Energy Expenditure, Lipolysis, and Glucose Production in Preterm Infants Treated with Theophylline
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003 1-3998/92/3206-0693$03.00/0 PEDIATRIC RESEARCH Val. 32, No. 6, 1992 Copyright 0 1992 International Pediatric Research Foundation, Inc. Printed in U.S.A. Energy Expenditure, Lipolysis, and Glucose Production in Preterm Infants Treated with Theophylline CARLA R. FJELD, F. SESSIONS COLE, AND DENNIS M. BIER Washington Univc~vsitySchool of Medicine, Department of Pediatrics, St. Louis, Missouri 63110 ABSTRACT. Theophylline is administered to preterm in- Theophylline is a xanthine derivative bronchodilator admin- fants with pulmonary disease to improve pulmonary func- istered in neonatal intensive care units to the majority of pre- tion and reduce apneic episodes. Because it potentially mature infants with apnea and/or respiratory disease. Its phar- mediates both a- and B-receptor-effector mechanisms, we macologic effects include relaxation of the bronchial smooth tested the hypothesis that it increases lipolysis, gluconeo- muscle (I), stimulation of the hypoxic ventilatory drive, in- genesis from glycerol, and energy expenditure in 16 pre- creased minute ventilation, increased diaphragmatic contractility term infants, eight of whom were treated therapeutically (2), decreased end-tidal Pcoz (I), and a reduced requirement for with theophylline for apnea of prematurity (T) and eight mechanical ventilation. It has several metabolic effects that could of whom were controls (C). Mean f SD postnatal ages potentially mediate fuel kinetics, energy storage, and growth in were 4.8 f 1.9 wk (T) and 2.4 f 0.9 wk (C) (p < 0.01). preterm infants, including stimulating thermogenesis (3), increas- Corrected gestational ages were 35 f 1.6 wk (T) and 34 f ing plasma glucose concentration (4), and augmenting lipolysis 0.5 wk (C) (p = NS). Body weights were 1.69 f 0.13 kg (5) with concomitant increases in circulating FFA concentrations (T) and 1.70 f 0.23 kg (C) (p = NS). All infants were and in FFA oxidation (3, 5-8). clinically stable, breathing room air, fed enterally, and In vitro, theophylline inhibits cAMP phosphodiesterase and receiving no diuretics, steroids, or antibiotics. Lipolysis, increases intracellular cAMP and fuel mobilization (9). This hepatic glucose production, and gluconeogenesis from glyc- mechanism, however, requires 300 pM theophylline (9,which erol were measured using [2-'3c]glycerol and [6,6-3H2] is three to ten times concentrations maintained clinically. Fur- glucose tracers. Body water and energy expenditure were thermore, therapeutic doses of theophylline increased diaph- measured by the 2H2's0method. Body water volumes were ragmatic contractility without increasing intracellular concentra- 68.5 f 3.4% body weight (T) and 70.2 f 3.4% (C) (p = tions of cAMP in rats (2). NS), suggesting fat was 10-13% of body weight in both Therapeutic doses (5-6 pg/mL, approximately 30 pM) increase groups. Mean daily energy expenditure was 65 f 22 kcall plasma norepinephrine (3) and/or epinephrine (7). Toxic doses kg body weightld (T) versus 59 f 5 kcallkg body weightld to canines produced hypokalemia, hypophosphatemia, hyper- (C) @ = NS). Between 4 and 6 h after a feeding, glucose glycemia, and increased concentrations of epinephrine and nor- production rates were 40.5 2 4.3 pmol/kg/min (T) and 37.6 epinephrine (10, 11). These observations and the fact that the f 4.8 pmol/kg/min (C) (p = NS). Plasma glycerol appear- effects in canines were prevented or reversed by propranolol(l0, ance rate, an index of lipolysis, was nearly equivalent in 12) imply mediation by P-adrenergic receptor-effector mecha- both groups, averaging 9.6 f 2 pmol/kg/min (T) and 9.3 f nisms. 2.4 pmol/kg/min (C). Glycerol accounted for 10 f 2% (T) Theophylline also is an adenosine receptor antagonist. Peters and 10 f 4% (C) of new glucose carbon (p = NS). We et al. (5) recently reported that theophylline (30 pM) increased conclude that energy expenditure, body composition, lipol- lipolysis during fasting. These effects occurred without concom- ysis, glucose produ%ion,and gluconeogenesis from giycerol itant increases in circulating catecholamine concentrations, are not altered in areterm infants with aDnea of ~rematuritv plasma glucose, insulin, or growth hormone. treated therapeutically with theophyGine, and therefore In preterm infants, theophylline increased energy expenditure speculate that theophylline treatment is not a major deter- without altering respiratory exchange ratios (13), suggesting that rent of weight gain in premature infants with lung disease. the increased rate of energy expenditure was unaccompanied by The data suggest further that lipid mobilization may al- alterations in the ratios of substrates oxidized to meet increased ready be stimulated maximally 4 to 6 h after the last fuel requirements. However, it is also known that lipolysis can feeding in preterm