Anesthesiology 1977 Apr;46(4):265-71
Inorganic fluoride nephrotoxicity: prolonged enflurane and halothane anesthesia in volunteers.
Mazze RI, Calverley RK, Smith NT.
The effects of prolonged enflurane and halothane administration on urine-concentrating ability were determined in volunteers by examining their responses to vasopressin before anesthesia and on days 1 and 5 after anesthesia. A significant decrease in maximum urinary osmolality of 264 +/- 34 mOsm/kg (26 per cent of the preanesthetic value) was present on day 1 after enflurane anesthesia, whereas subjects anesthetized with halothane had a significant increase in maximum urinary osmolality of 120 +/- 44 mOsm/kg. Serum inorganic fluoride level peaked at 33.6 muM and remained above 20 muM for approximately 18 hours. Thus, the threshold level for inorganic fluoride nephrotoxicity is lower than previously suspected.
It is well established that methoxyflurane administration in man and Fischer 344 rats results in a dose-related renal concentrating defect by virtue of anesthetic metabolism to inorganic fluoride. (2, 3) It is less clear whether enflurane metabolism to inorganic fluoride results in fluoride nephropathy. Also, the threshold level for inorganic fluoride nephrotoxicity is still debated.
With regard to the latter question, Cousins and Mazze (2) tested urine-concentrating ability in surgical patients anesthetized with methoxyflurane by comparing urinary osmolality, measured after overnight dehydration, before and after operation. Vasopressin concentration tests were administered only to patients who had abnormalities in the post-operative dehydration test. Defects in concentrating ability were recorded only when serum inorganic fluoride levels exceeded 50 uM. A similar threshold value has been determined in Fischer 344 rats. (3, 7, 8) Other investigators have measured inorganic fluoride levels in surgical patients anesthetized with methoxyflurane, but have not measured urine-concentrating ability. Nevertheless, it has been stated that serum inorganic fluoride values as high as 100 uM are safe. (9, 10)
Data relating enflurane anesthesia and post-anesthetic urine-concentrating ability are scarce. Clinical polyuric renal failure has been reported to occur in only three surgical patients, all of whom have had pre-existing renal disease. (11-13) Cousins et al. (14) reported a controlled, randomized, prospective study of surgical patients without renal disease, anesthetized with a mean enflurane dose of 2.7 + 0.3 MAC hours. Preoperatively, urine-concentrating ability was measured after overnight dehydration. Postoperatively, vasopressin was administered to determine urine-concentrating ability, in most cases 48 hours after the end of operation. Mean peak serum inorganic fluoride level in this study was 22.2 + 2.8 uM. Their results showed no significant difference between pre- and postanesthetic urine-concentrating abilities, nor was there a difference between groups of patients anesthetized with enflurane as compared with halothane. Interpretation of the results of this study would have been simplified had vasopressin been used to measure preanesthetic as well as postanesthetic urine-concentrating ability.
The present study overcomes many of the deficiencies of previous investigations. (1, 2, 10, 14-17) Highly reliable, identical methods of measuring urine-concentrating ability were employed before and after anesthesia. Subjects were free of systemic disease and were not operated upon. Inadvertently, subjects anesthetized with halothane received lactated Ringer's solution in 5 per cent dextrose, whereas subjects treated with enflurane generally received 0.45 per cent saline solution in 5 per cent dextrose. Because intravenous fluids were administered for only one day, it is unlikely that the differences in solute content of these solutions influenced the results of the study. Thus, the urine-concentrating defect observed in enflurane-treated subjects was probably due to anesthetic biodegradation to inorganic fluoride.
