Addition of metolazone to overcome tolerance to furosemide in infants with bronchopulmonary dysplasia.

A decreased response to the loop diuretic furosemide develops within a few doses in young infants. We tested the hypothesis that the use of the thiazide-like diuretic metolazone, in combination with furosemide, would inhibit water and electrolyte reabsorption and overcome pharmacologic tolerance to furosemide alone. Infants with bronchopulmonary dysplasia of similar gestational and postnatal ages were randomly assigned to one of three groups. Group 1 (n = 6) received furosemide (1 mg/kg per dose) intravenously every 24 hours for a total of five doses. Group 2 (n = 8) received the same treatment as group 1, but in addition metolazone (0.2 mg/kg per dose) was given enterally with doses 3 and 4 of furosemide. Group 3 (n = 8) received metolazone (0.2 mg/kg per dose) enterally every 24 hours for five doses. Urine was collected before the first diuretic dose and throughout the study for determination of the urine flow rate; urinary excretion of sodium, chloride, and potassium; and creatinine clearance. Urinary flow rate and urinary sodium and chloride excretion increased after the first dose in all groups. In the infants treated with either furosemide or metolazone, urinary flow rate and urinary and chloride excretion returned to baseline values after the last three doses. In contrast, when furosemide was administered with metolazone, urinary flow rate and urinary excretion of sodium, chloride, and potassium were greater than the values for baseline and for the previous dose, as well as for the corresponding doses of furosemide in group 1 and metolazone in group 3. Tolerance to furosemide (group 1) and metolazone (group 3) appeared to be explained by compensatory increased sodium and chloride reabsorption without changes in creatinine clearance. We conclude that the administration of metolazone with furosemide enhances diuresis, natriuresis, and chloruresis and overcomes the rapid development of tolerance to furosemide in infants with bronchopulmonary dysplasia by blocking the compensatory increase in renal sodium and chloride absorption.     

Gluconate calcium therapy and neonatal hypercalciuria

Nephrolithiasis was present in a 2-month-old premature infant with bronchopulmonary dysplasia who had been receiving furosemide and intravenous (IV) gluconate calcium therapy. This infant was found to be hypercalciuric. Furosemide therapy is known to increase calcium excretion. In the present study, we examined sick infants who were receiving gluconate calcium without furosemide to evaluate the effect of gluconate calcium therapy on urinary calcium excretion. The sick infants receiving gluconate calcium had higher values of urinary calcium than did the well infants taking regular formula feedings. Moreover, the calciuria appeared to increase progressively with continued gluconate calcium therapy. It appears that prolonged use of either furosemide or IV gluconate calcium leads to hypercalciuria, which, in turn, may predispose the premature infant to nephrolithiasis.     

Acute Oliguria in Preterm Infants with Hyaline Membrane Disease:

ABSTRACT. Ten premature infants with hyaline membrane disease and with acute oliguria were treated with furosemide or furosemide and dopamine. Furosemide alone did not increase diuresis. Furosemide when combined with dopamine, however, caused significant increases in urine output, sodium excretion, fractional sodium excretion and creatinine clearance. These data suggest that the increase in the sodium excretion was due not only to a reduction in the tubular sodium reabsorption but also to an increase in the glomerular filtration rate. Since in premature neonates the creatinine clearance is not a very precise index of the glomerular filtration rate, the extent of contribution of the increase in the glomerular filtration rate to the enhanced sodium excretion cannot be determined. Despite the increase in the sodium excretion, the serum sodium concentration did not fall significantly. We conclude that the combined treatment with dopamine and furosemide is useful for treating furosemide-resistant, severe functional renal failure in preterm infants with hyaline membrane disease.     

Acute oliguria in preterm infants with hyaline membrane disease: interaction of dopamine and furosemide

Ten premature infants with hyaline membrane disease and with acute oliguria were treated with furosemide or furosemide and dopamine. Furosemide alone did not increase diuresis. Furosemide when combined with dopamine, however, caused significant increases in urine output, sodium excretion, fractional sodium excretion and creatinine clearance. These data suggest that the increase in the sodium excretion was due not only to a reduction in the tubular sodium reabsorption but also to an increase in the glomerular filtration rate. Since in premature neonates the creatinine clearance is not a very precise index of the glomerular filtration rate, the extent of contribution of the increase in the glomerular filtration rate to the enhanced sodium excretion cannot be determined. Despite the increase in the sodium excretion, the serum sodium concentration did not fall significantly. We conclude that the combined treatment with dopamine and furosemide is useful for treating furosemide-resistant, severe functional renal failure in preterm infants with hyaline membrane disease.     

