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Anesth Analg 2000;91:206-212
© 2000 International Anesthesia Research Society

GENERAL ARTICLES

Low-Flow Desflurane and Sevoflurane Anesthesia Minimally Affect Hepatic Integrity and Function in Elderly Patients

Stefan W. Suttner, MD, Christian C. Schmidt, MD, Joachim Boldt, MD, Ingo Hüttner, MD, Bernhard Kumle, MD, and Swen N. Piper, MD

Department of Anesthesiology and Intensive Care Medicine, Klinikum der Stadt Ludwigshafen, Akademisches Lehrkrankenhaus der Universität Mainz, Ludwigshafen, Germany

Address correspondence and reprint requests to Prof. Dr. Joachim Boldt, Department of Anesthesiology and Intensive Care Medicine, Klinikum der Stadt Ludwigshafen, Bremserstr. 79, D-67063 Ludwigshafen, Germany.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Hepatic blood flow is reduced in a dose-related manner by all inhaled anesthetics now in use. We assessed hepatic function in elderly patients anesthetized with desflurane or sevoflurane. We measured the cytosolic liver enzyme {alpha} glutathione S-transferase ({alpha} GST), the formation of the lidocaine metabolite monoethylglycinexylidide (MEGX), and gastric mucosal tonometry-derived variables as sensitive markers of hepatic function and splanchnic perfusion. Thirty patients, 70 to 90 yr old, were allocated randomly to receive desflurane or sevoflurane anesthesia. Anesthetic exposure ranged from 2.1–4.5 minimum alveolar concentration hours. No significant changes in standard liver enzyme markers were seen throughout the study. In both anesthetic groups, tonometric measurements showed a significant decrease from baseline in regional PCO2, regional to arterial difference in PCO2, and intramucosal pH at 90 min after skin incision. {alpha} GST concentrations increased sig- nificantly in both groups (desflurane: median peak concentrations 5.8 µg/L [25th, 75th percentile 5.3 µg/L, 7.2 µg/L]; sevoflurane: 7.0 µg/L [5.8 µg/L, 7.3 µg/L]) without showing differences between both anesthetic groups. A return to baseline values in tonometric values and {alpha} GST levels was seen 24 h postoperatively. MEGX formation did not change significantly after surgery. Median MEGX concentrations postoperatively were 70.0 ng/mL (56.2 ng/mL, 102.0 ng/mL) and 70.0 ng/mL (60.0 ng/mL, 94.2 ng/mL) in the desflurane and sevoflurane groups, respectively. We conclude that, overall, liver function in elderly patients is well preserved during desflurane and sevoflurane anesthesia. Increased serum levels of {alpha} GST and changes of gastric tonometry-derived variables imply a reduction in splanchnic perfusion, leading to a temporary impairment of hepatocyte oxygenation.

Implications: We measured the lidocaine metabolite monoethylglycinexylidide, the cytosolic liver enzyme, {alpha} glutathione S-transferase, and gastric mucosal tonometry-derived variables to evaluate the effects of desflurane and sevoflurane on hepatic function in elderly patients. Liver function was well preserved, whereas increased {alpha} glutathione S-transferase levels and changes in tonometry-derived variables indicated a reduction in splanchnic blood flow and a temporary impairment of hepatocyte oxygenation for both anesthetics.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
The number of elderly patients undergoing surgery has markedly increased (1). Physiologic aging is almost inevitably associated with a generalized decline in organ function. This progressive loss of reserve in organ function of the elderly combined with coexisting diseases may considerably modify the pharmacokinetic and pharmacodynamic responses to drugs (2). The new inhaled anesthetics, desflurane and sevoflurane, have a lower solubility in blood and tissues than all previous volatile anesthetics (3). Impairment of hepatocellular integrity occurs after the administration of general anesthesia with all modern inhaled anesthetics (4,5). The cytosolic liver enzyme {alpha} glutathione S-transferase ({alpha} GST) has been measured in these studies as a more sensitive marker of hepatocellular damage than conventional liver enzyme markers. Advantages of using {alpha} GST as a marker of hepatocellular damage are the low molecular weight (51 kDa), a high cytosolic concentration (4%–5% of total hepatocellular protein), and short circulatory half-life (<90 min). Consequently {alpha} GST is rapidly released in quantity into circulation after hepatocellular damage and may be used as an indicator to track rapid changes in hepatocellular integrity (6).

