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Caffeine Citrate

A Review of its Use in Apnoea of Prematurity

Paediatric Drugs volume 3, pages 61–79 (2001)Cite this article

Summary

Abstract

Apnoea of prematurity is a common condition in neonates bom at less than 37 weeks’ gestational age; it affects approximately 90% of premature neonates weighing under 1000g at birth, and 25% of infants with a birthweight of less than 2500g. Caffeine, a methylxanthine which occurs naturally in many plants, has been used for over 20 years to treat apnoea of prematurity. In a recent doubleblind, placebo-controlled trial, apnoea was eliminated or reduced by at least 50% in significantly more neonates receiving caffeine citrate as first-line treatment than those receiving placebo. In a nonblind trial, caffeine citrate was more effective at reducing apnoeic episodes when compared with neonates receiving no treatment. Caffeine as first-line treatment demonstrated similar efficacy to theophylline or aminophylline (theophylline ethylenediamine) in 4 small randomised studies.

Caffeine citrate was generally well tolerated in short term clinical trials, with very few adverse events reported. Caffeine was associated with fewer adverse events than theophylline in randomised trials. No differences in the incidence of individual adverse events were reported between caffeine citrate and placebo in a double-blind, randomised trial. Long term tolerability data are not yet available.

Conclusions: Caffeine citrate was generally well tolerated by neonates in clinical trials and it decreased the incidence of apnoea of prematurity compared with placebo. It has demonstrated similar efficacy to theophylline, but is generally better tolerated and has a wider therapeutic index. Caffeine citrate should, therefore, be considered the drug of choice when pharmacological treatment of apnoea of prematurity is required.

Pharmacodynamic Properties

Caffeine acts via 3 main mechanisms of action. The mechanism most likely to mediate most of the pharmacological effects of caffeine is antagonism of the actions of adenosine at A1 and A2A receptors in the CNS. Activation of A1 receptors can produce sedation, antinociception, anticonvulsant effects, bradycardia, vasoconstriction, bronchoconstriction, antidiuresis and decreased glomerular filtration, and an increase in insulin sensitivity. Activation of the A2A receptors causes vasodilation, bronchodilation, central respiratory depression and peripheral respiratory stimulation, platelet inhibition, decreased locomotor activity and immunosuppression. At higher concentrations (in the millimolar range), caffeine is a weak inhibitor of phosphodiesterase activity. As millimolar concentrations of caffeine are likely to be toxic in vivo, inhibition of phosphodiesterase is unlikely to mediate most effects of caffeine at therapeutic doses. The third mechanism of action of caffeine is mobilisation of calcium from intracellular storage sites and inhibition of voltage-sensitive calcium channels; as relatively high concentrations of caffeine (≥250 μmol/L) are required for calcium mobilisation, this action may contribute more to the toxic effects of caffeine.

Caffeine increases mean respiratory rate and minute volume, stimulates central respiratory centres, increases pulmonary blood flow and increases the sensitivity of central medullary areas to hypercapnia. In premature neonates, caffeine was shown to improve the compliance of the respiratory system, reducing the strength of the Hering Breuer reflex (p < 0.05) and the inspired oxygen requirements over the 7-day study period. Caffeine has stimulant and somnolytic effects in the CNS (probably via blockade of adenosine receptors), and it has a direct effect on the myocardium, increasing ventricular output, stroke volume and mean arterial blood pressure in neonates. In contrast to aminophylline (theophylline ethylenediamine), caffeine has no significant effects on brain haemodynamics in preterm infants. Caffeine can affect the renal system, increasing glomerular flow rate, inducing diuresis, and increasing calcium excretion, urinary flow rate, creatine clearance and water input/output ratio over pretreatment levels.

Pharmacokinetic Properties

The pharmacokinetics of caffeine are largely independent of the route of administration. In premature neonates, orally administered caffeine citrate is rapidly and completely absorbed. There is almost no first-pass metabolism, and there is almost complete bioavailability of caffeine following oral administration. Following a single oral dose of caffeine citrate 20 mg/kg (a 20 mg/kg dose of caffeine citrate contains 10 mg/kg caffeine base), the mean peak plasma concentration of 12.8 mg/L occurred about 4.6 hours after administration of the dose. Steady-state plasma concentrations ranged from 7.4 to 19.4 mg/L after once daily administration of caffeine base 2.5 mg/kg. The mean terminal half-life of caffeine in neonates ranges from 65 to 102 hours.

Caffeine readily passes through most membranes in the body and does not accumulate in tissue. It has an apparent volume of distribution of approximately 0.8 L/kg. Caffeine is metabolised in the liver by cytochrome P450 1A2 (CYP1A2). Metabolism of caffeine is limited in neonates because of their immature hepatic enzyme system; approximately 86% is excreted unchanged in the urine. The terminal half-life of caffeine in infants decreases from birth until reaching adult values at approximately 60 weeks postconceptional age; premature neonates have a significantly longer caffeine half-life than neonates born at term.