Non-furosemide-related renal calcifications in premature infants with bronchopulmonary dysplasia

Renal calcification is a known complication of long-term furosemide therapy in infants with bronchopulmonary dysplasia (BPD). In a prospective study the clinical course and long-term renal sequelae of renal calcifications of 19 consecutive premature neonates (birthweight < 1250 g) with bronchopulmonary dysplasia who did not receive furosemide were examined. Infants were divided into two different groups on the basis of ultrasound evidence of renal calcifications (RC group) or absence of renal calcifications (NRC group). Serial examinations, performed at the age of 1, 2, 3, 6, 9 and 12 months, showed that 12 infants at the mean age of 68.5 ± 12.8 days of life had renal calcifications (63%), and 3 of them had nephrolithiasis; 8 had bilateral renal calcifications. Among the 9 survivors, 2 had chronic renal calcifications at the age of 9 months; however, all normalized at the age of 12 months. Twelve infants received hydrochlorothiazide and spironolactone (63%), 17 had prolonged courses of xanthines and dexamethasone (89.5%), while furosemide was not part of the routine pharmacological administration. Statistical analysis showed that birthweight, gestational age, Apgar score and length of parenteral nutrition were comparable in the RC and NRC group infants. Mean serum creatinine, creatinine clearance, fractional sodium excretion and urinary calcium excretion values during the 12-month study period were comparable in the RC and NRC groups. Mechanical ventilation and hospital stay length were instead associated with renal calcification occurrence. The strongest indicator of renal calcification risk for this high-risk population is the severity of the unresolved acute lung disease, where different facets of respiratory management, other than the addition of furosemide, represent sufficient stimuli and renal injury to potentiate stone formation.     

Furosemide pharmacokinetics in very low birth weight infants

The pharmacokinetics of furosemide were studied longitudinally during long-term administration in 10 very low birth weight infants with bronchopulmonary dysplasia. Mean birth weight of the infants was 829 +/- 217 g, mean gestational age at birth was 26.6 +/- 2.9 weeks, and mean postnatal age at the start of therapy was 2.4 +/- 1.0 weeks. Serial determinations of furosemide pharmacokinetic parameters were performed during 2 weeks to 3 months of long-term therapy. Plasma half-life was prolonged in infants less than 31 weeks postconceptional age (gestational + postnatal age), frequently exceeding 24 hours. All infants less than 29 weeks postconceptional age whose dosing schedule was once every 12 hours accumulated furosemide to potentially ototoxic levels. Furosemide renal clearance increased and plasma half-life decreased in association with increasing postconceptional age. Furosemide secretory clearance was very low in patients less than 31 weeks postconceptional age, resulting in a reliance on glomerular filtration to deliver drug to its main site of action within the lumen of the loop of Henle. Thus elevated plasma levels may be required to ensure adequate luminal delivery and adequate diuresis in these infants with low secretory clearance. Nevertheless, the current dosing schedule (once every 12 hours) of furosemide should be modified to once every 24 hours in infants of low postconceptional age to avoid possible toxic effects.     

The pharmacologic effects of furosemide therapy in the low-birth-weight infant.

The pharmacologic effects of furosemide were studied in six infants (mean gestation 30.7 weeks; mean birth weight 1,490 gm) at ages 10 to 57 days. Furosemide (for clinical indication, standardized at 1 mg/kg) was given intravenously over one minute; data were collected over the ensuing 24 hours. For three hours following furosemide administration, a significant diuresis was observed. Sodium excretion, percent fractional sodium excretion, and potassium excretion were significantly increased and urinary pH significantly decreased for six hours following the administration of furosemide. Creatinine and free water clearances were slightly elevated, although not significantly. Furosemide is an effective diuretic, the onset of pharmacologic action was within one hour, the peak action was sustained for three hours, and the duration of action was six hours. The net fluid, sodium, and potassium losses following a 1 mg/kg single dose were 28 ml, and 3.6 and 0.3 mEq/kg, respectively.     

