Acetazolamide and furosemide for posthemorrhagic hydrocephalus of the newborn. Effect of early furosemide administration in neonates with respiratory distress syndrome. International randomised controlled trial of acetazolamide and furosemide in posthaemorrhagic ventricular dilatation in infancy. International PHVD Drug Trial Group. Prophylactic furosemide in severe respiratory distress syndrome: blinded prospective study. Diuresis and pulmonary function in premature infants with respiratory distress syndrome. Randomized controlled trial of very early continuous distending pressure in the management of preterm infants. A randomised, double blind, placebo controlled trial of the effect of theophylline in prevention of vasomotor nephropathy in very preterm neonates with respiratory distress syndrome. Furosemide in hyaline membrane disease. Postpartum preeclampsia management with furosemide: a randomized clinical trial.
The authors evaluated the efficacy of acetazolamide (ACZ) and furosemide (FUR) in avoiding ventricular shunting procedures in preterm infants with posthemorrhagic hydrocephalus (PHH) and increased intracranial pressure (ICP). Preterm infants were screened for PHH (defined as ventriculomegaly [VM] and increased ICP measured with the Ladd fiberoptic monitor). PHH infants were randomized to ACZ and FUR treatment or serial lumbar puncture (LP) and monitored until not receiving medications or having undergone shunting. Of 69 infants with IVH screened for the study, 39 never developed VM, 14 developed VM, without increased ICP, and 16 developed PHH. Ten PHH infants were randomized to ACZ and FUR treatment and six to serial LP. Nine (90%) of the 10 infants assigned to the ACZ and FUR group avoided shunting. Nephrocalcinosis developed in a significant proportion of treated infants. Three (50%) of the six LP group infants did not require shunting procedures (P = 0.118). The authors conclude that ACZ and FUR therapy is useful in the treatment of preterm infants with PHH. Because a significant number of infants treated with both ACZ and FUR developed nephrocalcinosis, close monitoring for increased calcium excretion in the urine, or use of ACZ without FUR, is advised. 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. Furosemide and acetazolamide are widely used in the treatment of posthaemorrhagic ventricular dilatation (PHVD) in the hope of avoiding the need for surgical management, but this approach has not been evaluated in a controlled trial. This multicentre randomised controlled trial tested the hypothesis that these drugs would reduce the rate of shunt placement and increase disability-free survival at 1 year of age.
                Between 1992 and 1996, 177 infants aged less than 3 months past term, and with ventricular width more than 4 mm above 97th centile after intraventricular haemorrhage, were randomly assigned standard therapy alone or standard therapy plus treatment with acetazolamide (100 mg/kg daily) and furosemide (1 mg/kg daily). A minimisation algorithm ensured balance between groups with respect to both referral centre and the presence of a cerebral parenchymal lesion on cerebral ultrasonography at enrolment. The trial was stopped in September, 1996, because the data showed a clear advantage with standard therapy.
                We report outcomes for 151 infants whose expected date of delivery was before the end of 1995, with complete information at 1 year for 129 infants. The median gestational age was 28 weeks, mean birthweight 1299 g, and mean postnatal age at enrolment 25 days. 44% had a parenchymal lesion at randomisation. Death or shunt placement occurred in 49 of 75 infants allocated drugs plus standard therapy, compared with 35 of 76 allocated to standard therapy alone. The relative risk was 1.42 (95% CI 1.06-1.90; p=0.026), which is equivalent to one extra death or shunt placement for every five infants allocated drug therapy. 84% (52/62) of infants assigned drug therapy had died or were disabled or impaired at 1 year, compared with 60% (40/67) of those assigned standard therapy (relative risk 1.40 [1.12-1.76]; p=0.012).
