In this trial, infants were randomized to placebo or caffeine citrate at a loading dose of 20 mg per kg, followed by a maintenance dose of 5 mg.kg −1 per 24 hours, which could be increased to 10 mg.kg −1 per 24 hours for persistent apnea.
Caffeine half life pre teens trial#
The safety and efficacy of the standard dose regimen of caffeine was rigorously evaluated in the Caffeine for Apnea of Prematurity (CAP) trial 17. Although these studies demonstrated the beneficial effects of standard dose caffeine on apnea, there was concern based on pre-clinical studies of potential adverse neurocognitive effects of methylxanthines 16 and prior trials had not adequately assessed the long-term safety of caffeine.ī. Rigorous Evaluation of The Short- and Long-Term Safety and Efficacy of Standard-Dose Caffeine On the FDA drug label, the following dose of caffeine citrate was recommended: a loading dose of 20 mg per kg of caffeine citrate followed by a 5 mg per kg caffeine maintenance dose every 24 hours 14 with a similar approval by the European Medicines Agency 15. This study was used for US Food and Drug Administration (FDA) approval of caffeine for the labeled indication of short-term treatment of apnea of prematurity in infants between 28 and <33 weeks’ gestational age. Caffeine levels ranged from 4.5 to 16.5 mg per L, consistent with the target range of 5 to 20 mg per L suggested by Aranda et al. Of note, many infants in this trial were transferred to open-label caffeine use and 50% reduction in apnea in 69% of infants, compared to 43% of infants receiving placebo (P=0.02), with apnea eliminated in 24% of infants receiving caffeine compared to no infants receiving placebo. In this trial, 85 infants who were 28 to 32 weeks’ post-menstrual age and at least 24 hours old were randomized to caffeine or placebo for up to 10 days. 5 (20 mg per kg loading followed by 5 mg.kg −1 per 24 hours). In 2000, a double-blind randomized trial of caffeine citrate was performed in the US 13 using the dosing regimen initially recommended by Aranda et al. A study from 1991 of 15 preterm infants, provided additional support for a single daily maintenance dosing regimen, highlighting the long caffeine half-life 12. The first trial enrolled 50 spontaneous breathing infants 180 beats per min) in the 2.5 mg per kg caffeine citrate study arm, compared to the 5 mg per kg arm. In subsequent trials around this time, two different dosing strategies were used that evaluated a maintenance caffeine citrate dose of 2.5 mg.kg −1 per 24 hours as well as 10 mg.kg −1 per 24 hours. 6, 7 The standard dose regimen was also used in trials in 19 showing caffeine citrate had similar efficacy in reducing apnea frequency as theophylline 8, 9. This standard dose regimen was used in additional small trials of 18 and 23 preterm infants in 19, respectively, that also demonstrated the efficacy of caffeine in reducing apnea.
For this review, we refer to this as the “standard dose” regimen for caffeine. Based on the goal range of plasma concentrations of 5 to 20 mg per L, the investigators recommended the use of a caffeine citrate loading dose of 20 mg per kg followed by a maintenance dose of 5 mg.kg −1 per 24 hours. provided additional data on the pharmacokinetic profile of caffeine citrate using doses of 5 to 20 mg per kg in a dose finding study that highlighted the accumulation of caffeine 5. This target plasma concentration was based on similar plasma concentrations of theophylline being effective for bronchodilation to reverse airway obstruction in adults with asthma and toxicity observed at plasma concentrations above 20 mg per L 4. The authors noted their goal was to maintain a plasma concentration in the range of 5 to 20 mg per L. Based on this data, the dosing for subsequent infants in the study was changed to a 20 mg per kg intravenous loading dose of caffeine citrate followed by a maintenance dose of 5 to 10 mg.kg −1 once or twice per day started 2 to 3 days after the loading dose. Following this, plasma caffeine concentrations of 50 to 60 mg per L were obtained and a prolonged elimination of caffeine was noted.
In this study, infants were initially administered a dose of 20 mg.kg −1 of caffeine citrate once or twice daily by mouth.
In this study, 18 preterm infants with apnea were administered caffeine citrate and a marked reduction in apnea spells was observed from a mean of 14 per 24 hours before caffeine treatment to 2 per 24 hours following treatment. published the first study of caffeine used to treat apnea of prematurity 3. In 1973, Kuzemko and Paala reported on improvement in apnea among 10 preterm infants after the administration of 5 mg aminophylline suppositories 2. A. History and Evolution of “Standard Dose” Caffeine
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