The primary objective was to evaluate the correlation between maintenance dose and response rates in neonates less than 28 weeks gestational age. Secondary objectives included clinical indicators of response number of weight adjustments, dose increases, and mini-loads and tachycardia associated with caffeine therapy. This study was a retrospective analysis of neonates admitted to the North Carolina Children's Hospital from August to August Patients included were less than 28 weeks postmenstrual age and were treated with caffeine for apnea of prematurity. Patients were excluded if they were older than 28 weeks postmenstrual age, receiving caffeine therapy for other indications, or experiencing apnea from other conditions, or if therapy was initiated more than 7 days after birth.
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Apnea of prematurity consists in 15 to 20 sec. It is treated with caffeine citrate. The objectives of this article are to review: 1 the mechanisms of action, 2 the effects, 3 the metabolism, 4 the pharmacokinetics, and 5 the adverse effects of caffeine citrate in preterms.
Caffeine citrate is a stimulant of the respiratory and central nervous systems. It binds competitively to the receptors for adenosine A1 and A2 A , causing inhibition. Orally administered caffeine citrate is rapidly and completely absorbed.
There is a remarkable shortening of the half-life during neonatal maturation. Adverse effects of caffeine are usually mild, and include restlessness, vomiting, and functional cardiac symptoms.
Caffeine citrate is the drug of choice for the treatment of apnea of prematurity. It is an easy drug to use. Administered orally or intravenously once a day, it does not require monitoring of serum concentrations and has few side effects.
Apnea is the most important disorder in the control of breathing in the neonate. Pharmacological therapy to stimulate breathing consists of the methylxanthines. Schoen et al. They found that the therapy with caffeine is associated with fewer adverse effects and a wider therapeutic window when compared with theophylline.
Information on the effects of caffeine citrate, and on the fate of this drug in preterm infants has been published in different journals during the last thirty years, but it is scattered.
The objectives of this article are 1 to gather together and 2 to review the published data on a the mechanisms of action, b the effects, c the metabolism, d the pharmacokinetics, and e the adverse effects of caffeine citrate in preterm infants. The main objective of this work is to provide neonatologists with a tool that embraces all aspects of the clinical pharmacology of caffeine citrate in preterm infants. The following key words "caffeine citrate neonate", "caffeine citrate therapy for apnea of prematurity", "caffeine citrate therapy", "caffeine citrate pharmacokinetics neonate", "caffeine citrate metabolism neonate", and "caffeine citrate adverse effects neonate" were used.
There is 1 mg of caffeine base in 2 mg of caffeine citrate. The maintenance dose should be started 24 hours after the loading dose. Later apnea occurs in few infants at a postmenstrual age of more than 52 weeks.
The mechanism most likely to mediate most of the pharmacological effects of caffeine citrate is antagonism to the actions of adenosine at A1 and A2 A receptors in the 15 - 20 central nervous system.
These two receptors have different properties. Recent data raise the possibility that apnea of prematurity is genetically linked. Polymorphisms in the A1 and A2 A adenosine receptor genes account for variability in the subject's response to caffeine. They also observed that the adenosine receptor genes are responsible for the interindividual caffeine response variability in apnea of prematurity.
Single-nucleotide polymorphism on the A2 A is associated with a greater risk of apnea of prematurity. They also determined whether the polymorphisms in A1 and A2 A have any effect on bronchopulmonary dysplasia development. Recent evidence, relating to the use of caffeine citrate for apnea of prematurity suggests that it decreases the likelihood of bronchopulmonary disease development. Although the reason for the inter-individual caffeine response variability is unclear, there is evidence that some of the variability in the acute response to caffeine may have a genetic basis.
Table 1 summarizes the properties and the effects of caffeine citrate for the treatment of apnea of prematurity in neonates. The daily maintenance dose should be started 24 hours after the loading dose.
Caffeine citrate is a central stimulant agent: it inhibits adenosine receptors, affects release, turnover, and levels of several other transmitters, including biogenic amines dopamine, noradrenalin, serotonin , acetylcholine, and excitatory and inhibitory amino acids.
Clinical stimulation of preterm infant breathing with methylxanthines can evoke seizures. Aranda et al. Mean frequency of apneic spells decreased from Saliba et al. Stroke volume increased in 24 of 31 subjects, by 7. Heart rate increased in 28 of 31 infants, by 7.
Walther et al. The mean caffeine citrate plasma level was 9. Twenty clinically stable preterm infants were studied. The other ten infants were the controls. The mean caffeine plasma level was 9. This was accompanied by a higher mean arterial blood pressure on days 1 to 3. Caffeine was used as a probe to study development of CYP1A2 in neonates. Model development involved the scale-up of in vitro metabolic parameters, and adjusting metabolic function for the ontological pattern of CYP1A2.
Caffeine is also acetylated by N-acetyltransferase NAT2. It develops as early as 1 month of age, and may be higher in infants than in adults. Cattarossi et al. The infants were divided in 6 groups according to the gestational age. Thus, urinary levels of caffeine might be a useful means to assess therapeutic ranges of caffeine citrate. Romagnoli et al. De Carolis et al. A daily maintenance oral dose of 2.
Doses of caffeine citrate ranging from 2. The median caffeine plasma concentration was Thus, therapeutic drug monitoring is unnecessary when caffeine is used for the treatment of apnea of prematurity in neonates. The pharmacokinetic parameters of caffeine citrate are summarized in Table 2. Clearance of caffeine citrate occurs mostly via the kidneys. Le Guennec et al. The peak concentration of caffeine citrate was obtained at 1 to 1.
Early work has demonstrated an exceedingly slow elimination rate of caffeine citrate in premature and term infants. Lelo et al. Gorodischer and Karplus 47 studied the pharmacokinetics of caffeine citrate in 13 premature infants. Pearlman et al. Bonati et al. Table 2 summarizes the pharmacokinetic parameters of caffeine citrate obtained in 5 selected studies. Charles et al.
The median caffeine treatment period was 7 days. The mean clearance was 0. Lee et al. Mean clearance estimates were similar after administration of the low, medium, and high doses either at entry or exit from the study.
Falcao et al. Clearance was estimated at 0. Volume of distribution was 0. Thomson et al. The clearance estimate was 0. Skouroliakou et al. They were randomly assigned open-label to receive either theophylline or caffeine citrate for prevention of apnea. The primary outcome measure was to assess the difference in apnea frequency between theophylline and caffeine patient groups.
The intravenous loading dose of theophylline was 4. The plasma concentrations of caffeine citrate ranged from 5. Laubscher et al. Scanlon et al.
Caffeine was administered in two doses. Theophylline dosage was 7. The use of caffeine citrate for the treatment of neonatal apnea is recommended, because a single daily dose is more easily administered, and because it was found that plasma concentrations are more predictable than those of theophylline.
Brouard et al. Larsen et al. An aminophylline loading dose 6. Both treatments lasted 10 days. Aminophylline and caffeine citrate decreased the incidence of neonatal apnea and bradycardia to the same extent.
No differences were found between the two groups regarding the number of neonates who needed respiratory therapy and the number of episodes of apnea of bradycardia. The caffeine citrate group had a lower median heart rate on day 3 and a smaller amount of gastric aspirate on day 7. There were no differences in the frequency of respiratory distress syndrome or necrotizing enterocolitis between groups.
Based on these results, caffeine citrate seems to be the drug of choice for apnea and bradycardia prophylaxis in premature neonates. Lundstrom et al.
Apnea del prematuro
Apnea of Prematurity: Caffeine Dose Optimization