“You want to do what with what?” was the question accompanied by a strange look from my internal medicine attending physician when I mentioned the idea of nebulized furosemide. In reading around a dyspneic patient I had came across this seemingly bizarre treatment for breathlessness. I thought I’d share what I’ve learned.
IN THEORY DOES IT MAKE SENSE?
Surprisingly, yes! It turns out, as shown by Sudo et al. (2000), that furosemide activates pulmonary stretch receptors . When activated, stretch receptors signal to the brain that an adequate breath has been inspired. When not activated, the brain senses that air needs to be taken. Inadequate activation of stretch receptors can contribute to a sensation of dyspnea. This is particularly relevant in patients for whom restricted tidal volume is an issue (think COPD and asthma exacerbations).
Other mechanisms are also likely at play including alleviating bronchoconstriction, inhibiting irritant receptors and increasing dynamic tidal volume as outlined by Nishino (2009).
While talking about physiology it is also important to note that there are theoretical (and demonstrated) risks associated with nebulized furosemide that are related to the more typical ways that we give the drug. It is possible that with enough uptake into the circulation from the lungs, or accidental swallowing during nebulization, that over-diuresis will result.
DOES IT WORK?
A number of studies have been performed in healthy patients with induced dyspnea (exposed to allergens and AMP/bradkyinin challenges) but fewer high-quality intervention trials have been conducted.
- A systematic review of nebulized furosemide by Newton et al. (2008) included studies up to 2004 and is a good place to begin to review the literature. This SR captured 42 articles, 39 of which were randomized control trials with small sample sizes (35 in asthma, 2 in cancer, 1 in COPD and 8 in healthy patients). Only 5 of the studies reported subjective dyspnea as an outcome while the rest measured physiologic indicators.
This 2008 systematic review and captured papers, two recent RCTs (one in COPD and one in asthma), a more recent systematic review in cancer patients and the American Thoracic Society Guidelines 2012 were used in drawing the below conclusions.
- A 19 patient RCT by Ong et al. was the only COPD study included in the Newton systematic review. In patients with moderate-severe COPD, exercise induced dyspnea was less severe in patients treated with nebulized furosemide vs placebo (33.7mm vs 42.4mm on a 100mm visual scale p=0.014).
- A more recent study, “The adjunctive effect of nebulized furosemide in COPD exacerbation: a randomized control trial” by Vahedi et al. (2013) was a double-blind, RCT with 100 patients. Patients received 40mg of nebulized furosemide or placebo in addition to standard treatment for COPD exacerbations. The treatment group had a larger improvement in the severity of dyspnea (-2.7 vs -1.6 on a 10 point visual analogue scale p<0.001) and increase in FEV1 (11.5% vs 4.9% p<0.001) when compared to placebo. A number of secondary outcomes were also significantly more improved in the treatment group including resp rate, paO2 and pH. The downfall of this study is that it does not clearly outline randomization procedures and when examining baseline characteristics it seems that the patients in the treatment group were sicker. In addition, this study did not assess the possible systemic effects of nebulized furosemide and possible harms. These findings, if true, do seem clinically relevant.
EVIDENCE GRADE (B) AND SO WHAT?: The large RCT demonstrating benefit is convincing and is in line with previous literature though a multi-center verification of this data or another high quality RCT with analysis of adverse events would really improve the evidence base. I would consider prescribing this therapy for patients with acute COPD exacerbations if there were no contraindications to diuresis, what about you?
- As outlined in the Newton systematic review and the American Thoracic Society Update on Dyspnea there are a number of small RCTs evaluating nebulized furosemide and asthma. Some are positive, some are negative, and the cumulative results are really inconclusive.
- The abstract for a 2006 RCT “Effectiveness of nebulized furosemide added to nebulized salbutamol in children with acute asthma” seems to suggest no added benefit but the full text is in Spanish and I cannot access the article to perform a more comprehensive review. If you can access the article, take a look and share what you learn!
EVIDENCE GRADE (C) AND SO WHAT?: The literature on asthma is all over the place with different types of patients and clinical situations being addressed. Jury is still out on whether this treatment is beneficial or not which could be because:
1) There really is no benefit so we see studies falling to both sides of the “no effect” line. Perhaps there is minimal publication bias in the world of nebulized furosemide?
2) There has not been a definitive large, multi-center trial or meta-analysis (studies are too heterogenous to combine results) to appropriately and definitively answer a relevant clinical question.
With the availability of evidence right now in asthma I would not consider prescribing a patient with asthma nebulized furosemide.
Hard to say.
There are effective treatments for dyspnea in cancer but the theoretical and attractive advantage of nebulized furosemide is that it could offer an improvement in dyspnea without the side effect of sedation.
- A recent BMJ systematic review of nebulized furosemide for the palliation of dyspnea in cancer patients identified only 2 RCTs with small sample sizes (7 and 15) neither of which showed benefit.
EVIDENCE GRADE (C) AND SO WHAT?: The two, very small RCTs do not provide enough data to draw definitive conclusions about the benefit of dyspnea in cancer patients but the risk-benefit scale may end up balancing differently for a palliative cancer patient who remains breathless but doesn’t want to take more narcotics and in whom other options have been exhausted. I would say that an honest discussion about the lack of evidence and trial of this treatment (while coming up with a better long term plan) may be reasonable in a patient without contraindications to diuresis but am interested in your thoughts on this.
The primary drawback is the lack of high-quality evidence demonstrating benefit.
The possibility of over-diuresis must be considered. Of the 42 trials in the 2008 systematic review only fourteen explicitly studied adverse events. Ten studies reported no adverse events and four studies reported increased diuresis lasting up to 24 hours.
- In asthma patients Rodriguez et al. showed a non-signifcant increase in diuresis (510ml vs 310 ml) compared to placebo (25 subjects per group)
- In healthy patients with induced dyspnea 1/8 had increased diuresis in the study by Ventresca et al.
- In a small crossover RCT by Yeo et al. of 8 patients with mild asthma placebo and both nebulized furosemide and piretanide were studied. Furosemide and piretanide caused a significant increase in diuresis when compared to placebo maximal at 0-1.5 hours (300cc/hr furosemide vs 600cc/hr piretanide vs 100cc/hr placebo p<0.01)
- Yates et al. studied the chronic administration of inhaled furosemide over 4 weeks in a double-blind patient cross over RCT with 12 patients, one of whom reported increased diuresis without objective measurements.
There is a good proposed biologic mechanism for why furosemide might relieve dyspnea however the clinical research base for this treatment only reasonable for COPD and poor in asthma and cancer. For a COPD patient who is still symptomatic on standard therapy, and who does not have significant contraindications to diuresis, nebulized furosemide may be a reasonable option.