased AE throughout, end exp wheeze
                      CXR: increase AP diameter, decreased vascular markings, hyperinflated,
                       small heart, low/flat diaphragms, large retrosternal airspace, bullae
                      ABG: near normal ABG unless in acute failure




CHRONIC BRONCHITIS COMPONENT
    Clinical features of chronic ventilatory failure and secondary cor pulmonale
    Definition : Chronic mucous secretion (chronic productive cough) on most days for at least
     three months of the year in two successive years
    Pathophysiology
                      Obstruction from inflammation and edema
                      Inflammed, edematous endobronchial surface
                      Impaired mucociliary responses; don’t clear secretions thus prone to infection
                      Bronchitis usually viral but increased risk of pneumococcus, Hflu, Moraxella
                      Inflammation and secretions provide chronic obstruction and chronic cough
                      Pt fails to increase minute ventilation and chronic hypoxia leads to
                       pulmonary HTN, cor pulmonale, polycythemia
    Natural History
                      See Figure
                      A: smokers cough
                      B: chronic cough + exacerbations of sputum production
                      C: progressive SOB with more frequent exacerbations
                      D: chronic respiratory failure; hypoxemia, hypercarbia, polycythemia,
                       cyanosis, cor pulmonale
                      E: acute on chronic respiratory failure
    Clinical Features
                   Eventually is a Blue Bloater (BB) with chronic respiratory failure
                   Cyanosis related to hypoxia and polycythemia
                   Chronic cough predominates
                   Cor pulmonale: peripheral edema, anasarca, chronic JVD
                   Acute respiratory failure: irritable, somnolence, asterixis
                   PE: normal AP diameter, scattered crackles/wheeze, chronic visceral
                    congestion (HM, HJR) cor pulmonale (subxiphoid or substernal heave with
                    RVH, S4 with decreased LV compliance, S3 with LVF, tricuspid regurg)
                   CXR: normal volumes, normal or increased vascular markings, coarse
                    reticulation of lower lung fields, impingement upon retrosternal airspace by
                    enlarged RV on lateral
                   ABG: severe hypoxia and hypercapnia




INVESTIGATIONS
    Pulsoximetry
                   Hypoxia if < 95%
                   Many are hypoxic at baseline :. changes more important
    ABGs
                   Result depends on components and severity
                   Initially: mild decreased Pa02 with V/Q mismatch
                   Mild: Pa02 80-100
                   Moderate: Pa02: 60-80
                   Severe: Pa02 < 60
                   Later: hypoxemia < 60 mmHg and PaC02 < 35 with respiratory alkalosis
                    due to hyperventilations
                   End: hypoxemia, hypercapnia due to respiratory failure leads to acute
                    respiratory acidosis with metabolic compensation
                   C02 retension: work of hyperventilation eventually produces more C02 than
                    it blows off
                   Figure out baseline CO2: HCO3 increases by 2-4 for every 10 mmHg
                    increase in C02
                   Compensated: pH > 7.3
                   Uncompensated: pH < 7.25
    CXR
                   Findings dependant on emphysematous vs chronic bronchitis picture
                   Look for infiltration, pneumothorax, pleural effusion, CHF, atelectasis with
                    acute deterioration
    PFTs
                   Gold Standard for diagnosis
                   Decreased FEV1/FVC makes diagnosis
                   FEV1 defines severity: 70 - 100% mild; 60 - 70% moderate; 50 - 60%
                    mod severe; 35 - 50% severe; < 35% very severe
                   Also increase TLC and RV and decreased Dlco
                   NO role in acute event
    ECG
                   RVH suggest cor pulmonale
                   P - pulmonale (peaked p in II, III, aVF) suggests COPD
                   Classic findings nonsensitive/specific: low QRS voltage, clockwise rotation,
                    poor R wave progression
    Other
                   CBC: increased Hb (polycythemia)
                   Sputum: gram stain not useful; culture can be helpful
                   Theophylline level if they are on it




CHRONIC MANAGEMENT OF COMPENSATED COPD
    General
                   Definitions: Candian Thoracic Society required post-bronchodilator
                    FEV1/FVC < 0.7 or FEV1 < 80% to make the dx of COPDPneumococcal
                    and influenza vaccination
                   No prophylactic antibiotics: used in exacerbation only; prophylaxis not proven
                   Amantidine w/ influenza if treating early
                   Refer all patients to pulmonary rehab
    Categorizing Severity (post-bronchodilator; NOT validated)
                      Mild: FEV1 60-80%
                      Moderate: FEV1 40 - 60%
                      Severe: FEV1 < 40% predicted
   Chronic Corticosteriods
                      Should not be used w/o evidence of improvement during a steriod trial of
                       40 mg prednisone po for 2 - 4 weeks showing improvement in FEV1
                      Steroid trial should be done in all unless contraindicated
                      Predictors of response to corticosteroids include sign BD response, seasonal
                       variation, daily variability, nocturnal cough/SOB, eosinophilia in sputum
   Oxygen
                      ONLY drug to show mortality benefit (2 RCTs, RR death is 0.61
                       (0.46,0.82))
                      Must be worn for > 15 hours/day to achieve mortality benefit
                      NO survival benefit with patients that have adequate Pa02 (>55)
                      Pa02 supposed to be measured when patient stable: CAN WE DO THIS IN
                       THE ED??
                      ONLY shown to have mortality benefit with:
                              -       Pa02 < 55 mmHg on RA (when patient is stable)
                              -       Pa02 < 60 mmHg on RA with evidence of cor pulmonale
                                      (pulmn HTN, edema, Hct > 55)
                              -       Pa02 < 55 or Sa02 < 85% Hypoxemia on exercise
                              -       Hypoxemia during night in absence of hypoxemia during the
                                      day (without associated sleep apnea)
   Beta-agonists
                      Short acting
                              -       Ventolin (salbutamol) or Combivent (ventolin + atrovent)
                              -       MDI + spacer is best way to administer
                              -       Ventolin 100 ug/puff: 2 puffs qid + q1hr prn
                      Long acting
                              -       Serevent (Salmeterol) MDI/spacer: 25 ug, 2 puffs bid
                              -       Serevent (Salmeterol) diskus: 50 ug, 1 inhalation bid
                              -       Oxeze (Formoterol) turbuhaler: 6-12 ug bid
   Anticholinergics
                  Should be added to ventolin as 1st line b/c good response in COPD
                  Short acting
                           -         Atrovent (Ipatropium) MDI/spacer: 20 ug 4 puffs qid
                  Long acting
                           -         Spiriva (Tiotropium) handihaler: 18 ug, 1 inhalation od (must
                                     stop atrovent if using spiriva)




