Controlled trial of furosemide therapy in infants with chronic lung disease. Randomized trial of long-term diuretic therapy for infants with oxygen-dependent bronchopulmonary dysplasia. Diuresis and pulmonary function in premature infants with respiratory distress syndrome. Furosemide in hyaline membrane disease. Pulmonary effect of inhaled furosemide in ventilated infants with severe bronchopulmonary dysplasia. Effect of early furosemide administration in neonates with respiratory distress syndrome. Changes in body water compartments with diuretic therapy in infants with chronic lung disease. Double-blind, placebo-controlled trial of alternate-day furosemide therapy in infants with chronic bronchopulmonary dysplasia. Protocol-guided diuretic management: comparison of furosemide by continuous infusion and intermittent bolus.
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. 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. A prospective study of 99 premature infants with severe respiratory distress syndrome who were randomly assigned to receive diuretic treatment with either furosemide or chlorothiazide was analyzed to examine the relationship of diuretic administration and diuresis to survival and to the duration and degree of mechanical ventilatory support. Subjects were given a diuretic, usually beginning on the second or third day of life, if they had not initiated the expected spontaneous diuresis and did not show pulmonary improvement. Infants given furosemide experienced a postnatal weight loss nearly identical to that in infants who were deemed not to need a diuretic; infants given chlorothiazide lost weight more slowly and had significantly greater body weight on postnatal days 4 and 5. Four factors were independently correlated with improved survival: furosemide usage, high birth weight, low initial mean airway pressure, and the absence of intraventricular hemorrhage. Ventilator mean airway pressure on the seventh day of life and duration of mechanical ventilation were both related to diuresis. These data provide additional evidence for the importance of water homeostasis in determining the course of respiratory distress syndrome in premature infants and indicate that furosemide administration is beneficial when spontaneous diuresis does not occur. Furosemide may be particularly effective if combined with early closure of the ductus arteriosus. In a randomized clinical trial designed to evaluate the effect of diuresis on infants with hyaline membrane disease, seven infants were treated with furosemide (2 mg/kg intravenously) and five received 5% dextrose water in 0.225% sodium chloride (control group). Arterial blood gas analyses performed before and during the six hours after treatment showed no significant difference between control and treated infants. Urine output and urine sodium and calcium loss were significantly increased (P less than .05) in the infants receiving furosemide. The diuresis seemed to have no effect on left atrial size determined echocardiographically, whereas measurements of dynamic skinfold thickness suggested mobilization of subcutaneous water. One infant became seriously dehydrated and hypotensive secondary to a massive diuresis. We concluded that furosemide had a potent diuretic effect in infants with hyaline membrane disease but does not improve cardiorespiratory function acutely. This may be because of failure to mobilize pulmonary interstitial fluid in the time period tested. It may also be possible that the presence of pulmonary interstitial fluid does not play an important role in the impairment of gas exchange in the acute stage of hyaline membrane disease. When administered parenterally, furosemide, a loop diuretic, results in improved lung compliance and decreased airway resistance in infants with bronchopulmonary dysplasia (BPD). However, furosemide-induced diuresis results in hypokalemia, chloride deficiency, hypercalciuria, nephrocalcinosis, and rickets. In patients with asthma, inhaled furosemide has recently been demonstrated to inhibit the bronchoconstrictive effects of exercise, cold air hyperventilation, and antigen challenge. We hypothesized that inhaled furosemide will result in improved pulmonary mechanics in ventilated infants with BPD and will prevent the systemic complications of parenteral furosemide.
                To determine the efficacy and safety of a single dose of inhaled furosemide on pulmonary mechanics in infants with severe BPD who are ventilator dependent at 21 days of age.
                A randomized, double-blind, crossover study was performed on 9 infants with BPD, each serving as his own control. Each patient was randomized to receive an aerosol dose of furosemide (1 mg/kg in 2 mL of saline) or placebo (2 mL of saline) on the first day of the study and the other agent the following day of the study. Pulmonary mechanics were measured before and 1 and 2 hours after the inhalation using the Pulmonary Evaluation and Diagnostics System.
                Gestational age (mean +/- SEM) was 29 +/- 1 weeks; birth weight was 1.1 +/- 0.1 kg; age at study was 47 +/- 6 days; and weight at study was 1.8 +/- 0.2 kg. There was no significant change in the pulmonary function measurements before treatment and 1 or 2 hours after treatment with either placebo or furosemide. Baseline and 2-hour values were: dynamic compliance (mL/ cm H2O per kilogram): 0.46 +/- .03 to 0.50 +/- .03 (placebo) and 0.50 +/- 0.02 to 0.51 +/- 0.02 (furosemide); dynamic resistance (cm H2O/L per second): 118 +/- 9 to 106 +/- 7 (placebo) and 111 +/- 8 to 105 +/- 7 (furosemide); and tidal volume (mL/kg): 8.6 +/- 0.5 to 8.9 +/- 0.5 (placebo) and 8.9 +/- 0.2 to 9.4 +/- 0.3 (furosemide).
