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Anesth Analg 2000;91:434-439
© 2000 International Anesthesia Research Society

GENERAL ARTICLES

Compound A Concentrations During Low-Flow Sevoflurane Anesthesia Correlate Directly with the Concentration of Monovalent Bases in Carbon Dioxide Absorbents

Hideyuki Higuchi, MD*, Yushi Adachi, MD{dagger}, Shinya Arimura, MD*, Masuyuki Kanno, MD*, and Tetsuo Satoh, MD{dagger}

*Department of Anesthesia, Self Defense Force Central Hospital, Tokyo; and {dagger}Department of Anesthesiology, National Defense Medical College, Saitama, Japan

Address correspondence and reprint requests to Hideyuki Higuchi, MD, Department of Anesthesia, Self Defense Force Central Hospital, 1-2-24 Ikejiri, Setagaya, Tokyo 154-8532, Japan. Address e-mail to higu-chi{at}ka2.so-net.ne.jp


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Sevoflurane degrades to Compound A, which is nephrotoxic in rats. Potassium hydroxide (KOH) and sodium hydroxide (NaOH) are primary determinants of this degradation reaction. To address this, new carbon dioxide absorbents, such as Amsorb® (A; Armstrong Medical, Coleraine, Northern Ireland), which contains neither KOH nor NaOH, Drägersorb 800 Plus® (D; Dräger, Luebeck, Germany), and Medisorb® (M; Datex-Ohmeda, Bromma, Sweden), which contain some NaOH (1% to 2%) and only trace amounts of KOH (0.003%), were recently developed. We compared Compound A concentrations using these three CO2 absorbents during low-flow (1 L/min) sevoflurane anesthesia in surgical patients, with those using a conventional CO2 absorbent, Drägersorb 800 (C). The mean Compound A concentrations ± SD using C, A, D, and M were 18.7 ± 2.5, 1.8 ± 0.7, 13.3 ± 3.5, and 11.2 ± 2.6 ppm, respectively, with significant differences (P < 0.001; A versus C, A versus D, A versus M, C versus D, C versus M). Amsorb prevented the degradation of sevoflurane to Compound A, whereas Drägersorb 800 Plus and Medisorb decreased the degradation to Compound A.

Implications: Sevoflurane degradation to Compound A is decreased by lowering the concentration of monovalent bases in the carbon dioxide absorbent (Drägersorb 800 Plus® [Dräger, Luebeck, Germany] and Medisorb® [Datex-Ohmeda, Bromma, Sweden]) and is virtually eliminated in the absence of these bases (Amsorb® [Armstrong Medical, Coleraine, Northern Ireland]).


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Carbon dioxide absorbents can degrade sevoflurane to Compound A, which is nephrotoxic in rats (1–2) and is the subject of intense debate regarding possible nephrotoxicity in humans (3–8). Dry carbon dioxide absorbents can degrade desflurane, enflurane, and isoflurane to carbon monoxide (CO) (9,10). Production of CO and Compound A is greatly influenced by the basic components of the CO2 absorbents. Potassium hydroxide (KOH) was identified as a major determinant for the breakdown reaction of desflurane and sevoflurane. Sodium hydroxide (NaOH) is less active, causing only a partial decomposition of desflurane and sevoflurane (11–12). Therefore, new carbon dioxide absorbents, such as Amsorb® (Armstrong Medical, Coleraine, Northern Ireland) (13), which contains neither KOH nor NaOH, and Drägersorb 800 Plus® (Dräger, Luebeck, Germany) and Medisorb® (Datex-Ohmeda, Bromma, Sweden), which contain NaOH (1% to 2%) and only trace amounts of KOH (0.003%), were recently developed for the purpose of reducing the degradation of inhaled anesthetics. In vitro analysis revealed that Amsorb® is not chemically reactive with sevoflurane, enflurane, isoflurane, and desflurane (13). The results of this in vitro analysis, however, need to be confirmed under clinical conditions (12). Further, there is no information on Compound A concentration during low-flow sevoflurane anesthesia using Drägersorb 800 Plus® or Medisorb® in clinical situations. The purpose of the current study was to assess Compound A concentrations in an anesthetic system with these three new materials under clinical conditions.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The study was conducted at the Self Defense Force Central Hospital in Tokyo, Japan. The study was approved by the hospital ethics committee. An informed consent form was signed by each patient before participation in the study. The subjects were 38 patients undergoing general anesthesia for various surgeries. They were randomly assigned to one of four groups: the control group (Group C) (n = 10), the Amsorb® group (Group A) (n = 9), the Drägersorb 800 Plus® group (Group D) (n = 10), and the Medisorb® group (Group M) (n = 9). We selected Drägersorb 800® as the control CO2 absorbent. The composition of the four CO2 absorbents used in the current study are shown in Table 1.


