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Abstract Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. According to the Global Initiative for chronic Obstructive Lung Disease (GOLD), 264 million people suffer from COPD globally. Nebulized furosemide has been shown to improve pulmonary function in acute exacerbations of COPD, likely through resolution of pulmonary edema. Ipratropium bromide and salbutamol are short-acting anticholinergic and β2-agonist bronchodilators, respectively, commonly used for COPD symptom relief in combination. However, salbutamol may exacerbate tachycardia in patients with concomitant cardiac diseases such as heart failure, which is prevalent in up to 30% of COPD patients. As an add-on nebulized bronchodilator, furosemide may provide bronchodilation without increasing heart rate. Moreover, combining ipratropium, salbutamol and furosemide via nebulization is more affordable than alternate treatments including inhaled corticosteroids. Interestingly, the combination of ipratropium, salbutamol, and furosemide nebulizer appears to be cheaper than Budesonide vial, which could have significant implications for healthcare costs. Few studies on stable COPD patients were conducted and the majority of studies which evaluated inhaled furosemide were assessing the effect on COPD exacerbation cases. Such trials are insufficient because they did not address stable COPD as an additional treatment. Aim of the study: The primary aim of this study was to evaluate the effect of adding nebulized furosemide to ipratropium alone or in combination with salbutamol on lung function parameters in patients with very severe COPD Patients and methods: A triple-blinded, crossover, Randomized Controlled Trial that was conducted in the Chest Outpatients Clinic department, Alexandria University Hospital. Our study SUMMARY, CONCLUSION AND RECOMMENDATIONS 5 8 included 92 participants, 47 participants were enrolled in group A (which began with furosemide in the first episode followed by saline in the second episode), while 45 participants were enrolled in group B (started with saline in 1st episode followed by furosemide in 2nd episode). The analysis was donr using R version 4.2.1 associated with the following packages: (tidyverse, dplyr,rstatix, psych, geepack, ggeffects, emmeans,gee, wgeesel, and Geepack). An informed consent was signed by every patient to participate in the study. The study’s key findings were: • Furosemide inhalation alleviated the sensation of dyspnea as measured by spirometric parameters (FVC, FVC%, FEV1/FVC, PEF, PEF%, FEV25-75, FEV25-75%) and COPD assessment scales (Borg and CAT scales) in individuals with stable COPD (GOLD C and D) and that there was considerable bronchodilation following furosemide inhalation compared to saline in these patients. • The sequence of administering saline or furosemide had no significant effect on the improvement of patients. • There was no statistically significant difference after performing the pairwise-comparison between 1st and 2nd episodes, hence the sequence of administrating the nebulizer has no effect on the ipratropium-salbutamol combination. • Except for FEV%, all lung function parameters showed a statistically significant difference between furosemide and baseline. Saline likewise showed a statistically significant difference between treatment and baseline. • By running the GEE model, we found that adding furosemide to Combivent increases the FVC% response by 9.42% (3.26, 15.59), whereas adding nebulized saline increases the FVC% response by 5.83% (0.06, 11.61). • For CVD patients, FVC% will decrease by 10% (-15.69,-5.44). FVC% will decrease to 0.16% when the pack year smoking index rises (-0.19,-0.1). SUMMARY, CONCLUSION AND RECOMMENDATIONS 5 9 • When we used nebulizer furosemide, the ratio of FEV1/FVC increased by 3.32 with 95% CI (0.06, 6.58), but it was not statistically significant when we used nebulizer saline. • BMI has been observed to increase the FEV1/FVC ratio by 0.67 with a 95% CI of (0.46, 0.89). 6.2. Conclusion • Inhaling furosemide relieves dyspnea symptoms in people with stable COPD (GOLD C and D). This was assessed using COPD evaluation scales (Borg and CAT scales) and spirometric data (FVC, FVC%, FEV1/FVC, PEF, PEF%, and FEV25-75). • In individuals with stable COPD, there is much more bronchodilation after furosemide inhalation than after saline. • The order in which saline or furosemide is administered has no significant impact on how well patients are responding to therapy. The order in which the nebulizer is administered had no impact on the ipratropium-salbutamol combination since there was no statistically significant difference after performing the pairwise comparison between the first and second episodes. • The difference between baseline and furosemide was statistically significant for all lung metrics. The difference between treatment and baseline in saline was also statistically significant. • When furosemide is added to Combivent, the FVC% response is increased by 9.42% (3.26, 15.59), but when nebulized saline is added, the FVC% response is increased by 5.83% (0.06, 11.61) • Patients with CVD showed 10% decline in FVC% (-15.69, -5.44). With an increase in the pack-year smoking index (-0.19, -0.1), FVC% will fall to 0.16%. • The FEV1/FVC ratio increased by 3.32 with a 95% confidence interval of (0.06, 6.58) when nebulizer furosemide was used, but it did not reach statistical significance when nebulizer saline was utilized. • With a 95% confidence interval of 0.67 (0.46, 0.89), it has been shown that BMI raises the FEV1/FVC ratio by 0.67. SUMMARY, CONCLUSION AND RECOMMENDATIONS 6 0 6.3. Recommendations Based on the findings from this study, the following recommendations can be made: 1. Inhaled furosemide should be considered as an adjunct bronchodilator therapy for patients with stable COPD. Adding inhaled furosemide to standard COPD treatments like ipratropium-salbutamol leads to further improvements in lung function and symptoms. 2. Patients with COPD and comorbid cardiovascular diseases represent a high-risk group that may particularly benefit from inhaled furosemide. The diuretic and vagotonic effects appear to counteract adverse cardiopulmonary interactions, reducing fluid overload and exertional dyspnea. 3. Smoking cessation should continue to be strongly promoted for all active smokers with COPD in order to slow lung function decline. The dose-response relationship between pack-years smoked and worsening airflow indicates the pivotal importance of quitting smoking. 4. Longer duration studies are needed to better characterize the sustained effects of inhaled furosemide therapy in COPD. Lung function could be measured at four time points: baseline, after intervention, after washout period, and after control therapy. 5. As the mechanisms behind furosemide’s anti-dyspneic effects are still being elucidated, further studies are needed examining histologic, physiologic, and clinical impacts in COPD subpopulations. 6. Given the demonstrated improvements in exertional tolerance and capacity, future investigations |