A NEW INHALATION ANAESTHESIA TECHNIQUE FOR DAY SURGERY


	San Sebastian 2004 Session 2-3
	<Back to Abstract Home Page> <Previous Page> <Next Page> <Program>

Shouldn’t we finish the endless discussion: Compound A still a matter of concern? / No deberíamos acabar con la interminable discusión: ¿El compuesto A aún es motivo de preocupación?.

Prof. Jonny Hobbhahn, Clinic of Anaesthesiology; University of Regensburg, Regensburg, Germany.

Abstract

Sevoflurane, like all currently used volatile anaesthetics, is degraded by carbon dioxide absorbents. The most significant degradant is a haloalkene known as "compound A" being nephrotoxic in rats at an exposure of 150 – 340 ppm-h. Applying low-flow sevoflurane in volunteers one study group found an intact renal function using validated markers of renal function (creatinine clearance, serum BUN and creatinine), but a transient increase of experimental markers of renal function (urine excretion of protein, glucose, and certain tubular enzymes). This “transient renal injury” was attributed to compound A. Additionally, the study group claimed a threshold value of compound A of about 150 ppm-h to induce transient renal injury and postulated a similar renal sensitivity to compound A in humans as in rats.

However, over the years these results and conclusions could not be confirmed by other study groups. Several studies found that the renal uptake and metabolism of the glutathione and cysteine conjugates of compound A are different in rats and humans. Thus, the threshold for nephrotoxicity of compound A in rats does not apply to humans. Furthermore, summarizing all data about protein excretion on postoperative day 3 (as “sensitive marker” of renal dysfunction) after low-flow sevoflurane from surgical patients and volunteers did not show a threshold even though exposures up to almost 500 ppm-h had been documented.

Considering all of the studies published to date in patients or volunteers (other than that reported by Eger et al.), and even using proteinuria as a so-called “sensitive” (albeit unvalidated and experimental) marker of renal dysfunction, there is no difference between the renal effects of low-flow sevoflurane and other anaesthetics (isoflurane, desflurane, enflurane and propofol). This also applies to patients with preexisting renal impairement. Furthermore, there have been no case reports of compound A-associated renal injury reported in humans so far. Thus, low-flow, minimal-flow and closed-loop anaesthesia with sevoflurane is as safe as anaesthesia with other anaesthetics. In conclusion , compound A is no longer a matter of concern.

Compound A is produced by degradation of sevoflurane in the presence of soda lime or Baralyme. As such, it is not a metabolite produced by biotransformation of sevoflurane in the body, but is rather a degradation product generated in the anaesthesia circuit. Compound A is a haloalkene and is nephrotoxic in rats and, at higher doses, in nonhuman primates, causing proximal tubular necrosis.

Inhaled compound A concentrations are greatest at low flow rates, high sevoflurane concentrations, warmer absorbent, barium hydroxide vs soda lime, and drier absorbent. Typical inspired compound A concentrations during high-flow (3 – 6l/min), low-flow (£ 1l/min) and minimal-flow sevoflurane anaesthesia in humans are <10 ppm, 20 – 30 ppm and ~40 ppm, respectively (table 1). However, toxicity of inhaled toxins correlates less with the inspiratory concentrations but more closely with total exposition to the toxins, i.e. the product of inspiratory concentration and time of application (area under the curve = AUC) which is given in ppm-h. The inspiratory load of compound A to induce nephrotoxicity in rats was found to be 150 – 340 ppm-h.

The discussion whether compound A may induce transient subclinical nephrotoxicity in humans was initiated by a study of Eger and coworkers comparing prolonged low-flow anaesthesia of 10 MAC-h of sevoflurane (average exposure to Compound A: 328 ppm-h) with prolonged low-flow anaesthesia of 10 MAC-h desflurane in volunteers (1). Neither anaesthetic affected serum creatinine or BUN, nor impaired the ability of the kidney to concentrate urine in response to vasopressin. In the sevoflurane group, however, postanaesthetic urinary excretion of protein, glucose and urinary enzymes (alpha-GST and pi-GST ) increased transiently, which is considered to reflect glomerular and tubular damage. The authors classified this as “transient renal injury” due to compound A (1). This study and another one by the same group led the authors to postulate a threshold value of compound A to induce transient renal injury in humans of about 150 ppm-h (2).Thereby, they claimed a renal sensitivity to compound A in humans similar to rats.

The studies and conclusions drawn by Eger and coworkers induced a number of studies of other groups, resulting in a more thorough understanding of the nature of sevoflurane and its degradation products than any other volatile anaesthetic in history.

Several studies revealed that the mechanism of compound A nephrotoxicity in rats apparantely involves metabolism to glutathione and cysteine conjugates, and that their subsequent renal uptake and metabolism occurs by pathways that differ in rats and humans. It was shown that the toxification pathway of Compound A is sixfold higher in rats than in humans (3). This and other findings implicated that the threshold for nephrotoxicity of compound A in humans may be significantly higher than that in rats.

Two low-flow studies with sevoflurane in volunteers (10-MAC-h and 5 MAC-h corresponding to a compound A exposure of 240 and 152 ppm-h, respectively) gave no evidence of transient renal injury, even though similar “sensitive markers” of glomerular and tubular function had been measured (4,5).

