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• W2613180211 abstract "Original ArticlesTheophylline Therapy for Apnea of Prematurity in Saudi Preterm Infants: Therapeutic Serum Level and Dosage Khalid N. Haque, FRCP(Ed), FRCPI, DCH, DTM & H Mohammad Al-Kharashi, and MB, BS, DCH Chris WatersDPharm Khalid N. Haque From the Department of Pediatrics College of Medicine, King Saud University, Riyadh. Search for more papers by this author , Mohammad Al-Kharashi From the Department of Pediatrics College of Medicine, King Saud University, Riyadh. Search for more papers by this author , and Chris Waters From the Department of Pharmacy, College of Medicine, King Saud University, Riyadh. Search for more papers by this author Published Online::1 Mar 1989https://doi.org/10.5144/0256-4947.1989.178SectionsPDF ToolsAdd to favoritesDownload citationTrack citations ShareShare onFacebookTwitterLinked InRedditEmail AboutAbstractIn a controlled study, 150 Saudi preterm infants were treated with 1.5 mg/kg/day of theophylline for apnea of prematurity. In 96.8% of infants the apnea was either reduced by more than 50% or abolished completely. The effective therapeutic plasma level for these infants was 4.5 ±2.1 μg/mL. A loading dose was found to be unnecessary. Theophylline at these doses appears to be effective and safe treatment for apnea of prematurity in Saudi infants.IntroductionTheophylline, a methylxanthine derivative, is widely used in the treatment of apnea of prematurity.1,2 Although the pharmacokinetics of theophylline in preterm infants have been well studied,3,4 the dose-response relationship has not been clearly established. Serum theophylline concentrations between 6 and 15 μg/mL have been suggested as optimal maintenance levels1,5,6 for the treatment and prevention of apnea and bradycardia in preterm infants under 34 weeks of gestation. However, there is no general agreement,7 and levels as far apart as 1.3 and 17.7 μg/ mL have been found to abolish apnea in preterm infants.7This study on the use of theophylline in controlling apnea of prematurity set out to establish if a loading dose was necessary, and whether theophylline in a maintenance dose of 1.5 mg/kg/ day would be effective.PATIENTS AND METHODSOne hundred fifty infants with a gestational age of less than 34 weeks (assessed by maternal dates and Ballard scoring system8) were enrolled in the study. Apnea of prematurity was defined for this study as an absence of thoracic movement for more than 20 seconds or by a shorter arrest of respiration accompanied by bradycardia (heart rate less than 100 beats per minute)9 or by cyanosis. Standard criteria were used to exclude other causes of apnea. Also excluded from the study were infants with obstructive apnea. Heart rate and chest wall movements were monitored by continuous recordings of an impedance pneumograph. Infants who had apnea due to sepsis, metabolic causes, necrotizing entercolitis, intracranial hemorrhage, or sedative ingestion, and those gestationally past 34 weeks were excluded from the study.Infants matched for gestational age, sex, and weight were randomly allocated into two groups. Group A received 5 mg/kg of aminophylline (1.25 mg aminophylline equals 1 mg of theophylline) intravenously as a loading dose. Group B did not receive such a loading dose. Both groups were given regular maintenance therapy of 1.5 mg/kg/day every 8 hours. The maintenance dose was administered intravenously if the infant was not being fed orally; otherwise an equivalent amount of theophylline was given orally. Therapy was started when spells of apnea were prolonged and repeated (i.e., more than 2 to 3 spells per hour) or when the infants required frequent bag and mask ventilation to recover from apnea. The infants acted as their own controls, as it would be unethical to withhold treatment.Peak and trough levels were measured at 30 minutes and 360 minutes after the initial loading dose. Steady-state10 plasma levels were measured 30 minutes to 1 hour after the fifth dose. Theophylline levels were measured using high-pressure liquid chromatography,9 and duplicate tests were run on a fluorescence polarization analyzer.Serum caffeine levels were not measured, as it has been