   Combinations
                  Advair 500 diskus (salmeterol 50 ug + fluticasone 500 ug): 1 inhalation bid


                  Advair 250 MDI (salmeterol 25 ug + fluticasone 250ug): 2 inhalations bid
                  Symbicort 200 Turbuhaler (budesonide 200 ug + Oxeze 6 mg): 2
                   inhalations bid
   Pyramid approach to treatment
                  Stop smoking, refer to physio, pneumovax and influenza vaccination
                  Mild disease
                           -         Ventolin + Atrovent
                           -         Combivent alternative
                  Mild disease
                           -         Long acting bronchodilators: one or the other
                           -         Serevent, Oxeze, or Spiriva
                  Moderate to severe disease without frequent exacerbations (<3/year)
                           -         Long acting bronchodilators in combination
                           -         Serevent + Spiriva
                           -         Oxeze + Spirva
                  Severe COPD with frequent exacerbations (> 3/year)
                           -         Long acting bronchodilators + inhaled corticosteroids
                           -         Advair + Spiriva
                           -         Symbicort + Spiriva
   Theophylline/Aminophylline
                  Usually given orally; must monitor blood levels
                  s/e: nervousness, tremor, GI distress (significant), seizures, arrythmias; note
                    narrow therapeutic window
                   Clearance increased in smokers, phenytoin, phenobarb,rifampin
                   Withdrawl can make things worse
                   Clearance rates decreased in elderly, liver dz, CHF, cimetidine, erythromycin,
                    verapamil, ciprofloxacin, etc
    Other
                   Lung transplant, lung reduction surgery
                   Corpulmonale treatment is oxygen, not digoxin, not diuretics
                   Physical rehab: increased exercise tolerance, increased quality of life,
                    decreased hospital admissions; NO EFFECT on PFTs/survival/ABGs
                   Chronic oral steroids not be part of chronic mx




      COPD (AND CHRONIC BRONCHITIS) IN EXACERBATION

ETIOLOGY
    Pneumonia, bronchitis, URTI (infection in MCC)
    Pulmonary Embolism
    Pleural effusion,empyema                            THINK OF P.A.M.

    Pneumothorax
                                                          ALWAYS ASK: COPD
    Pulmonary edema: MI, ischemia, arrythmias
                                                          EXACERBATION DUE TO WHAT?
    Pulmonary trauma (contusion, rib #, splinting)
    Atelectatsis (acute lobar or subsegmental)
    Altitude changes, weather changes
    Asthmatic reaction: super-imposed asthma
    Medications
                   Bronchospasm: BB, NSAIDs, ASA, opiates
                   Resp depressants: narcotics, BZD, EtOH
                   Non-noncompliance
    Other
                   High flow oxygen use
                  Reduced ventilatory drive: DKA, uremia, hepatic encephalopathy, sedation
                  Respiratory muscle weakness: poor nutrition, low phoshpate, K+, Mg++, etc




ACUITY OF EXACERBATION
    Acute, sudden COPD exacerbation: Think of THE BIG THREE!
                  Pneumothorax: easily missed, chest pain often absent, expiratory film helps
                  PE: must suspect with acute deterioration, high viscosity is a RF
                  Acute lobar atelectasis: MC with ++ secretions, dehydration, impaired cough
    Subacute COPD exacerbation (hrs-days)
                  Acute bronchitis: increasing cough/sputum usu w/o fever/inc wbc
                  Pneumonia: may present with malaise, weakness, reduced activity, anorexia
                   more commonly than classic symptoms; infiltrate MAY be absent
                  Smaller PE: V/Q difficult to interpret, angio risks, should do dopplers
                  Pleural effusions: diuresis or thoracentesis
                  Rib #s: splinting, hypoventilation, stasis
                  Metabolic changes: potassium, magnesium, calcium, phosphate
    Chronic COPD deterioration
                   Continued smoking, other treatable pulmn dz (bronchiectasis, TB, sarcoid)




