Abstract
Apnea occurs commonly in preterm infants. Theophylline is used as prophylaxis and treatment. Apart from improving ventilatory function, theophylline may also have metabolic effects, including an effect on glucose metabolism and lipolysis. No data are available on the effect of theophylline on glucose production and lipolysis in preterm infants at start of medication. Ten preterm infants with gestational ages of ≤32 wk, postnatal ages of 16-84 h, and birth weights >900 g were recruited. Hepatic glucose production and lipolysis were measured by use of gas chromatography/mass spectrometry after constant rate infusion of [6,6-2H2]glucose and [2-13C]glycerol tracers. Plasma glucose levels increased after theophylline administration (mean ± SD, 4.0 ± 1.9 mmol/L before and 4.7 ± 2.1 mmol/L after start of therapy), whereas the rate of glucose production decreased (6.0 ± 2.5 mg · kg-1 · min-1 and 4.3 ± 1.9 mg · kg-1 · min-1, respectively). The plasma glycerol concentration did not show any change after theophylline administration (154 ± 257 µmol/L before and 217 ± 258 µmol/L after), and the same was true for the rate of glycerol production (5.9 ± 2.6 µmol·kg-1 · min-1 before and 6.7 ± 3.0 µmol · kg-1 · min-1 after). The fraction of glycerol converted into glucose did not change significantly, although the percentage of glucose derived from glycerol increased after theophylline administration. The results are in line with the lack of adverse metabolic effects at start of theophylline treatment in the preterm infant.
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Abbreviations
- CV :
-
coefficient of variation
- GPR :
-
hepatic glucose production rate
- R a :
-
appearance rate
References
Sinclair JC, Bracken MB ( eds) 1992 Effective Care of the Newborn Infant. Oxford University Press, Oxford
Andersson JM, Milner RDG, Strick SJ 1967 Effects of neonatal hypoglycemia on the nervous system: a pathological study. Neurol Neurosurg Psychiat 30: 295–310.
Siesjö BK 1988 Hypoglycemia, brain metabolism, and brain damage. Diabetes 4: 113–144.
Vannuci R 1978 Neurologic aspects of perinatal asphyxia. Pediatr Ann 7: 15–30.
Upton CJ, Milner AD 1992 Apnoea and bradycardia. In: Roberton NRC (ed) Textbook of Neonatology. Churchill-Livingstone, Edinburgh, 521–528.
Grassi V, Boschetti E, Tantucci C 1989 Round table on antiasthmatic drugs: beta-agonists and theophylline. Eur Respir J 2:( suppl): 551s–555s.
Kolbeck RC, Speir WA 1991 Theophylline, fatigue, and diaphragm contractility: cellular levels of 45Ca and cAMP. J Appl Physiol 70: 1933–1937.
Cathcart-Rake WF, Kyner JL, Azarnoff DL 1979 Metabolic responses to plasma concentration of theophylline. Clin Pharmacol Ther 26: 89–95.
Peters EJ, Klein S, Wolfe RR 1991 Effect of short-term fasting on the lipolytic response to theophylline. Am J Physiol 261:E500–E504.
Vonlanthen MG, McCarter RJ, Casto DT 1989 Metabolic effects of amino- phylline in rats. Am J Physiol 256:R1274–R1278.
Lupica CR, Jarvis MF, Berman RF 1991 Chronic theophylline treatment in vivo increases high affinity adenosine A1 receptor binding and sensitivity to exogenous adenosine in the in vitro hippocampal slice. Brain Res 542: 55–62.
Herlenius E, Lagercrantz H, Yamamoto Y 1997 Adenosine modulates inspiratory neurons and the respiratory pattern in the brainstem of neonatal rats. Pediatr Res 42: 46–53.
Wang LC, Man SF, Belcastro AN 1987 Metabolic and hormonal responses in theophylline-increased cold resistance in males. J Appl Physiol 63: 589–596.
Atuk NO, Blaydes MV, Westervelt FB, Wood JE 1967 Effects of aminophylline on urinary excretion of epinephrine and norepinephrine in man. Circulation 35: 745–753.
Kearney TE, Manoguerra AS, Curtis GP, Ziegler MG 1985 Theophylline toxicity and the beta-adrenergic system. Ann Intern Med 102: 766–769.