Quantitative measurement of the degree of liver impairment is difficult, and conventional "liver function tests," such as measurement of the aminotransferase activities, as well as other more specific enzyme markers, assess hepatobiliary injury rather than early hepatic dysfunction. The formation of the lidocaine metabolite monoethylglycinexylidide (MEGX) has been proposed as a dynamic and flow-dependent assessment of liver function (7). Initially the MEGX formation test has been used in liver transplant centers to assess and predict hepatic function in organ donors and organ recipients (8). The MEGX test has been advocated as a suitable tool for clinical evaluation of liver function after hypovolemic shock and as a predictor of multiple organ failure in intensive care patients (9,10). Gastric mucosal tonometry is a valid and reliable tool for the assessment of splanchnic perfusion in various clinical settings (11,12). Measurement of the regional gastric carbon dioxide tension (prCO2) and the calculation of the gastric intramucosal pH (pHi) and arterial-to-intramucosal-PCO2-difference [p(r-a)CO2] might provide additional information about blood flow in the splanchnic vascular bed (13,14).

Data on hepatic function after exposure to inhaled anesthetics in elderly patients are extremely scarce. The combination of the MEGX test, the measurement of {alpha} GST levels, and gastric tonometry-derived variables might provide valuable information about organ function and blood flow in the splanchnic area. We investigated the effects of desflurane and sevoflurane anesthesia on hepatic function in elderly surgical patients.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After approval by the local ethics committee, 30 ASA physical status II and III patients, aged 70 yr or more, scheduled for either elective orthopedic or peripheral vascular surgery gave written informed consent to participate in the study. Any history of known liver disease or preexisting liver dysfunction (alanine aminotransferase [ALT]/aspartate aminotransferase [AST] >40 U/L), renal insufficiency (creatinine >1,5 mg/dL), abuse of alcohol and drugs, unstable angina pectoris, and a history of myocardial infarction within the last 6 mo were defined as exclusion criteria. No patient had undergone general anesthesia in the preceding 3 mo. No patient known to have had an adverse anesthesia-related event after a previous inhaled anesthesia was included.

All patients were premedicated with midazolam (3.75–7.5 mg) orally before the induction of anesthesia. Patients were allocated randomly to receive either desflurane or sevoflurane inhalational anesthesia. Anesthesia in Group 1 (desflurane; n = 15) was induced with thiopental (3–5 mg/kg) and fentanyl (2–3 µg/kg). Rocuronium (0.6 mg/kg) was administered to achieve muscle relaxation before endotracheal intubation. The induction of anesthesia in Group 2 (sevoflurane; n = 15) was achieved as described for Group 1. Desflurane or sevoflurane (1.0 ± 0.2 minimum alveolar anesthetic concentration [MAC]) was used for the maintenance of anesthesia in Groups 1 and 2, respectively. A constant fresh gas flow of 1 L/min was used during the maintenance of anesthesia. Mechanical ventilation was performed in both groups with 60% nitrous oxide in oxygen by using a semiclosed rebreathing circuit. The MAC hours exposure was calculated from the percent anesthetic concentration and the duration of exposure. MAC values of 5.2 vol% and 1.4 vol% were used for desflurane and sevoflurane, respectively (15,16). The ventilation pattern was adjusted to keep SaO2 > 95% (continuous oximetry) and to maintain partial pressure of carbon dioxide (PCO2) and pH in the physiological range. In addition to routine intraoperative monitoring, a radial artery was cannulated for continuous measurement of mean arterial blood pressure and for obtaining blood samples. Hemodynamic stability was maintained by adjusting the inspired anesthetic concentration or by administering small doses of fentanyl. A threshold of hypotension was defined as a mean arterial pressure of <70 mm Hg for more than 10 min in both groups. Hypotensive episodes were treated by increasing the rate of fluid administration (lactated Ringer’s solution, gelatin solution) and/or by reducing the inspired anesthetic concentration. Packed red blood cells were given when the hemoglobin concentration was below 8.5 g/dL. A nasogastric tube was inserted in all patients. The correct positioning of the tube was confirmed by aspiration of gastric fluid and auscultation over the gastric area after injection of approximately 30 mL of air. prCO2 and pHi were measured by using the TonocapTM monitor (Tonometrics Division Instrumentarium Corporation, Helsinki, Finland). This monitoring device calculates pHi from the arterial pH, the PaCO2 entered by the user, and the measured prCO2 by using the Henderson-Hasselbalch equation (11). The p(r-a)CO2 is calculated from systemic PaCO2 and prCO2. Arterial blood samples were analyzed immediately after sampling for PaO2, PaCO2, and pH in an automatic blood gas analyzer. Measurements were performed at the induction of anesthesia (T1), 90 min after skin incision (90 min), at the end of surgery (T2), and 2 h postoperatively (T3).

