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Hashemian F, Ghorbanian MA, Hashemian F, et al. Effect of Topical Furosemide on Rhinosinusal Polyposis Relapse After Endoscopic Sinus Surgery: A Randomized Clinical Trial. JAMA Otolaryngol Head Neck Surg. 2016;142(11):1045–1049. doi:10.1001/jamaoto.2016.1249
What is the effect of topical furosemide on recurrence rate of rhinosinusal polyposis after endoscopic sinus surgery?
In this randomized clinical trial of 84 adults, the grade of polyps was 0 in 79% of the patients in the furosemide group compared with 38% in the placebo group.
In this trial, topical furosemide was a safe drug with no important adverse effects that substantially reduced the severity of polyposis after endoscopic sinus surgery.
Evidence from previous studies suggests that furosemide may be effective in reducing the recurrence of polyps after sinus surgery. However, the evidence is limited and insufficient, and further investigations are required.
To assess the effect of topical furosemide on recurrence rate of rhinosinusal polyposis after endoscopic sinus surgery.
Design, Setting, and Participants
Triple-blind randomized clinical trial of patients aged 18 to 60 years with chronic rhinosinusitis associated with polyposis who did not respond to medical treatment and were candidates for endoscopic sinus surgery at Besat Hospital, Hamadan University of Medical Sciences, from April 2014 to June 2015.
Patients were randomly assigned to receive postoperative nasal spray, 2 puffs twice a day for 2 months, either 300 µg of furosemide per day or placebo.
Main Outcomes and Measures
Six months after surgery, the patients were examined for nasal and paranasal sinus polyposis using Meltzer endoscopic grading, computed tomographic (CT) scan of paranasal sinuses (PNS) scoring, Sino-Nasal Outcome Test (SNOT-22) scoring, and visual analog scale (VAS).
Of 110 patients enrolled, 84 patients remained for analysis (53 men and 31 women; mean age in the furosemide group, 37.02 years, range, 18-58 years; mean age in the placebo group, 36.30 years, range, 18-60 years). Six months after the intervention, the grade of polyposis decreased in both groups, but this reduction was substantial in the furosemide group vs the placebo group. The severity of polyposis was significantly lower in the furosemide group vs the placebo group based on SNOT-22 scoring (difference, 8.05; 95% CI, 3.24-12.85) and VAS (difference, 0.81; 95% CI, 0.22-1.39) but not significantly different based on CT scan of PNS scoring (difference, 2.52; 95% CI, −0.35 to 5.39). The incidence of adverse effects (nasal irritation, headache, and constipation) were not significantly different between the 2 groups.
Conclusions and Relevance
These findings indicate that topical furosemide is a safe drug, with no important adverse effects, that can substantially reduce the severity of polyposis after endoscopic sinus surgery.
Iranian Registry of Clinical Trials registration number: IRCT201403143186N5
Nasal polyps are the most common types of nasal tumors and are associated with nasal congestion, postnasal drip, runny nose, sneezing, and olfactory disorder.1-3 They usually occur in chronic rhinosinusitis associated with allergy, inflammation, and submucosal edema.2 Nasal polyps occur in 1% to 4% of the adult population.2,4 The prevalence of the disease varies from 7% to 15% in patients with asthma and from 36% to 60% among people with hypersensitivity to nonsteroidal anti-inflammatory drugs.4,5
Sinus surgery is the main treatment for nasal polyps, but this approach is associated with a high recurrence rate of polyposis.2,6 Therefore, researchers are looking for approaches to reduce the recurrent episodes. One treatment recently suggested for this purpose is topical furosemide, which may reduce the recurrence rate of nasal polyps by affecting inflammation, edema, and the immune system.2,7
Kroflic et al8 examined the effect of topical nasal furosemide on the prevention of nasal polyp recurrence in a group of 40 patients with nasal polyposis. They reported that furosemide treatment had no significant effect on the inflammatory cell count, but it could significantly reduce edema. Passàli et al6 performed a randomized clinical trial to explore the long-term efficacy of intranasal furosemide in preventing relapses of chronic hyperplastic sinusitis with nasal polyposis. They concluded that use of intranasal furosemide could efficiently reduce the recurrence rate of chronic hyperplastic sinusitis with nasal polyposis. Another trial conducted by Passàli et al9 to assess the effect of furosemide on relapses of nasal polyps after surgical treatment revealed that the recurrence rate of nasal polyps in patients who received furosemide was significantly lower than that of control group.
