Compound A: toxicology and clinical importance

Sevoflurane,like all currently used volatile anaesthetics, is degraded by c arbon dioxide absorbents. The most significant degradant is a haloalkene kn own trivially as "compound A" Compound A is nephrotoxic in rats and, at hig her doses,in nonhuman primates, causing proximal tubular necrosis. There ha s been much interest in the potential for compound A toxicity in humans. In haled compound A concentrations are greatest at low flow rates, high sevofl urane concentrations, warmer absorbent, barium hydroxide vs soda lime,and d rier absorbent. Typical inspired compound A concentrations during low-flow and closed-circuit sevoflurane anaesthesia in humans are 8-24 and 20-32 ppm with soda lime and barium hydroxide lime, respectively. Renal effects of c ompound A production during sevoflurane anesthesia have been examined in su rgical patients and volunteers, using standard (creatinine clearance, serum BUN and creatinine)and experimental (urine excretion of protein, glucose, NAG, GST, AAP) markers of renal function. Investigations to date in surgica l patients show similar renal effects of low-flow sevoflurane, low-flow iso flurane or high-flow sevoflurane. There have been no case reports of compou nd A-associated renal injury in humans. In volunteers, one study found chan ges in experimental but not conventional renal markers, while other investi gations show no significant changes in either standard or experimental mark ers. The mechanism of compound A nephrotoxicity in rats appears to involve metabolism to glutathione and cysteine conjugates, and their subsequent ren al uptake and metabolism by pathways that are different in rats and humans.