Early furosemide therapy in premature infants (less than or equal to 2000 gm) with respiratory distress syndrome: a randomized controlled trial

Pulmonary edema has been demonstrated in the early stages of respiratory distress syndrome in premature infants. To evaluate whether early furosemide therapy (0 to 8 hours after birth) would affect the electrolyte balance, pulmonary status, and outcome, 57 infants (less than or equal to 2000 gm) with respiratory distress syndrome who required mechanical ventilation shortly after birth were randomized into two groups: 29 given furosemide (1 mg/kg/day intravenously for three doses) and 27 control. The clinical, biochemical, and laboratory characteristics of the groups were comparable before entry into the study. Administration of furosemide significantly enhanced the urinary excretion of Na and Cl at 0 to 24, 24 to 48 and 48 to 72 hours and of Ca at 24 to 48 and 48 to 72 hours after drug administration. There was no significant difference between the groups in urinary excretion of K and in serum Na, Cl, K, and Ca values. A spontaneous increase in urine output occurred in the control group at 48 to 72 hours after the initiation of the study (mean +/- SD 7.0 +/- 3.5 hours postnatal age), along with a decrease in mean airway pressure for mechanical ventilation. The use of furosemide (7.3 +/- 3.5 hours postnatal age) enhanced urine output at 24 to 48 and 48 to 72 hours after medication, resulting in further decrease in mean airway pressure and facilitating extubation. There was, however, no significant difference between the groups with respect to incidence of patent ductus arteriosus, morbidity from bronchopulmonary dysplasia, and mortality.     

Hyperkalemia in very low birth weight infants.

PURPOSE: To assess the frequency and pathogenesis of hyperkalemia in the very low birth weight infant. METHODS: Infants who weighed less than 1000 gm at birth were prospectively entered into the study within 12 hours of birth. Potential risk factors for hyperkalemia were assessed. Body weight, fluid and electrolyte balance, serum levels of sodium and potassium, creatinine clearance, fractional sodium excretion, and urine sodium/potassium ratio were measured every 8 hours for 72 hours. Measurements of plasma renin, serum aldosterone, and plasma atrial natriuretic factor were made at study entry and repeated when hyperkalemia (serum potassium greater than 6.5 mmol/L) occurred or at 72 hours. Infants in whom hyperkalemia developed were compared with those in whom it did not. RESULTS: Thirty-one infants completed the study; hyperkalemia developed in 16 (51.6%). The only difference in the occurrence of perinatal complications was the more frequent occurrence of pH less than 7.20 in infants with subsequent development of hyperkalemia. Creatinine clearance, urine output, and potassium excretion were significantly lower in the hyperkalemia group during the first 24 hours. Serum potassium concentration at 24 hours was inversely related to urine output in the prior 24 hours. Fractional sodium excretion, urine sodium/potassium ratio, and levels of renin, aldosterone, and atrial natriuretic factor did not differ between groups. CONCLUSIONS: Hyperkalemia is a frequent complication in very low birth weight infants. Infants with low urinary flow rates during the first few hours after birth are at greatest risk for the development of hyperkalemia.     

Mineral excretion in premature infants receiving various diuretic therapies

The association of various diuretic therapies with the renal handling of minerals, important factors in the development of nephrocalcinosis and osteopenia, was studied in low birth weight infants. Twenty-four-hour urine specimens (n = 65) were collected from 30 patients who were treated with (1) furosemide with or without spironolactone and hydrochlorothiazide (2) spironolactone with hydrochlorothiazide, (3) spironolactone alone, or (4) no diuretic (control; i.e., after diuretic). Hypercalciuria (urinary calcium greater than or equal to 0.15 mmol/kg/day) was observed in all but the control group. Covariate analysis demonstrated a significant effect of sodium, calcium, and vitamin D intakes (p less than 0.01) and sodium excretion (p less than 0.05) on urinary calcium excretion. Treatment with any of these diuretics in neonates may be associated with abnormal renal losses of calcium, sodium, chloride, and potassium. From a nutritional perspective, neonates requiring long-term diuretic therapy thereby require special consideration, including monitoring of mineral excretion and renal ultrasonography.     