NOTES ON COPD EXACERBATION PRECIPITANTS
    Acute Exacerbations of Chronic Bronchitis (AECB)
                  Lower respiratory tract infection/inflammation w/o signs of pneumonia
                  Clinical criteria: increased dyspnea, sputum production, sputum color change
                  Allergic precipitants: dust, smoke, pollens, polution, other
                  Infectious precipitants: viral is most common
                  Viral infections: influenza, parainfluenza, RSV, adenovirus, coronovirus are
                   MCC
                  Role of bacteria is controversial: bronchial secretions are shown to have
                   Hflu, pneumococcus, Moraxella but it is unclear if they are pathogens or
                   colonizers
                  Some thought that bacteria play a role in perpetuating increased
                      inflammation and mucous production in chronic bronchitis
                     Pneumococcus, Hflu, or Moraxella can be recovered from 30-50% of
                      patients with acute exacerbation; a similar percentage have the bugs during
                      quiescent intervals
    Pulmonary Embolism
                     Very hard to dx
                     All complaint of SOB in COPD exacerbations
                     V/Q indeterminate in majority
                     Investigate with dopplers and CT chest (V/Q if CXR normal)
                     When to investigate? no other precipitant identifiable, other risk factors for
                      PE present


PRESENTATION
    History
                     Recent URTI, increasing SOB, increasing cough/phlegm/wheeze, difficult
                      expectorating, increased env pollution, reduced mobility, fever, respiratory
                      distress, altered mental status
                     Use history to differentiate cause of exacerbation: recent URTI/LRTI,
                      sputum/fever/chills, taking meds, PE risk factors or symptoms, angina,
                      orthopnea/PND, palpitations, etc
    Physical Exam
                     Vitals: fever, tachy, tachypneic, pulsox paradoxus, low Sa02
                     Chronic COPD features: hyperinflation, cor pulmonale, hoover’s etc
                     Respiratory failure: SOB, confused, asterixis, diaphoresis, tacchycardic,
                      tacchypneic, accessory muscle use, retractions, pursed lips, cyanosis
                     Use physical exam to find cause of exacerbation: evidence of CHF,
                      DVT/PE, pneumonia


    Investigations
                     CXR
                     CBC, Ur, Cr, Lytes
                     Check Mg and P04: ? malnurished, increases resp muscle weakness
                     Sputum gram stain and c/s: not routinely recommended as the majority of
                   patients are colonized with respiratory pathogens
                  ECG: must r/o ischemia
                  Echo if in LV failure
                  FEV1 and PEFR measurements: have been shown to poorly correlate with
                   clinical status and have limited usefulness during acute exacerbation;
                   american thoracic society and canadian guidelines say there is no evidence
                   that pulmonary function helps guide management of acute exacerbations
                   thus it is not neccessary to perform in the acute setting
                  PE work up based on presentation
                  ABGs
                           -       must interpret based on pt normal chronic status
                           -       acute resp failure is decrease Pa02 by 10 - 15 mmHg
                           -       chronic hypercapnia renal compensation results in near
                                   normal pH; thus, if pH is < 7.30 there is acute respiratory
                                   failure for which the renal compensation doesn’t have time to
                                   work
MANAGEMENT OF COPD EXACERBATION
    Oxygenation
                  Use fixed Fi02 of 24 - 35% and titrate to keep sats b/w 88 - 90% initially
                  Give as little Fi02 as possible to keep sats adequate
                  Venti-mask is the way to get fixed Fi02
                  Nasal prongs deliver inconsistent Fi02
                  Order 28% 02 via ventimask or 2 L/min by NP
                  Reassess frequently
                  Watch pulsox but remember that pulsox doesn’t assess C02
                  Do NOT withhold oxygen based on reduction of hypoxic drive to breath.
                   V/Q mismatching is more important. Studies show that PC02 increases with
                   oxygen but minute ventilation does not change much. Patient at risk of
                   apnea is pt who is breathing inappropriately slowly; tacchypneic pt is not at
                   great risk.
                  Deterioration with oxygen therapy has two possibilities: (1) reduction of
                   hypoxic drive to breath and (2) worsening of underlying problem (3)
                   pneumo etc
   Ventilatory Support
          BiPAP
                   -       iPAP: 8-16
                   -       ePAP: 2-8 cm H20 with rate 12 - 16 per min
                   -       reduces need for intubation
                   -       BIPAP IS EFFECTIVE FOR COPD EXACERBATIONS
                                          Evidence: decreased intubation rates,
                                           decreased mortality rates, decreased LOS,
                                           decreased complications
                                          Cochrane review 2004
                                          Keenan Ann Int Med 2003 (benefits only in
                                           severe subgroups)
          ETT
                   -       inability to maintain 90% Sa02 w/ adequate Fi02
                   -       pH < 7.20 (not based on PC02)
                   -       respiratory failure: RR > 35, AMU, retractions, cyanosis
                   -       severe hypercarbia: stupor, narcosis, acidosis < 7.20
                   -       decision to intubate relies more on clinical status than ABGs
                   -       RSI: ketamine good induction agent b/c of bronchodilation
                   -       May not need RSI for severly obtunded pt
                   -       Post intubationCXR
                   -       May want NG tube to decompress stomach
                   -       Post intubation suctioning of tracheobronchial secretions
                   -       Don’t hyperventilate aggressively b/c respiratory alkalosis,
                           metabolic changes (esp w/ dec K+) lead to arrythmias, SZ
          Ventilation Strategies
                   -       Low rate: 10-12 bpm
                   -       Low volume: 6-8 ml/kg
                   -       Increased I:E ratio
                   -       Increase inspiratory flow rate: 80-100 L/min (vs 60 L/min)
                   -       Watch Peak insp pressures and plateau pressures
                   -       Sedate and paralyze prn
    BRONCHODILATORS IN COPD EXACERBATION

