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Canadian Journal of Anesthesia 50:249-252 (2003)
© Canadian Anesthesiologists' Society, 2003
General Anesthesia

Sevoflurane degradation by carbon dioxide absorbents may produce more than one nephrotoxic compound in rats

[La dégradation du sévoflurane par les absorbants de gaz carbonique peut produire plus d’un composé néphrotoxique chez les rats]

Caroline R. Stabernack, MD*, Edmond I Eger, II, MD{dagger}, Uwe H. Warnken, MD{ddagger}, Harald Förster, MD{ddagger}, Douglas K. Hanks, MD§ and Linda D. Ferrell, MD§

* From the Department of Anesthesia and Perioperative Care, and
{dagger} the Department of Pathology,
§ University of California, San Francisco, California, USA, and
{ddagger} the Department of Experimental Anesthesiology, University of Frankfurt, Germany.

Address correspondence to: Dr. Edmond I Eger, Department of Anesthesia and Perioperative Care, Box 0464, Science - 455, 513 Parnassus Avenue, University of California, San Francisco, California 94143-0464, USA. Phone: 415-476-6927; Fax: 415-476-9516; E-mail: egere{at}anesthesia.ucsf.edu


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Purpose: Degradation of sevoflurane by carbon dioxide absorbents produces compound A, a vinyl ether. In rats, compound A can produce renal corticomedullary necrosis. We tested whether other compounds produced by sevoflurane degradation also could produce corticomedullary necrosis.

Methods: Two groups of rats were exposed for four hours to sevoflurane 2.5% delivered through a container filled with fresh Sodasorb® and heated to 30°C or to 50°C, respectively. Compound A was added to produce an average concentration of 120 ppm in both groups. A third (control) group received 2.5% sevoflurane that did not pass through absorbent, and no compound A was added.

Results: As determined by gas chromatography, the higher temperature produced more volatile breakdown products, including compound A. Median necrosis of the corticomedullary junction in the 50°C group [10% (quartiles 1.0%–7.8%); n = 20] exceeded that in the 30°C group [5% (6.5%–15%); n = 18; P < 0.02], and both exceeded the median necrosis in the control group [0% (0.0%–0.2%); n = 10; P < 0.02]. The respective mean ± SD values for these three studies were: 12.8 ± 16.7%, 5.3 ± 4.4%, and 0.3 ± 0.5%.

Conclusion: Degradation products of sevoflurane other than compound A can cause or augment the renal injury in rats produced by compound A.


   Introduction
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 Abstract
 Introduction
Methods
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ARBON dioxide absorbents can degrade sevoflurane [(CH2F)-O-CH(CF3)2] to compound A [(CH2F)-O-C(CF3)(=CF2)].1 In rats, compound A can produce renal corticomedullary necrosis, proteinuria and enzymuria.2–4 Sevoflurane degradation also produces compound B [CH2F-O-CH(CF3)(CF2-O-CH3)],1,2 which, alone, is not toxic.2 Compounds C[(CF2=C)(O-CH2F) (CF2OCH3)], D[(CH3-O-)CF=C(CF3)(OCH2F)], and E (an isomer of D), but not free methanol, formaldehyde or formic acid, result from sevoflurane degradation by soda lime at 57°C.1,5

We hypothesized that some of these other degradation products might be nephrotoxic or augment the nephrotoxicity of compound A. To test this hypothesis, we exposed rats to identical concentrations of sevoflurane and compound A with the sevoflurane exposed to two absorbent temperatures, 30°C and 50°C, temperatures found in absorbents used during low-flow delivery of gases.6 Since more degradation products result at higher temperatures, we predicted that greater renal injury should result in rats receiving sevoflurane exposed to hotter absorbent.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Sevoflurane was purchased from Abbott Laboratories (Abbott Park, Illinois, USA). Compound A was donated by Baxter Healthcare Corporation. Cylinders containing compound A were prepared by injecting liquid compound A and pressurizing each cylinder with nitrogen. One cylinder provided a calibration standard (512 ppm) and the other (2,767 ppm) was used to augment compound A delivery to the rats. Sevoflurane and compound A concentrations were analyzed by gas chromatography, referenced to standards prepared by injecting an aliquot of liquid into a flask of known volume.

