Pharmacokinetic behavior of theophylline following PEEP in critically ill patients with acute lung injury

ABSTRACT

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] two 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 Vd=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 Vd and clearance of theophylline in critically ill patients