Are current pediatric dose recommendations for intravenous theophylline appropriate?

Theophylline, a first-line antiasthma drug, is often associated with severe toxicity even when taken in the recommended schedule. Theophylline toxicity has been associated with upper respiratory tract infections (URTI) due to reduced total-body clearance of theophylline. Some researchers believe this inhibition stems from a direct effect of viruses, but others postulate it is a result of the fever. We examined whether current theophylline dose recommendations are appropriate for children with acute asthma with a concurrent URTI. We also wished to elucidate whether the viral infection or the fever inhibits theophylline clearance. A total of 2254 medical records of asthmatic children admitted to The Hospital for Sick Children in Toronto were reviewed between 1987 and 1990. Clearance rate was calculated as the ratio between the infused dose rate and measured steady-state concentrations. Subsequently, these clearance rates were used to calculate steady-state concentrations that would be achieved by the recommended dose rates of theophylline. Reduced theophylline clearance was associated with the presence of URTI (p = 0.029) but not fever. Age correlated significantly with theophylline clearance (p = 0.027). If these children were to receive the recommended intravenous dose rate of theophylline, two-thirds of them would achieve steady-state serum concentrations above 15 mg/L, and one-third would achieve concentrations above 20 mg/L. Reevaluation of the present recommended theophylline dose rate is needed, as the majority of children requiring intravenous theophylline have a concurrent URTI with compromised total-body clearance. A correction factor of 60% is recommended to adjust the dose rate during an URTI. If utilized by prescribing physicians, it may reduce theophylline toxicity during an URTI episode.