Effect of oral diuretics on pulmonary mechanics in infants with chronic bronchopulmonary dysplasia: results of a double-blind crossover sequential trial. Randomized trial of long-term diuretic therapy for infants with oxygen-dependent bronchopulmonary dysplasia. Prevention of chronic lung disease in preterm infants by early postnatal dexamethasone therapy. Controlled trial of furosemide therapy in infants with chronic lung disease. Randomized, double-blind, controlled trial of long-term diuretic therapy for bronchopulmonary dysplasia. Changes in body water compartments with diuretic therapy in infants with chronic lung disease.
In a randomized double-blind crossover trial with sequential analysis, the effects of oral diuretics were compared with the effects of placebo on pulmonary mechanics in ten infants with bronchopulmonary dysplasia (BPD). Pulmonary mechanics were measured before and at the end of a week of treatment with oral diuretics (chlorothiazide, 20 mg/kg/dose and spironolactone, 1.5 mg/kg/dose) given twice daily, or placebo. Mean airway resistance decreased 35.3 cm H2O/L/s, mean specific airway conductance increased 0.095 1/L/s/cm H2O, and mean dynamic pulmonary compliance increased 1.74 mL/cm H2O during treatment with diuretics (all P less than .001), but not during treatment with placebo. The infants' rate of weight gain decreased on the first three days of diuretic treatment, but was thereafter comparable with weight gain during treatment with placebo. Fluid intake was similar in infants receiving diuretics and placebo. But, infants receiving diuretics not only had significantly increased urine output, osmolal clearance, and potassium and phosphorus excretion, but these infants also retained less fluid, and, in addition, excreted less calcium than infants receiving placebo. It is concluded that oral diuretics improve lung function in infants with chronic bronchopulmonary dysplasia; however, potassium and phosphorus depletion are potential complications of treatment. To determine whether long-term oral diuretic therapy would improve the pulmonary function of preterm infants with bronchopulmonary dysplasia.
                Randomized, double-blind, placebo-controlled study.
                Level III intensive care nursery.
                We randomly selected 43 stable patients with oxygen-dependent bronchopulmonary dysplasia to receive either orally administered spironolactone and chlorothiazide or placebo. These drugs were continued until the patients no longer required supplemental oxygen. Both groups received furosemide as needed.
                Each infant had pulmonary function tests at study entry, 4 weeks after study entry, 1 week and 8 weeks after being weaned to room air and off study drugs, and at 1 year of corrected age. Pulmonary function tests include dynamic pulmonary compliance, airway resistance, thoracic gas volume, and maximal expiratory flow at functional residual capacity; most of the infants had functional residual capacity measured. Between the first and second pulmonary function tests (while the infants were receiving diuretic or placebo), the infants in the diuretic group had a significant improvement in dynamic pulmonary compliance (46%; p < 0.001) and airway resistance (31%; p < 0.05); there were no changes in compliance or resistance in the placebo group. Although patients in both the diuretic and the placebo groups required progressively less supplemental oxygen, by 4 weeks after study entry the patients in the diuretic group needed less supplemental oxygen than did those in the placebo group (p < 0.01). There were no significant differences in results of serial pulmonary function tests in either group after discontinuation of diuretic therapy. Despite the significant differences in pulmonary function between the two groups, there was no significant difference between them in the total number of days that supplemental oxygen was required. Significantly more infantsin the placebo group received more than 10 doses of furosemide on an as-needed basis.
