Anesth Analg 2004;98:990-993
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000104581.22295.FB
ANESTHETIC PHARMACOLOGY
A Comparison of Liver Function After Hepatectomy in Cirrhotic Patients Between Sevoflurane and Isoflurane in Anesthesia with Nitrous Oxide and Epidural Block
Tomoki Nishiyama, MD, PhD,
Takahiro Fujimoto, MD, and
Kazuo Hanaoka, MD, PhD
Department of Anesthesiology, The University of Tokyo, Tokyo, Japan
Address correspondence and reprint requests to Tomoki Nishiyama, MD, PhD, 3-2-6-603, Kawaguchi, Kawaguchi-shi, Saitama, 332-0015, Japan. Address e-mail to nishit-tky{at}umin.ac.jp
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Abstract
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In this study, we compared postoperative liver function in patients with liver cirrhosis between isoflurane and sevoflurane anesthesia with nitrous oxide (N2O) and epidural block. Forty cirrhotic patients with Child-Pugh Grade A, aged 40 to 70 yr, scheduled for liver segmentectomy, had anesthesia induced with midazolam 0.1 mg/kg and fentanyl 4 µg/kg. For maintenance, intermittent epidural administration of 1.5% lidocaine 4 to 6 mL and sevoflurane (sevoflurane group) or isoflurane (isoflurane group) with N2O 3 L/min in oxygen 3 L/min was used. Aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase, choline esterase, albumin, prothrombin time, and platelet count were measured before and 1, 3, and 7 days after surgery. Aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase increased significantly, with the peaks at 3 days after surgery in both groups. The increases in these variables were significantly larger in the isoflurane group than those in the sevoflurane group. No patient developed hepatic failure. All increases in liver enzymes were small and of questionable clinical relevance. Whether sevoflurane might be a better anesthetic when combined with N2O and epidural block for cirrhotic patients than isoflurane with respect to liver damage remains to be determined.
IMPLICATIONS: In cirrhotic patients with Child-Pugh Grade A, isoflurane induced more of an increase in serum concentrations of liver enzymes after surgery than sevoflurane when combined with nitrous oxide and epidural block. However, the increases were small, and there was no clinical liver damage.
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Introduction
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We often anesthetize patients with liver cirrhosis. For inhaled anesthetics, isoflurane and sevoflurane are frequently used. Isoflurane seems to be better than sevoflurane because the former is less metabolized in the liver. However, previous studies (1,2) found that isoflurane increased serum levels of liver enzymes more often than did sevoflurane in patients without preoperative liver dysfunction.
After halothane anesthesia, liver dysfunction was more exacerbated in rats with moderate to severe liver cirrhosis than in rats without cirrhosis (3). However, no studies of liver function have been performed after isoflurane or sevoflurane anesthesia in patients with liver cirrhosis. The purpose of this study was to compare postoperative liver function in patients with liver cirrhosis between isoflurane and sevoflurane anesthesia with nitrous oxide and epidural block.
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Methods
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After we obtained approval from the hospital’s research committee and informed consent from the patients, 40 cirrhotic patients (Child-Pugh Grade A), aged 40 to 70 yr, scheduled for liver segmentectomy for hepatoma, were randomly divided into 2 groups by an envelope method (20 patients each). Those with a history of general anesthesia, renal dysfunction, habituation of any drugs affecting liver function (such as hypnotics or antidepressants), or bleeding tendencies (bleeding time >3 min, prothrombin time [PT] >13 s, and platelet count <8 x 104/µL) were excluded from the study.
