DOES UPTAKE OF COMPOUND A CORRELATE WITH RENAL INJURY?:

S170 INTRODUCTION: Sevoflurane degradation by CO2 absorbants produces compound A concentrations that can cause renal injury in humans [1] and rats [2]. Recent reports suggest a threshold for renal injury after exposure to compound A [1]. It is further suggested that this olefin compound generated may bind to the tissues resulting in renal injury. We designed this study to evaluate the kinetics of compound A in normal volunteers and attempt to correlate the kinetic parameters and renal toxicity. METHODS: After IRB approval and informed consent 11 healthy male volunteers between the ages of 18-30 and weighing >or=to to 80 kg participated in this open label study. Anesthesia was induced with propofol 2-3mg/kg and tracheal intubation facilitated with vecuronium 0.1 mg/kg. 3% end tidal sevoflurane (2.4% MAC) was achieved and maintained using an inflow of 8 L/min for 5 min. Gas flow was then lowered and maintained at 2 L/min for 8 hours. Inspired and expired gas samples were obtained for analysis of compound A and sevoflurane using a validated GC assay. The inter and intra-day coefficient of variation (%CV) of this assay is < 3% for compound A concentrations ranging from 1 - 70 PPM and < 1% for sevoflurane. At the end of 8 hours sevoflurane was terminated abruptly and the circuit transformed into a non rebreathing system. Expired samples were also obtained at 1 min, 5 min, 10 min, 15 min, and when possible 20 min after this conversion. 24 hour urine collections were obtained prior to and on days 1-5, & 14 days post exposure to sevoflurane. Urine samples were tested for glucose, albumin, and protein. RESULTS: Urinary, glucose, albumin, and protein increased in all the volunteers after exposure to sevoflurane. In 5 of 11 volunteers urinary glucose and protein increased significantly above normal. The maximum increase in urinary excretion of protein was seen at 3 days post exposure. The inspired concentration of compound A as well as the area under the curve for inspired compound A was significantly higher in volunteers who had a significant increase in urinary excretion of protein and glucose. In addition the uptake of compound A, defined as the difference between the inspired and expired concentration, was significantly higher in volunteers with renal injury. The elimination half-life of compound A was estimated to be 0.6 +/- 0.2 h-1. DISCUSSION: Our results not only indicate nephrotoxicity of compound A after 8 hours of exposure to 3% sevoflurane at 2 L/min inflow but also demonstrates that the extent of uptake of compound A is significantly higher in subjects demonstrating nephrotoxicity. The elimination half-life of compound A estimated in this study is most likely an underestimation of its true elimination due to the short sampling time.