                Long-term diuretic therapy in stable infants with oxygen-dependent bronchopulmonary dysplasia, after extubation, improves their pulmonary function and decreases their fractional inspired oxygen requirement, but does not decrease the number of days that they require supplemental oxygen. The improvement in pulmonary function associated with diuretic therapy is not maintained after treatment is discontinued. Recent studies suggest that early dexamethasone therapy may lessen the pulmonary inflammation in preterm infants with respiratory distress syndrome (RDS). To investigate whether early (<12 hr) postnatal dexamethasone therapy would reduce the incidence of chronic lung disease (CLD), a randomized, double-blind, controlled trial was conducted in 40 infants (birth weights from 500 to 1,999 gm) who had severe RDS and required mechanical ventilation within 6 hr of birth. All infants received one dose of Survanta before they were randomly assigned to control (saline placebo) or dexamethasone-treated groups (0.5 mg/kg/d for 1 week, then tapered over 3 weeks). Sequential analysis was performed with the end point of assessment being the presence or absence of CLD on postnatal Day 28. Statistical significance favoring dexamethasone was reached when 12 consecutive pairs in which one infant had CLD and the other did not have CLD showed that ten pairs favored dexamethasone and two pairs favored control treatment. Among the survivors, 12/15 were extubated in the dexamethasone group and 9/16 in the control group at the end of study. Infants in the treated group had transient hyperglycemia and hypertension. There was no difference between the groups in mortality and in incidence of sepsis or intraventricular hemorrhage. We conclude that early postnatal dexamethasone therapy is potentially effective in the lessening of CLD in preterm infants. To substantiate our result, large randomized controlled trials are needed and warranted. To study the effects of furosemide therapy in infants with chronic lung disease (CLD), a double-blind controlled trial was designed. Seventeen infants with evidence of CLD (oxygen requirements greater than 30% at greater than 3 weeks of age and chest radiographic findings consistent with CLD) were studied. Pulmonary function was measured immediately before, and after 48 hours and 7 days of treatment with furosemide (1 mg/kg/12 hr intravenously or 2 mg/kg/12 hr orally) or placebo. Clinical status improved in six of seven infants who received furosemide and in two of 10 infants who received placebo (P less than 0.002). In the furosemide group, ventilator and oxygen requirements decreased (P less than 0.003); minute ventilation, alveolar ventilation, and dynamic compliance increased; and venous admixture decreased (P less than 0.05). There were no significant changes in the placebo group. Our findings suggest that furosemide significantly improves lung function during therapy in infants with CLD and allows earlier weaning from ventilatory support and supplemental oxygen. The effects of continuous therapy with hydrochlorothiazide and spironolactone on pulmonary function in 34 premature infants with severe bronchopulmonary dysplasia were assessed in a randomized double-blind controlled trial. Subjects were greater than or equal to 30 days old, were supported by mechanical ventilation in greater than or equal to 30% oxygen, and had radiographic evidence of bronchopulmonary dysplasia. The treatment group (n = 19) and the placebo group (n = 15) were similar in all respects except for distribution of gender. Anthropometrics, ventilatory measurements, and the results of pulmonary function tests were evaluated at study entry and at 1, 4, and 8 weeks into therapy. Poststudy chest radiographs were compared with those obtained before the study. The proportion of infants alive at discharge was significantly increased (84%) in the treatment group compared with the placebo group (47%) (p = 0.05). There were no statistically significant differences in total hospital days or in total ventilator days. Total respiratory system compliance at 4 weeks was higher in the treatment group (0.61 +/- 0.18) than in the placebo group (0.45 +/- 0.13) (p = 0.016). No difference in outcome was detected between male and female infants in the treatment group. These results suggest that long-term diuretic therapy improves outcome in infants with bronchopulmonary dysplasia. The effects of diuretic therapy on body water compartments were studied in preterm infants with chronic lung disease. Gestational age of the infants ranged from 24 to 28 weeks, while the median postnatal age at the time of study was 40 days. Infants were randomized to receive furosemide (1.0 mg/kg/day) alone (n = 5) or combined with metolazone (0.2 mg/kg/day, n = 7) for 4 consecutive days. Treatment in both groups produced a significant decrease (P < 0.05) in extracellular water (ECW) without changes in plasma volume, total body water or body weight. The decrease in ECW with furosemide (503 +/- 28 to 446 +/- 19 ml/kg initial body weight) was of similar magnitude to that seen with combined furosemide plus metolazone (522 +/- 30 to 454 +/- 15 ml/kg initial body weight). Water and electrolyte intakes were similar in both groups and unchanged over the course of the study. These findings suggest that in infants with chronic lung disease, diuretic therapy induces intercompartmental shifts in body water, ultimately decreasing interstitial water while preserving PV. Only combined treatment with furosemide plus metolazone produced a significant increase in urine output, confirming the increased efficacy of combination therapy in inducing diuresis.
In preterm infants > 3 weeks of age with CLD, acute and chronic administration of distal diuretics improve pulmonary mechanics. However, positive effects should be interpreted with caution as the numbers of patients studied are small in surprisingly few randomized controlled trials.