After surgery, all patients were tracheally extubated and observed in the postanesthesia care unit for the next 2 h. Peripheral venous blood samples for {alpha} GST and aminotransferase measurements were taken at T1, T2, T3, and 24 h postoperatively (T4). {alpha} GST concentration in serum was measured by using the Enzyme Immunoassay HepkitTM-{alpha} Human GST-{alpha} (Biotrin, Dublin, Ireland). The test of this quantitative enzyme immunoassay is based on the sequential addition of sample, enzyme-conjugate, and substrate to microtiter wells coated with anti-{alpha} GST IgG. The reference range of {alpha} GST is 0–7.5 µg/L. The intraassay coefficient of variation was <7%. The MEGX test was performed according to Oellerich et al. (7) at T1 and T2. A subtherapeutic dose of lidocaine (1 mg/kg) was administered IV over 1 min. Serum samples were obtained immediately before and 15 min after lidocaine administration. The MEGX concentration was determined by using a fluorescence polarization immunoassay (TDx; Abbot, Wiesbaden, Germany). The preinjection concentration was subtracted from that at 15 min to calculate the amount of MEGX produced in 15 min. MEGX values above 90 ng/mL are considered normal, whereas values below 50 ng/mL are thought to reflect impaired liver function (7). Activity of aminotransferases and total bilirubin concentrations were mea- sured in routine hospital laboratory tests. Reference ranges for AST, ALT, {gamma}-glutamyltransferase, and total bilirubin were 5–19 IU/L, 5–23 IU/L,6–28 IU/L, and 0.2–1.2 mg/dL, respectively, as specified by the hospital’s department of clinical chemistry.

Data are shown as either mean ± SD or median (25th, 75th percentile). The assumption of normality was checked by using the Kolmogorov-Smirnov test. Continuous, normally distributed data were compared by using paired and unpaired Student’s t-tests or analysis of variance for repeated measures. When multiple comparisons were made, the Bonferroni correction was applied. Continuous, nonnormally distributed data were compared by using the Wilcoxon test. Binominal data were compared by using {chi}2 analysis and Fisher’s exact test. Before the study, the required sample size was determined by assuming that the minimum clinically important difference we wished to detect was a 25% decrease in MEGX formation after surgery. We estimated that the SD for MEGX values would be up to 20 ng/mL. The {alpha} error was set 0.05 (two-sided) and type II error was set at 0.2. The projected sample size was 14 patients per group.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Of the 32 patients initially screened for the study, 2 were excluded from analysis because of abnormal preoperative laboratory tests (AST > 40 U/L). Patient characteristics, intake of concomitant medication, and data from the perioperative period were comparable (Table 1). Mean dose of the volatile anesthetic and need for thiopental, fentanyl, and rocuronium were similar in both groups (Table 2). Blood loss and hemodynamics did not differ between anesthetic groups. During the study, 13 units of allogeneic packed red blood cells were transfused in 3 patients of each group (Table 2). One patient in the sevoflurane group received fresh frozen plasma (2 units).


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  		Table 1. Patient Characteristics and Perioperative Data
 

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  		Table 2. Anesthetic Exposure, Consumption of Additional Anesthetics, Fluid Management, and Hypotensive Episodes
 
Tonometric measurements showed significant changes from baseline in prCO2, p(r-a)CO2, and pHi at 90 min in both anesthetic groups (P < 0.05), without showing significant differences between both groups (Table 3). At T2 and T3, p(r-a)CO2, and pHi returned to baseline values, without a difference between the groups. There were no differences in arterial blood gas values within or between the groups. Preoperative data of ALT, AST, {gamma}-glutamyltransferase, and bilirubin were within normal limits in both groups. No significant changes in conventional liver function tests were seen throughout the study. Baseline values of {alpha} GST concentrations were normal in all patients and comparable between both groups (Figure 1). {alpha} GST concentrations were significantly (P < 0.05) higher than baseline at T2 and remained elevated at T3 in both groups. The largest median concentrations of this enzyme were detected at T2 (desflurane: 5.8 µg/L [5.3 µg/L, 7.2 µg/L]; sevoflurane: 7.0 µg/L [5.8 µg/L, 7.3 µg/L]). A return to baseline values was seen at the first postoperative day in both groups. There were no significant differences in {alpha} GST concentrations between anesthetic groups. There were no differences in baseline MEGX levels between the desflurane and sevoflurane groups (median MEGX concentration 80.0 ng/mL [60.7 ng/mL, 97.5 ng/mL] in the desflurane group; 74.0 ng/mL [51.5 ng/mL, 85.0 ng/mL] in the sevoflurane group). There were no significant changes in MEGX formation postoperatively. Median MEGX concentrations were 70.0 ng/mL (56.2 ng/mL, 102.0 ng/mL) and 70.0 ng/mL (60.0 ng/mL, 94.2 ng/mL) in the desflurane and sevoflurane groups, respectively (Figure 2).


