The effect of anesthetic duration on kinetic and recovery characteristics of desflurane versus sevoflurane, and on the kinetic characteristics of compound A, in volunteers.

UNLABELLED: This study documents the differences in kinetics of 2 h (n = 7) and 4 h (n = 9) of 1.25 minimum alveolar anesthetic concentration (MAC) of desflurane (9.0%) versus (on a separate occasion) sevoflurane (3.0%), both administered in a fresh gas inflow of 2 L/min. These data are extensions of our previous 8-h (n = 7) studies of these anesthetics. By 10 min of anesthetic administration, average inspired (F(I)) and end-tidal concentration (F(A)) (F(I)/F(A); the inverse of the more commonly used F(A)/F(I)) decreased to less than 1.15 for both anesthetics, with the difference from 1.0 nearly twice as great for sevoflurane as for desflurane. During all sevoflurane administrations, F(A)/F(I) for Compound A [CH2F-O-C(=CF2) (CF3); a vinyl ether resulting from the degradation of sevoflurane by Baralyme] equaled approximately 0.8, and the average inspired concentration equaled approximately 40 ppm. Compound A is of interest because at approximately 150 ppm-h, it can induce biochemical and histological evidence of glomerular and tubular injury in rats and humans. During elimination, F(A)/F(A0) for Compound A (F(A0) is the last end-tidal concentration during anesthetic administration) decreased abruptly to 0 after 2 h and 4 h of anesthesia and to approximately 0.1 (F(A) approximately 3 ppm) after 8 h of anesthesia. In contrast, F(A)/F(A0) for desflurane and sevoflurane decreased in a conventional, multiexponential manner, the decrease being increasingly delayed with increasing duration of anesthetic administration. F(A)/F(A0) for sevoflurane exceeded that for desflurane for any given duration of anesthesia, and objective and subjective measures indicated a faster recovery with desflurane. Times (mean +/- SD) to initial response to command (2 h 10.9 +/- 1.2 vs 17.8 +/- 5.1 min, 4 h 11.3 +/- 2.1 vs 20.8 +/- 4.8 min, 8 h 14 +/- 4 vs 28 +/- 8 min) and orientation (2 h 12.7 +/- 1.6 vs 21.2 +/- 4.6 min, 4 h 14.8 +/- 3.1 vs 25.3 +/- 6.5 min, 8 h 19 +/- 4 vs 33 +/- 9 min) were shorter with desflurane. Recovery as defined by the digit symbol substitution test, P-deletion test, and Trieger test results was more rapid with desflurane. The incidence of vomiting was greater with sevoflurane after 8 h of anesthesia but not after shorter durations. We conclude that for each anesthetic duration, F(I) more closely approximates F(A) with desflurane during anesthetic administration, F(A)/F(A0) decreases more rapidly after anesthesia with desflurane, and objective measures indicate more rapid recovery with desflurane. Finally, it seems that after 2-h and 4-h administrations, all Compound A taken up is bound within the body. IMPLICATIONS: Regardless of the duration of anesthesia, elimination is faster and recovery is quicker for the inhaled anesthetic desflurane than for the inhaled anesthetic sevoflurane. The toxic degradation product of sevoflurane, Compound A, seems to bind irreversibly to proteins in the body.

Time-dependent changes in heart rate and pupil size during desflurane or sevoflurane anesthesia.

UNLABELLED: To better characterize alterations in autonomic function associated with prolonged anesthesia, we tested the hypothesis that the time-dependent effects of sevoflurane and desflurane differ. We studied seven male volunteers, each anesthetized for 8 h with 1.25 minimum alveolar anesthetic concentration desflurane on one study day and with 8 h sevoflurane on another. These volunteers did not undergo surgery and were minimally stimulated during the study. Measurements included blood pressure, heart rate, pupillary size and light reactivity, concentrations of serum catecholamines, and carbon dioxide production. Over time, heart rate and pupil size increased significantly. During 6 of the 14 anesthetics (45%), heart rate at some point exceeded 95 bpm; similarly, pupil size at some time exceeded 5 mm during 8 anesthetics (57%). In contrast, plasma catecholamine concentrations and carbon dioxide production remained unchanged, and blood pressure remained nearly constant. There are thus substantial time-dependent changes in autonomic functions during prolonged anesthesia, even in unstimulated, nonsurgical volunteers, but we could not detect a difference in these changes during desflurane compared with sevoflurane anesthesia. IMPLICATIONS: Pupil size and heart rate changes are used to guide the delivery of anesthesia. In volunteers, pupil size and heart rate increased with increasing duration of constant desflurane or sevoflurane anesthesia. Thus, anesthetic duration alters heart rate and pupil size independent of surgery and changes in anesthetic delivery.

Dose-related biochemical markers of renal injury after sevoflurane versus desflurane anesthesia in volunteers.

