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Pulmonary Function and Electrolyte Balance Following Spironolactone Treatment in Preterm Infants with Chronic Lung Disease

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Pulmonary Function and Electrolyte Balance Following Spironolactone Treatment in Preterm Infants with Chronic Lung Disease Original Article ⅢⅢⅢⅢⅢⅢⅢⅢⅢⅢⅢⅢⅢⅢ Pulmonary Function and Electrolyte Balance Following Spironolactone Treatment in Preterm Infants With Chronic Lung Disease: A Double-Blind, Placebo-Controlled, Randomized Trial David J. Hoffman, MD born infants who receive intermittent positive pressure ventilation.1 Jeffrey S. Gerdes, MD Long-term diuretic therapy is an important component of the care Soraya Abbasi, MD received by premature infants with chronic lung disease.2 The combi- nation of oral chlorothiazide and spironolactone has been shown to OBJECTIVE: decrease mean airway resistance and increase airway conductance To study the effect of spironolactone on dietary electrolyte supplementa- and compliance in premature infants diagnosed with bronchopulmo- 3 tion, pulmonary function, and electrolyte balance in premature infants nary dysplasia. The use of Aldactazide (a 1:1 mixture of spironolac- with chronic lung disease. tone and hydrochlorothiazide), however, did not improve pulmonary mechanics or oxygenation despite the occurrence of a diuresis.4 Fur- STUDY DESIGN ther, potassium depletion is a known complication of diuretic admin- A double-blind, randomized, and placebo-controlled trial was designed to istration. A common medical practice among neonatologists is to add study two groups of low birth weight infants with chronic lung disease at spironolactone to the diuretic regimen to decrease the degree of hypo- Pennsylvania Hospital. The placebo group received chlorothiazide and a kalemia and hyperkaliuria.5 Despite the addition of this potassium- placebo, and the spironolactone group received chlorothiazide and spi- sparing diuretic, many neonates still require dietary supplementation ronolactone during the 2-week study period. A two-tailed t-test was used with potassium chloride and/or sodium chloride. However, the addi- to determine equivalence between the two groups. tive effect of spironolactone to thiazide therapy on pulmonary me- chanics and electrolyte balance has not been studied. Because the RESULTS distal convoluted tubule in the premature infant is less responsive to Pulmonary compliance, resistance and tidal volume, serum sodium and the effects of aldosterone than in older children,6 the administration potassium, and FIO , were not statistically different between the two 2 of spironolactone, the synthetic antagonist of aldosterone, may not groups. The need for sodium and/or potassium chloride did not differ have an important role in the maintenance of potassium balance or between the two groups, nor did the quantity of each salt. in the improvement of pulmonary mechanics in low birth weight CONCLUSION infants with chronic lung disease. The addition of spironolactone did not reduce the requirement for sup- This double-blind, placebo controlled randomized study was plemental electrolytes, nor did it improve pulmonary mechanics or elec- performed to determine whether the addition of spironolactone to a trolyte balance. chlorothiazide regimen would decrease the need for electrolyte sup- Journal of Perinatology 2000; 1:41–45. plementation. The secondary aim was to determine whether spirono- lactone improved pulmonary mechanics and electrolyte balance in premature infants with chronic lung disease. Chronic lung disease may develop in premature infants who re- quire mechanical ventilation and prolonged high concentrations METHODS of inspired oxygen for the management of respiratory distress Study Population syndrome. This disease affects from 5% to 20% of premature new- This study was approved by the Research Review Committee of Penn- Department of Neonatology (D. J. H.), Reading Hospital Medical Center, West Reading, PA; sylvania Hospital. A total of 33 infants with a postconceptional age of and Section on Newborn Pediatrics (J. S. G., S. A.), Pennsylvania Hospital, and Department 26–36 weeks were enrolled. An equal number of infants with an age of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA. of Յ32 weeks and Ͼ32 weeks, respectively, were randomized to each Address correspondence and reprint requests to Jeffrey S. Gerdes, MD, University of Pennsyl- vania School of Medicine, 800 Spruce Street, Philadelphia, PA 19107. group. Informed consent was obtained from one or both parents by one of the principal investigators after the nature of the study was This work was funded by the Newborn Pediatrics Research Fund. D. J. H. was supported in part by a training grant from the National Institutes of Health (HL-07027). explained. The eligibility criteria were: the presence of chronic lung Presented in part at the annual meeting of The Society for Pediatric Research, Washington, disease (defined by oxygen dependency beyond 28 days of life coexis- DC, May 1997. tent with characteristic radiographic abnormalities), the establish- Journal of Perinatology 2000; 1:41–45 © 2000 Nature America Inc. All rights reserved. 