GENERAL
    All patients have some reversibility
    Certain patients will respond better to bronchodilators
    Predictors of response to bronchodilators
                    PFTs that show reversible component
                    Should we do pre and post PEFR in ED?
    Evidence Summary
                    14 randomized trials
                    Evidence is limited by heterogenous populations, variable definitions of
                     COPDE, variable enpoints, different doses, pulmonary function outcomes
                    B-agonists and anticholinergics have comparable effects
                    Some patients benefit from the comination of B-agonists and anticholinergics
                     after the maximum dose of the initial BD is reached
                    B-agonists and anticholinergics have more effect than methylxanthines
                    Optimal dose/frequency not established: ATS recommends q 30-60 min but
                     more frequent use may be of benefit in some


EFFECTS OF BRONCHODILATORS
    Backman 1985
                    RCT, N=40
                    Fenoterol 0.5mg tid showed increased FEV1 after 60 min
                    Ipratopium showed slight improvements in FEV1 throughout 7 days
    Karpel 1990
                    RCT, N=32
                    Crossover study of ipratropium and metaproteronol by MDI
                    Received 54 ug of ipratropium or 1.95 mg of isoproteronol then switched
                     drugs at 90 minutes and FEV1 measured at 0,30,60,90 minutes after each
                     dose
                   Ipratropium: 260 ml improvement in FEV1 at 90 min post treatment
                   Metraproteronol: 230 ml improvement in FEV1 at 90 min post tx
                   Crossover did not increase FEV1 any further
    Zehner 1995
                   RCT
                   Asthma or COPD!!
                   Albuterol 2.5 mgor terbutaline
                   Albuterol showed improved RR, dyspnea socre, resp distress score
                    compared to terbutaline
    Emerman 1997
                   RCT N=86
                   Albuterol 2.5mg q20 min X 2hrs vs Albuterol 2.5 mg Q1hr X 2hrs
                   No difference in FEV1 at 2hours (? lack of power)
                   Subgroup of pretreatement FEV1 < 20% predicted had significant
                    improvement in FEV1 at 1 and 2 hours (higher dose better in more severe)
                   Actually best evidence of more frequent use




    Cochrane Database Reviews 2004
                   Beta2 agonists versus anticholinergics for acute exacerbations of COPD
                   Beta2 agonists and anticholinergics have equivalent effects on FEV1 for
                    short term and longer term pulmonary function outcomes
                   No benefit of addition could be found
    Methylxanthines are dead
                   Every guideline published recently recommends not using methylxanthines
                    because beta-agonists/anticholinergics are as effective without the side-
                    effects
                   Cochrane Systemic Reviews 2004: minimal benefit over placebo; significant
                    increase in nausea, vomiting, palpitations, and arrhythmias




COMBINATION OF BRONCHODILATORS: 6 RCTS
    Cydulka 1995
                    RCT, N=57
                    Albuterol 2.5 mg vs Albuterol + glycopyrrolate 2mg (then albuterol X 2 more
                     nebs on q1hr frequency) with outcome of FEV1 at 1 and 3 hours
                    Note: only added anticholinergic to first dose
                    Combination lead to more increase in FEV1 at one and three hours
                             TIME             Combination      Albuterol alone P
                             1hr              29% abs. incr 6% increase            0.04
                             3hr              56% abs incr 19%                     0.01
    Shrestha 1991
                    RCT, N68
                    Isoetharine 5 mg q1hr vs Isotharine + Ipratropium 54 ug by MDI q1hr
                    LOS 91 min less in combination than isoetharine group (p<0.05)
                    No difference in PFTs
                    Criteria for discharge not strictly defined!
    Negative studies for FEV1 improvement with combinations
                    O’Driscoll Lancet 1989.
                    Moayyedi. Thorax 1995: ventolin 5mg qid +/-atrovent 500ug qid on
                     admitted patients (no diff in LOS, PFTs, etc)
                    Patrick 1990
                    Rebuck 1987: negative but underpowered




METHYLXANTHINES
    Advantages: studies show synergy with beta agonists and anticholinergic for physiologic
     outcomes
    Disadvantages: toxicity, have to monitor levels, complicated dosing, many drug interactions,
     no clinically important outcomes ever documented when used in addition to beta agonists
     and anticholinergics
    Withdraw can cause exacerbation: don’t stop it if they are on it
    Loading: 5 mg/kg iv over 10 min
    Maintenance: 0.5 mg/kg/hr
    Desired level: 10 ug/ml
     Dose changes: liver dz, CHF, age, many other drugs (LOOK UP!)




          STEROIDS AND COPD EXACERBATION

GENERAL
     Controversies
                     Does PFTs documenting reversible component predicts benefit of steroids?
                     Do the studies look specifically at this subgroup?
                     Should steroids be used in pts with obvious pneumonia or patients with
                      other precipitants of copd (PE etc)? Do the studies look at this subgroup?
                     Inhaled corticosteroids have not be shown to be effective in acute
                      exacerbations
                     What effect of steroids have been shown?
                     What is the optimal dose and duration?