Several controlled clinical studies with low-flow sevoflurane (6-10) or minimal-flow sevoflurane anaesthesia (11) did not show a specific disadvantageous effect of sevoflurane on renal function in patients without preexisting renal disease. Some of these studies found significant increases in urine glucose, protein, and albumin in the postoperative days suggesting transient renal injury, however, these changes occurred similarly in all control groups, i.e. also after desflurane, isoflurane and propofol [fig. 1]. Thus, the only conclusion that can be drawn from these clinical studies is, that alterations in postoperative renal excretory function are common and unrelated to the choice of anaesthetic (fig. 2) (10,12). Again, none of these studies revealed a change of serum creatinine, BUN, or creatinine clearance which are established indices of renal function and prognostically significant in clinical medicine. In contrast, measurement of urinary enzyme excretion (NAG, alpha- and pi-GST) has not been validated as a reliable indicator of clinically significant renal injury in humans.

The question whether patients with preexisting renal disease might be more sensitive to compound A has also been addressed in controlled studies recently. Low-flow sevoflurane anaesthesia was not associated with a deteriorated renal function in these patients, i.e. low-flow sevoflurane is considered as safe as low flow isoflurane in patients with stable preexisting renal disease (fig. 3 and table 2) (13,14). These results confirm previous studies in patients with renal insufficiency, conducted at higher flow rates, which showed no significant differences in the renal effects of sevoflurane and other volatile anaesthetics (15-19).

The advocates of a pathogenic role of compound A in clinical anaesthesia argue that the compound A exposure in the majority of clinical studies has been too small to generate “transient renal injury”. In fact, many of the trials found an average exposure to compound A below 150 ppm-h and 240 ppm-h, the purported thresholds for subclinical nephrotoxicity in humans postulated by Eger and Goldberg in their investigations in volunteers (1,20). However, duration of anaesthesia and surgery in these clinical studies reflect typical clinical care with procedures lasting as long as 3 h (11), 4h (6) , 5 h (10), 6h (9), and 9h (8) in the average. Thus, the question arises at which clinical procedure at all patients with low-flow or minimal-flow sevoflurane would be at risk to reach the purported thresholds for “transient renal injury”. Furthermore, summarizing all data about protein excretion on postoperative day 3 after low-flow sevoflurane from surgical patients and volunteers (including those of Eger and Goldberg), did not show a threshold even though exposures up to almost 500 ppm-h had been documented [fig. 5] (12). Thus, the threshold for toxicity of compound A in humans remains to be established.

In conclusion, compound A is no longer a matter of concern. It is time to stop the unfounded fears about sevoflurane nephrotoxicity.

Table 1:

Typical inspired compound A concentrations during sevoflurane anaesthesia in humans

Table 2:

Quantitative 24-h Urine Protein and Glucose. From (14).

Figure 1:

Urine parameters (mean ± SD) before and for 3 days after surgery with desflurane, sevoflurane, or propofol anaesthesia. Albumin and protein were significantly increased above preoperative levels for the 3 days postoperatively, but the increases were not different between anaesthetics. Glucose was significantly increased above preoperative (and normal) levels on day 1 after surgery. *P < 0.05, significantly different from preoperative value on all postoperative days; †P < 0.05, significantly different from preoperative value on postoperative day 1. From (10).

Figure 2:

Effect of anaesthesia on urine protein excretion. Results are from postoperative day 3, which is typically the time of maximum proteinuria. Low-flow (< 2 l/min) sevoflurane data are from surgical patients (n = 120) (6,8,10,21-23) surgical patients with chronic renal insufficiency (n = 56) (14), and normal volunteers (n = 71)(1,2,4,5,20). Data from Eger and from Goldberg are redrawn from figure 3 of Goldberg, multiplying albumin excretion by 1.25 to estimate protein concentration (20). Comparator data are from low-flow isoflurane in patients with normal renal function (n = 83), (6,8,21,23) patients with renal insufficiency (n = 53), (14), and volunteers (n = 4) (4,5), high-flow sevoflurane patients (n = 40) (21-23) low-flow desflurane patients (n = 18)(10) and propofol patients (n = 10)(10). Box plots show the median, mean (dashed lines), 25th and 75th percentiles (box boundaries), 10th and 90th percentiles (whiskers), and outliers outside the 10th and 90th percentiles. The reference range based on data from healthy nonsurgical subjects is shown by the dotted line. There were no significant differences between the groups (p = 0.25, Mann–Whitney rank sum test). From (12).

Figure 3:

Serum creatinine values after low-flow sevoflurane and low-flow isoflurane anaesthesia in patients with stable renal insufficiency. There was no statistically significant difference between groups. From (14).

Figure 4:

Relationship between protein excretion and compound A exposure (area under the curve of inspired compound A concentration vs. time) during low-flow sevoflurane anaesthesia. Results are from postoperative day 3, which is typically the time of maximum proteinuria. Data are from surgical patients (n = 94), (6,8,10,21-23) and normal volunteers (n = 68) (1,2,4,5,20). Data from Eger and from Goldberg are redrawn from figure 3 of Goldberg, multiplying albumin excretion by 1.25 to estimate protein concentration. The data indicate that there is no threshold for an increased renal protein excretion even though compound A exposure amounted to almost 500 ppm-h (12).

