To the Editor:—

The recent report by Conzen et al.  concluding “… that low dose sevoflurane anesthesia is safe in patients with chronically impaired renal function”1raises some interesting issues both regarding its specific design and conduct (and the resultant conclusions) and the use of sevoflurane in research in human subjects that was outside the recommendations in the package insert.

First, it is not clear that the authors’ data support their conclusions. On the basis of existing literature, the authors acknowledged that renal injury is most likely related to Compound A exposure. Accordingly, they took measures to “increase compound A exposure … to produce as high compound A concentrations as possible during routine clinical low-flow conditions.” The resulting average compound A dose was 44 ± 31 ppm-h. However, previous work suggests that the threshold for injury is approximately fourfold greater, 150–200 ppm-h. 2–5Some patients received minimal doses of compound A; one patient had a reported inspired dose of zero (0) ppm-h (see table 7 of the article). In addition, the data for compound A dose are skewed, and two thirds of the 55 patients for whom compound A data are available had values less than 44 ppm-h. Only four patients had compound A doses exceeding 100 ppm-h, and for these four the highest dose was 138 ppm-h. Although the authors saw no evidence of renal injury, the relatively low Compound A exposures were not adequate to test their thesis.

In addition, variability in the measured concentrations of the various markers of renal injury was very large. For example, the SD for glucose was four times the mean value. This, again, suggests that the results are skewed, and the variability might obscure a modest nephrotoxic effect of compound A.

Second, the study raises some questions about the use of sevoflurane in patients when there was a possibility of injury but no benefit. Specifically, the sevoflurane package insert approved by the U. S. Food and Drug Administration limits the exposure at low flows, and the authors did not adhere to this directive. We would therefore like to ask the following questions:

1. Were the patients enrolled from American institutions informed in writing of the Food and Drug Administration mandated warning in the package insert that “sevoflurane exposure should not exceed 2 MAC-hours at flow rates of 1 to less than 2 l/min. Fresh gas flow rates less than 1 l/min are not recommended”? Were the institutional review boards at those institutions similarly informed?

2. Although the results of many studies attest to the safety of low-dose sevoflurane, were the patients and the respective institutional review boards informed that results from three studies suggest that prolonged exposure to high concentrations of compound A causes changes suggestive of renal injury, albeit transiently, in humans without renal dysfunction? 2–4 

Conzen PF, Kharasch ED, Czerner SFA, Artru AA, Reichle FM, Michalowski P, Rooke GA, Weiss BM, Ebert TJ: Low-flow sevoflurane compared with low-flow isoflurane anesthesia in patients with stable renal insufficiency. A nesthesiology 2002; 97: 578–584
Higuchi H, Sumita S, Wada H, Ura T, Ikemoto T, Nakai T, Kanno M, Satoh T: Effects of sevoflurane and isoflurane on renal function and on possible markers of nephrotoxicity. A nesthesiology 1998; 89: 307–22
Goldberg ME, Cantillo J, Gratz I, Deal E, Vekeman D, McDougall R, Afshar M, Zafeiridis A, Larijani G: Dose of compound A, not sevoflurane, determines changes in the biochemical markers of renal injury in healthy volunteers. Anesth Analg 1999; 88: 437–45
Eger EI II, Koblin DD, Bowland T, Ionescu P, Laster MJ, Fang Z, Gong D, Sonner J, Weiskopf RB: Nephrotoxicity of sevoflurane versus desflurane anesthesia in volunteers. Anesth Analg 1997; 84: 160–8
Eger EI, II, Gong D, Koblin DD, Bowland T, Ionescu P, Laster MJ, Weiskopf RB: Dose-related biochemical markers of renal injury after sevoflurane versus desflurane in volunteers. Anesth Analg 1997; 85: 1154–63