SUMMARY OF EVIDENCE
     Admitted patients: faster improvements in FEV1, decreased LOS in hospital, less treatemtent
      failures
     ED patients discharged: faster improvements in FEV1, lower relapse rates, longer time
      period until relapse if it is going to occur
     Majority of evidence in ED patients thus applicability to outpatients is unknown
     Variable dose, duration of steroids thus ideals not known
     Never shown to have a mortality benefit thus must weigh pros/cons
     Hyperglycemia is the most common reported s/e: psychiatric, weight gain,
     Majority of evidence is in moderate to severe subgroup and effect in mild subgroup less
      clear


WHAT IS THE EFFECT OF STEROIDS FOR INPATIENTS? (Prospective RCTs)
     Niewoehner et al. NEJM 1999; 340:1941-7
                     Best and largest study looking at effect of steroids
                     Multicenter, DBRCT, N=271
                   Steroids X 8 weeks, steroids X 2 weeks, vs placebo
                   Steroids X 8 weeks= solumedrol 125 q6hr X 3/7 then pred 60 mg po od
                    with taper down to 5 mg over 8 weeks
                   Steroids X 2 weeks = solumedrol 125 mg q6hr X 3/7 then 60 mg po od
                    with taper down over 2 weeks
                   Primary endpoint = treatment failure (death any cause, intubation,
                    readmission after discharge, intensification of pharmacotherapy of
                    steroid/theophylline/both)
                   Secondary endpoints = FEV1, spirometry
             Outcome                 Both roid grps Plc    Stats
             Treatment failure 30d 23%                     33%       P=0.04, ARR 10, NNT10
             Hospital stay           8.5d                  9.7d     0.03
                   No diff b/w 2wk and 8wk steroid groups
                   Difference maintained at 90 days but not 182 days
                   Increased rate of improvement of FEV1 (p,0.005)
                   NOTE: majority of combination endpoint was intensification of therapy (ie: no
                    diff detected in death, intubation, readmission; decision for discharge not by
                    controlled criteria!


   Davies et al. Lancet 354. 1999
                   RCT of 56 inpatients
                   Prednisone 30 mg po od vs placebo X 14 days
                   Outcomes: FEV1, hospital stays
                   Change in absolute FEV1 faster with steroids (post bronchodilator)
             Outcome                 Steroids       Pl     Stats
             LOS                     7d             9d     p=0.02
                   Decision to d/c based on physician judgement and not controlled thus
                    makes LOS a weak outcome and FEV1 resolution isn’t the best clinical
                    outcome either
   Others
                   See Table 2 in Singh review article
                   Albert et al 1980: N=44 inpatients; Methylpred 0.5mg/kg iv q6hr X 3d;
                    Outcome was improved FEV1 b/w groups
                   Rosteom: no benefit
                   Wood-Baker: no benefit


EFFECT OF STEROIDS FOR PATIENTS D/C’D FROM ED (prospective RCTS)
     Other
                   Bullard et al 1996: showed improvement in FEV1 but didn’t exclude
                    asthmatic patients
                   Emerman et al 1989: single dose methylpred had no benefit but only were
                    observed for 4hrs, no other outcomes
                   Thompson et al 1996: N=27 showed faster improvements in FEV1 and no
                    treatment failures in steroid group
     Aaron, Stiell, Rowe, Wells, Cass etc. NEJM 348;26: 2618-25
                   Best, largest study of outpatient tx with steroids after ED visit
                   DBRCT, N=147
                   COPD exacerbation = 2/3 incr dyspnea/sputum volume/sputum purulence
                   Incl: previous dx of COPD or >1yr hx chronic dyspnea dn sputum
                    production; > 35yrs; minimum 15 pack years; IRREVERSIBLE airflow
                    obstruction ( FEV1/FVC < 0.7, FEV1 < 70% predicted, and FEV1 increase
                    < 20% with bronchodilators)
                   Exl: asthma, admission, atopy, steroids w/i 30d, pneumonia or chf on cxr
                   Prednisone 40 mg po od vs placebo X 10d
                   Outcome = relapse in 30 days (ED visit or unscheduled GP visit)
                   Relapse rate 27% in steroid grp compared to 43% in placebo (p=.05)
                   ARR 16% or NNT 6 to prevent one relapse
                   Increased time to relapse (7d vs 23d p=.04)
                   Improved dyspnea scores
                   Improved FEV1 from day 1 to day 10 (34% vs 15%) p=.007
                   No diff in subsequent admission rates
                   All got abx (sulpha or doxy!) and all got bronchodilators
                   Critique: DBRCT, good definitions, good incl/excl, good control of
                    confounders, good outcome, minimal loss to f/u
                   Best evidence for steroids in patients we are sending home
                   Note no mortality benefit was shown; outcome is relapse
                  Note effect in those with “irreversible” disease thus steroids are beneficial in
                   those that don’t primarily have an asthma component


SYSTEMIC REVIEWS
    Cochrane 2004
                  7 RCTs
                  Variable outcomes
                  Inpatients and outpatients
                  Increased rate of FEV1 over 6-72hrs
                  No conclusions for more clinical outcomes
                  Limitations: heterogenous population, treatments, etc; used primary outcome
                   of FEV1; not enough numbers for other outcomes; trends for decrease
                   treatment failures, decrease relapse, decrease repeat hospitalization
                  ? does this include the Aaron study?


