Changes in body water compartments with diuretic therapy in infants with chronic lung disease. Pulmonary function and electrolyte balance following spironolactone treatment in preterm infants with chronic lung disease: a double-blind, placebo-controlled, randomized trial. Randomized trial of long-term diuretic therapy for infants with oxygen-dependent bronchopulmonary dysplasia. Randomized, double-blind, controlled trial of long-term diuretic therapy for bronchopulmonary dysplasia. Effect of spironolactone-hydrochlorothiazide on lung function in infants with chronic bronchopulmonary dysplasia. Effect of oral diuretics on pulmonary mechanics in infants with chronic bronchopulmonary dysplasia: results of a double-blind crossover sequential trial.
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. To study the effect of spironolactone on dietary electrolyte supplementation, pulmonary function, and electrolyte balance in premature infants with chronic lung disease.
                A double-blind, randomized, and placebo-controlled trial was designed to study two groups of low birth weight infants with chronic lung disease at Pennsylvania Hospital. The placebo group received chlorothiazide and a placebo, and the spironolactone group received chlorothiazide and spironolactone during the 2-week study period. A two-tailed t-test was used to determine equivalence between the two groups.
                Pulmonary compliance, resistance and tidal volume, serum sodium and potassium, and FIO2, were not statistically different between the two groups. The need for sodium and/or potassium chloride did not differ between the two groups, nor did the quantity of each salt.
                The addition of spironolactone did not reduce the requirement for supplemental electrolytes, nor did it improve pulmonary mechanics or electrolyte balance. 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. 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. To test the hypothesis that spironolactone-hydrochlorothiazide (Aldactazide) will improve urine output and lung function in infants with bronchopulmonary dysplasia, we studied 21 hospitalized, spontaneously breathing, oxygen-dependent infants with chronic bronchopulmonary dysplasia. Infants were randomly assigned to receive either a 1:1 mixture of spironolactone and hydrochlorothiazide orally (n = 12) (3 mg/kg/day of both compounds) or no treatment (n = 9) for 6 to 8 days each. Dynamic lung compliance, total pulmonary resistance, and hemoglobin oxygen saturation were measured on the first and last days of each study period. Fluid intake and urine output were measured each day. Although the treatment significantly increased urine output, neither lung mechanics nor oxygenation were improved by the drug. The magnitude of the diuresis achieved with spironolactone-hydrochlorothiazide treatment was comparable to the diuresis achieved in a previous study of furosemide treatment (J Pediatr 1986:109;1034-9). Statistical analysis indicated that a type II error was an unlikely explanation for our failure to detect a beneficial effect. In three patients, doubling the oral dose did not improve lung mechanics or oxygenation. We speculate that diuresis per se is not responsible for lung function improvement during treatment with other drugs with diuretic properties. 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.
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.