Fifty Years Ago in The Journal of Pediatrics:
Aminophylline (theophylline ethylenediamine) poisoning in children
Article Outline
White BH, Daeschner CW. J Pediatr 1956;49:262-71
White and Daeschner reported four cases of theophylline toxicity, two with seizures, and a summary of 16 previous reports in the literature. It was noteworthy because it brought to light iatrogenic theophylline toxicity in children. Many of the patients had been prescribed adult-size doses of rectal suppositories containing aminophylline. Subsequently, the use of suppositories declined and theophylline was mostly prescribed for children as a combination product containing ephedrine and a sedative (Marax, Tedral).
In 1975, synergistic toxicity between theophylline and ephedrine was demonstrated1 and physicians subsequently switched to monotherapy with theophylline. As a result of the relationship between serum concentration, efficacy and toxicity,2 and variable rates of metabolism,3 it was common to individualize dosage based on serum concentration measurements.4 Nevertheless, history was doomed to be repeated for those physicians who did not pay close attention to the complexity of theophylline dosing. With the widespread use of this drug as maintenance therapy for persistent asthma, particularly in slow-release dosage forms, reports of iatrogenic seizures, arrhythmias, and deaths from theophylline began to appear again in the literature.5, 6, 7 In the years to follow, lawsuits against prescribers and product liability suits against manufacturers often resulted in juries awarding large sums of monies to plaintiffs.8
With the recognition of the importance of inflammation in the pathogenesis of asthma in the 1990s and the risk of toxicity from theophylline, inhaled corticosteroids rapidly replaced it as maintenance medication for persistent asthma. Now, 50 years after White and Daeschner’s report was published, theophylline is rarely used in either children or adults and the issue of iatrogenic toxicity has essentially disappeared. Randomized, controlled trials indicate that theophylline still has a potential role in the intensive care unit treatment of acute asthma in children9 and in addition to inhaled corticosteroids in severe persistent asthma.10 However, the complexity of dosing this drug and its infrequent use suggest that most pediatric residents will not gain sufficient experience to use theophylline safely.
References
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- . Evaluation of oral bronchodilator therapy in asthmatic children (Bronchodilators in asthmatic children) . J Pediatr . 1974;84:421–427
- . Relationship of theophylline clearance to oral dosage in children with chronic asthma . J Pediatr . 1977;91:655–660
- . Guide to oral theophylline therapy for the treatment of chronic asthma . Am J Dis Child . 1978;132:876–880
- . Acute pediatric theophylline overdose: a summary of 28 cases . J Pediatr . 1983;102:474–476
- . Theophylline toxicity in children . J Pediatr . 1986;109:538–542
- . Life-threatening events after theophylline overdose: a 10-year prospective analysis . Arch Intern Med . 1999;159:989–994
- . Theophylline injuries resulting in litigation . J Pharm Pract . 1992;5:224–233
- . Efficacy of IV theophylline in children with severe status asthmaticus . Chest . 2001;119:1480–1488
- . Immunomodulation by theophylline in asthma (Demonstration by withdrawal therapy) . Am J Respir Crit Care Med . 1995;151:1907–1914
PII: S0022-3476(06)00687-1
doi:10.1016/j.jpeds.2006.07.023
© 2006 Mosby, Inc. All rights reserved.
