Fluorinated anaesthetic nephrotoxicity: an update

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Abstract
The potential for fluorinated anaesthetic agents to cause nephrotoxicity can be summarized in two figures: Figure 2 illustrates the time course of anaesthetic defluorination following administration of methoxyflurane, enflurane and isoflurane; Figure 5 depicts changes in urinary osmolality in response to ADH administration versus peak serum fluoride levels after anaesthesia. Figure 2 clearly demonstrates that the shapes of the serum inorganic fluoride curves are different after methoxyflurane, enflurane and isoflurane anaesthesia. Despite the fact that inorganic fluoride has a half life in blood of only 90 minutes, peak levels were maintained for three days after administration of methoxyflurane. By contrast, peak fluoride levels after administration of the other two agents were reached shortly after the end of anaesthesia and they declined rapidly in the postanaesthetic period. To account for the prolonged postanaesthetic elevation of fluoride levels, one only must realize that methoxyflurane is approximately ten times more lipid soluble than either enflurane or isoflurane. Thus, methoxyfiurane is present in the body for days after its administration has ended and is available for postoperative metabolism to inorganic fluoride. Peak fluoride levels also are considerably higher after methoxyflurane anaesthesia than after administration of the other two agents. That is because, on a molar basis, methoxyflurane is biochemically more unstable than either enflurane or isoflurane and is metabolized more per unit of time. Consequently, the area under the fluoride curve is much greater after methoxyflurane anaesthesia than after either enflurane or isoflurane. It is the area under the curve which probably best correlates with nephrotoxicity. Figure 5 demonstrates the strong correlation between changes in urinary osmolality after ADH administration and serum inorganic fluoride levels. Patients anaesthetized with halothane, in whom serum inorganic fluoride levels ranged from 1–3 μM, showed a small increase in urinary osmolality. Volunteers anaesthetized with enflurane in whom fluoride levels were 3–5 μM five days after anaesthesia showed no change in maximum urinary osmolality, whereas an average decrease of approximately 250 mOsm/kg was seen the day after anaesthesia when the mean fluoride level was 33.6 μM. Following high-dose methoxyflurane anaesthesia, fluoride levels ranged from 80– 250 μM and the decrement in maximum urinary concentrating ability ranged from 400 to 600 mOsm/kg. It appears then that the answers to the questions regarding inorganic fluoride nephrotoxicity are clear. Methoxyflurane is a dose-related nephrotoxin; if it is to be used at all, it should be administered only in those clinical situations where it is specifically indicated and when total dosage will be low (less than 2 MAC hours). Enflurane would appear to be safe in almost all patients including those with mild to moderate renal impairment. Isoflurane and halothane are completely devoid of nephrotoxic potential.