Srinivasan G, Pildes RS, Jaspan JB, Singh J, Shankar H, Yeh TF, Tiruvury A 1981 Metabolic effects of theophylline in preterm infants. J Pediatr 98: 815–817.
Bergstrand H 1980 Phosphodiesterase inhibition and theophylline. Eur J Respir Dis 109:( suppl): 37–44.
Fredholm BB 1985 On the mechanism of action of theophylline and caffeine. Acta Med Scand 217: 149–153.
Fjeld CR, Cole FS, Bier DM 1992 Energy expenditure, lipolysis, and glucose production in preterm infants treated with theophylline. Pediatr Res 32: 52–58.
Food and Drug Administration 1987 Guideline on Validation of Limulus Amebocyte Lysate Test As End Product Endotoxin Test for Human and Animal Parenteral Drugs, Biological Products, and Medical Devices. Food and Drug Administration, Washington, DC
Sunehag A, Ewald U, Larsson A, Gustafsson J 1993 Glucose production rate in extremely immature neonates (<28 wk) studied by use of deuterated glucose. Pediatr Res 33: 52–58.
Sunehag A, Ewald U, Gustafsson J 1996 Extremely preterm infants (<28 wk) are capable of gluconeogenesis from glycerol on their first day of life. pediatr Res 40: 553–557.
Kalhan SC, Bier DM, Savin SM, Adam PAJ 1980 Estimation of glucose turnover and 13C recycling in the human newborn by simultaneous [1-13C]glucose and [6:6-2H2]glucose tracers. J Clin Endocrinol Metab 50: 456–460.
Corssmit EP, Romijn JA, Endert E, Sauerwein HP 1994 Pentoxyfylline inhibits basal glucose productions in humans. J Appl Physiol 77: 2767–2772.
Zarlengo KM, Battaglia FC, Fennessey P, Hay WW 1986 Relationship between glucose utilization rate and glucose concentration in preterm infants. Biol Neonate 49: 181–189.
Bougnères PF, Castano C, Rocchiccioli F, Gia HP, Leluyer B, Ferre P 1989 Medium-chain fatty acids increase glucose production in normal and low birth weight newborns. Am J Physiol 256:E692–E697.
Farrag HM, Nawrath LM, Healey JE, Dorcus EJ, Rapoza RE, Oh W, Cowett RM 1997 Persistent glucose production and greater peripheral sensitivity to insulin in the neonate vs. the adult. Am J Physiol 272:E86–E93.
Bougnères PF, Karl IE, Hillman LS, Bier DM 1982 Lipid transport in the human newborn. Palmitate and glycerol turnover and the contribution of glycerol to neonatal hepatic glucose output. J Clin Invest 70: 262–270.
Patel D, Kalhan S 1992 Glycerol metabolism and triglyceride-fatty acid cycling in the human newborn: effect of maternal diabetes and intrauterine growth retardation. Pediatr Res 20: 52–58.
Sunehag A, Gustafsson J, Ewald U 1996 Glycerol carbon contributes to hepatic glucose production during the first eight hours in healthy, term infants. Acta Pediatr 85: 1339–1343.
Beylot M, Martin C, Beaufrere B, Riou JP, Mornex R 1987 Determination of steady-state and nonsteady-state glycerol kinetics in humans using deuterium-labeled tracer. J Lipid Res 28: 414–422.
Bortz MW, Paul P, Haff AC, Holmes WL 1972 Glycerol turnover and oxidation in man. J Clin Invest 51: 1537–1546.
Janson A, Rawet H, Perbeck L, Marcus C 1998 Presence of thyrotropin receptor in infant adipocytes. Pediatr Res 43: 1–4.
Acknowledgements
The authors thank Elisabeth Söderberg and the staff of the NICU, Uppsala University Childrens Hospital, for skillful assistance.
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Supported by grants from the Medical Research Council (project no. 11282), Gillberg's Foundation, Nordisk Insulinfond, and Novo Nordisk Pharma AB.
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Diderholm, B., Ewald, U. & Gustafsson, J. Effect of Theophylline on Glucose Production and Lipolysis in Preterm Infants (≤32 Weeks). Pediatr Res 45 (Suppl 5), 674–679 (1999). https://doi.org/10.1203/00006450-199905010-00011
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DOI: https://doi.org/10.1203/00006450-199905010-00011


