Population Pharmacokinetics of Theophylline during Paediatric Extracorporeal Membrane Oxygenation (ECMO)
Hussain Mulla, Fazal Nabi, Sanjiv Nichani, Richard K Firmin, Graham Lawson, David R Upton
Introduction: Aminophylline is used to increase diuresis in critically ill children with fluid overload. ECMO is a life support technique used in the management of children with severe cardiopulmonary failure unresponsive to conventional treatment modalities including mechanical ventilation. However, ECMO is known to affect the disposition of drugs as a result of an expanded circulating volume and drug losses associated with the extacorporeal circuit. The purpose of this study was thus to determine the population pharmacokinetics of theophylline during ECMO from routine monitoring data.
Patients and Methods: Retrospective and prospective data from 75 term neonates and children receiving aminophylline during ECMO were eligible for investigation.A total of 160 plasma concentrations,sampled at time intervals ranging 10 to 432 hours, were included. Drug concentrations were measured using the Olympus System, enzyme immunoassay OSR6412 (Olympus Diagnostica GmbH). Population PK analysis and model building using demographic and clinical covariables was carried out using WinNonMix (Version 2.0.1).
Results: A one-compartment model with first order elimination associated to an additive error model was found to be the most suitable. Covariates collected were: Age (post natal in neonates) (median 39 (range 2 – 6205) days), bodyweight (median 4.0 (range 2.1 – 85) Kg), urea and creatinine (mmol/l), renal replacement therapy (e.g. Haemofiltration), ECMO flow rate, Veno-venous or Venoarterial ECMO cannulation, co-medication, c- reactive protein, congenital diaphragmatic hernia, cardiac disease and pneumonia. Of the covariables tested, bodyweight significantly influenced clearance and volume of distribution whilst age was also an important determinant of clearance, as adjudged by the differences in the minus 2 * log likelihood (p<0.005) and the residual error value. The final model parameters were estimated as: clearance (L/hour) = 0.023 * bodyweight + 0.000057 * Age (days), volume of distribution (L/kg) = 0.57. The interindividual variability in clearance and volume of distribution was 38%, and 40% respectively. The residual variance (additive error) corresponded to an estimated standard deviation of 3.5mg/L.
Conclusion: This is the first report of population PK of theophylline in paediatric ECMO patients. The estimated clearance is significantly lower than previously reported in this age group. These differences are probably as a result of the expanded circulating volume, but also altered renal and hepatic physiology in this extremely critically ill group. Large interindividual variability also reflects the heterogeneous nature of patients treated on ECMO.