                We conclude that, under the conditions of our study, a single dose of 1 mg/kg inhaled furosemide does not improve the pulmonary mechanics in ventilator-dependent infants with severe BPD. The effect of early furosemide-induced diuresis was prospectively evaluated in 39 neonates less than 24 hr of age with clinical respiratory distress syndrome (RDS) who received either four doses of furosemide (1 mg/kg) or no diuretic. Measurements of FiO2 alveolar-arterial oxygen gradient (P[A-a]O2), peak inspiratory pressure (PIP), and urine output as a fraction of intake (O/I) were averaged for every 8 hr. The furosemide group overall showed a significant decrease (P less than 0.01) in FiO2, P[A-a]O2, and PIP with an earlier (32 hr vs 52 hr) and more pronounced diuresis (35% greater O/I) when compared to the controls. This effect was accentuated in the subgroup with 1,000-1,500 g birth weight (significantly lower FiO2 and P(A-a)O2 from 16 to 48 hours), while no increase in urine output was observed for the infants weighing less than 1,000 g. A significant reduction in supplemental oxygen and need for ventilatory support at 96 hr of age was observed in the furosemide-treated, less than 1,500-g infants. The incidence of patent ductus arteriosus was not increased following furosemide therapy, and no significant difference in echocardiographic parameters was observed in 21 infants from both groups, who were followed daily during the first week of life. This study suggests that early furosemide-induced diuresis, particularly in infants weighing 1,000-1,500 g at birth, promotes improvement in pulmonary functions in RDS and leads to faster reduction in oxygen and ventilatory support. 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 test the hypothesis that alternate-day administration of furosemide will result in a sustained improvement in pulmonary function without causing alterations in electrolyte or mineral homeostasis, we conducted a randomized, double-blind, placebo-controlled study of 11 hospitalized, oxygen-dependent, spontaneously breathing infants with chronic bronchopulmonary dysplasia. Infants were randomly selected to receive either furosemide, 4 mg/kg in two divided doses on alternate days orally, or placebo for 8 days, followed by crossover to the alternate-therapy for an additional 8-day period. The two study periods were separated by a 48-hour washout period. Dynamic compliance, total pulmonary resistance, the concentration of electrolytes in serum, and the concentrations of calcium and creatinine in urine were measured on nontreatment days. Alternate-day furosemide therapy increased dynamic lung compliance by 76 +/- 112% and decreased total pulmonary resistance by 20 +/- 39%, compared with placebo (both variables p = 0.032). Alternate-day furosemide therapy did not result in increased urine output, electrolyte abnormalities, or increased urinary calcium excretion. We conclude that this simplified treatment regimen may be useful in the management of infants with chronic bronchopulmonary dysplasia. The results support our previous speculation that furosemide improves pulmonary function by mechanisms unrelated to its diuretic properties. To evaluate the safety and relative effectiveness of two diuretic protocols in the intensive care unit (ICU).
                Prospective, randomized comparative study.
                Thirty-three cardiac and medical ICU patients with pulmonary edema or fluid overload for which aggressive diuresis was intended.
                Enrolled patients were randomized to fluid management strategies combining fluid restriction and individually adjusted diuretic therapy by either continuous or bolus infusions of furosemide, titrated to achieve negative hourly fluid balance.
                Cumulative intake minus output (primary endpoint); change in serum creatinine, and length of ICU and hospital stay (secondary endpoints). Diuresis by either protocol was feasible, safe, and effective. The main outcome measures were not significantly different for either group managed with a standardized protocol.
                Protocol-guided diuretic management, with individualized titration of dosage to defined physiologic endpoints can be readily and safely implemented in the ICU. Both continuous and bolus diuretic regimens appear equally effective in achieving negative fluid balance. Larger studies with a randomized control arm are needed before these protocols can be recommended as routine practice.
In view of the lack of data from randomized trials concerning effects on important clinical outcomes, routine or sustained use of systemic loop diuretics in infants with (or developing) CLD cannot be recommended based on current evidence.
Randomized trials are needed to assess the effects of furosemide administration on survival, duration of ventilatory support and oxygen administration, length of hospital stay, potential complications and long-term outcome.