References

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

2. Eger EI, Gong D, Koblin DD, et al. Dose-related biochemical markers of renal injury after sevoflurane versus desflurane anaesthesia in volunteers. Anesth Analg 1997;85:1154-63.

3. Kharasch ED, Jubert C. Compound A uptake and metabolism to mercapturic acids and 3,3,3- trifluoro-2-fluoromethoxypropanoic acid during low-flow sevoflurane anaesthesia: biomarkers for exposure, risk assessment, and interspecies comparison. Anesthesiology 1999;91:1267-78.

4. Ebert TJ, Messana LD, Uhrich TD, Staacke TS. Absence of renal and hepatic toxicity after four hours of 1,25 minimum alveolar anaesthetic concentration sevoflurane anaesthesia in volunteers. Anesth Analg 1998;86:662-7.

5. Ebert TJ, Frink EJ, Kharasch ED. Absence of renal and hepatic toxicity following 8 hours of 1,25 MAC sevoflurane anaesthesia in volunteers. Anesthesiology 1998;88:601-10.

6. Kharasch ED, Frink EJ, Zager R, et al. Assessment of low-flow sevoflurane and isoflurane effects on renal function using sensitive markers of tubular toxicity. Anesthesiology 1997;86:1238-53.

7. Groudine SB, Fragen RJ, Kharasch ED, et al. Comparison of renal function following anaesthesia with low-flow sevoflurane and isoflurane. J Clin Anesth 1999;11:201-7.

8. Kharasch ED, Frink EJ, Artru A, et al. Long-duration low-flow sevoflurane and isoflurane effects on postoperative renal and hepatic function. Anesth Analg 2001;93:1511-ents.

9. Bito H, Ikeuchi Y, Ikeda K. Effects of low-flow sevoflurane anaesthesia on renal function: comparison with high-flow sevoflurane anaesthesia and low-flow isoflurane anaesthesia. Anesthesiology 1997;86:1231-7.

10. Ebert TJ, Arain SR. Renal responses to low-flow desflurane, sevoflurane, and propofol in patients. Anesthesiology 2000;93:1401-6.

11. Goeters C, Reinhardt C., Gronau E., et al. Minimal flow sevoflurane and isoflurane anaesthesia and impact on renal function. Eur J Anaesthesiol 2001;18:43-50.

12. Kharasch EDM, Conzen PMD, Michalowski PMD, et al. Safety of Low-flow Sevoflurane Anaesthesia in Patients with Chronically Impaired Renal Function is not Proven: In Reply. [Letter]. Anesthesiology 2003;99:752-4.

13. Higuchi H, Adachi Y, Wada H, et al. The effects of low-flow sevoflurane and isoflurane anaesthesia on renal function in patients with stable moderate renal insufficiency. Anesth Analg 2001;92:650-5.

14. Conzen PF, Kharasch ED, Czerner SF, et al. Low-flow sevoflurane compared with low-flow isoflurane anaesthesia in patients with stable renal insufficiency. Anesthesiology 2002;97:578-84.

15. Conzen PF, Nuscheler M, Melotte A, et al. Renal function and serum fluoride concentrations in patients with stable renal insufficiency after anaesthesia with sevoflurane or enflurane. Anesth Analg 1995;81:569-75.

16. Tsukamoto N, Hirabayashi Y, Shimizu R, Mitsuhata H. The effects of sevoflurane and isoflurane anaesthesia on renal tubular function in patients with moderately impaired renal function. Anesth Analg 1996;82:909-13.

17. Nishiyama T, Aibiki M, Hanaoka K. Inorganic fluoride kinetics and renal tubular function after sevoflurane anaesthesia in chronic renal failure patients receiving hemodialysis. Anesth Analg 1996;83:574-7.

18. Mazze RI, Callan CM, Galvez ST, et al. 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. Anesth Analg 2000;90:683-8.

19. Story DA, Poustie S, Liu G, McNicol PL. Changes in plasma creatinine concentration after cardiac anaesthesia with isoflurane, propofol, or sevoflurane: a randomized clinical trial. Anesthesiology 2001;95:842-8.

20. Goldberg ME, Cantillo J, Gratz I, et al. Dose of compound A, not sevoflurane, determines changes in the biochemical markers of renal injury in healthy volunteers. Anesth Analg 1999;88:437-45.

21. Higuchi H, Sumita S, Wada H, et al. Effects of sevoflurane and isoflurane on renal function and on possible markers of nephrotoxicity. Anesthesiology 1998;89:307-22.

22. Higuchi H, Wada H, Usui Y, et al. Effects of probenecid on renal function in surgical patients anesthetized with low-flow sevoflurane. Anesthesiology 2001;94:21-31.

23. Obata R, Bito H, Ohmura M, et al. The effects of prolonged low-flow sevoflurane anaesthesia on renal and hepatic function. Anesth Analg 2000;91:1262-8.