infants studied 1 mo after birth. (Pediatr increase without detectable alterations in fuel oxidation ratios Res 32: 693-698,1992) (14). Alterations in the kinetics of fuel mobilization secondary to therapeutic doses of theophylline have not been measured in preterm infants, but may be of potential physiologic and clinical Abbreviations importance because the preterm infant's fat and energy reserves GCMS, gas chromatography/mass spectrometry are less developed than those of term infants and are more difficult to achieve and maintain. Mechanisms that regulate fatty acid transport are intact in newborn term infants (15). Thus, increases in lipolytic rates by theophylline could generate in- creased fuel supplies for oxidation. Because similar data are Received May 4, 1992; accepted August 3, 1992. lacking for the preterm infant, we tested the hypothesis that rates Correspondence: Carla R. Fjeld, PH.D.. Washington University School of Med- of lipolysis, hepatic glucose production, gluconeogenesis (from icine, Department of Pediatrics, 660 S. Euclid Ave., Box 8127, St. Louis, MO glycerol), and energy expenditure are increased secondary to 631 10. Supported in part by NIH Grants RR0538928, RR00954, RR06021, and HD- treatment with theophylline for apnea of prematurity in preterm 20805, and by Ross Laboratories and Mead Johnson. infants at 2 to 7 wk of postnatal life. 69 3 694 FJELD ET AL. MATERIALS AND METHODS laboratory according to federal guidelines. In preparation for the tracer infusions in the infants, a needle was inserted into a Subjects. Sixteen appropriate for gestational age preterm in- peripheral vein 2 h after a feeding, and 1 h before the start of the fants were recruited from the neonatal intensive care unit and infusion, except in one theophylline-treated infant, discussed assigned to either the theophylline treatment group or to the below. The i.v. line was kept patent by infusing normal saline at control group according to whether or not they were medicated 5 mL/h. Heparin was not used for this purpose. Sixty rnin after with theophylline for apnea of prematurity, which was the only inserting the needle, the heel was warmed for a minimum of 5 entry criterion distinguishing the two groups. Control infants min and a baseline blood sample of 0.5 to 0.6 mL was obtained were free of apnea during the study. Decisions to prescribe by heel stick for determination of theophylline concentration, theophylline for symptoms of apnea were made independently glucose concentration, and the natural abundance of I3C in from the study by a nonparticipating physician. Apnea was glucose and glycerol. The isotopes were infused continuously by defined as cessation of breathing for 215 to 20 s, detected by means of a calibrated Harvard syringe pump (Harvard Apparatus chest plethysmography and bradycardia (<lo0 beatslmin). Co., Inc., So. Natick, MA) starting 175 + 27 min after the Known causes of apnea apart from prematurity had been ruled previous feeding (range, 170-200 min) for 180 min. In one out. Theophylline was administered as an oral solution, 80 mg/ theophylline-treated infant, the i.v. line was inserted at the com- 15 mL (Roxane Laboratories, Inc., Columbus, OH) at doses of pletion of a feeding, and the infusion was started at 85 rnin from 2 to 4 mg/kg every 8 h with feedings throughout the study. Doses the previous feeding. In all infants, the average rate of glycerol per kg body weight were maintained during the study. At entry, infusion was 0.32 + 0.02 pmol/kg/min, and the glucose was all infants had an estimated gestational age by Dubowitz score infused at an average rate of 0.22 k 0.01 pmol/kg/min. Exact of 27 to 32 wk, were between 1.5 and 2 kg in body weight, were infusion rates for each infant were determined from the fed enterally 2100 kcal/kg/d, were clinically stable, breathing calibrated pump rates and the measured isotope concentrations room air, without evidence of infection, and were not receiving in the infusate material. Blood samples (0.3-0.4 mL each) were steroid or diuretic medications. Infants were kept either in servo- drawn at 20-min intervals beginning 60 rnin after the start of the controlled isolettes set to a skin temperature of 36.2 to 36.5"C or isotopic infusions; the serum was separated and frozen at -80°C. in open-air cribs. Infants in open-air cribs had stable body The total amount of blood drawn did not exceed 5% of the temperatures for at least 48 h before the study. All infants were estimated blood volume (85 mL/kg). Infants remained in their fed every 3 to 4 h with Similac (Ross Laboratories, Columbus, isolettes, usually asleep. Infants were not fed during the infusion OH) or Enfamil Preterm Formula 20 or 24 (Mead-Johnson, study; blood sugar levels were monitored periodically at the Evansville, IN) and had been gaining weight consistently for at bedside to confirm normoglycemia. [1,1,2,3,3-2H5]glycerol least 3 d before the study (range, 8-25 g/kg/d).