Surfactant phospholipids and surface activity among preterm infants with respiratory distress syndrome who develop bronchopulmonary dysplasia

Our objective was to determine if preterm infants with respiratory distress syndrome who develop bronchopulmonary dysplasia have abnormalities in surfactant phospholipids and/or function. Tracheal aspirate samples obtained from preterm infants with respiratory distress syndrome on days 1, 3-5, 7-10, 14-17, 21-24 and 27-30 were analyzed for total phospholipids and phospholipids fractions by determination of total phospholipid phosphorus and thin layer chromatography, respectively. Surfactant properties were assessed with captive bubble surfactometer. Sixteen out of 56 (29%) infants died during the first 30 d of life. Infants who died were more immature, required more ventilatory support and had a surfactant with lower surface-tension-reducing properties than infants who survived (p < 0.05). Surviving infants were divided into group I (no bronchopulmonary dysplasia at 27-30 d, n = 25) and group II (with bronchopulmonary dysplasia at 27-30 d, n = 15). No significant differences in concentrations of surfactant phospholipids nor measurements of surface tension were noted among groups of infants. Surfactant therapy after birth was associated with a significant increase in concentrations of total phospholipids, lecithin, phosphatidylinositol and lower surface-tension measurements at 3-5 d of age among surviving infants (p < 0.01). Abnormalities in concentrations of surfactant phospholipids or surfactant function could not be demonstrated during the first month of life among preterm infants with respiratory distress syndrome who develop bronchopulmonary dysplasia.     

Angiotensin und Saluretika beim Diabetes insipidus renalis im frühen Säuglingsalter

Summary Renal regulation is studied in a 7 weeks old infant with nephrogenic diabetes insipidus using Angiotensin II and saluretics.Infusion of synthetic Angiotensin II produces marked antidiuresis and mild antinatriuresis. At the same time there is a decrease in urine excretion, Inulin- and PAH-clearances caused by vasoconstriction and reduced renal blood flow. There is only a minimal fall in sodium clearance which makes doubtful and increased sodium reabsorption.Sulfonamide saluretics such as Furosemide, Hydrochlorothiazide and Chlorthalidone temporarily increase sodium excretion several times. For a brief period serum sodium concentration and body temperatures are normal. Additional treatment with Spirolactone prolongs this interval. Hypernatremia however only is subsided by consequent restriction of sodium intake. The sodium requirement is remarkably low in this infant.Sodium and chloride concentrations in the sweat were increased, before treatment was started returning to normal under saluretic treatment. When therapy is interrupted they again rise.     

Growth and development of preterm infants with respiratory distress syndrome and bronchopulmonary dysplasia

This study examines the growth and development of 37 preterm infants, 20 with respiratory distress syndrome and 17 with bronchopulmonary dysplasia. The groups were balanced by sex, parity, family configuration, and socioeconomic status and were studied at either 12 or 18 months after hospital discharge. Findings indicate that infants with bronchopulmonary dysplasia are at greater risk for growth retardation in their second year than infants with respiratory distress syndrome. Furthermore, results from cognitive, sensorimotor, and language measures (the Bayley, Uzgiris-Hunt, and Receptive-Expressive Emergent Language scales) demonstrate that infants with bronchopulmonary dysplasia perform significantly less well than infants with respiratory distress syndrome. The group performance of the infants with respiratory distress syndrome suggests that their developmental scores are comparable to those of average, healthy full-term infants of the same age. In contrast, the group of infants with bronchopulmonary dysplasia performed in the low-average to delayed range. Moreover, regression analyses show that type of respiratory illness explains more of the variance in cognitive outcomes than such neonatal factors as birth weight or gestational age. Thus, this study demonstrates that infants with bronchopulmonary dysplasia are at high risk for developmental problems in their second year, and that the contribution of bronchopulmonary dysplasia to explanations of differential cognitive outcomes cannot be reduced to between-group differences in perinatal status.     