0743–8346/00 $15 www.nature.com/jp 41 Hoffman et al. Efficacy of Spironolactone Treatment in Preterm Infants ment of enteral feeding, and the decision by the attending physician Table 1 Baseline Characteristics of Subjects in the Chlorothiazide- to prescribe oral diuretics. Infants were excluded from the study if at the Spironolactone and Placebo Groups time of enrollment they were receiving the early portion of a course of CTZ ϩ SP group CTZ ϩ placebo group p dexamethasone (0.1 to 0.5 mg/kg per day), hyperalimentation, intrave- (n ϭ 17) (n ϭ 16) nous fluids, or furosemide, or if renal anomalies were known. Birth weight (gm) 838 Ϯ 204 859 Ϯ 160 NS Study Protocol Study weight (gm) 1357 Ϯ 370 1438 Ϯ 323 0.04 A total of 33 infants were enrolled in the study and randomized to a Gestational age (weeks) 26.1 Ϯ 1.4 26.2 Ϯ 1.7 NS spironolactone or a placebo group. Infants in the spironolactone Postconceptional age at 32.8 Ϯ 3.5 32.7 Ϯ 1.7 NS study entry (weeks) group (n ϭ 17) received the combination of chlorothiazide (20 Apgar score at 5 minutes* 7 7 NS mg/kg per dose orally twice a day) and spironolactone (1.5 mg/kg per dose orally twice a day). Infants in the placebo group (n ϭ 16) re- CTZ, chlorothiazide; SP, spironolactone; NS, not significant. Ϯ ceived the same dose of chlorothiazide and a placebo. To mask the *Values are mean SD or median. identities of either spironolactone or placebo, the order was written for “chlorothiazide” and “study medication,” respectively. The placebo and spironolactone doses were prepared in identical unit aliquots with For infants on continuous positive airway pressure, the nasal prongs equal volumes and colors of the solution. Only the pharmacists were were temporarily removed, and a face mask was applied. Simulta- aware of the randomization schedule. neous signals of airflow, tidal volume, and transpulmonary pressure Pulmonary function testing, serum electrolyte determinations were relayed to a custom-designed software program for data analysis obtained from heel stick capillary samples, fluid intake and output, and graphic display. Airflow was measured by a pneumotachometer oxygen saturations, and the need for and the quantity of dietary so- (Fleish model 00, OEM Medical, Richmond, VA) attached to a face dium chloride (NaCl) or potassium chloride (KCl) supplementation mask or endotracheal tube. Esophageal pressure was measured with a were monitored at the following intervals: day 0 (baseline) and day 14 polyvinyl balloon (Mallinckrodt, Argyle, NY) measuring 0.40 mm in length and 7.5 mm in width containing 0.2 ml of air, placed in of the 2-week study period. NaCl supplementation was prescribed for the distal esophagus. Transpulmonary pressure was measured by a serum concentrations of sodium of Ͻ130 mEq/liter. KCl was given Celesco differential pressure transducer (model P7, Celesco Trans- for potassium or chloride serum concentrations of Ͻ3.5 mEq/liter ducer Products, Canoga, NY). Simultaneous records of airflow volume and 95 mEq/liter, respectively. Baseline studies were performed at 3 to and transpulmonary pressure were sampled and recorded at a rate of 5 days after the last dose of furosemide to allow for adequate renal 75 Hz per channel. Any breaths with artifact in flow or pressure sig- clearance,7 given the plasma half-life of 24 hours.8 At the baseline nals, difference in inspiratory and expiratory tidal volume, or a tidal point of the study, four infants in the spironolactone group and two volume of Ͻ0.5 ml were excluded. Values for lung mechanics were infants in the placebo group were intubated and required mechanical calculated from 25 to 45 breaths by least mean squares analysis. ventilation. Continuous positive airway pressure delivered through nasal prongs was required by three infants in the spironolactone Statistical Analysis group and one infant in the placebo group. At the 14-day endpoint, The primary aim of this study was to determine whether there was a mechanical ventilation was required by one infant in the spironolac- difference in the need for dietary electrolyte supplementation between tone group and two infants in the placebo group, nasal continuous the two groups. A power analysis, performed during the design of the positive airway pressure was administered to two infants in the spi- study, was based on the expected requirement for KCl supplementa- ronolactone group, but was not given to any infants in the placebo tion for infants who received the combination of chlorothiazide and group. All of the infants received methyl xanthine therapy during the spironolactone (spironolactone group) and those that received chlo- study. A total of 12 infants in each group received a low, tapering dose rothiazide and placebo (placebo group). The two treatments would of dexamethasone during the study period. Total fluid intake with have been considered to be equivalent with regard to the need for commercial infant formula (Similac Special Care, Ross Laboratories, potassium supplementation if the difference between the two Columbus, OH) or breast milk was similar in both groups. Two in- groups was not Ͼ25%. A minimum of 15 infants in each group fants in the spironolactone group were fed Pregestimil (Mead-John- was required to test this hypothesis with 80% power and a signifi- son, Evanston, IL).
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