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A Study of Dose Response in Man

Michael J. Cousins, MB; Richard I. Mazze, MD

JAMA. 1973;225(13):1611-1616.

Abstract
Dose-related abnormalities in renal function occurred in ten of 18 patients following administration of methoxyflurane (Penthrane) with the usual anesthetic adjuvants. Eight control patients anesthetized with halothane (Fluothane) showed no abnormalities in renal function.

Subclinical toxicity occurred following methoxyflurane at minimum alveolar concentration (MAC) for 2.5 to 3 hours, that is 2.5 to 3 MAC hours (serum inorganic fluoride, >50 micromols/liter), while clinical toxicity was present in all patients at dosages greater than five MAC hours (serum inorganic fluoride, >90 micromols/liter). Superimposed on the dose-response relationship were other factors that probably increased nephrotoxicity. These were as follows: individual variations in metabolism of methoxyflurane; increased sensitivity to the nephrotoxic effects of inorganic fluoride; presence of enzyme induction; and interaction of methoxyflurane with other nephrotoxic drugs.

The use of methoxyflurane in clinical anesthesia should be restricted to situations where it offers specific advantages and where dosages less than 2.5 MAC hours can be attained.

Author Affiliations
From the Departments of Anesthesia, Stanford University School of Medicine, Stanford, and Veterans Administration Hospital, Palo Alto, Calif.

Footnotes
Reprint requests to Department of Anesthesia, Stanford University School of Medicine, Stanford University Service, Veterans Administration Hospital, Palo Alto, CA 94304 (Dr. Cousins).

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