Evidence from previous studies suggests that furosemide may be effective in reducing the recurrence of polyps after sinus surgery. However, the evidence is limited and insufficient, and further investigations are required to determine whether topical furosemide can prevent or at least reduce the recurrence of nasal polyps after sinus surgery. Therefore, we conducted a randomized clinical trial to explore the effect of topical furosemide on the recurrence rate of rhinosinusal polyposis after endoscopic sinus surgery.
This triple-blind randomized clinical trial was performed in Besat Hospital, affiliated with Hamadan University of Medical Sciences, in the west of Iran, from April 2014 to June 2015. Written informed consent was received from all patients. The Hamadan University of Medical Sciences ethics committee approved the trial in February 2014 (see trial protocol in the Supplement). There was no change in methods after trial commencement.
We included patients aged 18 to 60 years with chronic rhinosinusitis associated with polyposis, who did not respond to medical treatment and were candidates for endoscopic sinus surgery. Patients with any of the following characteristics were excluded from the study: (1) hypersensitivity to furosemide; (2) being pregnant; (3) known systemic diseases such as cardiovascular diseases, hypertension, or hypokalemia; (4) previous history of tinnitus; or (5) sensorineural hearing loss.
According to the results of a clinical trial conducted by Passáli et al,9 the recurrence rate of polyposis after sinus surgery was 6.25% among patients in the treatment group, who received furosemide, and 30.0% among the control group, who received placebo. On the basis of these results, we arrived at a sample size of 41 for each group and a total sample size of 82 at 95% significance level and 80% statistical power.
The eligible patients were randomly assigned to 2 groups using the balance block randomization method. For this purpose, we prepared 4 sheets of paper, writing on 2 sheets “F” for “furosemide” and on 2 sheets “P” for “placebo.” The paper sheets were pooled, placed in a container, and randomly drawn 1 at a time for each patient without replacement until all 4 sheets were drawn. The 4 paper sheets were then placed back into the container, and this action repeated until the sample size was reached. The allocations remained concealed during the study. For this purpose, the random allocation was conducted by a resident (M.A.G.), who was the coordinator of the trial group, so no one could predict the allocation.
We set up a triple-blinded design. For this purpose, a pharmacologist (F.H.) provided identical spray bottles for both furosemide and placebo. Therefore, neither the patients nor the surgeon, who evaluated the effect of the interventions, were aware of the administered drugs. In addition, the statistical analyst was unaware of the trial groups until the data were analyzed and the labels were decoded.
We used high-performance chromatography to determine the amount of furosemide in each nasal spray puff. We checked the validation of the method to ensure that the concentration of the formulation had adequate precision, accuracy, and ruggedness. We used an analytical scale to determine the weight of furosemide in each puff. We used a Nikon D3000 digital camera to examine the exit angle and distribution pattern of the spray. All stages of the preparation of furosemide and placebo spray were undertaken in the Department of Pharmaceutical Sciences, Islamic Azad University, Tehran branch.
All the patients received 30 mg of oral prednisolone, 400 mg of oral cefixime, and fluticasone spray, 2 puffs twice a day in each nostril, for 10 days preoperatively. After surgery, the 2 groups received 400 mg of oral cefixime for 10 days and fluticasone spray, 2 puffs twice a day for 1 month and then 1 puff a day for 5 months. The intervention group received furosemide spray, 2 puffs twice a day for 2 months, including 300 µg of furosemide per day, while the control group received placebo spray, 2 puffs twice a day for two months. The placebo spray was prepared by the Department of Pharmacy of the Islamic Azad University, Tehran branch. The containers of furosemide and placebo sprays were identical.
The primary outcome of interest was nasal and paranasal sinus polyposis, which was evaluated at baseline and after 6 months using Meltzer endoscopic grading,10 computed tomographic (CT) scan of paranasal sinuses (PNS) scoring, Sino-Nasal Outcome Test (SNOT-22) scoring, and visual analog scale (VAS). Nasal endoscopic findings were classified using Meltzer scores10 as follows: (0) no polyps; (1) small polyps in the middle meatus/edema; (2) blocked middle meatus; (3) polyps extending beyond the middle meatus without complete obstruction; and (4) massive nasal polyposis. The involvement of paranasal sinuses, airway, and nasal cavity was evaluated by CT scan of PNS and was scored from 0 to 30. The VAS pain scale ranged from 0 to 10, 0 denoting no pain, and 10 denoting the most severe pain that the patient had ever experienced. The secondary outcomes of interest were episodes of irritation, hypersensitivity, or any local or systemic adverse effects. These were evaluated by the researchers in periodic visits in the first, third, and sixth months after surgery.
