Theophylline and Caffeine

Also Known As

Aminophylline

Formal Name

Theophylline

Caffeine

This article was last reviewed on

January 29, 2019.

This article waslast modified on September 23, 2019.

At a Glance

Why Get Tested?

To determine the concentration of theophylline or caffeine in your blood to establish an appropriate dose and to maintain a therapeutic level; also important to determine if you are experiencing toxicity

When To Get Tested?

At the start of drug therapy and at regular intervals to monitor the drug's concentration; when indicated, to detect low or excessive (potentially toxic) concentrations

Sample Required?

A blood sample drawn from a vein or from pricking an infant's heel; the sample is typically collected just prior to the next dose when the drug concentration is expected to be at its lowest level (trough level).

Test Preparation Needed?

None

What is being tested?

Theophylline and caffeine are drugs that ease breathing and stimulate respiration (methylxanthines). These tests measure the amount of theophylline or caffeine in the blood to help establish an appropriate dose, to maintain a therapeutic level, and to evaluate toxic concentrations.

Theophylline is one of several medications that may be taken by children and adults who have asthma and by adults who have chronic obstructive pulmonary disease (COPD). It is a bronchodilator and functions to relax the muscles in the lungs. Theophylline has a narrow therapeutic window, in which too little theophylline is ineffective and too much can cause toxicity. Both short-acting and long-acting formulations are available for asthma treatments. Acute theophylline toxicity presents with rapid heart rate and nausea. Chronic theophylline toxicity is associated with an increased risk of seizures and abnormal heart rhythms (cardiac dysrhythmias). Both acute and chronic toxicity can be life-threatening.

Caffeine is frequently used for adults as a pain reliever (analgesic), migraine remedies, and to remain alert and/or awake. It is also the preferred medication to treat apnea in premature newborns who stop breathing. Apnea compromises the amount of oxygen available to the body. It is a common and serious condition in premature newborns that must be promptly treated and closely monitored. While both medications can reduce episodes of apnea, caffeine has fewer side effects than theophylline and, thus, a lower risk of toxicity. At very high doses, symptoms similar to those found with theophylline toxicity may be seen.

Establishing and maintaining therapeutic doses can be a challenge. Both theophylline and caffeine levels may need to be monitored because the range of concentrations in which the drugs are effective but not toxic is narrow and in some cases the dose given does not always correlate well with concentrations in the blood.

The rate at which the drugs are processed by the body (metabolized) will vary from person to person. Metabolism is decreased in both the very young and the elderly and increased in smokers. The drug levels may also be affected by underlying conditions such as pneumonia, liver disease, hypothyroidism, and by acute infection or illness. Many drugs interact and interfere with the metabolism of theophylline and caffeine. They may increase or decrease its rate of metabolism.

Common Questions

How are the tests used?

Theophylline and caffeine tests are used to monitor the amount of the drugs in the blood to establish appropriate doses, maintain therapeutic levels, and evaluate toxicity.

Theophylline is usually ordered as a trough level – prior to the next dose when the concentration is expected to be at its lowest level. Tests may also be ordered if a healthcare practitioner suspects that a person may be experiencing theophylline toxicity. A series of blood samples may be collected and tested over a period of time to track theophylline concentrations if you have had high theophylline levels, until therapeutic concentrations are reached.

Caffeine blood levels are not used to monitor therapy as routinely as theophylline tests. Usually, newborns receiving caffeine are monitored clinically for episodes of apnea and signs of toxicity, and physiological effects of the drug are closely watched. The majority of those treated respond to standardized doses of the medication without the need for monitoring blood caffeine levels. The test is primarily ordered if an infant is not responding to therapy as expected or if the infant is demonstrating signs of toxicity. Since daily doses and an extended half-life in the premature neonate generally result in stable drug levels, the sample collected is usually a random level, not a trough level.
When are they ordered?
When beginning theophylline treatment, the theophylline test may be ordered several times as the dosage is adjusted as needed, until therapeutic levels are attained. The test may be ordered whenever you have symptoms that your healthcare practitioner suspects are due to theophylline toxicity and whenever you are not responding as expected to therapy. The healthcare practitioner may order a test when you experience a significant change in health status and/or when you start or stop taking a drug that is known to affect the metabolism of theophylline.

Symptoms associated with acute theophylline toxicity may include:

Low blood pressure

Rapid heart rate

Restlessness

Tremors

Nausea

Abdominal pain

Confusion

Loss of appetite

A caffeine test may be ordered whenever a premature neonate is not responding as expected to treatment and/or whenever an infant has symptoms that the healthcare practitioner suspects are related to high caffeine levels. Signs and symptoms associated with high caffeine levels in a newborn may include:

Inability to take in or digest infant formula or breast milk

Jitteriness, shakiness

Irritability

Tremors

Rapid heart rate

Convulsions
What does the test result mean?

