Management of acute exacerbation of COPD in hospitalized patients Prof. Nasser Behbehani 1st Kuwait North America update in Internal Medicine 4th medical scientific conference Mubarak Alkabeer hospital

question On a beautiful Friday afternoon like today I’d rather be A) outside with the family having fun B) sitting here listening to Naser Behbehani

1st question If a 70 year old man ex heavy smoker comes to your hospital ED with dyspnea, cough , wheeze, his saturation is 75%, he has bilateral wheeze. What is the most likely initial form of oxygen that he will receive A) venturi mask at 24% B) nasal canulas at 3-5 litres per minute C) re -breather mask D) simple oxygen mask E) don’t know

2nd question What is the most likely initial antibiotic that patients with AECOPD and infection is suspected to be the trigger admitted to your hospital will receive A) Amoxicillin-clavulinic acid B) Ceftriaxone + Clarithromycin C) 3rd generation cephalosporin alone D) 2nd generation cephalosporin alone E) a respiratory quinolone ( levofloxacin- Moxifloxacin )

3rd question the most likely steroid dose that patients admitted with AECOPD will receive at our hospital A) Hydrocortisone 100 mg 3 or 4 time per day at least for 48 hrs. then switch to oral prednisone B) Hydrocortisone 100 mg 3 or 4 time per day until almost ready for discharge C) prednisone 40 mg daily D) Methylprednisolone 40-60 mg IV 3-4 time per day E) higher doses

4th question Almost all patients admitted with AECOPD receive nebulized steroid ( budesonide ) on top of IV or oral steroids A) yes B) No

Case presentation 75 year old man ex smoker known to have , COPD Type II diabetes mellitus hypertension he presented to ED with 1 month history of increasing dyspnea , no significant cough or sputum Frequent ED visits over last 1 month Compliant with his medications

Case presentation Physical examination CXR ABG Heart rate 90/ min , Resp rate 26 , saturation 96% on room air, Temp 37.0 Marked bilateral wheeze CXR ABG Ph 7.51, PO2 26.9 Kpa, 3.13 Kpa , HCO3 18 mmole

Course in hospital Admitted 16th Feb to 7th March ( 3 weeks) In hospital treatment Nebulized ( Salbutamole 0.5 ml + iparatropium Bromide 1 ml ) every 4 hrs. Nebulized Budesonide 500 mcg twice per day Seretide ( Fluticasone + salmeterole) discuss Tiotropium Bromide ( spiriva) once daily Hydrocortizone 100 mg every 6 hrs. for then overlapped with Prednisone 40 mg daily until discharge Ceftriaxone + clarithromycin for 10 days

Course in hospital Echo was done CT chest was done no spirometry done ( daily notes say bilateral expiratory wheeze) treatment on discharge

On discharge Total steroid dose 1) Equivalent to 80 mg prednisone per day for 6 days 2) 40 mg daily for 15 days 3) After discharge 40 to 5 mg over 40 days

Final outcome

Larger dose does not mean better

Acute exacerbation of COPD Definition according to WHO document Significant increase in any of these symptoms beyond day today variation Cough in severity or frequency Sputum in volume or colour dyspnea

Infection in Acute exacerbation of COPD Anthonisen NR et al. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med 1987;106:196–204. three groups Type 1 : increased breathlessness , sputum volume and purulence type 2 : presence of two of these symptoms, and type 3: the presence of one of these symptoms in + either recent URTI( 5 days), fever, increase wheezing or cough , increased HR or Resp rate > 20 % baseline addition to one of the following: an upper

Acute exacerbation of COPD etiology CAUSES OF ACUTE EXACERBATIONS OF COPD Respiratory infections 50-70% ( bacteria, viruses atypical organisms) 10 % due to environmental pollution 30 % unknown etiology heart failure Pulmonary emboli

Prospective cohort study in a single centre in France Pulmonary Embolism in Patients with Unexplained Exacerbation of Chronic Obstructive Pulmonary Disease: Prevalence and Risk Factors. Tillie-Leblond et al , Ann Intern Med. 2006;144:390-396. Prospective cohort study in a single centre in France 211 consecutive patients admitted with unexplained AECOPD not requiring (NIV) All patients underwent CTPA, venous doppler US within 48 hrs. 197 had were analyzed ( 14 patients were excluded) 49 of 197 patients (25% [95% CI, 19% to 32%]) had PE Most important risk factors previous thromboembolic disease (risk ratio, 2.43 [CI, 1.49 to 3.94], malignant disease (risk ratio, 1.82 [CI, 1.13 to 2.92]) decrease in PCO2 of > 5 mm Hg (risk ratio, 2.10 [CI, 1.23 to 3.58].