The independent t test was used for analysis of continuous variables, and the Fisher exact test for nominal variables. All statistical analyses were performed at a significance level of .05 using Stata software, version 11 (StataCorp LP).
Of 110 patients identified, 5 were ineligible, and 13 declined to participate. The randomization was based on the remaining 92 patients, of whom 46 patients were allocated to the furosemide group and 46 to the control group. Seven patients declined follow-up, including 3 patients in the furosemide group and 4 patients in the control group. One additional patient in the furosemide group was excluded from the study because of being pregnant. The analysis was based on data from the remaining 84 patients (53 men and 31 women) including 42 in the furosemide group and 42 in the control group (Figure).
The baseline characteristics of the study population are given in Table 1. The mean age of the patients in the furosemide group was 37.02 (95% CI, 33.73-40.31) years (range, 18-58 years); mean age in the control group was 36.30 (95% CI, 32.95-39.65) years (range, 18-60 years). In the furosemide group, 30 (71%) of 42 patients were men, while 23 (55%) of 42 in the placebo group were men, for a difference of 16% (95% CI, −3% to 37%). There was no statistically significant difference in the severity of polyposis between the 2 groups based on CT scan of PNS scoring (difference, 0.30; 95% CI, −2.50 to 3.12), SNOT-22 scoring (difference, 3.45; 95% CI, −3.21 to 10.11), and VAS (difference, 0.21; 95% CI, −0.41 to 0.84) before intervention. In addition, 3 patients had Samter triad, 1 in the furosemide group and 2 in the control group.
During the 6 months of follow-up, no clinically significant adverse effects were seen in the 2 groups. Among the patients who received furosemide, 1 reported nasal irritation, 2 reported constipation, and 1 reported headache. Among the patients who received placebo, 1 reported nasal irritation, and 2 reported headache. The symptoms, reported by the patients were not severe; therefore, those patients remained in the trial.
The effect of topical furosemide vs placebo on the severity of polyposis based on Meltzer grading is summarized in Table 2. There was no statistically significant difference in the grade of polyposis between the 2 groups before the intervention. A majority of the patients in both groups had polyps of grade 3 or 4 before the intervention. Six months after the intervention, the grade of polyposis had decreased in both groups, but this reduction was substantial in the furosemide group vs the placebo group. The grade of polyps was 0 in 79% of the patients in the furosemide group (n = 33) compared with 38% in the placebo group (n = 16).
The effects of topical furosemide vs placebo on the severity of polyposis on the bases of CT scan of PNS scores, SNOT-22 scores, and VAS are summarized given in Table 3. The severity of polyposis was significantly lower in the furosemide group vs the placebo group based on SNOT-22 scoring (difference, 8.05; 95% CI, 3.24-12.85) and VAS (difference, 0.81; 95% CI, 0.22-1.39) but not significantly different based on CT scan of PNS scoring (difference, 2.52; 95% CI, −0.35 to 5.39).
We analyzed for SNOT-22 change in scores between preintervention and postintervention, considering a score change of 8 or greater clinically meaningful. In the furosemide group, 40 (95%) of 42 patient achieved a change in SNOT-22 score of 8 or greater, while 41 (98%) of 42 in the placebo group achieved such a change, for a difference of 3% (95% CI, −8% to 13%).
Endoscopic sinus surgery is the most effective treatment of rhinosinusal polyposis with short-term and long-term response. The surgical procedure helps remove the inflammatory tissue from the sinuses and nose. However, elimination of all microscopic inflammatory tissues of the sinuses and nose by sinonasal drainage is not possible. As long as the inflammatory tissue exists in the nose and sinuses, the recurrence of polyps will occur.2
Several nonsurgical adjuvant therapies have been suggested to reduce postsurgical inflammation and thus to reduce the recurrence of polyposis. Topical and systemic steroids can help reduce the inflammation of the mucus after endoscopic sinus surgery.11 Recently, some randomized clinical trials have reported that topical furosemide can reduce the recurrence of polyposis after sinus surgery.6,8,9
Furosemide is a loop diuretic that is used alone or in combination with other drugs to treat fluid retention (edema) in patients with congestive heart failure, liver disease, or a kidney disorder. It is also used to treat patients with hypertension.12 Loop diuretics including furosemide may have an important inhibitory role in cell proliferation regulation.13 Since mucosal tissue inflammation and mucosal edema play an important role in the mechanism of nasal polyps, it has been suggested that the inhibitory effect of furosemide may have an effect on prevention of polyposis relapse.
