Start Date
Expiration Date
CPT Codes
Reference Test
ATLAS Test Code

Specimen Information


Red, Plain


1.0 ml

Transport Info

Centrifuge and immediately transfer serum to separate plastic tube

Fasting Required?
Patient Instructions

Reference Range

Serum Concentrations (neonates only):
- Therapeutic: 5-20 µg/mL
- Half-life: 30-230 hours
- Time to peak: 1-2 hours
- Volume of distribution (mean): 0.9 L/kg
Critical High Value:
Potentially toxic: ≥ 40 µg/mL
Lethal: 79-181 µg/mL


Enzyme Immunoassay (EIA)

Clinical Significance

Monitor serum concentration in newborns receiving caffeine for the treatment of apnea.

Methylxanthines are used to control and prevent neonatal apnea, which is defined as the cessation of breathing for more than 20 seconds. The respirogenic action of methylxanthines is due to their ability to stimulate the central nervous system.Apnea, which is most frequently seen in premature infants, is a significant contributor to the morbidity of low-birth-weight infants. Apnea occurs in approximately 25% of the infants weighing less than 2500 grams at birth and in 85% of the infants weighing less than 1000 grams at birth.Reportedly, the methylxanthine theophylline has been successfully used in treating neonatal apnea. Published reports have stated that caffeine has also been administered to treat neonatal apnea. However, the use of caffeine for the treatment of apnea in premature infants is not an approved use of the drug in the United States.Premature infants receiving theophylline have significant levels of caffeine in their blood because they metabolize theophylline to caffeine. Caffeine is a pharmacologically active metabolite of theophylline. Because the theophylline concentration is a poor indictor of the serum caffeine level, both caffeine and theophylline should be measured in premature infants receiving theophylline. By doing so, the total methylxanthine level can be assessed, thus avoiding toxicity.In premature infants receiving theophylline, caffeine has a long half-life and is therefore easily accumulated. The caffeine half-life in infants varies from 30 to 200 hours. As the metabolism of premature infants matures during the first 3 to 6 months of life, their caffeine half-life reaches adult rates of 4 to 6 hours. The wide range seen in premature infants is due to individual variations in caffeine metabolism.The methods historically used to measure serum levels of caffeine as a metabolite are high-performance liquid chromatography (HPLC), radioimmunoassay, and gas chromatography/mass spectrometry (GC/MS).The assay accurately quantitates caffeine concentrations in serum containing 1.0-30 µg/mL (5.2-155 µmol/L) of caffeine.It has been reported that the serum caffeine concentration reaches 30% to 57% of the theophylline concentration in premature infants receiving theophylline, thus significantly adding to the total active methylxanthine level. Because of this additive pharmacologic effect, it has been recommended that caffeine serum concentrations be determined along with theophylline serum levels.The therapeutic range for the total plasma methylxanthine concentration (theophylline plus caffeine) has not yet been established. It has been reported that an oral theophylline dose of 3 mg/kg/24h in premature infants produced approximately 5 mg/L theophylline and 1 to 2 mg/L caffeine in most subjects (19). Studies suggest that some infants receiving a theophylline dose considered to be therapeutic may have a total methylxanthine level approaching toxic due to the increasing caffeine concentration. In two reported cases, neonates being treated with theophylline developed toxic symptoms after a week of therapy. Their theophylline levels were approximately 15 mg/L, a level considered to be therapeutic, while the caffeine levels were approximately 38 mg/L, indicating a significantly higher total active methylxanthine load.