Furosemide in preterm infants treated with indomethacin for patent ductus arteriosus

Objective: To evaluate the effect of furosemide on renal function and water balance in preterm infants treated with indomethacin (3 × 0.2 mg/kg at 12-h intervals) for symptomatic patent ductus arteriosus.
Patients and Methods: We performed a retrospective multi-centre double cohort study in preterm infants <32 weeks of gestational age. Thirty-two infants treated with furosemide (1 mg/kg i.v.) before each indomethacin dose (furosemide group) were matched with 32 infants with indomethacin treatment alone (control-group). Renal effects (urine output, weight gain, serum creatinine, sodium concentration) were registered.
Results: The study groups were comparable for gestational age, birth weight and day of therapy. Pretreatment differences were observed for urine output, weight and serum sodium. However, no differences were noticed in day-to-day urine output change or weight gain between the groups. A significant increase in serum creatinine concentration (50% vs. control, 18%; p < 0.05) and a concomitant significant decrease in serum sodium (–9 vs. control, –3 mmoL/L; p < 0.05) in the furosemide group was observed 72–96 h after starting therapy.
Conclusion: Furosemide before each indomethacin dose resulted in a significant increase in serum creatinine and hyponatremia, without increasing urine output.     

Control of water balance in infants with bronchopulmonary dysplasia: role of endogenous vasopressin

Babies with chronic bronchopulmonary dysplasia (BPD) can sometimes develop pallor, systemic and pulmonary edema, oliguria, and hyponatremia not attributable to cardiopulmonary or renal impairment. These signs and symptoms might, however, be explained by inappropriate control of vasopressin secretion. To test this hypothesis, we measured plasma vasopressin and osmolality, serum sodium and potassium concentrations, urine output and osmolality, and free water clearance in 26 normoxic infants with BPD aged 1-4 months. All of these infants required supplemental oxygen (FiO2 0.41 +/- 0.03, mean +/- 1 SE) to maintain O2 saturation of greater than 88%, and six infants also required mechanical ventilation. As controls, 10 infants of similar age but without BPD were also studied. None of the infants had been discharged from the nursery and was receiving any medications, and all were clinically stable when studied. Compared to control infants, infants with BPD had significantly elevated plasma vasopressin concentrations (control 5.2 +/- 0.9 pg/ml; BPD 42.4 +/- 5.1; mean +/- SE, p less than 0.05). Moreover, infants with BPD had hyponatremia and hypotonic plasma, and both urine output and free water clearance were significantly reduced. These data suggest that some infants with chronic BPD have elevated vasopressin levels that are functionally significant. We speculate that excessive stimulation of vasopressin secretion may explain some of the pulmonary and nonpulmonary signs and symptoms in infants with chronic BPD.     

Renal follow up of premature infants with and without perinatal indomethacin exposure

AIMS: To evaluate early childhood renal growth, structure, and function in children born at less than 33 weeks gestation and to investigate possible independent effects of perinatal indomethacin exposure. METHODS: A total of 66 children born at less than 33 weeks gestation, 31 of them with perinatal indomethacin exposure (study group) and 35 without (control group), were examined at 2-4 years of age. Serum cystatin C and protein; plasma creatinine, sodium, and potassium; urine protein, calcium:creatinine ratios, and alpha(1) microglobulin; and glomerular filtration rate (GFR) were determined. Renal sonography examinations were performed. RESULTS: The mean serum cystatin C concentrations were slightly higher in the control group than in the study group. Mean values of serum protein, and plasma creatinine and sodium did not differ between the groups, neither did median plasma potassium concentrations and urine protein:creatinine and calcium:creatinine ratios. None had tubular proteinuria. Abnormal GFR (<89 ml/min/1.73 m(2)) was found in one case in each group and renal structural abnormalities in five in each group. In logistic regression analysis the duration of umbilical artery catheter (UAC) use and furosemide treatment emerged as the significant independent risk factors for renal structural abnormalities. Furosemide treatment and assisted ventilation remained the risk factors associated with renal abnormalities in general-that is, functional and/or structural abnormal findings. CONCLUSION: Perinatal indomethacin does not seem to affect long term renal growth, structure, or function in children born at less than 33 weeks gestation. Duration of UAC use, furosemide treatment, and assisted ventilation may be correlated with later renal structural and functional abnormalities.     