WHAT IS THE OPTIMAL DOSE AND DURATION OF STEROIDS?
    Duration
                  Canadian guidelines: 5 days to 2 weeks
                  Sayiner Chest 2001: 10 days superior to 3 days
                  SCCOPE trial: 2 weeks as effective as 8 weeks
                  2 week course shown to be as good as an 8 week taper
                  Most people treat for 10 days
    Dose
                  Optimal dose controversial
                  SCCOPE trial used high dose initially (methylprednisone 125 mg iv q6hr X
                   72hr)
                  Prednisone 50 mg po X 10 days
                  Solumedrol if can’t take po
                  No taper required after 10 day dose



       ANTIBIOTICS AND COPD EXACERBATION
WHAT IS THE ROLE OF BACTERIA IN ACUTE EXACERBATIONS OF CHRONIC BRONHCITIS?
    Controversial
    Viral, bacterial, smoke, dust, allergens, pollutants precipitate AECB
    Up to 50% thought to be due to bacterial precipitant
    Problem is that bacteria can be isolated from tracheobronchial tree when asymptomatic
     (colonization) and when in acute exacerbation (pathogens)
    Some evidence tat bacterial exacerbations lead to declining lung function
    Sethi NEJM 2002: New strains of bacteria and exacerbations of COPD
                    Older studies: bacterial isolation rates were equivalent in stable dz and
                     exacerbations suggesting that bacteria aren’t the predominate ppt
                    Older studies did NOT look at bacterial strains
                    Prospective study, N=81 outpatients, 1975 visits, 374 exacerbations
                    New bacteria or new strain isolated in 33% of exacerbations compared to
                     15% of stable visits (p<0.001), RR exacerbation 2.15 (1.83, 2.5) with new
                     bug or strain
                    Suggests new bugs/strains have a role in exacerbations
    Viral isolates can be found in 30%
    Exact role of bacteria unclear but are related to exacerbation


GENERAL
    Different groups
                    COPD exacerbation due to pneumonia: antibiotics indicated
                    COPD exacerbation due to AECB (ie: increased dyspnea + sputum change
                     in color or volume): antibiotics controversial
    Indications for Antibiotics in ACEB (2/3 of the following)
                    Increased dyspnea
                    Increased sputum volume
                    Increased sputum purulence
    Antibiotic choices
                    Many differenct guidelines and recommendations
                    Important general principles
                             -       Not everyone needs a big gun
                             -       Start with a small gun, reassess and broaden spectrum for
                                    treatment failures
                            -       Local resistance patterns may guide empiric treatment
                            -       Certain patient predictors can help select antibiotics (more
                                    severe disease, bigger guns)
                            -       Cost and compliance should be considered
                            -       Guidelines are for COPD exacerbation, NOT pneumonia


NOTES ON SPECIFIC ANTIBIOTICS
    Bugs you must cover
                   Pneumococcus
                   Hflu
                   Moraxella
    Cephalexin
                   Poor activity against intermediate penicillin resistant pneumococcus
                   No coverage of haemophilus or Moraxella
    Cefaclor, Cefixime
                   Cefaclor has no activity against pcn resistant pneumococcus and marginal
                    coverage of Moraxella
                   Cefixime has no activityagainst pcn resistant pneumococcus and excellent
                    coverage of Moraxella
    Ceftriaxone
                   Good coverage but is too big of a gun for initial management
    Macrolids
                   Erythromycin and Clarithromycin hav poor activity against Hflu and Moraxella
                   Azithromycin has good coverage of Hflu and Moraxella
    Fluroquinolones
                   Ciprofloxacin does not cover pneumococcus
                   Levo, Moxi, Gatifloxacin all excellent coverage but are big guns!


CHR COPD MANAGEMENT GUIDELINES FOR AECOPD
    General
                   Differences from AMA guidelines b/c of local suceptibility
                   Failure of abx treatment: switch to different class
    Indications for abx
                    2/3 of ...
                    Increased dyspnea
                    Increased sputum volume
                    Increased sputum purulence
    Antibiotics for Mild to Moderate disease (FEV1 > 40% and with < 3 exacerbations per
     year)
                    Azithromycin 500 mg po X 1 then 250 mg po od X 4/7
                    Clarithromycin 500 mg po bid X 7/7
                    Cefuroxime axetil 250 mg po bid X 7/7
                    Doxycycline 200 mg po X 1 then 100 mg po od X 5/7
                    Septra DS 1 po bid X 7/7
    Antibiotics for Severe disease (FEV1 < 40% and > 3 exacerbations per year)
                    Levofloxacin 500 mg po od X 7/7
                    Clavulin 500 mg po tid X 7/7
                    Other fluoroquinolones




AMA GUIDELINES
    NO antibiotics in last 6 weeks, and < 4 exacerbations in last year
                    Amoxil 500mp po tid X 7 days
                    Doxycycline 200 mg po X 1 then 100 mg po od X 7/7
                    Septra DS 1 po bid X 7/7
    Antibiotics in last 6 weeks or >4 exacerbations in last year
                    Azithromycin 500 mg po X 1 then 250 mg po od X 4/7
                    Clarithromycin 500 mg po bid X 7/7
                    Cefuroxime axetil 250 mg po bid X 7/7
                    Clavulin 500 mg po tid X 7/7
    Treatment Failure = clinical deterioration after 72hrs of antibiotics or no improvement in
     symptoms after 7-10 days of antibiotics
                    Amoxil, doxy, or septra -----> go to cefuroxime, azithro, clavulin, or clarithro
                    Azithro, Clarithro, Cefuroxime, Clavulin --------> go to levoflox or moxiflox
                    Levofloxacin 500 mg po od X 5-10 days; Moxifloxaxin 400 mg od X 5- 10d


ROSEN’s RECOMMENDATIONS
    Outpatient:: macrolide, doxycycline, or fluroquinolone
    Inpatient: cefuroxime/ceftriaxone, macrolid, fluoroquinolone
    ICU: azithromycin or fluoroquinolone + ceftriaxone