previously shown by Takieddine11 that “measurement of caffeine levels is superfluous in premature infants on theophylline therapy.” Therapeutic outcome was considered to be optimal when apneic attacks ceased altogether, satisfactory when apneic attacks were reduced by 50% or more, and failed if the improvement was less than satisfactory.RESULTSThe clinical data of the infants studied are shown in Table 1. Peak and trough serum theophylline levels obtained in the two groups are shown in Table 2.Table 1. Clinical data.Table 1. Clinical data.Table 2. Serum theophylline levels.Table 2. Serum theophylline levels.The mean steady state value was found in group A to be 7.56 μg/mL and 7.69 μg/mL in group B; the dose of 1.5 mg/kg/day given every 8 hours was enough to achieve an optimal to satisfactory response. The effective therapeutic plasma level to abolish apnea or to reduce its frequency by 50% or more was 4.5 ± 2.1 μg/mL.Response to therapy and the amount of time required for the therapeutic response to occur are shown in Table 3.Table 3. Therapeutic outcome.*Table 3. Therapeutic outcome.*DISCUSSIONDespite the increasing use of theophylline in the treatment of neonatal apnea,1,2,11-14 no clear recommendation has established an optimal therapeutic range, which is considered to be as wide as 1.3 to 17.7 μg/mL.1,3,7,14-18When theophylline is given for control of apnea in preterm infants, the maintenance dose is adjusted, based on serum drug levels, thereby ensuring optimal response and preventing toxic manifestations. Thus, it is important to establish a therapeutic range for a given population.Shannon et al1 and Stark,17 when measuring serum theophylline levels, have noted varying drug concentrations and response even when using the same dosage. This may be partly explained by the different rate of conversion of theophylline to caffeine in individual infants. The biotransformation of theophylline to caffeine in preterm infants includes N-methylation at N2 position, whereas the known pathway followed by theophylline in adults involves oxidative reactions such as N-demethylation (N1, N3) and C-8 oxidation18 and may be as high as 100%.16 Estimation of serum caffeine levels in preterm infants receiving theophylline for apnea has not been considered useful by some authors.11Studies on the efficacy of theophylline in preterm infants have reported a reduction of apneic episodes by 60% to 90%.17 Theophylline increases minute ventilation, decreases alveolar and arterial PCO2, shifts the CO2 response curve to the left, increases oxygen consumption,12,17 improves diaphragmatic contractility, and makes the diaphragm less susceptible to fatigue.21We are aware that the impedance pneumograph used to monitor apnea in this study (Hewlett-Packard neonatal monitor model 8000A) is not a research tool because of the high levels of false-positive and false-negative alarms. In our unit and in many other neonatal units, only such monitoring equipment is available. Since the same equipment was used for assessment of both groups of patients, no difference in the result is expected from this factor alone.Beneficial results were obtained while maintaining a therapeutic range of 4.5 ± 2.1 μg/mL using a dosage regimen of 1.5 mg/kg/day given at 8-hour intervals. It is possible that the infants who failed to improve satisfactorily may have done so had we given them a larger dose of theophylline with concomitant increase in the risk of toxicity.2,13,22Attaining serum levels of 4.5 ± 2.1 μg/mL while using a dosage schedule of 1.5 mg/kg/day would suggest that Saudi preterm infants eliminate theophylline remarkably slowly. Myers et al15 could only obtain serum levels between 2.8 and 3.9 μg/mL using theophylline at a dose of 2 mg/kg/ day in American infants. An alternative explanation could be the difference in the bioavailability of the preparations used (Neophylline, Eisai Co. Ltd., for intravenous therapy, and Choledyl syrup, Warner Lambert Ltd., for oral therapy).We found no advantage in giving the loading dose; in fact, two infants (2.6%) in group A showed signs of theophylline toxicity in the form of vomiting and abdominal distention. Our data demonstrate that a low dose of theophylline is an