Acute exacerbation of COPD Management issues

Acute exacerbation of COPD treatment Oxygen therapy Pharmacological intervention Bronchodilators Steroids Antibiotics methylxanthines Assisted ventilation Non invasive invasive

Treatment : oxygen therapy Response to oxygen administration — 3 possible outcomes The patient's clinical state and PaCO2 may improve or not change The patient may become drowsy but arousable in these cases, the PaCO2 generally rises slowly by up to 20 mmHg and then stabilizes after approximately 12 hours The patient rapidly becomes unconscious, cough becomes ineffective, and the PaCO2 rises at a rate of 30 mmHg or more per hour complete withdrawal of oxygen if hypercapnea worsens is more dangerous .

PaCO2 increased by 23 mm Hg on average Effects of the administration of O2 on ventilation and blood gases in patients with chronic obstructive pulmonary disease during acute respiratory failure. Aubier M et al , Am Rev Respir Dis. 1980;122(5):747. Patients with severe COPD in ARF were given 100% oxygen and the effect on ventilation, RR, TV, PaCO2 were measured minute ventilation was reduced by 14% but returned to within 93% of baseline within 12 minutes PaCO2 increased by 23 mm Hg on average This was due to several factors ( haldane effect , worsening V/Q mismatch)

BTS guideline for emergency oxygen use in adult patients, B R O’Driscoll Thorax 2008;63(Suppl VI):vi1–vi68 Look for oxygen alert card that patient may have People at risk for hypercapnea , initially one should use venturi mask at 24%. ( nasal canula 1- liters per minute) urgent ABG should be done for such patient Follow up ABG should be done within 30-45 minutes after initiating oxygen therapy Pre specified target oxygen saturation should be used For COPD or risk of hypercapnea 88-92% Other conditions 94-98%

Bronchodilator therapy solution contains in Mcg How much does 1 ml of salbutamole solution (not nebules) contains in mg 2.5 mg 5 mg How much does 1 ml of ipratropium Bromide contains in Mcg It comes in 2 concentration ( nebule) 250 mcg per 2.5 nebule 500 mcg per 2.5 ml nebule

86 patients presented to ED with AECOPD. A Randomized Controlled Trial To Assess the Optimal Dose and Effect of Nebulized Albuterol in Acute Exacerbations of COPD S Nair et al CHEST 2005; 128:48–54 86 patients presented to ED with AECOPD. Patients randomized to either 2.5 mg or 5 mg of Salbutamole every 4 hrs. after initially had multiple doses of Salbutamole by MDI The patients were followed until discharge and prior to discharge again a dose response curve after MDI was constructed

86 patients presented to ED with AECOPD. A Randomized Controlled Trial To Assess the Optimal Dose and Effect of Nebulized Albuterol in Acute Exacerbations of COPD S Nair et al CHEST 2005; 128:48–54 86 patients presented to ED with AECOPD. Patients randomized to either 2.5 mg or 5 mg of Salbutamole every 4 hrs. after initially had multiple doses of Salbutamole by MDI

A Randomized Controlled Trial To Assess the Optimal Dose and Effect of Nebulized Albuterol in Acute Exacerbations of COPD S Nair et al CHEST 2005; 128:48–54 Dose response curve to MDI Patient on 2.5 mg by neb N = 40 Dose response curve to MDI Patient on 5 mg by neb N = 46 On discharge On discharge On admission On admission

Recommendation for bronchodilators Either MDI wit spacer or nebulizer can be used Adding short acting anticholinergic was shown to be beneficial in some studies. More frequent doses ( every 20 minutes) for three doses then hourly may be needed.

Steroid therapy Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. Dennis Niewoehner et al , N Engl J Med 1999;340:1941-7. Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the REDUCE randomized clinical trial. Leuppi JD et al , JAMA. 2013 Jun;309(21):2223-31.

271 patients admitted for AECOPD Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. Dennis Niewoehner et al , N Engl J Med 1999;340:1941-7 RCT in 25 centres in the US. 271 patients admitted for AECOPD 80 received steroid for 8 weeks 80 received steroids for 2 wks 111 received placebo Steroid dose Solumedrole 125 mg IV q 6 hrs. for 3 days then oral treatment 60 mg daily Follow up for 6 months (180 days) Primary outcome is treatment failure defined as Death, intubation, readmission for COPD, escalation of therapy

Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. Dennis Niewoehner et al , N Engl J Med 1999;340:1941-7 results

Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. Dennis Niewoehner et al , N Engl J Med 1999;340:1941-7 results

Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. Dennis Niewoehner et al , N Engl J Med 1999;340:1941-7 Conclusion Steroid therapy does have moderate benefit in AECOPD. 2 wks. therapy is similar to 8 wks. There is significant hyperglycemia in the steroid group. A number of patients in the 8 wks. Group was admitted for serious infection.

REDUCE (Reduction in the Use of Corticosteroids in Exacerbated COPD) Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the REDUCE randomized clinical trial. Leuppi JD et al , JAMA. 2013 Jun;309(21):2223-31. REDUCE (Reduction in the Use of Corticosteroids in Exacerbated COPD) 314 patients presenting to ED with AECOPD to 5 swiss teaching hospitals, (289, 92% admitted to hospital. Intervention 5 days of Prednisone 40 mg daily VS 14 days outcome Primary end point time to next exacerbation Secondary outcomes (FEV1, Death ) Follow up for 6 months

Time to re-exacerbation Intention to treat analysis Per protocol analysis Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: The REDUCE randomized clinical trial. Leuppi JD et al , JAMA. 2013 Jun;309(21):2223-31.