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  		Table 1. CO2 Absorbent Compositiona and Priceb
 
Thirty minutes after receiving an IM injection of 0.5 mg of atropine and 0.08 mg/kg midazolam, each patient was given an IV injection of 100–200 µg of fentanyl, 2–2.5 mg/kg propofol, and 0.1 mg/kg vecuronium to facilitate tracheal intubation. Anesthesia was then maintained with sevoflurane, 4 L/min N2O, and 2 L/min O2. After 5 min, the fresh gas flow rate was reduced to 1 L/min. The flow rates of N2O and O2 were set at 600 and 400 mL/min, respectively. The flow rates of N2O and O2 were adjusted to maintain the inspiratory O2 concentration at approximately 40%. Ventilation was controlled with a tidal volume of 8–10 mL/kg, and the ventilatory rate was adjusted to maintain an end-tidal PCO2 of 35–40 mm Hg. End-tidal concentrations of sevoflurane were analyzed using a gas analyzer (Capnomac Ultima; Datex, Helsinki, Finland) that was calibrated immediately before each study. The anesthetic concentration was adjusted by the anesthesiologist to maintain mean arterial blood pressure within ± 20% of baseline. If it was not possible to maintain the mean arterial blood pressure within +20% of baseline at more than 3% sevoflurane end-tidal concentration, 50–100 µg fentanyl was administered.

The CO2 absorbent was changed before the administration of anesthetics to each patient. The anesthesia machine was a Narcomed IIB (Dräger, Telford, PA). A temperature probe (DT-300; Intermedical, Tokyo, Japan) was inserted into the center of the upper absorbent canister and the temperature of the CO2 absorbent was recorded at 5-min intervals. After skin closure, anesthetic administration was discontinued and the fresh gas inflow rate was changed to 6 L/min of oxygen. Once the patients opened their eyes and took a deep breath on verbal command, the endotracheal tube was removed.

Gas samples were obtained from the inspiratory limbs of the anesthetic circuit distal to the one-way valves via a capped stopcock port, using gas-tight glass syringes for Compound A analysis. Inspiratory limb gas samples were obtained from the inspiratory limb every 30 min after intubation and at the end of anesthesia by using a gas-tight locking syringe. The gas was injected into a gas chromatograph (GC-14A; Shimazu, Tokyo, Japan). A glass column 5 m in length with an internal diameter of 3 mm packed with 20% dioctyl phthalate on a Chromosorb WAW (GL Science, Tokyo, Japan) 80/100 mesh was maintained at 110°C in the gas chromatogram. The injection port was maintained at 130°C. A carrier stream of nitrogen flowing at 30 mL/min was delivered through the column to a hydrogen flame ionization detector. The gas chromatograph was calibrated by preparing standard calibration gases from stock solutions of Compound A supplied by Maruishi Pharmaceutical (Osaka, Japan).