                These preliminary results suggest that the use of acetazolamide and furosemide in preterm infants with PHVD is associated with a higher rate of shunt placement and increased neurological morbidity, and so cannot be recommended. To further characterize the place for furosemide in the treatment of newborn infants with respiratory distress syndrome requiring mechanical ventilation, we conducted a blinded, prospective study comparing early prophylactic use (1 mg/kg every 12 hours for four doses beginning at 24 hours of age) with prn use of this drug. Prophylactic administration of furosemide produced no beneficial effect on any measure of pulmonary function compared with use of this drug as needed (prn). However, patients receiving the prophylactic furosemide regimen were found to have more rapid postnatal weight loss, higher pulse rate, and greater sympathomimetic drug requirement during the period of diuretic administration. Patients in the prophylactic group did not demonstrate the moderate expansion in plasma volume between 48 and 96 hours of age seen in the control group. These data suggest that the prophylactic regimen produced an undesirable degree of volume depletion. Further studies should be conducted to develop objective criteria for the selection of the subgroup of patients with respiratory distress syndrome who may benefit from furosemide. 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. Application of continuous distending pressure at birth (very early CDP) should stabilize the immature airways and reduce the severity of respiratory distress syndrome (RDS) in preterm infants. Eighty-two preterm infants of less than 32 weeks gestation were randomly assigned at birth to early treatment group (TG), in which CDP of 6 cm water pressure was applied at birth by the nasopharyngeal route (NP-CDP), or to control group (CG), in which CDP was applied when indicated for established criteria (pO2 less than 50 mmHg in FiO2 greater than 0.5). Characteristics of the infants in the two groups were comparable. No statistically significant difference between the two groups was found in the incidence of RDS. The course of RDS, and oxygen and ventilatory requirements also did not appear to be changed. In blood gas parameters of most of the time frames, no significant difference was found between the two groups when the results were analyzed according to the assigned group. When the results were analyzed separately for the infants who developed RDS, infants in TG appear to have fared worse from the therapy in terms of oxygenation, as indicated by significantly higher FiO2 (P less than 0.01) and lower a/A (P less than 0.01) values on the third day of the course of RDS, as compared to infants in CG. The incidence of complications was comparable in the two groups. Four infants from TG (9.3%) and one from CG (2.6%) died (P = NS). We conclude that VECDP by nasopharyngeal route does not reduce the incidence of RDS and does not appear to improve the outcome and may worsen the severity of RDS when compared to application of CDP for established criteria. Vasomotor nephropathy is a common renal dysfunction in very preterm neonates.
                To determine whether theophylline could prevent vasomotor nephropathy in very preterm infants with respiratory distress syndrome.
                A randomised, double blind, placebo controlled trial of 50 preterm infants of gestational age < or = 32 weeks needing assisted ventilation. Infants received an intravenous dose of theophylline (1 mg/kg) or placebo for three days. The 24 hour urine volume was measured daily. On days 2, 5, and 11, blood samples and 12 hour urine collections were analysed for electrolytes, creatinine, and urea.
                On day 1, urine output was significantly higher in the theophylline (2.4 (0.9) ml/kg/h) than the placebo (1.6 (1.0) ml/kg/h; p = 0.023) group (values are mean (SD)). The incidence of oligoanuria was significantly lower in the theophylline treated (5%) than the placebo (33%) group. Twenty four hours after the first administration of theophylline/placebo, serum creatinine concentration was significantly lower in the theophylline (0.76 (0.23) mg/dl) than the placebo (1.0 (0.41) mg/dl; p = 0.025) group. On day 5 an increase in serum creatinine was observed in both groups. On day 11 a significant reduction in serum creatinine was observed, compared with day 5, with no difference between the two groups.
                The results suggest that, in very preterm infants with respiratory distress syndrome, early theophylline administration improves renal function during the first two days of life. 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. This investigation was undertaken to estimate whether a brief postpartum course of furosemide for patients with preeclampsia benefits recovery and shortens hospitalization by enhancing diuresis, lessening severe hypertension, and reducing the need for antihypertensive therapy.
                Two hundred sixty-four patients with preeclampsia were enrolled. After spontaneous onset of postpartum diuresis and discontinuation of intravenous magnesium sulfate, patients were randomly assigned to receive either no therapy or 20 mg oral furosemide daily for 5 days with oral potassium supplementation. Patient outcomes were compared between treatment groups with regard to classification of hypertensive disease.
                Only postpartum patients with severe preeclampsia (n = 70) who received furosemide compared with controls had significantly lower systolic blood pressure by postpartum day 2 (142 +/- 13 mm Hg compared with 153 +/- 19 mm Hg, P < .004) and required less antihypertensive therapy during hospitalization (14% compared with 26%, P = .371) and at discharge (6% compared with 26%, P = .045). No benefit was shown for patients with mild preeclampsia (n = 169) or superimposed preeclampsia (n = 25). Neither length of hospitalization nor frequency of delayed postpartum complications was positively affected by the intervention.
                Brief postpartum furosemide therapy for patients with severe preeclampsia seems to enhance recovery by normalizing blood pressure more rapidly and reducing the need for antihypertensive therapy. Shortening of hospitalization and reduction of delayed postpartum complications were not benefitted.
There are no data to support routine administration of furosemide in preterm infants with RDS. Elective administration of furosemide to any patient with RDS should be carefully weighed against the risk of precipitating hypovolemia or developing a symptomatic patent ductus arteriosus. There are not enough data to support routine administration of low-dose theophylline in preterm infants with RDS.