The therapeutic concentration for theophylline, when used as a bronchodilator to treat asthma, is generally considered to be 5–15 mcg/mL (28-83 micromol/L) for adults, 5–10 mcg/mL (28–55 micromol/L) for children and neonates. Levels greater than 20 mcg/mL (111 micromol/L) are considered toxic. Some people may experience significant side effects at concentrations less than 20 mcg/mL (111 micromol/L). When theophylline is used to treat apnea in premature neonates, the therapeutic range is 6-11 mcg/mL (33-61 micromol/L).

Therapeutic concentration for caffeine for the treatment of premature neonate apnea is much wider, 5-20 mcg/mL (25-103 micromol/L), while concentrations greater than 20 mcg/mL (103 micromol/L) are considered toxic, and greater than 50 mcg/mL (257 micromol/L) are considered critical values.

Low levels of theophylline and caffeine may indicate that the drug has not reached a therapeutic level for the individual tested and there is insufficient drug present to be effective.

Blood levels in the therapeutic range mean that most people will have their symptoms relieved without experiencing significant side effects. Adverse side effects and the risk of seizures increase with higher concentrations of these drugs.
Is there anything else I should know?

The use of theophylline as a bronchodilator has decreased as other more effective and less toxic asthma treatments have become available. It is still in use throughout the United States but is not generally the first treatment choice.

In infants, a significant amount of the theophylline dose (8.5%) is metabolized to caffeine. This occurs to a much lesser degree in children and adults. In cases where the theophylline concentration is within the therapeutic range but the infant is showing signs of toxicity, caffeine levels should be determined. Likewise, theophylline is one of the metabolites of caffeine.
Can other drugs I take affect theophylline levels?

Theophylline can affect, and be affected by, a wide variety of drugs and compounds. When your healthcare practitioner prescribes theophylline, it is important for you to list and discuss all of the prescribed and over-the-counter medications that you are taking, including oral contraceptives and any herbal supplements such as echinacea, chamomile, and gingko. Your healthcare provider will also want to know the amount of caffeine and alcohol that you consume and whether or not you smoke.
Should I tell all of my doctors that I am taking theophylline?

Yes; this is an important part of your medical history and will have an effect on other treatment plans.
How long does a premature neonate have to take caffeine?

In most cases, the caffeine is a short-term treatment, given for a few weeks until the baby matures and ceases to have apneic episodes.

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The reference ranges for your tests can be found on your laboratory report. They are typically found to the right of your results.

If you do not have your lab report, consult your healthcare provider or the laboratory that performed the test(s) to obtain the reference range.

Laboratory test results are not meaningful by themselves. Their meaning comes from comparison to reference ranges. Reference ranges are the values expected for a healthy person. They are sometimes called "normal" values. By comparing your test results with reference values, you and your healthcare provider can see if any of your test results fall outside the range of expected values. Values that are outside expected ranges can provide clues to help identify possible conditions or diseases.

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For more information, please read the article Reference Ranges and What They Mean.

View Sources

Sources Used in Current Review

2019 review performed by Kamisha L. Johnson-Davis, PhD, DABCC, FAACC, Associate Professor, University of Utah; Medical Director, ARUP Laboratories.

Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. Burtis CA, Ashwood ER, Bruns DE, 6th eds. St. Louis: Elsevier Saunders. Chapter 40: Therapeutic drugs and their management.

Henry's Clinical Diagnosis and Management by Laboratory Methods. McPherson R, Pincus M, 23rd eds. Philadelphia, PA: Saunders Elsevier. Chapter 23: Toxicology and therapeutic drug monitoring.

(Revised 4/15/17) Theophylline. MedlinePlus. Available online at https://medlineplus.gov/druginfo/meds/a681006.html. Accessed January 2019.

(Review Date 6/13/2018) Apnea of prematurity. MedlinePlus. Available online at https://medlineplus.gov/ency/article/007227.htm. Accessed January 2019.

(January 2018) Pitone M. Apnea of prematurity. KidsHealth. Available online at https://kidshealth.org/en/parents/aop.html. Accessed January 2019.

Sources Used in Previous Reviews

Wu, A. (2006). Tietz Clinical Guide to Laboratory Tests, Fourth Edition. Saunders Elsevier, St. Louis, Missouri. Pp 1280, 1490-1491.

Ram, F. (2006 March 8). Use of Theophylline in Chronic Obstructive Pulmonary Disease: Examining the Evidence. Medscape From Current Opinion in Pulmonary Medicine [On-line information]. Available online at http://www.medscape.com/viewarticle/524508. Accessed on 9/14/08.

Kirkland, L. and Horn, A. (2008 May 29). Toxicity, Theophylline. eMedicine [On-line information]. Available online at http://www.emedicine.com/med/TOPIC2261.HTM. Accessed on 9/14/08.

(2007 December). Asthma Medications Chart. American Lung Association [On-line information]. Available online at http://www.lungusa.org/site/pp.asp?c=dvLUK9O0E&b=263990. Accessed on 9/14/08.

Buck, M. (2008 June). Caffeine Citrate for the Treatment of Apnea of Prematurity. Pediatric Pharmacotherapy v14 (6) [On-line information]. Available online at http://www.healthsystem.virginia.edu/internet/pediatrics/pharma-news/. Accessed on 9/14/08.

