Clinical Studies on the Safety of Low-Flow Sevoflurane

The clinical use of low-flow anesthesia has garnered interest as anesthesiologists have sought to reduce waste, lower costs, and minimize environmental impact while maintaining patient safety. Sevoflurane is particularly well suited for low-flow techniques due to its rapid onset and offset, low blood-gas solubility, and predictable hemodynamic profile. However, early in its clinical adoption, concerns were raised about harmful byproducts being produced by reactions between sevoflurane and carbon dioxide absorbents under low-flow conditions, motivating clinical studies to confirm its safety. Since the byproduct compound A caused renal injury in animal models, clinical studies were conducted to determine if there were similar risks in human patients.

Human clinical trials evaluating prolonged low-flow sevoflurane anesthesia have consistently shown no clinically significant impairment of renal or hepatic function. Obata and colleagues examined patients undergoing extended surgical procedures with low fresh gas flows and found no meaningful postoperative changes in serum creatinine, blood urea nitrogen, or liver enzymes(1).

Subsequent comparative studies have reinforced these results. Nogami et al. evaluated long-duration, low-flow sevoflurane and isoflurane anesthesia and found no differences in postoperative renal or hepatic function between the two (2). Notably, renal biomarkers remained stable, suggesting that the higher exposure to compound A associated with sevoflurane did not result in measurable organ damage in clinical settings. These studies helped establish that observations from animal models were not directly applicable to humans at clinically relevant exposure levels.

Since compound A is processed by the kidneys, researchers also sought to better understand its renal metabolism during anesthesia. One approach involved using probenecid, a drug known to inhibit renal tubular transport of organic acids. Satoh et al. used probenecid as a pharmacological tool to examine whether altering renal handling of compound A would reveal hidden nephrotoxic effects during low-flow sevoflurane anesthesia (3). Although probenecid altered the processing of compound A, renal function remained stable, and no clinically relevant kidney injury occurred. This study provided further reassurance that exposure to compound A during low-flow sevoflurane anesthesia is well tolerated in humans.

The safety of low-flow sevoflurane has also been evaluated in patients with preexisting renal disease, who are considered particularly vulnerable. Ebert et al. conducted a randomized trial comparing low-flow sevoflurane and low-flow isoflurane in patients with stable renal insufficiency (4). Although fluoride ion and compound A exposure were higher in the sevoflurane group, postoperative renal outcomes were similar between groups, and no significant deterioration in kidney function was detected. This work was instrumental in supporting the use of low-flow sevoflurane in higher-risk patients.

Overall, clinical studies demonstrate that low-flow sevoflurane is a safe and practical anesthetic technique. Across a wide range of surgical procedures and patient populations, including those with renal impairment, kidney and liver function are preserved. These data support the continued use of low-flow sevoflurane as a reliable component of modern anesthetic practice.

References

1. Obata R, Bito H, Ohmura M, et al. The effects of prolonged low-flow sevoflurane anesthesia on renal and hepatic function. Anesth Analg. 2000;91(5):1262-1268. doi:10.1097/00000539-200011000-00039

2. Kharasch ED, Frink EJ Jr, Artru A, Michalowski P, Rooke GA, Nogami W. Long-duration low-flow sevoflurane and isoflurane effects on postoperative renal and hepatic function. Anesth Analg. 2001;93(6):. doi:10.1097/00000539-200112000-00036

3. Satoh T, et al. Effects of probenecid on renal function in surgical patients anesthetized with low-flow sevoflurane. Anesthesiology. 2001;94(1):21-31.

4. Ebert TJ, Frink EJ Jr, Kharasch ED. Low-flow sevoflurane compared with low-flow isoflurane anesthesia in patients with stable renal insufficiency. Anesthesiology. 2002;97(3):578-584.