Effects of Inhaled Anesthetics

There is a well-recognized renal nephrotoxic effect of the older volatile inhaled anesthetics that is attributed to the

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Sevoflurane appears to act as enflurane does in regard to the generation of inorganic fluoride as a result of metabolism.^{[53] [54] [55] [56]} Sevoflurane undergoes approximately 5% metabolism, and the primary metabolites are fluoride and hexafluoroisopropanol. Once formed, hexafluoroisopropanol is conjugated in the liver with glucuronic acid and excreted. The oxidative defluorination of sevoflurane in the liver causes liberation of free fluoride ions. Concerns have been raised that sevoflurane might impair the ability of the kidneys to concentrate urine (as methoxyflurane does).^[54] Earlier research indicated that renal dysfunction from methoxyflurane was likely to occur when dose or duration of administration resulted in serum fluoride concentrations that exceeded 50 µM/L.^[51] This presumed threshold for toxicity has been extrapolated for other halogenated anesthetic agents, including enflurane and sevoflurane. However, because sevoflurane is defluorinated by the cytochrome P450 enzyme system, renal defluorination of sevoflurane is not clinically significant. In American Society of Anesthesiologists (ASA) class I and II patients, it was shown that serum fluoride levels averaged 36.6 ± 4.3 µM/L after 9 MAC hours of sevoflurane anesthesia.^{[53] [57]} These fluoride levels peaked 2 hours after the end of anesthesia and decreased by 50% within 8 hours. The rapid decline of plasma fluoride was attributed to the insolubility and rapid pulmonary elimination of sevoflurane. Desmopressin was used to test urine-concentrating ability before anesthesia and on days 1 and 5 after 9.5 MAC hours of sevoflurane and enflurane anesthesia. ^[57] Mean plasma fluoride levels were approximately twice as high in volunteers receiving sevoflurane as in those receiving enflurane, and 43% of volunteers receiving sevoflurane had plasma fluoride levels that exceeded 50 µM/L. Despite these results, the kidneys of the volunteers receiving sevoflurane were not impaired in their ability to concentrate urine, whereas 20% of volunteers receiving enflurane had transient concentrating deficits on day 1. The investigators postulated that intrarenal production of fluoride ion was a more important factor in the pathogenesis of nephrotoxicity than the association between plasma fluoride levels and nephrotoxicity.^[56] The intrarenal metabolism of methoxyflurane is fourfold greater than the intrarenal metabolism of sevoflurane.

All inhaled anesthetic agents interact with carbon dioxide absorbents to produce toxic compounds. A controversy has arisen concerning the relationships among sevoflurane, nephrotoxicity, and compound A. In circuit systems under conditions of high temperature and low flow rates, carbon dioxide absorbents degrade sevoflurane, resulting in detectable concentrations of fluoromethyl-2,2-difluoro-1-(trifluoroethyl) vinyl ether (i.e., compound A). These degradation products are conjugated in the liver with glutathione. Cysteine conjugates formed in the bile ducts and kidney by the conjugates are metabolized in the kidney by an enzyme (cysteine-conjugate β-lyase) to form end products that result in renal injury, which is characterized by diuresis, glycosuria, proteinuria, and elevated serum BUN and creatinine levels. This renal injury in experimental models was a function of the concentration and the duration of exposure of compound A.^[58] The threshold for injury was exposure to compound A at 50 to 114 parts per million (ppm) for 3 hours, and the lethal dose of compound A was 331 ppm over 3 hours, 203 ppm over 6 hours, or 127 ppm over 12 hours.^[59] The disparity between the results in humans and those in experimental rats may be caused by differences in the metabolic pathway of compound A in the species. Of the four recognized metabolic pathways for compound A, three do not involve renal β-lyase and do not result in organ toxicity. Humans have a 10-fold to 30-fold relative absence of the renal β-lyase enzyme pathway compared with rats, which may account for the apparent absence of renal injury from sevoflurane in humans. One study^[60] evaluated the safety of low-flow sevoflurane anesthesia compared with low-flow isoflurane anesthesia in patients scheduled to have prolonged surgery (>6 hours). The average MAC hours in the sevoflurane group and in the isoflurane group were similar, and the average compound A concentration in the sevoflurane group was 20 ± 7 ppm. Markers of renal injury, including BUN, creatinine, N-acetyl-β-D-glucosaminidase (NAG), and alanine aminopeptidase, were increased similarly in all groups during the prolonged exposure to the volatile anesthetics.

The highest concentrations of compound A possible during anesthesia (mean arterial pressure, 56 mm Hg) was evaluated with sevolfurane in human volunteers. ^[61] Fresh carbon dioxide absorbent was used, and sevoflurane was given (without nitrous oxide) at 1.25 MAC while the esophageal temperature was maintained at 37°C. Volunteers were exposed to the anesthetic gas for 8 hours. In that study, compound A levels approached 50 ppm in the inspired limb of the breathing circuit, and the volunteers were asked to bring in 24-hour urine collections for 3 consecutive days after the anesthetic exposure. In most subjects, there were transient elevations of urinary protein, albumin, glucose, α-glutathione S-transferase (α-GST), and π-glutathione S-transferase (π-GST). No such increases were observed after a similar exposure to desflurane. The glutathione S-transferase (GST) protein protects cells by using reduced glutathione to inactivate reactive compounds before their excretion into the urine (or bile). The isolated forms (α-GST or π-GST) are specific to cells of the proximal and distal renal tubules and are released into the urine after renal damage. Urinary α-GST is a sensitive marker of tubular damage after nephrotoxic and ischemic insults.^[62]

Another study^[63] evaluated the safety and efficacy of sevoflurane versus isoflurane in patients during conditions of flow of less than 2 L/min. Patients from multiple institutions undergoing elective surgery lasting 2 to 8 hours were evaluated. Fresh Baralyme was used for

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