UNLABELLED: Sevoflurane (CH2F-O-CH[CF3]2) reacts with carbon dioxide absorbents to produce Compound A (CH2F-O-C[=CF2][CF3]). Because of concern about the potential nephrotoxicity of Compound A, the United States package label (but not that of several other countries) for sevoflurane recommends the use of fresh gas flow rates of 2 L/min or more. We previously demonstrated in humans that a 2-L/min flow rate delivery of 1.25 minimum alveolar anesthetic concentration (MAC) sevoflurane for 8 h can injure glomeruli (i.e., produce albuminuria) and proximal tubules (i.e., produce glucosuria and urinary excretion of alpha-glutathione-S-transferase [alpha-GST]). The present report extends this investigation to fasting volunteers given 4 h (n = 9) or 2 h (n = 7) of 1.25 MAC sevoflurane versus desflurane at 2 L/min via a standard circle absorber anesthetic system (all subjects given both anesthetics). Markers of renal injury (urinary creatinine, albumin, glucose, alpha-GST, and blood urea nitrogen) did not reveal significant injury after anesthesia with desflurane. Sevoflurane degradation with a 2-L/min fresh gas inflow rate produced average inspired concentrations of Compound A of 40 +/- 4 ppm (mean +/- SD, 8-h exposure [data from previous study]), 42 +/- 2 ppm (4 h), and 40 +/- 5 ppm (2 h). Relative to desflurane, sevoflurane given for 4 h caused statistically significant transient injury to glomeruli (slightly increased urinary albumin and serum creatinine) and to proximal tubules (increased urinary alpha-GST). Other measures of injury did not differ significantly between anesthetics. Neither anesthetic given for 2 h at 1.25 MAC produced injury. We conclude that 1.25 MAC sevoflurane plus Compound A produces dose-related glomerular and tubular injury with a threshold between 80 and 168 ppm/h of exposure to Compound A. This threshold for renal injury in normal humans approximates that found previously in normal rats. IMPLICATIONS: Human (and rat) kidneys are injured by a reactive compound (Compound A) produced by degradation of the clinical inhaled anesthetic, sevoflurane. Injury increases with increasing duration of exposure to a given concentration of Compound A. The response to Compound A has several implications, as discussed in the article.

Recovery and kinetic characteristics of desflurane and sevoflurane in volunteers after 8-h exposure, including kinetics of degradation products.

BACKGROUND: Desflurane and sevoflurane permit speedier changes in anesthetic partial pressures than do older halogenated anesthetics. The authors determined the kinetic characteristics of desflurane and sevoflurane and those of compound A [CH2F-O-C(=CF2)(CF3)], a nephrotoxic degradation product of sevoflurane. METHODS: Volunteers received 1.25 minimum alveolar concentration of desflurane or sevoflurane, each administered for 8 h in a fresh gas inflow of 2 l/min. Inspired (F(I)) and end-tidal (F(A)) concentrations of anesthetic and compound A were measured during administration, and F(A) relative to F(A0) (the last end-tidal concentration during administration) during elimination. The indices of recovery were also measured. RESULTS: The ratio F(I)/F(A) rapidly approached 1.0, with values greater for sevoflurane (desflurane 1.06 +/- 0.01 vs. sevoflurane 1.11 +/- 0.02, mean +/- SD). The ratio F(A)/F(I) for compound A was approximately 0.8. The F(A)/F(A0) ratio decreased slightly more rapidly with desflurane than with sevoflurane, and objective measures indicated faster recovery with desflurane: The initial response to command (14 +/- 4 min vs. 28 +/- 8 min [means +/- SD]) and orientation (19 +/- 4 vs. 33 +/- 9 min) was quicker, and recovery was faster as defined by results of the Digit Symbol Substitution, P-deletion, and Trieger tests. Desflurane produced less vomiting (1 [0.5, 3]; median [quartiles] episodes) than did sevoflurane (5 [2.5, 7.5] episodes). The F(A)/F(A0) ratio for compound A decreased within 5 min to a constant value of 0.1. CONCLUSIONS: These anesthetics have kinetics consistent with their solubilities. Sevoflurane's greater biodegradation probably increases F(I)/F(A) differences during anesthetic administration and decreases F(A)/F(A0) differences during elimination. The F(A) for compound A differs from F(I) by 20% (F(A)/F(I) = 0.8) because of substantial degradation. Recovery from anesthesia proceeds nearly twice as fast with desflurane than with sevoflurane. Differences in ventilation, or alveolar or tissue elimination, do not completely explain the slower recovery with sevoflurane.

Nephrotoxicity of sevoflurane versus desflurane anesthesia in volunteers.

Present package labeling for sevoflurane recommends the use of fresh gas flow rates of 2 L/min or more when delivering anesthesia with sevoflurane. This recommendation resulted from a concern about the potential nephrotoxicity of a degradation product of sevoflurane, "Compound A," produced by the action of carbon dioxide absorbents on sevoflurane. To assess the adequacy of this recommendation, we compared the nephrotoxicity of 8 h of 1.25 minimum alveolar anesthetic concentration (MAC) sevoflurane (n = 10) versus desflurane (n = 9) in fluid-restricted (i.e., nothing by mouth overnight) volunteers when the anesthetic was given in a standard circle absorber anesthetic system at 2 L/min. Subjects were tested for markers of renal injury (urinary albumin, glucose, alpha-glutathione-S-transferase [GST], and pi-GST; and serum creatinine and blood urea nitrogen [BUN]) before and 1, 2, 3, and/or 5-7 days after anesthesia. Desflurane did not produce renal injury. Rebreathing of sevoflurane produced average inspired concentrations of Compound A of 41 +/- 3 ppm (mean +/- SD). Sevoflurane was associated with transient injury to: 1) the glomerulus, as revealed by postanesthetic albuminuria; 2) the proximal tubule, as revealed by postanesthetic glucosuria and increased urinary alpha-GST; and 3) the distal tubule, as revealed by postanesthetic increased urinary pi-GST. These effects varied greatly (e.g., on postanesthesia Day 3, the 24-h albumin excretion was < 0.03 g (normal) for one volunteer; 0.03-1 g for five others; 1-2 g for two others; 2.1 g for one volunteer; and 4.4 g for another volunteer). Neither anesthetic affected serum creatinine or BUN, nor changed the ability of the kidney to concentrate urine in response to vasopressin, 5 U/70 kg subcutaneously (i.e., these measures failed to reveal the injury produced). In addition, sevoflurane, but not desflurane, caused small postanesthetic increases in serum alanine aminotransferase (ALT), suggesting mild, transient hepatic injury.