In Reply:--My editorial [1]was focused only on my thoughts concerning the article by Kharasch et al. [2]in the same issue. The toxicity of compound A, hexafluoroisopropanol toxicity, and other aspects of sevoflurane, both political and scientific, were not discussed. The editorial was strictly confined to commentaries of the novel concept that local renal production and hence high local renal concentrations of fluoride ion may be of greater importance in renal toxicity from fluorinated inhalation anesthetics than is hepatic fluoride production as measured by the plasma fluoride concentration. Contrary to Tinker and Baker's contention, neither my editorial (nor Kharasch et al.'s original paper [2]) discounted the nephrotoxic potential of fluoride ions. The issue was whether renal or hepatic production of fluoride was the more important vector of nephrotoxicity with inhalation anesthetics. The fact remains that several publications have documented plasma fluoride concentrations well in excess of 50 micro Meter, whether from sevoflurane, enflurane, isoflurane, or fluoride ion intoxication, [3]without evidence of renal toxicity.
Tinker and Baker refer repeatedly to "heavy biotransformation." Let me supply the facts. Eight percent of the enflurane dose and 3-5% of the sevoflurane dose [4,5]are metabolized. Tinker and Baker are correct that some anesthetic toxicity is due to biotransformation. I am not convinced of their contrapositive argument that all biotransformation results in toxicity. No clinical pharmacologist believes this either. It is unfortunate that Tinker and Baker are prepared to pontificate with the statement that sevoflurane "is a step backward," a statement obviously made without access to the facts established with the clinical development of sevoflurane.
I again propose that the major hypothesis that nephrotoxicity is agent-specific, occurs primarily because of intrarenal fluoride ion production, and is not primarily dependent on fluoride ion plasma concentration is impressive. [6]It underscores the rule that medicine can never rest on its laurels [1]: minds should remain open, vigilance should be maintained, and new data should be continually sought.
Burnell R. Brown, Jr., M.D., Ph.D., F.R.C.A., Professor Emeritus, Department of Anesthesiology, University of Arizona, College of Medicine, Tucson, Arizona 85724.
(Accepted for publication April 29, 1995.)