The minimum alveolar anesthetic concentration hours (MAC-h) were calculated as 1 MAC = 1.71% (14). The Compound A exposure was calculated from the areas under the curve (AUC) of Compound A concentration versus time, using the trapezoid rule. Values were expressed as the mean ± SD. Inter- and intragroup comparisons of laboratory data were performed using two-way repeated measures analysis of variance using Scheffé’s F-test. Patients’ demographic data and Compound A data were analyzed with analysis of variance by using Scheffé’s F-test. P <0.05 was considered statistically significant.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
There were no differences between the groups in age, height, body weight, duration of anesthesia and surgery, fentanyl dose, and MAC-h (Table 2). End-tidal sevoflurane concentration ranged between 0.7% and 3.2% for the four groups, with no significant difference among the groups (Table 3, Fig. 1). The temperature of the CO2 absorbent in the four groups increased over 3 h and did not change thereafter, with no significant difference among the groups (Table 3). There was no significant difference in the maximum temperature of the CO2 absorbent among the four groups (Table 2). No sign of rebreathing was observed throughout the study.


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  		Table 2. Patient Demographics, Compound A Concentrations, and Temperatures of CO2 Absorbent
 

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  		Table 3. Timely Compound A Concentration, End-Tidal Sevoflurane Concentration, and Temperature of CO2 Absorbent in Each Group
 


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  		Figure 1. Relationship between Compound A concentration and end-tidal sevoflurane concentration in the control group (r2 = 0.70, P < 0.001), the Amsorb® (Armstrong Medical, Coleraine, Northern Ireland) group (r2 = 0.03, P > 0.05), the Drägersorb 800 Plus® (Dräger, Luebeck, Germany) group (r2 = 0.73, P < 0.001), and the Medisorb® (Datex-Ohmeda, Bromma, Sweden) group (r2 = 0.53, P < 0.001).

 
Of all 96 samples in the Group A, Compound A was detected in 85 samples, and these Compound A concentrations were <4 ppm (Table 2, Fig 1). Compound A was detected in the anesthesia circuit at all points of measurement in the C, D, and M groups (Fig. 1). Time-courses of Compound A concentrations in the four groups are shown in Figure 2A. Compound A concentrations in Group A were significantly lower than those in the Group C at all sampling times, at which statistical comparisons were performed (P < 0.001–0.05; Table 3, Fig. 2A). There were significant differences in Compound A inspired AUC, the maximum and mean Compound A concentrations between Group A and the other three groups (P < 0.001–0.01; Table 3). There were also significant differences in Compound A inspired AUC and the maximum and mean Compound A concentrations between Groups M and C (Table 3). There were significant differences in the maximum and mean Compound A concentrations between Group D and Group C (Table 3).



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  		Figure 2. A, Time-courses of Compound A concentrations in the anesthesia circuit in the control group, the Amsorb® (Armstrong Medical, Coleraine, Northern Ireland) group, the Drägersorb 800 Plus® (Dräger, Luebeck, Germany) group, and the Medisorb® (Datex-Ohmeda, Bromma, Sweden) group. *P < 0.05 versus the control group, ¶P < 0.05 versus the Drägersorb 800 Plus® group. Values are mean ± SD. B, Time-courses of the ratio of Compound A concentrations to end-tidal sevoflurane concentration in the control, the Amsorb®, the Drägersorb 800 Plus®, and the Medisorb® groups. *P < 0.05 versus the control group, ¶P < 0.05 versus the Drägersorb 800 Plus® group. Values are mean ± SD.

 
There were positive correlations between the end-tidal sevoflurane concentration and Compound A concentrations in Groups C, D, and M (Fig. 1). There was no correlation between the end-tidal sevoflurane concentration and Compound A concentration in Group A. Figure 2B shows the ratio of Compound A concentration to end-tidal sevoflurane concentration in the four groups. On the whole, there were significant differences in the ratio of Compound A concentration to end-tidal sevoflurane concentration between Group A and the other three groups, between Group C and Group D, and between Group C and Group M (Fig. 2B).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The results of the current study confirm those of the in vitro study by Murray et al. (13) in that Amsorb® efficiently scavenged carbon dioxide and did not degrade sevoflurane to Compound A during low-flow sevoflurane anesthesia. Compound A concentrations, <4 ppm, detected in Group A did not result from sevoflurane degradation, because Compound A is normally present as a contaminant of sevoflurane at these concentrations (13). The current study also revealed that Compound A generation was inhibited by using Drägersorb 800 Plus® and Medisorb®, which contain virtually no KOH (0.003%), compared with Drägersorb 800®, which contains 3% KOH.