Natarajan, G. et. al. (2007 May 1). Therapeutic Drug Monitoring for Caffeine in Preterm Neonates: An Unnecessary Exercise? Pediatrics Vol. 119 No. 5 May 2007, Pp. 936-940. [On-line information]. Available online at http://pediatrics.aappublications.org/cgi/content/abstract/119/5/936. Accessed on 9/14/08.

(2007 August 1, Reviewed). Theophylline. MedlinePlus Drug Information [On-line information]. Available online at http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a681006.html. Accessed on 9/14/08.

Perez, E. (2008 January 23). Aminophylline overdose. MedlinePlus Medical Encyclopedia [On-line information]. Available online at http://www.nlm.nih.gov/medlineplus/ency/article/002572.htm. Accessed on 9/14/08.

(© 2007). American Academy of Allergy, Asthma and Immunology. Tips to Remember: Asthma and allergy medications [On-line information]. Available online at http://www.aaaai.org/patients/publicedmat/tips/asthmaallergymedications.stm. Accessed on 9/14/08.

Pesce, A. et. al. (1998). Standards of laboratory practice: theophylline and caffeine monitoring. Clinical Chemistry 44:5 1124–1128 [On-line information]. Available online at http://www.clinchem.org/cgi/content/full/44/5/1124.

Klein, J. (2008 June 26, Modified). Management of Neonatal Apnea. Iowa Neonatology Handbook: Pulmonary [On-line information]. Available online at http://www.uihealthcare.com/depts/med/pediatrics/iowaneonatologyhandbook/pulmonary/managementapnea.html. Accessed on 9/21/08.

Baselt, R.C., (2002). Disposition of Toxic Drugs and Chemicals in Man, Sixth Edition. Biomedical Publications, Foster City, CA. Caffeine, Pp. 149 – 152; Theophylline, Pp. 1013 – 1017.

Hammett-Stabler, C.A., and A. Dasgupta (2007). Therapeutic Drug Monitoring Data: A Concise Guide, Third Edition. AACC Press, Washington, D.C., Pp. 222 – 230.

Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. Burtis CA, Ashwood ER, Bruns DE, eds. St. Louis: Elsevier Saunders; 2006. Appendix, Pp. 2304 and 2314.

Yew, D. and Laczek, J. (Updated 2011 May 6) Caffeine Toxicity. Medscape Reference [On-line information]. Available online at http://emedicine.medscape.com/article/821863-overview. Accessed February 2012.

Hymel, G. (Updated 2011 July 12). Theophylline Toxicity in Emergency Medicine. Medscape Reference [On-line information]. Available online at http://emedicine.medscape.com/article/818847-overview. Accessed February 2012.

(2011 February 1). How Is Asthma Treated and Controlled? National Heart Lung and Blood Institute [On-line information]. Available online at http://www.nhlbi.nih.gov/health/health-topics/topics/asthma/treatment.html. Accessed February 2012.

Heller, J. (Updated 2011 January 19). Aminophylline overdose. MedlinePlus Medical Encyclopedia [On-line information]. Available online at http://www.nlm.nih.gov/medlineplus/ency/article/002572.htm. Accessed February 2012.

(Updated 2012 January 6). Asthma Medicines: Long-term Control. Healthychildren.org [On-line information]. Available online at http://www.healthychildren.org/English/health-issues/conditions/allergies-asthma/pages/Asthma-Medicines-Long-term-Control.aspx. Accessed February 2012.

(© 1995–2012). Test ID: CAFF8754 Caffeine, Serum. Mayo Clinic Mayo Medical Laboratories [On-line information]. Available online at http://www.mayomedicallaboratories.com/test-catalog/Overview/8754. Accessed February 2012.

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Wise, R. (Modified 2010 January). Chronic Obstructive Pulmonary Disease. Merck Manual for Healthcare Professionals [On-line information]. Available online through http://www.merckmanuals.com. Accessed February 2012.

Reviewer June 2015: Irene Shu, PhD, DABCC, Assistant Laboratory Director, USDTL.

National Heart, Lung and Blood Institute. National Asthma Education and Prevention Program (2007 August 28) Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. P 335.

Pesce AJ., Rashkin M. and Kotagal U. (1998). Standards of laboratory practice: theophylline and caffeine monitoring. Clin Chem, 44, 1124-1128.

(2015, April 1, Revised) Mayo Clinic. Drugs and Supplements Theophylline (oral route). Available online at http://www.mayoclinic.org/drugs-supplements/theophylline-oral-route/description/drg-20073599. Accessed on 6/3/2015.

(2013, December 19, Revised) Medscape. Theophylline Level. Available online at http://emedicine.medscape.com/article/2090395-overview. Accessed on 6/3/2015.

Hymel, Greg MD (2013 March 8, Revised). Medscape. Theophylline Toxicity Clinical Presentation. Available online at http://emedicine.medscape.com/article/818847-clinical. Accessed on 6/3/2015.

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