Atropine 0.01 mg/kg (maximum, 0.5 mg) and midazolam 0.04 mg/kg were administered IM as premedication 15 min before anesthesia induction. After insertion of an epidural catheter into T7-8, anesthesia was induced with midazolam 0.1 mg/kg and fentanyl 4 µg/kg. Endotracheal intubation was facilitated by IV vecuronium 0.15 mg/kg. The radial artery was cannulated to monitor arterial blood pressure, and the internal carotid vein was cannulated to monitor central venous pressure. Anesthesia was maintained with intermittent epidural administration of 1.5% lidocaine 4 to 6 mL and sevoflurane (sevoflurane group) or isoflurane (isoflurane group) with nitrous oxide 3 L/min in oxygen 3 L/min. Ventilation was controlled to keep PaCO2 between 30 and 40 mm Hg. Pancuronium was used as a muscle relaxant during surgery. Hepatic blood flow occlusion by taping vessels (Pringle method) for 15 min was performed several times with 5-min intervals. After surgery, patients were followed up in the intensive care unit for 3 days and thereafter in the ward. Postoperative analgesia was provided by intermittent epidural administration of 0.25% bupivacaine.
Arterial blood pressure was monitored continuously by using a radial arterial catheter during surgery and on the first postoperative day and intermittently with a noninvasive method thereafter. Heart rate was monitored with electrocardiogram during surgery and on the first postoperative day and with pulse rate thereafter. Serum concentrations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, alkaline phosphatase, choline esterase, albumin, PT, and platelet count were measured before and 1, 3, and 7 days after surgery.
Data are expressed as mean ± SD. Statistical analysis was performed with Student’s t-test for demographic data and two-way repeated-measures analysis of variance followed by the Student-Newman-Keuls test, a multiple-comparisons correction, as a post hoc test for arterial blood pressure, heart rate, and the laboratory data. P < 0.05 was considered statistically significant.
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Results
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There were no significant differences in demographic data between groups (Table 1). Arterial blood pressure and heart rate were not different between groups (Table 2), and no patients required vasopressors.
AST, ALT, and alkaline phosphatase increased significantly, with the peaks at 3 days after surgery in both groups. The increases in these variables were significantly larger in the isoflurane group than those in the sevoflurane group. Albumin decreased significantly after surgery, and PT transiently increased 1 day after surgery in both groups; there were no differences between groups (Table 3). No patient experienced hepatic failure or clinical liver damage after surgery.
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Discussion
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After hepatectomy in cirrhotic patients, serum concentrations of liver enzymes increased more in the patients anesthetized with isoflurane than in those anesthetized with sevoflurane in combination with nitrous oxide and epidural block in this study. Isoflurane and sevoflurane are not viewed as hepatotoxins. However, fulminant liver failure was reported after repeated isoflurane anesthesia in one patient (4). Liver necrosis was also seen after isoflurane anesthesia (5). The significant increases in 
-glutathione S-transferase concentrations in patients receiving isoflurane suggest a transient disturbance of hepatocellular function (6). After sevoflurane anesthesia, severe liver damage was also reported (7), but the role of sevoflurane is unclear.
There are many factors of general anesthesia that can induce liver damage, such as decreased liver blood flow during anesthesia, increased intracellular calcium concentration (8), or metabolites of anesthetics (9). Portal and hepatic arterial blood flows are reported to be similar during sevoflurane and isoflurane anesthesia (10). The arterial ketone body ratio, which indicates mitochondrial energy charge and liver blood flow during anesthesia, was not significantly different between sevoflurane and isoflurane anesthesia (2). A prolonged increase in Ca2+ concentrations has been implicated in the mechanism of hepatotoxicity; halothane, enflurane, and isoflurane stimulated the release of intracellular Ca2+ (8). The effect of sevoflurane is unknown. Therefore, the possibility of different effects on Ca2+ between isoflurane and sevoflurane as a factor to induce different postoperative liver function should be further studied.
Nitrous oxide and epidural block would also have some effects on liver function. However, the total doses we used were not different between groups, which suggests no different effects on the two groups. In addition, in the postsurgical period, many factors—such as antibiotics, hemodynamics, water balance, and epidural block—would have some effects on liver function. We could not control all of these factors after surgery; therefore, these effects should be considered. Only arterial blood pressure and heart rate were found not to be different between the two groups without administration of any vasopressors.