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  		Table 3. Changes of Intramucosal pH (pHi), Regional pCO2 (prCO2), and Regional-to-Arterial pCO2 [p(r-a)CO2]
 


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  		Figure 1. Concentrations of serum {alpha} glutathione S-transferase ({alpha} GST). T1= induction of anesthesia, T2= end of surgery, T3 = 2 h postoperatively, T4 = 24 h postoperatively. Values are displayed as box-and-whisker plots. The horizontal lines in the box denote the 25th, 50th (median), and 75th percentile values. The error bars denote the 10th and 90th percentile values. All values for the variable above the 90th percentile and below the 10th percentile are plotted separately as open squares to display outliers. *P < 0.05, significantly different from baseline value.

 


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  		Figure 2. Serum monoethylglycinexylidide (MEGX) concentration. Values are displayed as box-and-whisker plots. The horizontal lines in the box denote the 25th, 50th (median), and 75th percentile values. The error bars denote the 10th and 90th percentile values. All values for the variable above the 90th percentile and below the 10th percentile are plotted separately as open squares to display outliers. Open boxes = desflurane, shaded boxes = sevoflurane.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Normal aging is associated with declines in basic organ function. Function of most organ systems is reduced by approximately 1% per year beyond the age of 30 years (17). Among these physiologic age-related changes, liver weight and hepatic blood flow may decrease significantly (2,18). Consequently, hepatic dysfunction or subclinical hepatic injury might occur in the elderly surgical patient. We found a short-lasting, statistically significant increase in {alpha} GST concentrations after both desflurane and sevoflurane anesthesia, suggesting a mild disturbance of hepatocellular integrity. Other investigators have confirmed that {alpha} GST concentrations increase transiently after the administration of anesthesia with isoflurane, sevoflurane, desflurane, and propofol (4,5,19).

Several mechanisms have been proposed to account for the hepatotoxic effects of inhaled anesthetics. One reason seems to be the oxidative biotransformation of inhaled anesthetics with the formation of toxic metabolites (20). Fulminant hepatic necrosis and jaundice termed "halothane hepatitis," a very rare but often fatal event, might follow halothane anesthesia administration. Highly active oxidative intermediates of halothane metabolism, such as trifluoroacetyl chloride with trifluoroacetic acid (TFA) as an end product, have been identified as promoting this type of liver damage as part of an immune response in susceptible individuals (20).

The new inhaled anesthetics differ greatly in their resistance to in vivo metabolism. Desflurane is almost inert to biodegradation, with a calculated breakdown of 0.02%. However, small but significant levels of TFA were found after exposure to desflurane (21). The metabolism of sevoflurane is approximately 100 times greater (3%–5%), but happens by different mechanisms and will therefore not form TFA. Hexafluoroisopropanol (HFIP) and inorganic fluoride are the main products of sevoflurane metabolism. The HFIP produced is transformed to HFIP-glucuronide, which is rapidly excreted by the kidneys (22). Although we did not measure metabolites of desflurane or sevoflurane breakdown, it seems unlikely that sevoflurane, per se, or its organic metabolite causes hepatocellular damage. This is supported by the low chemical reactivity and protein binding capacity of this compound, which may preclude the initiation of an immune response (20,22).

With desflurane, there is a remaining theoretical potential for hepatotoxicity by cross-sensitivity with other inhaled anesthetics. But, this possibility seems to be extremely remote, because serum TFA concentrations are approximately 1000-fold smaller after the administration of desflurane anesthesia compared with halothane anesthesia (21). The time course of the changes in {alpha} GST concentrations in our study did imply a minor derangement of hepatocellular integrity, most likely explained by inadequate hepatocyte oxygenation rather than an immune response to metabolite-modified hepatic proteins (20). In contrast to the increase in {alpha} GST concentrations, no significant overall changes in routine liver function tests (aminotransferase activities, bilirubin concentrations) were found throughout the study.