effective and safe treatment of apnea of prematurity in this population.CONCLUSIONWe conclude that theophylline in doses of 1.5 mg/kg/day is effective in the treatment of apnea of prematurity by appreciably reducing or completely averting apneic episodes in 98.6% of infants. This dose attains a serum theophylline level of 4.5 ±2.1 μg/mL in Saudi preterm infants. We would suggest further studies to establish the optimal therapeutic level and dosage schedule in different populations; in the meantime, we recommend using serum levels of 4.5 ± 2.1 μg/mL rather than the more customary 7 to 12 μg/mL.17ARTICLE REFERENCES:1. Shannon DC, Gotay F, Stein IM, et al.. Prevention of apnea and bradycardia in low-birthweight infants . Pediatrics. 1975; 55(5):589-94. Google Scholar2. Uauy R, Shapiro DL, Smith B, et al.. Treatment of severe apnea in prematures with orally administered theophylline . Pediatrics. 1975; 55(5):595-8. Google Scholar3. Aranda JV, Sitar DS, Parsons WD, et al.. Pharmacokinetic aspects of theophylline in premature newborns . N Engl J Med. 1976; 295(8):413-6. Google Scholar4. Giacoia G, Jusko WJ, Menke J, et al.. Theophylline pharmacokinetics in premature infant with apnea . J Pediatr. 1976; 89(5):829-32. Google Scholar5. Aranda JV, Gorman W, Bergsteinsson H, et al.. Efficacy of caffeine in treatment of apnea in low-birth-weight infant . J Pediatr. 1977; 90(3):467-72. Google Scholar6. Simons FE, Rigatto H, Simons KJ. Pharmacokinetics of theophylline in neonates . Semin Perinatol. 1981; 5(4):337-45. Google Scholar7. Boutroy MJ, Vert P, Royer RJ, et al.. Caffeine, a metabolite of theophylline during the treatment of apnea in the premature infant . J Pediatr. 1979; 94(6):996-8. Google Scholar8. Ballard JL. Scoring system: a simplified assessment of gestational age (abstract) . Paediatr Res. 1977; 11(4):374-5. Google Scholar9. Spitzer AR, Fox WW. Infant apnea . Pediatr Clin North Am. 1986; 33(3):561-8. Google Scholar10. Sitar DS, Piafsky KM, Rangno RE, et al.. Plasma theophylline concentrations measured by high-pressure liquid chromatography . Clin Chem. 1975; 21(12):1774-6. Google Scholar11. Takieddine F. Monitoring theophylline and caffeine levels in premature infants on theophylline treatment . Proceedings of the 8th Saudi medical meeting, Riyadh,. 1983:158. Google Scholar12. Kuzemko JA, Paala J. Apnoeic attacks in the newborn treated with aminophylline . Arch Dis Child. 1973; 48:404-6. Google Scholar13. Bednarek FJ, Roloff DW. Treatment of apnea of prematurity with aminophylline . Pediatrics. 1976; 58(3):335-9. Google Scholar14. Davi MJ, Sankaran K, Simons KJ, et al.. Physiologic changes induced by theophylline in the treatment of apnea in preterm infants . J Pediatr. 1978; 92(1):91-5. Google Scholar15. Myers TF, Milsap RL, Krauss AN, et al.. Low-dose theophylline therapy in idiopathic apnea of prematurity . J Pediatr. 1980; 96(1):99-103. Google Scholar16. Bada HS, Khanna NN, Somani SM, Tin AA. Intercon-version of theophylline and caffeine in newborn infants . J Pediatr. 1979; 94(6):993-5. Google Scholar17. Stark A. In: Cloherty J, Stark AR, eds. Manual of neonatal care. Toronto: Little Brown, 1983:190-4. Google Scholar18. Bory C, Baltassat P, Porthault M, et al.. Metabolism of theophylline to caffeine in premature newborn infants . J Pediatr. 1979; 94(6):988-93. Google Scholar19. Milsap RL, Krauss AN, Auld PAM. Efficacy of low-dose theophylline . Semin Perinatol. 1981; 5(4):321-5. Google Scholar20. Gerhardt T, McCarthy J, Bancalari E. Effect of aminophylline on respiratory center activity and metabolic rate in premature infants with idiopathic apnea . Pediatrics. 1979; 63(4):537-42. Google Scholar21. Aubier M, DeTroyer A, Sampson M, et al.. Aminophylline improves diaphragmatic contractility . N Engl J Med. 1981; 305(5):249-52. Google Scholar22. Aranda JV, Dupont C. Metabolic effect of theophylline in the premature neonate (letter) . J Pediatr. 1976; 89(5):833-4. Google Scholar Previous article Next article FiguresReferencesRelatedDetails Volume 9, Issue 2March 1989 Metrics History Accepted11 June 1988Published online1 March 1989 InformationCopyright © 1989, Annals of Saudi MedicinePDF download" @default.
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