Therapeutic Efficacy

First-Line Therapy: Caffeine citrate has shown efficacy in the treatment of apnoea of prematurity in 1 randomised, double-blind, placebo-controlled trial in 82 evaluable premature neonates. The frequency of apnoeic episodes was reduced by ≥50% or eliminated in significantly more neonates receiving caffeine citrate than placebo. In another study (n = 18), apnoeic episodes were significantly less frequent in neonates receiving caffeine citrate compared with neonates receiving no treatment. Caffeine has demonstrated similar efficacy to theophylline or aminophylline in 4 small randomised studies.

Second-Line Therapy: Caffeine has shown efficacy in the treatment of apnoea which did not respond to theophylline treatment in 2 small, nonblind, noncomparative studies. Over 80% of the 27 neonates responded to caffeine with a reduction in the frequency of apnoeic episodes.

Prophylactic Use: Mixed results have been obtained from 3 trials assessing caffeine citrate as a prophylactic agent for the prevention of apnoeic episodes in premature neonates. A double-blind, placebo-controlled study (n = 50) did not show any benefit of caffeine citrate treatment in preventing hypoxaemic or bradycardic episodes in premature neonates. However, a smaller (n = 37) nonblind study showed caffeine citrate to be significantly more effective than no treatment in preventing apnoea. A third trial (n = 180) found no difference in the frequency of apnoeic or bradycardic episodes between caffeine citrate and aminophylline groups over a 10-day period (there was no placebo group in this study).

Tolerability

Caffeine citrate has, generally, been well tolerated in clinical trials of premature neonates, with very few adverse events reported. No differences in the incidence of individual adverse events were reported between caffeine citrate and placebo treatment groups in a double-blind trial. The discontinuation rate due to adverse events was 4.4% for caffeine citrate and 2.7% for placebo groups. Caffeine was associated with fewer adverse events than theophylline in randomised trials. Caffeine toxicity has not been reported at the therapeutic plasma concentrations required to treat apnoea of prematurity.

Caffeine is a CNS and cardiovascular stimulant and has been associated with irritability, restlessness, jitteriness, tachycardia and other cardiovascular effects, although these events have generally been absent from randomised trials of caffeine in premature neonates with apnoea. The long term outcomes of caffeine treatment in neonates have yet to be determined, but evidence from nonblind studies suggests that growth and neurological development are not affected. In cases of accidental caffeine overdose recovery was usually complete.

Dosage and Administration

The recommended dosage regimen of caffeine citrate for the short term treatment of apnoea of prematurity in previously untreated infants between 28 and <33 weeks’ gestational age is 20 mg/kg infused intravenously over 30 minutes using a syringe infusion pump, followed by maintenance therapy of 5 mg/kg once daily given orally or by intravenous infusion. Serum concentrations of caffeine should be monitored periodically; the therapeutic range is 8 to 20 mg/L. Caffeine clearance and half-life change rapidly in the postnatal period and it may be necessary to adjust dosage regimens as infants increase in age.

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  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand

    Alison M. Comer, Caroline M. Perry & David P. Figgitt

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Additional information

Various sections of the manuscript reviewed by: J. Bhatia, Section of Neonatology, Department of Pediatrics, Medical College of Georgia, Augusta, Georgia, USA; C. Dani, Department of Neonatology, University of Florence, Azienda Ospedaliera Careggi, Florence, Italy; A. Erenberg, Department of Pediatrics, University of Arizona Health Sciences Center, Tucson, Arizona, USA; A. Greenhough, Child Health, King’s College Hospital, London, England; D.J. Henderson-Smart, NSW Centre for Perinatal Health Services Research, Queen Elizabeth II Research Institute, University of Sydney, Sydney, New South Wales, Australia; C.F. Poets, Department of Neonatology and Paediatric Pulmonology, Hannover Medical School, Hannover, Germany; C. Romagnoli, Division of Neonatology, Catholic University of the Sacred Heart, Rome, Italy; F.J. Walther, Harbor-UCLA Research and Education Institute, Torrance, California, USA.

Data Selection

Sources: Medical literature published in any language since 1966 on caffeine citrate, identified using Medline and EMBASE, supplemented by AdisBase (a proprietary database of Adis International, Auckland, New Zealand). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: Medline search terms were ‘caffeine citrate’. EMBASE search terms were ‘caffeine citrate’. AdisBase search terms were ‘caffeine citrate’. Searches were last updated 14 Dec 2000.

Selection: Studies in neonates with apnoea of prematurity who received caffeine citrate. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Caffeine citrate, apnoea of prematurity, pharmacodynamics, pharmacokinetics, therapeutic use.

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Comer, A.M., Perry, C.M. & Figgitt, D.P. Caffeine Citrate. Paediatr Drugs 3, 61–79 (2001). https://doi.org/10.2165/00128072-200103010-00005

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Keywords

  • Caffeine
  • Theophylline
  • Aminophylline
  • Methylxanthine
  • Premature Neonate