In inhaled anesthetics, halothane has a risk of liver damage. Halothane produces two types of hepatotoxicity. The first is a mild form that is seen in 20% of patients given halothane anesthesia (11) and is characterized by nausea, lethargy, low-grade fever, and mild transient increases in liver enzymes (AST and ALT). This kind of liver damage is relevant to this study. In contrast, a fulminant hepatic necrosis occurs in approximately 1 in 20,000 adult patients exposed to halothane (12). Covalent binding to subcellular proteins by the trifluoroacetyl acid (TFA) chloride intermediate, a common metabolite of halothane and isoflurane (9) generated by oxidative biotransformation by the cytochrome P450 in the liver, is implicated as a mechanism of centrilobular necrosis of the liver (9). In this respect, sevoflurane and desflurane, which do not have chloride, might be safer than other chlorinated anesthetics. However, desflurane also could form a TFA adduct. Immune sensitization to the anesthetic could have contributed to impaired liver function (13). It is possible that enflurane, isoflurane, and desflurane might cause hepatotoxicity by a mechanism similar to that of halothane, but less frequently, because the degree of anesthetic metabolism appears to be directly related to the potential for hepatic injury (4,14–16).
Only sevoflurane does not produce TFA as a metabolite. However, sevoflurane enhances enzyme induction and increases liver cytochrome P450, which suggests that sevoflurane might induce liver damage (17). Liver cirrhosis would also have some effects on enzyme induction and on stimulation of cytochrome P450 induction. Therefore, in cirrhotic patients, the effect of isoflurane or sevoflurane on postoperative liver function might be different from that in noncirrhotic patients. In the study by Baden et al. (18), halothane, enflurane, and isoflurane induced a mild degree of acute liver dysfunction, and the dysfunction was similar in both cirrhotic and noncirrhotic rats. However, in their later study (3), liver dysfunction was exacerbated more by halothane anesthesia in rats with moderate to severe liver cirrhosis than in rats without cirrhosis. Baden (19) also reported that liver cirrhosis does not increase the risk of acute hepatotoxicity of isoflurane in rats. In this study in humans, isoflurane increased the serum concentration of liver enzymes more than sevoflurane after surgery in combination with nitrous oxide and epidural block in cirrhotic patients. These results are consistent with our previous studies in noncirrhotic patients (1,2), whereas some other studies did not report the difference in liver function between isoflurane and sevoflurane anesthesia in noncirrhotic patients (20–23). The discrepancy between our previous studies (1,2) and others (20–23) might be due to different backgrounds. The studies by Bito and Ikeda (20), Frink et al. (21), and Kharasch et al. (22) used low flow (
2 L/min), whereas ours (1,2) used high flow (6 L/min). Low-flow sevoflurane anesthesia increases Compound A, which might cause organ toxicity (20). Darling et al. (23) did not show total flow, but the duration of anesthesia in their study might have been too short to expose the liver to anesthetics enough to produce the different effects between sevoflurane and isoflurane. We also used nitrous oxide and epidural block during anesthesia, but these were not used together in other studies (22–23). In this study, surgical invasion of the liver might have produced a great but different interaction between sevoflurane and isoflurane. In addition, approximately a 10% difference in exposure to anesthetics (isoflurane > sevoflurane, MAC · h), although not significant, might induce approximately a 20% difference (isoflurane > sevoflurane) in liver enzyme levels.
Although an increase in liver enzymes does not mean hepatotoxicity, it shows damage to some liver cells. Therefore, considering both this and our previous studies (1,2) in cirrhotic and noncirrhotic patients, isoflurane might affect the liver more than sevoflurane when combined with nitrous oxide (and epidural block); however, the clinical importance of this finding might be limited because of the small number of patients tested and the small increases in liver enzyme concentrations.
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Accepted for publication October 16, 2003.
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Abstract
Introduction