Is chloride depletion an important contributing cause of death in infants with bronchopulmonary dysplasia?

A retrospective analysis of infants with bronchopulmonary dysplasia requiring prolonged hospitalization (greater than 100 days) was carried out to determine those factors associated with fatal outcome. Twenty-three infants made up the study population. Eleven infants died and 12 survived (survivors). No differences were noted between the groups regarding ventilator requirement, radiographic changes, and medication use (digoxin, aldactazide), except for furosemide which was used twice as frequently in the group of infants who died v the group of infants who survived (P less than .001). Differences noted between the groups included moderate hypochloremia (chloride less than 80 mEq/L) in all 11 infants who died v six of 12 survivors, severe hypochloremia (chloride less than 70 mEq/L) in the nine of 11 infants who died v two of 12 survivors, metabolic alkalosis (pH greater than 7.45) in nine of 11 infants who died v three of 12 survivors, hypertension (systolic BP greater than 113 mm Hg) in eight of 11 infants who died v one of 12 survivors, decrease in head growth in ten of the 11 infants who died v one of the 12 survivors; these differences were all significant (P less than .001). The metabolic alkalosis and head growth changes appear to be related to the hypochloremia. The data suggest that chloride deficiency may be an important contributing factor in the genesis of poor outcome in infants with bronchopulmonary dysplasia and that close attention to chloride supplementation might influence outcome.     

Furosemide effect on mineral status of parenterally nourished premature neonates with chronic lung disease

In this study, the effect of prolonged furosemide administration on calcium and phosphorus homeostasis was examined in 16 parenterally nourished very low birth weight infants with chronic lung disease. Patients received one of three different dosages of phosphorus: low, 0.91 +/- 0.06 mmol/kg per day; moderate, 1.24 +/- 0.02 mmol/kg per day; and high, 1.64 +/- 0.06 mmol/kg per day. All furosemide-treated patients had high levels of urinary calcium (12.1 +/- 2.2 mg/kg per day), phosphate (19.1 +/- 2.7 mg/kg per day), and cyclic 3'5'-adenosine monophosphate (76.8 +/- 6.7 nmol/kg per day) excretion, independent of their phosphorus intake. Parathyroid hormone concentrations were high in furosemide-treated patients (0.95 +/- 0.15 ng/mL) compared with patients not treated with furosemide and receiving either moderate (0.49 +/- 0.05 ng/mL) or low (0.42 +/- 0.07 ng/mL) phosphorus intakes. Furosemide administration may lead to secondary hyperparathyroidism.     

Effect of oral diuretics on pulmonary mechanics in infants with chronic bronchopulmonary dysplasia: results of a double-blind crossover sequential trial

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.     

Alternating sequential dosing with furosemide and ethacrynic acid in drug tolerance in the newborn

Drug tolerance seems to develop rapidly after the administration of sequential doses of the same loop diuretic. We evaluated whether alternating different loop diuretics could achieve the same initial diuretic response in the newborn. In a randomized double crossover study, we examined the diuretic and saliuretic effects of alternating doses of furosemide and ethacrynic acid (1 mg/kg administered intravenously every 24 hours) in 10 newborns, who received the drugs in the following sequential order: (1) furosemide, (2) ethacrynic acid, and (3) furosemide (group 1, n = 5); and (1) ethacrynic acid (2) furosemide, and (3) ethacrynic acid (group 2, n = 5). Hourly urine specimens were collected for the determination of rates of urinary and fractional excretion of sodium, chloride, and potassium and of urinary flow, before and 6 hours after dosing. There were no differences between the groups at each dose for all parameters measured. A significant decrease in prediuretic and postdiuretic rates of urinary flow, in sodium and chloride excretion, and in the fractional excretion of these electrolytes was observed before and after dosing. The associated reduction in patients' weights suggested a depletion in plasma volume. In conclusion, consecutive alternation of furosemide and ethacrynic acid in the same newborn does not prevent the development of pharmacologic tolerance to loop diuretics, since diuresis, natriuresis, and chloriuresis decrease after successive sequential administration of these drugs.