Compound A formation is greater with lower fresh gas flow rates, larger sevoflurane concentrations, and use of barium hydroxide lime as compared with soda lime
(8). Numerous clinical investigations have evaluated Compound A formation and postoperative renal function after low-flow and closed-circuit sevoflurane, in which maximum inspired Compound A concentrations typically averaged 824 ppm and 2032 ppm with soda lime and barium hydroxide lime, respectively (
9
16). Compound A exposures (AUCinsp) in these investigations averaged 65
(12), 67
(9), 79
(15), 120
(10), 124
(14), 192
(16), 250
(11), and 260
(13) ppm · h. Most of these investigations evaluated standard clinical measures of renal function (creatinine clearance, serum creatinine, and BUN) and found no clinically significant effect of low-flow sevoflurane on renal function in surgical patients (
9
16), as did others in which Compound A was not measured (
17,
18). Because proteinuria, glucosuria, and enzymuria are more sensitive than serum BUN and creatinine in detecting Compound A nephrotoxicity in rats (
3,
5,
19), interest arose in applying these biomarkers in humans. Using these theoretically more sensitive, although clinically unvalidated, markers of perioperative renal tubular integrity (
20,
21), two initial investigations found no significant renal effect of low-flow (1 L/min) sevoflurane, assessed with both conventional and experimental markers of renal toxicity (
14,
15). Low-flow sevoflurane was considered as safe as low-flow isoflurane (
14,
15,
21).
The Food and Drug Administration subsequently permitted a change in the sevoflurane labeling, from a recommended lower limit of 2 to 1 L/min, but with a 2 minimum alveolar anesthetic concentration-hour (MAC-h) maximum exposure (because of a lack of data under the latter con-ditions
)
