The specter of potential nephrotoxicity looms for two reasons: (1) sevoflurane reacts with carbon dioxide absorbents to produce a vinyl ether known as Compound A; (2) sevoflurane undergoes biotransformation to inorganic fluoride, a property that might cause polyuric vasopressor-resistant nephropathy similar to that encountered three decades ago with methoxyflurane. However, this second reason for concern has largely been laid to rest. Unlike the experience with methoxyflurane, there has been no correlation between peak fluoride levels after sevoflurane in excess of 50µM and increased postanesthetic serum creatinine or blood urea nitrogen (BUN) values. Indeed, even with peak fluoride levels averaging 101 ± 21 µM, volunteers were able to concentrate urine normally when given vasopressin [2]. Probably the most likely explanation for the difference between methoxyflurane and sevoflurane is that the former is biotransformed to fluoride in the kidneys and liver, whereas sevoflurane undergoes significant biotransformation only in the liver.

The current study by Mazze and colleagues explored the postoperative effects on serum creatinine and BUN in 22 different controlled clinical trials that included 3,436 surgical patients (American Society of Anesthesiologists physical status I-IV) anesthetized with either sevoflurane (n = 1,941) or one of three control anesthetics (isoflurane, enflurane, or propofol; n = 1,495). The patients ranged in age from 17 to 93 years. Duration of anesthesia ranged from less than 30 minutes to approximately 11 hours. Up to 15.1 MAC hr of volatile anesthetic was administered, but most patients (97%) were exposed to less than 4 MAC hr. Propofol was given at rates ranging from 33 µg/kg/min to 264 µg/kg/min, with patients receiving total doses of 400 to 8620 mg. Either a nonrebreathing or rebreathing anesthesia circuit was used, the latter with soda lime or baralyme for carbon dioxide absorption. Total fresh gas flow (FGF) rates ranged from 1 L/min to 10 L/min, with 91% of patients receiving FGF rates greater than 2 L/min. A clinically significant increase in serum creatinine was defined as an increase of 0.5, 1.0, or 1.5 mg/DL, for patients with baseline creatinine values 1.9, 2.0–4.9, or 5.0 mg/DL, respectively. A significant increase in BUN was defined as an increase 25% greater than the upper limit of normal for patients with normal or low baseline values or an increase 25% greater than baseline for patients with preoperative BUN values greater than normal. Raw data from each patient were analyzed rather than the mean data from each of the 22 trials.

The investigators concluded that, based on their analysis of serum creatinine and BUN data from 22 well controlled trials involving 3,436 patients, sevoflurane was not linked to evidence of renal toxicity, regardless of the FGF rate at which the agent was administered. Moreover, this apparent lack of nephrotoxicity was true when baseline creatinine and BUN levels were greater than normal and when potentially nephrotoxic antibiotics were concurrently administered.

Given that there are now more than 60 urinary tests of renal function, the heart of the matter is how to best assess renal function in surgical patients. Eger and associates claim that serum creatinine and BUN are not sensitive enough indicators of abnormal renal function in patients given sevoflurane [2]. They documented increased urinary excretion of albumin, glucose, alpha-glutathione-s-transferase, and -glutathione-s-transferase in volunteers given 1.25 MAC sevoflurane for eight hours. These alterations in urinary markers were transient, peaking on day 3 and returning to normal by day 7. There were no changes in serum creatinine or BUN levels in these volunteers anesthetized with sevoflurane. Of interest, however, is the fact that these results could not be duplicated by Ebert and colleagues who used a similar protocol but found no difference in the preanesthetic to postanesthetic values of the urinary markers nor in serum creatinine or BUN values in volunteers anesthetized with sevoflurane [3].

In an accompanying editorial, Bedford and Ives underscore three limitations to the study by Mazze and colleagues [4]. First, because 91% of the patients received FGF's greater than 2 L/min, these relatively high inflow rates limit rebreathing and therefore minimize Compound A concentrations. Thus, the potential for Compound A to produce renal injury was not rigorously tested. Second, 97% of patients received less than 4 MAC hr of anesthetic and, therefore, the investigators did not adequately test the effects of prolonged sevoflurane anesthesia. Finally, reliance on serum creatinine level as the primary marker of renal insult may be inadequate because it is not a good indicator of increased glomerular permeability nor of tubular integrity. (Interestingly, increasing concentrations of Compound A above a threshold of approximately 160 ppm-hr in humans seems to be associated with dose-related albuminuria, glucosuria, and enzymuria).

How can we prevent increased Compound A concentrations? In a circle absorber anesthesia circuit, Compound A concentrations correlate directly with sevoflurane concentrations and absorbent temperature and inversely with FGF rate. Therefore, increasing FGF rate decreases Compound A formation by decreasing rebreathing of gas from the absorbent and by decreasing the amount of CO2 that reaches the absorbent (the amount of CO2 determines the temperature of the absorbent). Concerns, however, about degradation of anesthetics by carbon dioxide absorbents to toxic compounds may become moot as the availability and popularity of absorbents, such as calcium hydroxide or lithium hydroxide, increase. These absorbents contain neither sodium hydroxide or potassium hydroxide, both of which enhance Compound A production.

Lastly, we must ask ourselves whether transient albuminuria, glucosuria, and enzymuria reflect renal injury or merely functional abnormalities. Are certain patients potentially more vulnerable to more serious degrees of injury? Answers to these important issues are eagerly awaited.

1. The effects of sevoflurane on serum creatinine and blood urea nitrogen concentrations: a retrospective, twenty-two-center, comparative evaluation of renal function in adult surgical patients.

2. Eger EI, Koblin DD, Bowland T, et al. Nephrotoxicity of sevoflurane versus desflurane. Anesth Analg. 1997;84:160-8.



3. Ebert TJ, Frink Jr EJ, Kharasch ED. Absence of biochemical evidence for renal and hepatic dysfunction after 8 hours of 1.25 minimum alveolar concentration of sevoflurane anesthesia in volunteers. Anesthesiology. 1998;88:601-10.



4. Bedford RF, Ives HE. The renal safety of sevoflurane (editorial). Anesth Analg. 2000;90:505-8.