Survival curve Death Death or exacerbation Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: The REDUCE randomized clinical trial. Leuppi JD et al , JAMA. 2013 Jun;309(21):2223-31.

Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: The REDUCE randomized clinical trial. Leuppi JD et al , JAMA. 2013 Jun;309(21):2223-31. FEV1

Steroid dose for exacerbation Conclusion Systemic steroid Oral treatment is as effective as IV. If you use IV , restrict to 24 or 48 hrs. 5 days is adequate NO need for tapering or overlap There is no evidence for concomitant addition of nebulized steroid during exacerbation Inhaled steroid

Use of antibiotics indication for starting antibiotics Increase sputum volume or purulence Severe exacerbation ( requiring NIV) Some advocate use it for all hospitalized patients   The indication for antibiotics in OPD exacerbation without symptoms suggestive of infection is weak Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Schuetz P, Cochrane Database Syst Rev. 2012;9:CD007498.

Use of antibiotics in AECOPD Atypical organisms e.g Chlamydia, Mycoplasma. legionella are rare in AECOPD Use of antibiotics in AECOPD Frequency of pathogens

Choice of antibiotics Risk of pseudomonas infection recent hospitalization in the past 90 days. frequent administration of antibiotics (≥4 courses within the past year). severe COPD (FEV1 <50 percent of predicted). isolation of Pseudomonas aeruginosa during a previous exacerbation, colonization during a stable period, and systemic glucocorticoid use

Choice of antibiotics in hospitalized patients

Take home message AECOPD is different from pneumonia Appropriate treatment Appropriate oxygen therapy from ED Proper dose and frequency of bronchodilators Steroid therapy for 5 days only without tapering Most patients with hospitalized AECOPD needs antibiotics ( single agent is adequate) NIV for any patient with respiratory acidosis

Inadequate response of symptoms to outpatient management Marked increase in dyspnea Inability to eat or sleep due to symptoms Worsening hypoxemia Worsening hypercapnia Changes in mental status Inability to care for oneself (ie, lack of home support) Uncertain diagnosis High risk comorbidities including pneumonia, cardiac arrhythmia, heart failure, diabetes mellitus, renal failure, or liver failure

A high FiO2 is not required to correct the hypoxemia associated with most acute exacerbations of COPD. Inability to correct hypoxemia with a relatively low FiO2 (eg, 4 L/min by nasal cannula or 35 percent by mask) should prompt consideration of pulmonary emboli, acute respiratory distress syndrome, pulmonary edema, or severe pneumonia as the cause of respiratory failure. (

Response to oxygen administration — There are three possible outcomes when administering uncontrolled oxygen therapy to a patient with COPD and respiratory insufficiency [28]: The patient's clinical state and PaCO2 may improve or not change The patient may become drowsy but can be roused to cooperate with therapy; in these cases, the PaCO2 generally rises slowly by up to 20 mmHg and then stabilizes after approximately 12 hours The patient rapidly becomes unconscious, cough becomes ineffective, and the PaCO2 rises at a rate of 30 mmHg or more per hour The risk for developing severe hypercapnia and CO2 narcosis is greater in patients with a low initial pH and/or PaO2 [28,29]. In a retrospective study of 95 patients with COPD and hypercapnia who presented with acute respiratory distress, oxygen therapy targeting a PaO2 >74 mmHg was associated with increased length of stay, increased need for noninvasive mechanical ventilation, and increased rate of admission to an ICU [30]. A causal relationship cannot be concluded, however, due to the study's observational design. Effect of withdrawing oxygen — The major danger facing patients who develop hypercapnia during treatment with oxygen is that the abrupt removal of supplemental oxygen may cause the PaO2 to fall to a level 

PROGNOSIS — Acute exacerbations of COPD are associated with increased mortality after hospital discharge. It is estimated that 14 percent of patients admitted for an exacerbation of COPD will die within three months of admission [47,48]. Among 1016 patients with an acute exacerbation of COPD and a PaCO2 of 50 mmHg or more, the 6 and 12 month mortality rates were 33 and 43 percent, respectively [49]. In a study of 260 patients admitted with a COPD exacerbation, the one year mortality was 28 percent [50]. Independent risk factors for mortality were age, male gender, prior hospitalization for COPD, PaCO2≥45 mmHg (6 kPa), and urea >8 mmol/L. Patients hospitalized for a COPD exacerbation who have a Pseudomonas aeruginosa in their sputum have an increased risk of mortality at three years than those without (59 versus 35 percent, HR 2.33, 95% CI 1.29-3.86), independent of age, comorbidity, or COPD severity [51]