Get Your Personalized Supplement StackSupplement Stack Quiz

Caffeine Citrate

Also known as: Caffeine citrate, Citrated caffeine, 1,3,7-trimethylxanthine citrate salt, Caffeine Citrate

Overview

Caffeine citrate is a citrate salt formulation of caffeine, primarily used as a first-line pharmacotherapy for apnea of prematurity (AOP) in preterm infants. It belongs to the methylxanthine derivative class and acts as a respiratory stimulant. Research indicates that caffeine citrate has a superior safety profile compared to other methylxanthines like aminophylline. While preclinical models suggest potential neuroprotective effects, clinical evidence is still limited. Its efficacy is well-established through numerous randomized controlled trials (RCTs) and meta-analyses. Caffeine citrate is available in both intravenous and oral forms, offering flexibility in administration. The evidence supporting its use is considered high-quality, with systematic reviews and meta-analyses confirming its benefits in reducing apnea and preventing bronchopulmonary dysplasia.

Benefits

Caffeine citrate is primarily used to reduce apnea in preterm infants, demonstrating equivalent efficacy to aminophylline (OR 1.05, 95% CI 0.40-2.74). Early administration of caffeine citrate has been shown to reduce the risk of bronchopulmonary dysplasia (BPD) by 33% (95% CI 0.56-0.81). Secondary benefits include a lower incidence of feeding intolerance compared to aminophylline (OR 0.40, 95% CI 0.23-0.70) and a 78% lower risk of tachycardia (OR 0.22, 95% CI 0.13-0.37). It is most effective in infants less than 34 weeks gestation. High-quality meta-analyses support these findings, highlighting the clinical significance of caffeine citrate in neonatal care.

How it works

Caffeine citrate primarily works through non-selective adenosine receptor antagonism. This mechanism stimulates the central respiratory center and improves diaphragmatic contractility, leading to reduced apnea. Caffeine citrate exhibits near-complete bioavailability via both intravenous and oral routes. In preterm infants, it has a half-life of 72-96 hours due to immature hepatic CYP1A2 enzymes, which are responsible for its metabolism. The drug's interaction with adenosine receptors plays a crucial role in its respiratory effects, making it an effective treatment for apnea of prematurity.

Side effects

Common side effects of caffeine citrate include tachycardia (less than 5% incidence, compared to 15-20% with aminophylline) and feeding intolerance (8-12% incidence, compared to 20-25% with aminophylline). Rare risks involve seizures (less than 1%) and necrotizing enterocolitis, although no causal relationship has been definitively established. Caffeine citrate can have synergistic effects with other stimulants, and its clearance may be reduced by CYP1A2 inhibitors. It is contraindicated in patients with severe cardiac arrhythmias. Caution should be exercised when administering caffeine citrate to infants with a history of seizures or gastrointestinal issues. Monitoring for adverse effects is essential during treatment.

Dosage

The recommended loading dose of caffeine citrate is 20 mg/kg caffeine base, which is equivalent to 40 mg/kg caffeine citrate. The standard maintenance dose ranges from 5-10 mg/kg/day, while a higher dose of 10-20 mg/kg/day may improve efficacy (RR 1.37, 95% CI 1.18-1.60). Serum levels should be monitored, with a target range of 10-20 μg/mL. Caffeine citrate can be administered intravenously or orally. Dosage adjustments may be necessary based on individual patient response and serum caffeine levels. It's important to adhere to these guidelines to minimize potential side effects and optimize therapeutic outcomes.

FAQs

How quickly does it work?

Clinical effects are typically observed within 1-3 days of administration. However, meta-analysis data indicates no significant short-term efficacy difference compared to aminophylline for apnea reduction in preterm infants.

What are the long-term neurodevelopmental effects?

High-quality evidence on long-term neurodevelopmental effects is limited. Some studies suggest potential benefits, but these findings require further confirmation through more extensive research.

Can caffeine citrate replace CPAP?

Caffeine citrate is an adjunct therapy and should not be used as a substitute for respiratory support methods like CPAP. It complements respiratory support by stimulating breathing and reducing apnea episodes.

Is caffeine citrate safe for all preterm infants?

While generally safe, caffeine citrate is contraindicated in infants with severe cardiac arrhythmias. Caution is advised in infants with a history of seizures or gastrointestinal issues. Monitoring is essential.

Research Sources

https://pubmed.ncbi.nlm.nih.gov/36121807/ – A 2022 meta-analysis of 10 RCTs (n=923) found that caffeine citrate has equivalent efficacy to aminophylline in reducing apnea in preterm infants. However, caffeine citrate demonstrated a superior safety profile compared to aminophylline, suggesting it is a preferable first-line treatment. The study acknowledges heterogeneity in outcome measures as a limitation.
https://pmc.ncbi.nlm.nih.gov/articles/PMC5338164/ – This article discusses the benefits of early caffeine therapy administration in preterm infants. It highlights that early caffeine administration can lead to a 33% reduction in bronchopulmonary dysplasia (BPD), suggesting that early intervention may confer additional pulmonary benefits. The analysis is based on a pooled analysis of 2 RCTs.
https://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0274882 – This study investigates the efficacy and safety of caffeine citrate for apnea of prematurity. It provides a comprehensive overview of the drug's mechanism of action, clinical benefits, and potential side effects. The research emphasizes the importance of appropriate dosing and monitoring to optimize therapeutic outcomes and minimize adverse events.
https://onlinelibrary.wiley.com/doi/10.1155/2018/9061234 – A 2018 dose-response meta-analysis of 13 RCTs (n=1,515) found that a high-dose regimen of caffeine citrate (10-20 mg/kg) improves treatment success in preterm infants with apnea. The study reported a relative risk of 1.37 (95% CI 1.18-1.60) with higher doses. Variable follow-up durations were noted as a limitation.
https://karger.com/neo/article/121/1/7/869965/Early-versus-Late-Caffeine-Therapy-Administration – This article compares the effects of early versus late caffeine therapy administration in preterm infants. It suggests that early initiation of caffeine therapy may confer additional pulmonary benefits, potentially reducing the risk of bronchopulmonary dysplasia. The study highlights the importance of timing in caffeine administration for optimal outcomes.