Anesth Analg 2008; 106:830-837
© 2008 International Anesthesia Research Society
doi: 10.1213/ane.0b013e3181616fc9
ANESTHETIC PHARMACOLOGY
Hepatic Energy Metabolism and the Differential Protective Effects of Sevoflurane and Isoflurane Anesthesia in a Rat Hepatic Ischemia-Reperfusion Injury Model
Nurdan Bedirli, MD*,
Ebru Ofluoglu, PhD
,
Mustafa Kerem, MD
,
Gulten Utebey, MD*,
Murat Alper, MD
,
Demet Yilmazer, MD,
Abdulkadir Bedirli, MD,
Onur Ozlu, MD*, and
Hatice Pasaoglu, MD
From the *Department of Anesthesiology, Diskapi Training and Research Hospital; Departments of Biochemistry and General Surgery, Gazi University Medical School; and Department of Pathology, Diskapi Training and Research Hospital, Ankara, Turkey.
Address correspondence and reprint requests to Nurdan Bedirli, MD, Mesa Koru Sit. Fulya Blok, 85/39, 06810, Cayyolu, Ankara, Turkey. Address e-mail to nurbedirli{at}yahoo.com.
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Abstract
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BACKGROUND: We investigated the effects of isoflurane and sevoflurane in a warm liver ischemia-reperfusion (IR) model on cytokines, hepatic tissue blood flow (HTBF), energy content, and liver structure.
METHODS: Seventy-two Wistar rats were randomly assigned into 1 of 3 groups: Control group, no volatile anesthetics; sevoflurane group, 2% sevoflurane; isoflurane group, 1.5% isoflurane. Thirty minutes after the start of volatile anesthetics, rats were subjected to 45 min hepatic ischemia and 2 and 4 h of reperfusion. Rats were killed at the end of ischemia, 2 and 4 h of reperfusion. Aspartate aminotransferase and alanine aminotransferase, HTBF, malondialdehyde, tumor necrosis factor (TNF)-
, interleukin (IL)-1β, energy charge, and histologic examination were used to evaluate the extent of liver injury.
RESULTS: Serum alanine aminotransferase and aspartate aminotransferase levels were similar in control and isoflurane groups while there was a significant decrease in the sevoflurane group in the postischemic period (P < 0.01). HTBF was remarkably better in the sevoflurane group than in the isoflurane group and worse in the control group. Tissue malondialdehyde levels were significantly low in the sevoflurane group compared with the isoflurane group at 2 h of reperfusion (P < 0.05) and reached its maximum value in the postischemic period in the control group. After ischemia, 2 and 4 h of reperfusion, tumor necrosis factor- and interleukin-1β values were lowest in the sevoflurane group and highest in the control group but it was not statistically significant (P > 0.05). In the sevoflurane group, hepatic adenosine triphosphate and energy charge were significantly high at all measurement times. At the postischemic period, energy charge was lower compared with the sevoflurane and isoflurane groups. The degree of hepatocyte injury was small in the sevoflurane group.
CONCLUSIONS: Clinically relevant concentrations of sevoflurane given before, during, and after hepatic ischemia protected the liver against IR injury, whereas the effects of isoflurane on hepatic IR injury were not notable.
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Introduction
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Intraoperative temporary interruption of liver blood flow sometimes occurs during surgical procedures. This hepatic ischemia and subsequent reperfusion can lead to liver dysfunction or severe hepatic failure, depending on the severity and duration of the ischemia. The balance between hepatic oxygen supply through hepatic tissue blood flow (HTBF) and oxygen consumption by hepatocytes is an essential factor in hepatic metabolism.1 The reduction of HTBF may impair hepatic energy metabolism. Ischemia causes functional and structural damage to liver cells.2 The status of energy metabolism is one of the more important functional disorders for predicting the viability of the ischemic organ. Reperfusion after ischemic injury triggers activation of several transcription factors, including nuclear factors, which, in turn, alter the transcription of multiple genes associated with inflammatory response, including intercellular adhesion molecule-1, interleukin (IL)-1β, IL-8, and tumor necrosis factor (TNF)-.3 Kupffer cell activation is a central hepatic pathophysiologic mechanism of the reperfusion injury. Activated Kupffer cells release reactive oxygen species, which leads to the generation of end-products of lipid peroxidation, such as malondialdehyde (MDA).4
Inhaled anesthetics, besides their anesthetic effects, have significant nonanesthetic physiologic effects. For some years, data have been accumulating from in vivo and in vitro experiments suggesting that inhaled anesthetics, such as sevoflurane and isoflurane, exert protective effects against ischemia-reperfusion (IR) injury in various organs.5–9 Previous studies have shown that these anesthetics could protect against IR injury of the heart,10 brain,11 and liver.12 Specifically, pretreatment with volatile anesthetics before cardiac ischemia protects against IR injury.10,13 The mechanisms of organ protection by volatile anesthetics are unclear; however, several studies have suggested that inhaled anesthetics protect the heart via activation of adenosine triphosphate-dependent potassium (K+ ATP) channels.14 Other studies suggest that inhaled anesthetics protect against IR injury in the heart15 and lung6 via antiinflammatory effects.