The present study helps to define the threshold of inorganic fluoride nephrotoxicity. Serum inorganic fluoride level peaked six hours after enflurane anesthesia at a concentration of approximately 33 uM (fig. 2). Twelve hours later, by which time serum inorganic fluoride level had decreased to 21 uM, vasopressin was administered. By the end of the vasopressin test, serum inorganic fluoride level had decreased to approximately 8 uM. Thus, during the 24-hour test period, average serum inorganic fluoride level was only 15 uM, yet subjects had a 25 per cent reduction in maximum urine-concentrating ability compared with preanesthetic values. What, then, is the threshold of inorganic fluoride nephrotoxicity? Since a no-effect level was not achieved, a precise threshold cannot be defined. Also, organ toxicity is related not only to the peak level of the toxic substance, but to the length of time the organ is exposed to high levels, i.e., the area under the curve. In the present study, the kidneys were exposed to a mean peak serum inorganic fluoride level of 33.6 uM, with values above 20 uM for 18 hours; this combination proved to be nephrotoxic. Whether peak serum inorganic fluoride level is a more significant determinant of nephrotoxicity than is duration of elevation cannot be established from these data.
What are the clinical implications of a concentrating defect of the magnitude demonstrated in the present study? They are probably inconsequential in patients without renal disease. All subjects evidenced considerable renal reserve, in that they were able to concentrate urine to an osmolality at least twice that of plasma. Also, the rapid decrease of serum inorganic fluoride level after enflurane anesthesia suggests that maximum urine-concentrating ability may have returned to preanesthetic values even sooner than the fifth postanesthetic day, the day on which the second vasopressin test was carried out. Since surgical patients generally are exposed to lower enflurane doses than were the volunteers in the present study, and, therefore, have lower serum inorganic fluoride levels, (14) it is likely that enflurane anesthesia will not adversely aifect their renal function and fluid homeostasis. On the other hand, surgical patients with pre-existing renal disease could be harmed by superimposing an inorganic fluoride load on already-damaged kidneys. In these individuals, a urine-concentrating defect might be of longer duration than in the volunteers examined in the present study, since excretion of inorganic fluoride would be impaired.
The more-than-twofold differences in peak serum inorganic fluoride levels among subjects anesthetized with essentially the same dose of enflurane are not unexpected (fig. 3). Since subjects were not known to have been exposed to enzyme-inducing drugs or chemicals, this difference probably represents normal biologic variation. Differences in drug metabolism of this magnitude are common and are thought to be under genetic control; they have been found with anesthetic (2, 10, 14-18) as well as nonanesthetic compounds. (19) The genetic aspect of control of metabolism in the present study is illustrated by identical twin subjects, both anesthetized with enflurane. Their peak inorganic fluoride levels were the lowest measured in the study and were virtually the same, 21.6 and 24.3 uM.
Finally, this study confirms the findings of Johnstone et al. (20) and Tinker et al. (21) regarding serum inorganic bromide levels in subjects anesthetized with halothane. Values approaching 3 mEq/1 were measured, with peak levels persisting until five days after anesthesia, when the experiment was concluded. Psychoactive levels of inorganic bromide are thought to be in the range of 6-10 mEq/1, with levels of 25-75 mEq/1 encountered in cases of deep coma. (22) At present, it is not known whether the levels noted in our subjects were psychoactive. Since the half-life of bromide in human blood is approximately 11.5 days, (23) it is possible that psychoactive bromide levels could be achieved if halothane anesthetics were repeated frequently, as in patients having burn-dressing changes.
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17. Young SR, Stoelting RK, Peterson C, et al: Anesthetic biotransformation and renal function in obese patients during and after metboxyflurane or halothane anesthesia. ANESTHESIOLOGY 42: 451-457, 1975
18. Cascorbi HF, Vesell ES, Blake DA. et al: Genetic and emironmental influence on halothane metabolism in twins. Clin Pharmacol Ther 12:50-55, 1971
19. Vesell ES: Drug therapy: Pharmacogenetics. N Engl J Med 287:904-909, 1972
20. Johnstone RE, Kennell EM. Behar MG, et al: Increased serum bromide concentration after halothane anesthesia in man. ANESTHESIOLOGY 42:598-601, 1975
21. Tinker JH, Gandolfi AJ, Van Dyke RA: Elevation of'plasma bromide levels in patients following halothane anesthesia: Time correlation with total halothane dosage. ANESTHESIOLOGY 44:194-196, 1976
22. Andrews S: Blood bromide levels in psychiatric patients taking bromureides. Med J Aust May 1, 1965, pp 646-652
23. Soremark R: The biological half-life of bromide ions in human blood. Acta Physiol Scand 50:119-123, 1960
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