Sevoflurane in oxygen was delivered via a humidifier (to ensure, as in low-flow clinical anesthesia, gas humidification) to an absorber placed in a waterbath to control temperature in the absorbent [2 kg fresh (i.e., not desiccated) Sodasorb® (Grace & Co., Atlanta, Georgia, USA) containing 15% water] at either 30°C or 50°C (measured in the centre of the absorbent REF 402/702A, YSI Inc., Yellow Springs, Ohio, USA; FigureGo). The sevoflurane vaporizer was adjusted to deliver 2.5% sevoflurane (measured every 5–15 min) to the rats despite sevoflurane degradation. Degradation produced more compound A at 50°C than at 30°C. Downstream from the absorbent we added compound A from the source cylinder to produce an overall concentration delivered to the rats of 120 ppm regardless of absorbent temperature (FigureGo). The dose selected (120 ppm) was estimated from previous studies to produce some renal injury but not injury so severe as to obscure an increase in injury should it occur.4 We condensed water in the absorbent effluent with an ice trap to prevent condensation in the cylinders containing the rats and to preclude exposing the rats to increased temperatures.



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  		FIGURE This line drawing depicts the course of gas flow delivered to the rats. Sevoflurane is added to oxygen, and the combination is delivered to a humidifier placed in a waterbath at either 30°C or 50°C. After traversing the humidifier, the gases flow through Sodasorb® enclosed in a container in the waterbath. The gases leave the Sodasorb® and pass through a cold trap (a bottle surrounded by ice). Compound A may be added to the effluent from the cold trap in order to ensure (for the two test groups but not the control group) that the gases delivered to the rats contained 120 ppm compound A (as determined in a "sample for analysis"). In the case of the control studies, the humidifier-Sodasorb®-cold trap steps are bypassed and compound A is not added. For all study groups, the delivered sevoflurane concentration, as determined in "sample for analysis," is approximately 2.5%.

 
After approval by the University of California Committee on Animal Research, we purchased 48 male Wistar rats (Charles River Lab., Wilmington, Massachusetts, USA) weighing 150–200 g. Each rat ate standard rat chow and water ad libitum in housing that provided a 12-hr light/dark cycle. Food was withdrawn 18 hr before study to mimic the fasting status of patients preoperatively.

Each rat was placed in a clear cylinder sealed at each end (except for holes for gas flow) with rubber stoppers, and anesthetized with sevoflurane. Rectal temperature was sustained at 36.6°C to 38.2°C. Gas flow through each cylinder maintained a carbon dioxide concentration of < 7 mmHg.

The study began by diverting the sevoflurane delivered from the vaporizer to the Sodasorb® (except for control rats where sevoflurane without compound A was administered without passage through Sodasorb®). Compound A was added from the source as indicated. The concentrations of sevoflurane and compound A were adjusted so that the target concentrations, on average, were achieved.

Exposure to 2.5% sevoflurane with/without compound A was discontinued after four hours. The oxygen flow of 4–8 L•min-1 continued for several minutes during recovery. The rats were returned to their cages and given water and rat chow ad libitum Two days later, the rats were killed by administration of 100% carbon dioxide. The right kidney was removed, bivalved and immediately placed in 10% buffered formalin. Tissue slices were stained with hematoxylin and eosin, randomly arrayed, and examined by a pathologist blinded to the condition of exposure (D.K.H.) who estimated the percentage of necrotic cells plus dying (apoptotic) cells (cells with acidophilic nuclear changes) at the corticomedullary junction.

Data for the percentage of necrotic/apoptotic cells were skewed. Thus, we applied the Mann-Whitney U test and present the results as median values and quartiles, as well as means and standard deviations. We accepted that P < 0.05 indicated statistical significance.