Concentrations of Compound A depend on several factors, including fresh gas flow (15–16), end-tidal sevoflurane concentration (17), soda lime temperature (16), and type, freshness, and dryness of the absorbent (16–19). In the current study, we uniformly used 1 L/min as the total gas flow, and used fresh carbon dioxide for each patient. Further, there were no significant differences in end-tidal sevoflurane concentration, the temperature of the CO2 absorbent, and MAC-h among the four groups. Therefore, the difference of Compound A concentration among the four groups probably reflects only differences in absorbent composition.

Compound A is formed by the elimination of hydrogen fluoride from sevoflurane, which is initiated by proton abstraction (12,13). Although the presence of NaOH or KOH is required to initiate the reaction that forms Compound A, many studies report that KOH is the primary determinant of this reaction (11,13,20). Indeed, Compound A generation was decreased from the control, Drägersorb 800®, when Drägersorb 800 Plus® or Medisorb® were used. Medisorb® and Drägersorb 800 Plus® contain essentially no KOH. Moreover, sevoflurane was not degraded at all using Amsorb®, which contains neither KOH nor NaOH. Consequently, these results suggest that the degradation of sevoflurane to Compound A is directly related to the presence of monovalent hydroxide bases.

There was a strong correlation between end-tidal sevoflurane and Compound A concentrations using Drägersorb 800®; and the ratio of Compound A concentration to end-tidal sevoflurane concentration was consistent (approximately 10 ppm per percentage, i.e., 0.001) with our previous study (7) using the same soda lime with a fresh gas flow of 1 L/min. In addition, there was also a strong correlation between end-tidal sevoflurane and Compound A concentrations using Drägersorb 800 Plus® and Medisorb®. The ratio of Compound A concentration to end-tidal sevoflurane concentration using Medisorb® was approximately 40% that of Drägersorb 800®. The inhibition ratio for Compound A generation (40%) is slightly less than that in the in vitro study by Funk et al. (21), who compared total amounts of Compound A over 20 min using Drägersorb 800® with Sofnoline (Molecural Products, Essex, United Kingdom), which is similar to Medisorb® with respect to the composition of the base (40% vs 50% to 60%). Funk et al. (21) washed 8% sevoflurane in oxygen (6 L/min) into an absorbing canister, using a circle system. Sofnoline contains 2.6% NaOH and no KOH. The slight difference in the inhibition of Compound A generation might be because of the difference in the brands of the CO2 absorbent and the temperature of the CO2 absorbent, because the temperature did not increase in the study by Funk et al (21).

Although the cost of Amsorb® is approximately twice that of Medisorb®, Amsorb® is ideal with respect to the degradation of sevoflurane (Table 2) (12). Moreover, Amsorb® can free anesthesiologists from the issue of Compound A, which is still debatable on nephrotoxicity, although clinically significant renal effects in surgical patients have not been demonstrated (3–8,17–19). Further, Amsorb® also might free us of the issue of CO because Amsorb® does not degrade desflurane, enflurane, and isoflurane to CO in vitro (13).

In summary, sevoflurane degradation to Compound A is decreased by decreasing the concentration of monovalent bases in the carbon dioxide absorbent (Drägersorb 800 Plus® and Medisorb®) and is virtually eliminated in the absence of these bases (Amsorb®). Widespread use of absorbents without monovalent bases will decrease or eliminate concerns regarding Compound A toxicity from sevoflurane and carbon monoxide toxicity from desflurane, enflurane, or isoflurane.


   Acknowledgments
 
Supported, in part, by the 44th Welfare Work Subsidy of Chiyoda Life Insurance Health Enterprise Group, Tokyo, Japan. Armstrong Medical, Dräger, and Datex-Ohmeda did not donate any funds to this Research Foundation, nor have any of the authors received any support from any of the these commercial organizations.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Morio M, Fujii K, Satoh N, et al. Reaction of sevoflurane and its degradation products with soda lime: Toxicity of the byproducts. Anesthesiology 1992;77:1159–64.
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Accepted for publication April 24, 2000.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2000 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press