AMERICAN JOURNAL OF PERINATOLOGY/VOLUME 9, NUMBER 5/6
DEVELOPMENTAL ASPECTS OF PERCUTANEOUS CAFFEINE ABSORPTION IN PREMATURE INFANTS M. Amato, M.D., P. Hiippi, M. Isenschmid, and H. Schneider
Caffeine is widely used in the treatment of apnea in premature infants. A number of kinetic evaluations have been done on premature infants after oral or intravenous administration.1 Although drug absorption through the skin is usually considered a hazard, it may provide an alternative route for drug therapy, particularly in preterm infants less than 32 weeks' gestation.2 Caffeine has been chosen as a suitable drug for this study. It is widely used in the early weeks of life when the newborn infant's skin is not a complete barrier to the absorption of externally applied agents. In the early neonatal period, very immature infants have a poorly developed epidermidis, which is readily permeable to drugs.3 Considering these issues, we studied 56 preterm infants with idiopathic apnea to assess percutaneous absorption of caffeine at various gestational ages and birthweights.
PATIENTS AND METHODS The study comprised 56 preterm infants with idiopathic apnea admitted to the neonatal intensive care unit (NICU) between July 1988 and December 1989. The gestational age (GA) was assessed from maternal dates, using the criteria of Ballard et al,4 and was confirmed by examination of the anterior vascular capsule of the lens.5 It ranged from 26 to 34 weeks (mean, 29.3 ± 1.9 weeks) and birthweight from 680 to 1480 gm (mean, 1108 ± 260 gm). Informed parental consent was obtained for all patients. Caffeine was applied to the abdominal skin (2 cm in diameter) in the form of a gel (0.1 ml equals 15 gm caffeine), using standard doses of 7.5 to 10 mg of caffeine in a fat emulsion. Commercial preparations of caffeine gel are not available. However, the drug can be obtained from
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Caffeine is commonly used in the treatment of apnea of prematurity. The skin of preterm infants varies considerably in its level of maturity. To understand skin absorption in low birthweight infants (less than 1500 gm) with gestational age between 26 and 34 weeks, a group of 56 preterm babies was studied after percutaneous application of 7.5 mg twice daily of caffeine for babies with birthweight less than 1000 gm and 10 mg twice daily for babies with birthweight more than 1000 gm. The reported technique is a useful alternative method of drug administration in premature babies. This study indicates an inverse relationship between gestational age and skin absorption contributing to a better understanding of skin barrier function in the newborn.
many drug or chemical companies and can be easily prepared by suspending the caffeine in a fat emulsion. A standard dose of 7.5 to 10 mg twice a day was used for babies with idiopathic apnea after other treatable causes such as hypoxemia, electrolyte imbalance, hypocalcemia, hypomagnesemia, infection, hypoglycemia, anemia, polycythemia, patent ductus arteriosus, or gastroesophageal reflux were ruled out by appropriate diagnostic tests. Pharmacokinetic measurements were performed after 4 and 10 doses during the course of treatment. Serial heparinized blood samples were collected just prior to the next caffeine administration. The patients enrolled in the study did not receive either endotracheal (intermittent mandatory ventilation) or nasal continuous positive airway pressure. Caffeine serum levels were estimated performing high-pressure liquid chromatography. Caffeine levels were considered in a therapeutic range between 25 and 100 (xmol/liter. Multiple regression, multiple logistic regression, and simple linear regression, including statistical inference in regression and correlation, Mann-Whitney test, and nonpaired t test were used for statistical analysis of the data.
During the study period, 56 low birthweight (LBW) infants were treated at a mean postnatal age of 2.5 days. Caffeine serum levels were within therapeutic range at about 48 hours after the first dose was applied. Mean serum levels at this time (after four doses) were 49 jimol/ liter. At 120 hours (after ten doses), caffeine levels increased to 82.1 |xmol/liter. Infants with a birthweight less than 1000 gm were treated with an initial dose of 15 mg/
Division of Neonatology, Department of Obstetrics and Gynecology, University of Berne, Berne, Switzerland Reprint requests: Dr. Amato, Division of Neonatology, Children's Hospital, 5001 AARAU, Switzerland Copyright © 1992 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.
AMERICAN JOURNAL OF PERINATOLOGY/VOLUME 9, NUMBER 5/6 Sept/Nov 1992 Table 1. Strength of Relationship Between Caffeine Serum Levels and Gestational Age and Birthweight Are Estimated by the Coefficient of Multiple Correlation (r) r Caffeine Caffeine Caffeine Caffeine
level level level level
(4 doses) in ELBW infants 0.70