CANADIAN GUIDELINES FOR MX OF AECB
    Treat all with 2/3 increased dyspnea, incr sputum vol, incr sputum purulence
    Stratify antibiotic choice by patient risk
    Low risk
                    Definition = no high risk features
                    Antibiotic choices
                              -       Azithromycin, clarithromycin
                              -       Cefuroxime
                              -       Septra
                              -       Doxycycline
                              -       Amoxil
    High Risk
                    Definition = one or more of the following:
                              -       FEV1 < 50% predicted at baseline
                              -       >4 exacerbations per year
                              -       Heart dz
                              -       Home 02
                              -       Chronic oral steroids
                              -       Antibiotics w/i 3 months
                    Antibiotic
                              -       Clavulin
                              -       Levofloxacin, moxi/gatiflox
    High Risk for Pseudomonas
                    Definition = daily purulent sputum production, bronchiectasis, FEV1 < 35%,
                     chronic steroids, frequent exacerbations, recent hospitalization
                    Antibiotic: ciprofloxacin
WHAT IS THE EFFECT OF ANTIBIOTICS
    Anthonisen 1987
                    Origin of 2/3 criteria
                    Showed improvement with anbiotics if 3/3 or 2/3 but NOT 1/3
                    RCT of antibiotics vs placebo, N=173
                    Antibiotic (sulpha, amoxil, doxycyline) vs placebo X 10 days
                    All got bronchodilators, steroid use = between groups
                    Outcome = treatment success at 21 days (followed q3days), failure to
                     resolve, deterioration
               Group Success Rate             Placebo       Abx              P
                     All comers               55%           68%              <0.01
                     3/3 criteria             43%           63%              ?
                     2/3 criteria             60%           70%              ?
                     1/3 criteria             70%           74%              ?
                    All comers: ARR 13%, NNT 8
                    2/3: ARR 10%, NNT 10
                    3/3: ARR 20%, NNT 5
    Allegre
                    Benefit of clavulin vs placebo
                    Italian!
    Nouira Lancet 2001
                    93 ventilated patients
                    Fluroquinolones vs placebo
                    Decreased mortality, LOS, duration of ventilation, need for additional abx
    Adams. Chest 2000
                    Retrospective study of predictors of relapse N=362
                    Relapse rate was 19% with abx vs none 32%(p,.001)
                    Limited by retrospective design and inability to control for confounders such
                     as severity, other treatments, etc
    Saint. JAMA 1995
                    Metananylsis of all RCTS for abx and COPD
                    9 RCTs included
                    Included inpatients and outpatients
                    Studies varied in size from 33-310
                    Anbiotics variable: tetracycline, ampicillin, chloramphenicol, amoxil, doxy
                    Variable antibiotic duration (all at least > 5 days)
                    Outcome measures: days of illness, severity score by physician, changes in
                     PEFR
                    Outcome measures were transformed into effect size = mean outcome
                     difference in antibiotic vs pooled (essentially relative risk reduction!)
                    Outcome of metanalysis was average effect size compared with normal
                     standard distribution
                    Overall effect size advantage for abx was 0.22 (95% 0.10, 0.34) or about
                     1/4 of one standard deviation for each outcome
                    See figure 1
                    PEFR 10.75 L/min (4-16) (? is this clinically important?)
                    Conclusion: small benefit for abx




WHICH ANTIBIOTIC?
    General
                    Drug sponsored studies
                    Limited if any proof of superiority of big guns
                    The more expensive drug is really cheaper!!
    Grossman Chest 1998
                    High risk for treatment failure (severe dz, copd > 10yrs, comorbidities, > 4
                     exacerbations per year)
                    Cipro vs usual care (sulpha, amoxil, tetracycline, )
                    Trend toward quicker resolution
                    Trend towards higher quality of life
                    Concludes that cipro may be drug choice for high risk but didn’t prove it!
    Destache 1999
                  Retrospective study N=224
                  First line = amoxil, sulpha, tetracycline, erythro
                  Second line = cefuroxime, cefaclor
                  Third line = clavulin, azithro, cipro
                  Failure rates: first line 19%, third line 7% (p,.05)
                  Hosp w/i two weeks: 18% vs 5% (p,.02)
                  Time to next exacerbation longer with third line agents
                  Retrospective thus can’t control for patient severity, other treatments, failure
                   criteria, admission criteria
   Warren. Curr Ther Res 1995; 56:10
                  DBRCT
                  Azithro 500 po od X 1/7 then 250 X 5/7 vs Clavulin 500 mg po tid X
                   10/7
                  Equal efficacy
   Weiss. Clin Ther 2002
                  Open label, randomized study
                  10 days of clarithromycin 500 bid, levoflox 500 po od, cefuroxime 250 bid
                  Clinical efficacy and tolerability was equivalent with all three
   Amsden. Chest 2003
                  DBRCT, N235
                  Azithro 500X1, 250X4 versus Levoflox 500 mg po do X 7/7
                  Clinical efficacy 89% with azithro vs 92% levo (p-0.2) by day 4
                  Clinical efficacy 82% and 85% by day 24 (p=0.5)
                  Bacterial eradication equivalent
                  Concluded azithro X 5/7 = levo X 7/7
   What about Moxiflox?
                  Chodosh Respir Med 2000
                  Wilson. J Antimicr Chemother 1999: Moxiflox X 5/7 vs clarithro X7/7; no
                   diff
                  DeAbate Respir Med 2000: Moxiflox X 5/7 vs azithro: no diff
                  MOSAIC study
   Summary of second generation macrolides (azith/clarith) vs new fluoroquin (moxi, levo,
    gati)
                  Comparable clinical cure and bacteriological cure rates at day 7,14,21
                  DeAbate Respir Med 2000, Kreis JCOM 2000, Bauernfreind Infection 1995,
                   Warren Curr Therapeutic Res 1995, Chodosh Clin Infect Dis 1998, Shu
                   Chemotherapy 1997.
                  Some guidelines recommend bigger guns because of resistance patterns but
                   this has not been proven by evidence
    MOSAIC study: Chest Mar 2004
                  Multicenter, DBRCT chronic bronchitis pts, N=730
                  Moxifloxacin 400 mg po od X 4/7 vs standard therapy X 7/7 (amoxil 500
                   po tid, clarithro 500 bid, cefuroxime 250 bid)
                  Outcome = clinical response 7-10 days post treatment with telephone f/u
                  Clinical success = improved or back to baseline and no further abx
                  Clinical cure = back to baseline and no further abx
           Outcome                 Moxiflox        STD              Diff
           ITT Clinical success    87.6            83.0             4.6 (-0.7, 9.5)
           PP clinical success     87.2            84.2             3.0 (-3, 8.5)
           ITT clinical cure       70.9            62.8             8.1(1.4,14.9)
           PP clinical cure        69.7            62.1             5.6(0.3,15.6)
                  Concluded that moxi equivalent for primary outcome of clinical success but
                   better for clinical cure and bacteriologic eradication