Other studies dealing with the effects of inhaled anesthetics on human hepatic function produced similar results (4,23). Elevated serum levels of aminotransferase activity were regarded as the "gold standard" for anesthetic-related hepatic toxicity. However, the measurement of these enzymes lacks specificity, because a variety of organs other than the liver contain aminotransferases. This limits the usefulness of these enzymes as a marker of mild, transient hepatic injury that was found in our study. A reduction in hepatic blood flow in relation to metabolic demand might explain the temporary increase in {alpha} GST concentrations. Hepatic perfusion is reduced in a dose-related manner by all inhaled anesthetics now in use (22). Studies in experimental animals have shown that sevoflurane might reduce hepatic portal blood flow when arterial hepatic blood flow is compromised (24). Similar effects on hepatic portal blood flow were seen for desflurane in the chronically instrumented dog (25). Unfortunately, clinical monitoring of splanchnic circulation or liver blood flow in humans is difficult.

Gastric mucosal tonometry is a noninvasive mea- surement to assess splanchnic perfusion. Hepatic clearance techniques with substances, such as indocyanine green, as well as invasive techniques such as angiography, hepatic vein catheterization, or laser Doppler velocimetry are other techniques to monitor changes in blood flow within the splanchnic vascular bed (26). Using gastric mucosal tonometry, we found short-lasting, significant increases in prCO2 and p(r-a)CO2 during the perioperative period and a decrease in pHi. Transient episodes of gastric intramucosal acidosis caused by a relative cardiorespiratory instability during general anesthesia, suggesting impaired splanchnic tissue perfusion, is relatively common in patients undergoing surgical procedures (13). An impaired oxygen availability to the liver, in particular to centrilobular hepatocytes, might have been the result of an altered hepatic blood flow. This may be reflected by the temporary elevations in {alpha} GST concentrations and the transient changes in gastric mucosal tonometry-derived variables within the perioperative period. Blood loss, surgical stress, the mode of ventilation, especially positive end-expiratory pressure ventilation, or depression of general hemodynamics might exacerbate these effects on hepatocytes. An even more pronounced dysregulation might be found within aging organ systems, with a decreased margin of reserve for adaptation to acute stress during the perioperative period. The degree of cytosolic liver enzymes elevation might reflect the severity of hepatocellular injury, but does not necessarily characterize hepatic function.

The MEGX formation test has been proposed as an easy and safe test for the quantitative assessment of liver function in clinical practice (7,27). Although no explicit reference ranges for geriatric patients are given in the literature, the MEGX concentrations in our patients at baseline were within the reference range shown for adult healthy individuals (28). After surgery, there was no significant change in MEGX concentrations in either anesthetic group. We found a large interindividual variability of lidocaine metabolism in our patients. Values ranged from 40 to 180 ng/mL. This is in agreement with the results of Oellerich et al. (7,29), reporting sex-related differences in MEGX formation, as well as the interference of certain drugs, with the MEGX test. In our study, there was no significant difference between the groups in the use of sedatives, hypnotics, analgesics, muscle relaxants, or any other drug. The interindividual differences in our patients might be explained by the varying catalytic activities of cytochrome P450 enzymes (30). Pharmacokinetic considerations also have to be taken into account in the interpretation of the lidocaine metabolism test.

A possible limitation of the MEGX test for measuring liver function is the fact that lidocaine metabolism is subject to variations in volume of distribution and protein binding. Lidocaine metabolism may be enhanced or reduced by previous administration of drugs that affect the microsomal oxidizing system. Therefore, interpretation of MEGX levels must consider medication that can influence the results (28). In our study, there were no significant differences between the groups in the use of sedatives, hypnotics, analgesics, muscle relaxants, or any other drug. It is the principle of the lidocaine metabolism test that lidocaine is rapidly metabolized by the liver through a first pass, mixed-function oxidative process to form the metabolites MEGX and glycinexylidide. MEGX formation is mainly dependent on mixed-function oxidase capacity (cytochrome P450 system) within liver microsomes and liver blood flow (7). Therefore, this test represents the current status of hepatocyte function and is quite distinct from traditional liver function tests that monitor enzyme levels secondary to cellular damage.

It is assumed that overall hepatocyte function in elderly patients, as determined by the MEGX formation test, is well preserved during the administration of desflurane and sevoflurane anesthesia. However, a mild disturbance of hepatocellular integrity, indicated by a transient increase of {alpha} GST levels and short-lasting changes of variables of gastric tonometry [prCO2, p(r-a)CO2, and pHi] imply a reduction in splanchnic perfusion, which may lead to a temporary impairment of hepatocyte oxygenation.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication April 12, 2000.





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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press