   Results
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 Abstract
 Introduction
 Methods
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Discussion
 References
 
Average sevoflurane concentrations for the four hour exposures were 2.39 ± 0.05% (control rats; n = 10), 2.53 ± 0.09% (Sodasorb® at 30°C; n = 18; in one run only eight rats were available), and 2.51 ± 0.14% (Sodasorb® at 50°C; n = 20). Average compound A concentrations were 121.0 ± 23.4 and 120.4 ± 14.7 ppm, respectively, for the last two groups. Average absorbent temperatures were 31.6 ± 0.9°C and 50.4 ± 1.9°C, close to the waterbath temperatures.

Kidneys from control rats (no compound A added) displayed no significant corticomedullary junction necrosis (TableGo). Both groups of rats exposed to compound A had necrosis (P < 0.005). Necrosis was significantly greater in rats exposed to sevoflurane passed through absorbent at 50°C than absorbent at 30°C (P < 0.02).


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  		TABLE Effect of sevoflurane with and without compound A with and without other degradation products on injury to the renal corticomedullary junction
 

   Discussion
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 Abstract
 Introduction
 Methods
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References
 
Our results suggest that degradation products other than compound A may cause renal injury or augment the injury. But are studies in rats relevant to humans? Rats2–4 show a dose-related nephrotoxicity from compound A evidenced by proteinuria, enzymuria, and necrosis of the corticomedullary junction. Humans6–9 show proteinuria and enzymuria at approximately the same compound A doses that produce these effects in rats. Unless one assumes that the correlation of these markers with necrosis applies in rats but not humans, humans also have necrosis. However, in humans the finding of injury may be rare because it takes prolonged sevoflurane anesthesia at high concentrations and at low inflow rates and with fresh soda lime to produce injury, and even then the injury is transient.6–9 The clinical relevance of renal injury from compound A (and now, other compounds) continues to be debated.

Our results may have implications concerning the differences in results of studies of the renal effects of compound A in humans. Some studies find proteinuria and enzymuria after prolonged sevoflurane anesthesia,6–9 while others do not.10 The studies that find proteinuria and enzymuria were conducted in warmer rooms. Perhaps a warmer environment increases the remote risk of renal injury from sevoflurane anesthesia.


   Footnotes
 
Reprints will not be available from the author.

Dr. Eger is a paid consultant to Baxter Healthcare Corporation. This study was not funded by Baxter Healthcare Corporation (nor by any other external source), who did, however, supply compound A for these studies.

Revision received November 11, 2002. Accepted for publication August 20, 2002.


   References
TOP
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
1 Wallin RF, Regan BM, Napoli MD, Stern IJ. Sevoflurane: a new inhalational anesthetic agent. Anesth Analg 1975; 54: 758–65.[Abstract/Free Full Text]

2 Morio M, Fujii K, Satoh N, et al. Reaction of sevoflurane and its degradation products with soda lime. Toxicity of the byproducts. Anesthesiology 1992; 77: 1155–64.[Medline]

3 Keller KA, Callan C, Prokocimer P, et al. Inhalation toxicity study of a haloalkene degradant of sevoflurane, compound A (PIFE), in Sprague-Dawley rats. Anesthesiology 1995; 83: 1220–32.[Medline]

4 Gonsowski CT, Laster MJ, Eger EI II, Ferrell LD, Kerschmann RL. Toxicity of compound A in rats. Effect of increasing duration of administration. Anesthesiology 1994; 80: 566–73.[Medline]

5 Förster H, Warnken UH, Asskali F. Various reactions of sevoflurane with the individual components of soda lime (German). Anaesthesist 1997; 46: 1071–5.[Medline]

6 Eger EI II, Koblin DD, Bowland T, et al. Nephrotoxicity of sevoflurane versus desflurane anesthesia in volunteers. Anesth Analg 1997; 84: 160–8.[Abstract]

7 Eger EI II, Gong D, Koblin DD, et al. Dose-related biochemical markers of renal injury after sevoflurane versus desflurane anesthesia in volunteers. Anesth Analg 1997; 85: 1154–63.[Abstract]

8 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.[Medline]

9 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.[Abstract/Free Full Text]

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




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