Passàli et al6 performed a randomized clinical trial to demonstrate the long-term efficacy of intranasal furosemide in preventing relapses of rhinosinusitis with polyposis after surgery. They enrolled 170 patients with chronic hyperplastic sinusitis with nasal polyposis. The recurrence rate of nasal polyposis was 17.5% in patients who received furosemide and 30.0% in patients who did not receive therapeutic treatment (P < .05).
Kroflic et al8 conducted a randomized clinical trial on 40 patients with nasal polyposis. They assessed the effect of 7-day preoperative treatment with topical nasal furosemide vs oral steroid on nasal symptoms, polyp size, severity of inflammation, and blood loss during surgery. They reported that steroid significantly reduced eosinophil count but had no effect on mastocytes and edema. Furosemide treatment had no significant effect on the inflammatory cells count but reduced edema significantly.
Another randomized clinical trial was conducted by Passàli et al9 to demonstrate whether furosemide can prevent relapses of rhinosinusal polyps after surgical treatment. They assigned 64 patients with rhinosinusal polyposis to the intervention (topical furosemide) group and 40 patients to the control group (no treatment). Six years after the operation, only 4 cases of relapse were diagnosed in the intervention group (10%), whereas there were 12 relapses (30%) in the control group. The results of previous randomized clinical trials as well as our results favor the significant effect of furosemide on the relative reduction of rhinosinusal polyposis after sinus surgery.
The main limitation of our study was the short-term follow-up period. We followed up with the patients for 6 months. Longer-term follow-up studies may provide better evidence about the long-term effect of topical furosemide on the recurrence rate of rhinosinusal polyposis after sinus surgery. Furthermore, our study population was limited, and more evidence based on different populations and different settings is required to ensure the generalizability of the results. Despite these limitations, this trial addressed the polyposis relapse and severity by different methods, including Meltzer grading, CT scan of PNS scoring, SNOT-22 scoring, and VAS.
Endoscopic sinus surgery is an effective procedure for treatment of rhinosinusal polyposis. However, using topical furosemide, which is a safe drug with no important adverse effects, can be used as an adjuvant treatment after sinus surgery to reduce the rate of relapse and severity of polyposis after surgery.
Corresponding Author: Jalal Poorolajal, MD, PhD, Research Center for Health Sciences and Department of Epidemiology, School of Public Heath, Hamadan University of Medical Sciences, Shahid Fahmideh Ave, Hamadan 6517838695, Iran (email@example.com).
Accepted for Publication: April 15, 2016.
Published Online: July 14, 2016. doi:10.1001/jamaoto.2016.1249
Author Contributions: Drs Hashemian and Poorolajal had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Farnaz Hashemian, Farshad Hashemian, Mortazavi, Poorolajal.
Acquisition, analysis, or interpretation of data: Farnaz Hashemian, Ghorbanian, Farshad Hashemian, Mortazavi, Sheikhi, Jahanshahi, Poorolajal.
Drafting of the manuscript: Farnaz Hashemian, Mortazavi, Sheikhi, Poorolajal.
Critical revision of the manuscript for important intellectual content: Farnaz Hashemian, Ghorbanian, Farshad Hashemian, Jahanshahi, Poorolajal.
Statistical analysis: Ghorbanian, Poorolajal.
Administrative, technical, or material support: Farnaz Hashemian, Ghorbanian, Farshad Hashemian, Mortazavi, Jahanshahi, Poorolajal.
Study supervision: Farnaz Hashemian, Farshad Hashemian, Mortazavi, Poorolajal.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Funding/Support: This study was funded by the Vice Chancellor of Research and Technology, Hamadan University of Medical Sciences.
Role of the Funder/Sponsor: The funder had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: We thank the Vice Chancellor of Research and Technology of Hamadan University of Medical Sciences for financial support of this work. The Vice Chancellor received no compensation for the contributions beyond that received in the normal course of employment.
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