Pulmonary Effect of Inhaled Furosemide in Ventilated Infants With Severe Bronchopulmonary Dysplasia

Abstract

To the Editor. We read with interest the article by Kugelman et al in the January 1997 issue of Pediatrics entitled “Pulmonary effect of inhaled furosemide in ventilated infants with severe bronchopulmonary dysplasia.”1In the article the authors conclude that a single dose of 1 mg/kg inhaled furosemide does not improve the pulmonary mechanics in ventilator-dependent infants with bronchopulmonary dysplasia (BPD).When a drug is administered by nebulization, only a fraction of the dose administered reaches terminal bronchioles and alveoli. Because the exact mode and site of action of nebulized furosemide on lung mechanics is not known, it may be important for the drug to reach the distal part of the tracheobronchial tree for it to have any effect on pulmonary mechanics. Hence, the lack of pulmonary response in this study may be due to furosemide not reaching the distal bronchial tree.We have previously shown that 1 mg/kg body weight of furosemide administered by nebulization significantly improved pulmonary compliance and tidal volume compared with a single identical dose of furosemide administered intravenously.23 The pulmonary beneficial effects of furosemide were independent of its diuretic action. We nebulized furosemide with a side flow of 2 liters per minute. With a side flow of 5 to 6 liters per minute as used by the authors in this study, in infants who are on low ventilatory settings, it would take less than 2 minutes to nebulize 2 mL of furosemide solution. Therefore, it is possible that much of the drug has gone into the expiratory limb without reaching the lung. Administering the drug over a longer period with lower side flow may enhance the proportion of the drug reaching the distal airway.Also, the infants studied by Kugelman et al are comparatively older (mean age: 47 ± 6 days) than the infants studied by us (mean age: 27 ± 13 days). It is possible that the nebulized furosemide improves pulmonary mechanics when used well before the chronic lung disease of prematurity is fully established.In Reply. We appreciate the comments of Drs Prabhu and Dhanireddy, who reported recently on a positive response to inhaled furosemide in infants with bronchopulmonary dysplasia (BPD).1-1 They reported increased pulmonary compliance in 15 preterm infants after nebulized furosemide (1 mg/kg) as compared with intravenous furosemide; neither nebulized nor intravenous furosemide had any significant effect on airway resistance.1-1Furosemide, a loop diuretic, has been shown to improve pulmonary mechanics when administered parenterally to infants with BPD.1-21-3 Specific improvement in clinical status, airway resistance, and dynamic pulmonary compliance has been observed.1-21-3 Furthermore, Rastogi et al1-4 have shown in a preliminary study that inhaled furosemide improved respiratory compliance and resistance in preterm infants with BPD. Our preliminary study1-5 and a report of Raval et al,1-6 both randomized, double-blind, controlled studies, failed to show improvement in pulmonary mechanics in ventilated infants with severe BPD with a single dose of 1 mg/kg of inhaled furosemide. Negative results using aerosolized furosemide have also been reported in another double-blind study involving wheezing infants at 2 to 18 months of age.1-7 It is possible that the latter studies1-5-1-7 highlight the need for placebo-controlled studies of new therapies (ie, inhaled furosemide) when assessing efficacy in diseases with a high degree of variability such as BPD.The lack of response to inhaled furosemide in intubated infants could be attributed to technical and physiological factors as discussed in our article.1-5 We agree with Drs Prabhu and Dhanireddy that furosemide may not affect pulmonary mechanics because of poor delivery to the distal part of the tracheobronchial tree, and that the mode of delivery of presently available systems1-5-1-7 has to be improved or perhaps a higher dose should be used. Using a lower side flow as a method to improve delivery is a speculation that has to be studied further. However, attention should be given to keeping the same ventilator pressures and to the increased dead space at the time of furosemide delivery when it is prolonged.Our patients were older (mean age, 47 ± 6 days) compared with those in the report of Prabhu et al (27 ± 13 days), and had lower baseline respiratory compliance when compared with the report of Rastogi et al.1-4 Thus, different results could be explained by different severity of lung disease.In summary, further study is required to resolve whether there is a role for inhaled furosemide in the treatment of infants with BPD, and to define the dose, mode of delivery, and the target population.