Pharmacokinetic Behavior of Theophylline following PEEP in Critically Ill Patients with Acute Lung Injury

The effect of Positive End Expiratory Pressure (PEEP) on the hepatic elimination of low to moderate extraction ratio drugs has not been clearly defined. We prospectively investigated the effect of PEEP on the clearance of theophylline in 30 (20 males and 10 females) intubated critically ill adult patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS). The Mean (±SD) age was 57±17 years, creatinine clearance 86±36 ml/min, serum albumin 3.2±0.57 mg/dl and the median APACHE (acute physiology and chronic health evaluation) II score was 25 (with a range of 16 to 34). Critically ill patients who had met the diagnostic criteria for ALI/ARDS were enrolled on PEEP in low (5-9 cmH2O) and high (10-15 cmH2O) levels. All patients received the ordered dose of aminophylline infusion (3 mg/kg over 30 min and then 15 mg/h) after 2 h of initiating PEEP. Blood samples were collected after the loading dose, 2 and 6 h the aminophylline continuous infusion. Vital signs were recorded before and after 2 h of PEEP and each blood sampling interval. Cirrhotic patients and those who had received any drug which could interact with the metabolism and clearance of theophylline, were not included. The Mean(±SD) value of the pharmacokinetic key parameters of theophylline in high (n=17) and low (n=13) PEEP groups were as follows: V_d=0.42(±0.15) L/kg and 0.54(±0.13) L/kg, clearance = 0.035(±0.024) L/h/kg and 0.056 (±0.025) L/h/kg. Mean measured theophylline concentrations following loading dose were 7.08 mg/L and 5.09 mg/L. The calculated volume of distribution (P<0.03), clearance (P<0.05) and theophylline serum concentration (P<0.05), in high versus low peep group, were found to be significantly different. Positive ventilation tends to reduce V_d and clearance of theophylline in critically ill patients.