Date:  February 5, 2014

Guest Skeptic: Dr. Katrin Hruska (Sweden)

Case Scenario: 73yo man presents to the emergency department with an exacerbation of his COPD. He quit smoking two days ago when his breathing got worse. He has a history of hypertension but no history of congestive heart failure. He has been taking all his medication and puffers as prescribed. Vital signs are BP165/85, HR 95, Temp 37.2C, RR 22 and O2 Sat 92% on room air.

Questions: Would nebulizer furosemide help treat his COPD exacerbation.

Background: COPD is defined by the WHO as a lung disease characterized by chronic obstruction of lung airflow that interferes with normal breathing and is not fully reversible. The more familiar terms ‘chronic bronchitis’ and ’emphysema’ are no longer used, but are now included within the COPD diagnosis. COPD is not simply a “smoker’s cough” but an under-diagnosed, life-threatening lung disease.

The most common cause of COPD in the western world is cigarette smoking. There is no cure for COPD but there are effective treatments. These include the most important and most difficult – stop smoking. Other treatments include bronchodilators, anticholinergics and steroids. Pulmonary rehabilitation programs have also proven to be effective.

Hypothesis that nebulizer furosemide might work in COPD came form some early studies suggesting it could modulate vagal afferent activity in animal models, reduce induced dyspnea in healthy subjects and help patients with asthma and lung cancer.

Reference: Vahedi et al. The Adjunctive Effect of Nebulized Furosemide in COPD Exacerbation: A Randomized Controlled Clinical Trial. Respiratory Care 2013

  • Population: 100 patients, aged >18. with a diagnosis of COPD and presenting with COPD exacerbation. Patients with a history of asthma, congestive heart failure, atopy and lung cancer were excluded. The study was conducted at a tertiary hospital in Teheran, Iran. Teheran is one of the most polluted cities in the world, which is estimated to cause more than 5 000 excess deaths per year. Mean age was 73,1. 63% were male.The mean baseline FEV1 (during the acute exacerbation) was 54%.
  • Intervention: Inhalation of 40mg nebulizer furosemide
  • Comparison: Conventional therapy alone
  • Outcome:
    • Primary outcome: changes in FEV1 and dyspnea severity
    • Secondary outcomes: changes in other physiological parameters

Authors Conclusions“The addition of nebulized furosemide to conventional therapy improves dyspnea and physiologic respiratory paramaters in paitents with COPD exacerbation.”

Quality Checklist:20121123-215657

  1. The study population included or focused on those in the ED. Comment: Agree. All patients were enrolled in the ED
  2. The patients were adequately randomized. Comment: Randomization was achieved using SPSS 15, but is otherwise not described in the paper. There were exactly 50 patients in both groups.
  3. The randomization process was concealed. Comment: Not described in the paper.
  4. The patients were analyzed in the groups to which they were randomized. Comment: Not mentioned, but probable since nebulized furosemide is not standard treatment. They may, however, The mean baseline FEV1 was 54% (which in stable COPD corresponds to moderate COPD indicating that these were not very sick patients.) have got oral or intravenous furosemide during their stay in the ED. End-point analyses were performed one hour after treatment, which should reduce this risk.
  5. The study patients were recruited consecutively (i.e. no selection bias). Comment: Disagree. The selection process is not described. Only patients who were clinically stable, ie not in need of mechanical ventilation (which is not defined), were included. It is not described how these stable patients were selected.
  6. The patients in both groups were similar with respect to prognostic factors. Comment: Disagree. The placebo group was significantly more tachycardic (101 bpm vs 89), had less pronounced respiratory acidosis (NS) with less compensatory metabolic alcalosis. The placebo group also had a lower FEV1 % (52,7 vs 54,8). The baseline characteristics are not complete, eg a common differential diagnosis to COPD is pneumonia, but fever is not mentioned. A higher pulse rate in the placebo group could indicate more cases of bacterial pneumonia, which would not respond to conventional bronchodilation therapy. Comorbidities are not described.
  7. All participants were unaware of group allocation. Comment: Unsure. All furosemide vials were labeled 1 and placebo 2. (Two earlier studies on healthy young people who were given nebulized furosemide doses of 28 to 40 mg found, however, that than only one subject experienced an urge to urinate within an hour.)
  8. All groups were treated equally except for the intervention. Comment: So it seems. It is, however, not adequately described if the intervention treatment was provided by the regular staff or by the researchers themselves. If the physiologic parameters and dyspnea severity were followed in a more structured manner than usual, this could have resulted in better care than usual for both groups. The conventional treatment included, in addition to hydrocortisone, low doses of salbutamol and ipratropium, not to be repeated, and only 0,5 l/min supplemental oxygen for 30 min. With mean SaO2% of 82,8-84-8% it seems unlikely that no patient got more oxygen.
  9. Follow-up was complete. Comment: Follow-up was a 100%, but not commented on in the paper.
  10. All patient-important outcomes were considered. Comment: There were two primary outcomes for some reason. FEV1% is not patient oriented and not very relevant in the acute setting. Dyspnea is an important patient outcome. What is the baseline dyspnea score for a patient with mild-moderate COPD? Admission would have been relevant. Were the secondary outcomes even predefined?
  11. The treatment effect was large enough and precise enough to be clinically significant. Comment: Difficult to say what would be a relevant improvement in dyspnea score. Besides, the VAS scale used was numbered and patients were asked to point to a number from instead of marking on from 1-10, instead of marking on an analogue scales with scores of 1-100 (which was the method used in the study they used to calculate power.)


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  • Primary outcomes: Change in FEV1% 11,5 for treatment group vs 4,9 (p<0,001) Change in dyspnea score: -2,7 vs -1,6 (p<0,001)
  • Secondary endpoints: See table

BEEM Commentary: This study was designed to evaluate the hypothesis that nebulized furosemide could improve COPD. However, they had poor methods, possible unblinding, multiple surrogate markers and questionable clinical significance. In addition, there was no mention of harm.

The Bottom Line: No nebulized furosemide for COPDers until we have more data.

Case Resolution: You treat his COPD exacerbation with conventional therapy, encourage him to stay a non-smoker and give him a flu shot.

KEENER KONTEST:  Last weeks winner was Rory Spiegel @CaptainBasilEM. He knew Dr. Charles R. Drew was the African-American surgeon who was a pioneer in blood banks which helps save countless lives in World War I

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