DURATION OF ABX?
    Masterton 2001
                  RCT, N=532
                  Levoflox 500mg po od X 5/7 vs 7/7
                  Outcome = clinical response 7-10days post treatment
                  Clinical success rate 82.8% in 5/7 vs 84% in 7/7 (NS)
                  Bacterial eradication rates the same
                  No difference in any subgroup (age, severity, comorbidities)
                  Good study showing 5 day = 7 day
                                          OTHER


MUCOKINETICS
     Saline or other oral expectorants
     No evidence for use


RESPIRATORY STIMULANTS
     Many things have been studies
     None currently used


MANAGEMENT OF COMPLICATIONS
     Cor pulmonale: keep lungs dry with diuretics, home 02, phlebotomy
     MultiAtrial Tacchycardia
                    Uncommon rhythm in general but common in COPD
                    Often misdx as Afib, different tx
                    Diltiazem (avoid metoprolol)
                    Verapamil 2.5 - 5.0 mg q 3min X 3 (watch for hypotension)
                    NO role for cardioversion or digoxin


DISPOSITION
     Consider severity
                    Mild to moderate: < 3 exacerbations per year, FEV1 > 50% predicted, no
                     comorbidities
                    Moderate-Severe: < 3 exacerbations per year, FEV1 > 50% predicted, one
                     or more comorbidities (CAD, CHF), chronic steriod use, home oxygen
     American Thoracic Society: Indications for admission
                    Failure of outpatient mx
                    Inability to walk between rooms
                    Inability to eat or sleep due to dyspnea
                    Cannot manage at home
                    Altered mentation
                 Worsening hypoxemia
                 New or worsening hypercarbia
                 Comorbidities
                 Etiology of exacerbation requires admission (PE, etc)




                       ROAD TEST THE COPDer WHO YOU ARE
                        PLANNING ON DISCHARGING HOME




   Prediction of relapse: McCrory et al. Chest 2001 review
                 Review of 7 studies looking at predictors of relapse
                 Consistent predictors
                          -        Lower pretreatment FEV1
                          -        Lower posttreatment FEV1
                          -        More bronchodilator treatment during visit
                          -        Higher rates of prior relapse
                 Best predictive model for relapse w/i 14 days: Murata 1992; logistic
                  regression to develop predictive model for relapse within 48hrs; rate of
                  previous relapses, previous visit in last 7 days, number of bd nebs in ed,
                  aminophylline)
                          -        Sensitivity 57%
                          -        Specificity 72%
   Kim, Cydulka, B. Rowe. Chest Feb 2004
                 Prospective cohort of COPD exacerbations in ED that are sent home, N140
                 Telephone f/u at 2 weeks
                 Overall relapse rate 21%
                 Outcome was relapse w/i 2 weeks
                 Multivariate model to predict relapse
                 Predictors of relapse
                          -        Number of copd exacerbation visits w/i last year (OR
                                   relapse 1.49 per visit)
                            -       Self reported limitation in activity moderate to severe (OR
                                    2.93 per unit on four point scale)
                            -       RR at presentation (OR 1.76 per 5 bpm > 16/min)




WHAT’S NEW IN COPD
    Levalbuterol: several studies showing equivalence of levalbuterol (® isomer) equivalent
     bronchodilation to racemic albuterol (R+S isomers) with lower side-effects
    Tiatropium bromide: once daily anticholinergic being studied
    Leukotrience receptor antagonists
    NAC: has been shown in one small study to reduce frequency of exacerbations
    Recombinant leukocyte protease inhibitors
    Phosphodiesterase inhibitors SB207499
    ED Mx of acute exacerbations: Cydulka JAGS 2003
                   Multicenter Airway Research Collaboration
                   Brian Rowe
                   Prospective cohort, N397
                   Low adherence to guidelines
                   43% had relapse within two weeks
                   ? related to low adherence to guidelines (can prove b/c not rct)
    Hospital at home (resp RN or RT does daily visits): Cohran review; not enough evidence
    Heliox: Cochrane review; not enough evidence

				
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