title: Assessment of low-flow sevoflurane and isoflurane effects on renal function using sensitive markers of tubular toxicity.
abstract: BACKGROUND
  Carbon dioxide absorbents degrade sevoflurane, particularly at low gas flow rates, to fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (compound A). Compound A causes renal proximal tubular injury in rats but has had no effect on blood urea nitrogen (BUN) or creatinine concentrations in patients. This investigation compared the effects of low-flow sevoflurane and isoflurane on renal tubular function in surgical patients using conventional (BUN and creatinine) and finer indices of renal injury, specifically those biomarkers sensitive for compound A toxicity in rats (glucosuria, proteinuria, and enzymuria [N-acetyl-beta-D-glucosaminidase (NAG) and alpha-glutathione-S-transferase (alpha GST)]).
  
  
  METHODS
  Consenting patients with normal preoperative renal function at two institutions were randomized to receive sevoflurane (n = 36) or isoflurane (n = 37) in oxygen and air. Total gas flow was 1 l/min, opioid doses were minimized, and barium hydroxide lime was used to maximize anesthetic degradation. Inspiratory and expiratory compound A concentrations were quantified every 30-60 min. Blood and urine were obtained before and 24-72 h after anesthesia for laboratory evaluation.
  
  
  RESULTS
  Sevoflurane and isoflurane groups were similar with respect to age, weight, sex, American Society of Anesthesiologists status, anesthetic duration (3.7 or 3.9 h), and anesthetic exposure (3.6 or 3 minimum alveolar concentration [MAC]-hour). Maximum inspired compound A concentration (mean +/- standard deviation) was 27 +/- 13 ppm (range, 10-67 ppm). Areas under the inspired and expired compound A concentration versus time curves (AUC) were 79 +/- 54-ppm-h (range, 10-223 ppm-h) and 53 +/- 40 ppm-h (range, 6-159 ppm-h), respectively. There was no significant difference between anesthetic groups in postoperative serum creatinine or BUN, or urinary excretion of protein, glucose, NAG, proximal tubular alpha GST, or distal tubular pi GST. There was no significant correlation between compound A exposure (AUC) and protein, glucose, NAG, alpha GST, or pi GST excretion. Postoperative alanine and aspartate aminotransferase concentrations were not different between the anesthetic groups, and there were no significant correlations between compound A exposure and alanine or aspartate aminotransferase concentrations.
  
  
  CONCLUSIONS
  The renal tubular and hepatic effects of low-flow sevoflurane and isoflurane were similar as assessed using both conventional measures of hepatic and renal function and more sensitive biochemical markers of renal tubular cell necrosis. Moderate duration low-flow sevoflurane anesthesia, during which compound A formation occurs, appears to be as safe as low-flow isoflurane anesthesia.
authors.affiliation: Department of Anesthesiology, University of Washington, Seattle 98195, USA. kharasch@u.washington.edu
authors.forename: E D
authors.initials: ED
authors.lastname: Kharasch
authors.forename: E J
authors.initials: EJ
authors.lastname: Frink
authors.forename: R
authors.initials: R
authors.lastname: Zager
authors.forename: T A
authors.initials: TA
authors.lastname: Bowdle
authors.forename: A
authors.initials: A
authors.lastname: Artru
authors.forename: W M
authors.initials: WM
authors.lastname: Nogami
mesh_terms: D000118:Acetylglucosaminidase / Q000652:urine; D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000097:blood; D000768:Anesthesia, General / Q000009:adverse effects* / Q000379:methods*; D018685:Anesthetics, Inhalation / Q000008:administration & dosage* / Q000009:adverse effects* / Q000378:metabolism; D001219:Aspartate Aminotransferases / Q000097:blood; D015415:Biomarkers / Q000032:analysis; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000097:blood; D004987:Ethers / Q000008:administration & dosage* / Q000009:adverse effects* / Q000378:metabolism; D005260:Female; D005459:Fluorides / Q000097:blood; D005982:Glutathione Transferase / Q000652:urine; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000009:adverse effects / Q000378:metabolism; D007530:Isoflurane / Q000008:administration & dosage* / Q000009:adverse effects*; D007668:Kidney / Q000187:drug effects* / Q000502:physiology; D007683:Kidney Tubular Necrosis, Acute / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism*; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000502:physiology; D008297:Male; D008738:Methyl Ethers; D008875:Middle Aged; D000077149:Sevoflurane
chemical_list: D018685:Anesthetics, Inhalation; D015415:Biomarkers; D004987:Ethers; D006845:Hydrocarbons, Fluorinated; D008738:Methyl Ethers; D000077149:Sevoflurane; C078742:fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether; D003404:Creatinine; D007530:Isoflurane; D007770:L-Lactate Dehydrogenase; D005982:Glutathione Transferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000118:Acetylglucosaminidase; D005459:Fluorides