The aim of this study was to investigate the effects of administration of isoflurane and sevoflurane before ischemia in a rat model of warm liver IR on systemic cytokine levels, HTBF, energy charge, and liver histology.
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METHODS
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The experimental protocols were conducted with the approval of the Animal Research Committee at Gazi University, Ankara. All animals were maintained in accordance with the recommendations of the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals.
Animals and Experimental Design
Seventy-two male Wistar rats weighing 280–315 g were housed at 22°C with a 12-h light–dark cycle and free access to food and water. The rats were randomly divided into three groups, control (n = 24; no volatiles), sevoflurane (n = 24; 2% sevoflurane), and isoflurane (n = 24; 1.5% isoflurane). The rats were anesthetized by IM injection of 50 mg/kg ketamine hydrochloride (Ketalar, Parke Davis, Berlin, Germany) and 0.01 mg atropine. All rats were placed on an electric heating pad under a warming light. Electric cardiography was monitored. After ketamine injection, within approximately 5 min, tracheostomy was performed with a 16-gauge cannula, intratracheal intubation was established, and the lungs were ventilated with volatile anesthetics without muscle relaxants. The right femoral artery was cannulated to monitor mean arterial blood pressure (MABP) and for blood gas analysis. Hydration was maintained by hourly intraperitoneal injection of 5 mL saline solution. Both volatile anesthetics were carried in 100% oxygen and the flow of oxygen gas was set at 4 L/min with the anesthesia apparatus.
Surgical Procedure
The rats were placed on the operating table in a supine position with a baseline period of inhalation of anesthesia (30 min), during which there was no surgical intervention. After this period, with local anesthesia achieved using 1% lidocaine, a midline abdominal incision was made. The liver was exposed and all structures in the portal triad (hepatic artery, portal vein, and bile duct) to the left lateral and median liver lobes were interrupted (Fig. 1A) for 45 min with a vascular clip (Harvard Apparatus, Inc., Hollinston, MA). This method of partial hepatic ischemia prevented mesenteric venous congestion by permitting portal decompression through the right and caudate lobes. A laser Doppler miniprobe was placed on the left lateral lobe to monitor HTBF (Fig. 1B). After 45 min of ischemia, the clip was removed to allow 4 h of reperfusion.
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Figure 1. A, Liver partial ischemia. Schematic representation. B, A laser Doppler miniprobe was placed on the left lateral lobe to monitor blood flow.
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Rats in the sevoflurane and isoflurane groups were exposed to 2% sevoflurane (Abbott Laboratories, Queenborough, UK) and 1.5% isoflurane (Abbott Laboratories), respectively, with an agent-specific vaporizer until the end of reperfusion. From each group, eight rats were killed at the end of ischemia, 2 and 4 h of reperfusion. Blood samples were withdrawn for the measurement of liver enzymes aspartate aminotransferase (AST) and alanine aminotransferase (ALT), TNF-, IL-1β, and liver samples from the left lateral and median hepatic lobes (segment II–IV) were collected for the measurement of MDA concentration, ATP, adenosine S'-diphosphate (ADP), adenosine 5'-monophosphate (AMP) content, and histologic examination. All surgical procedures were maintained with volatile anesthetic administration.
HTBF
HTBF was measured with a laser Doppler flowmeter (Periflux 5000, Perimed, Sweden) before ischemia, at 5, 15, and 45 min after initiation of ischemia, and at 5, 15, 30, and 60 min after reperfusion. At each time point, a mean of three values obtained at three different lobes was calculated. HTBF was expressed as a percentage of the preischemic value.
Biochemical Determinations
Serum AST and ALT activities were measured on the Aeroset autoanalyzer (Abbott Laboratories) and reported in units per liter.
TNF- and IL-1β Immunoassay
Serum TNF- and IL-1β levels were detected in a 96-well microtitre plate by using a commercial enzyme-linked immunosorbent assay kit (BioSource International, Inc., Camarillo, CA) according to the manufacturer's guidelines. All samples were tested in duplicate. The plate was read on ELx800 automated microplate reader (Bio-Tek Instruments, Inc., Winooski, VT) at 450 nm. The concentrations of TNF- and IL-1β were calculated from a standard curve and expressed in picogram per milliliter (pg/mL). The lower limit of detection for enzyme-linked immunosorbent assay was 8–16 pg/mL.
MDA Measurement
The extent of lipid peroxidation in the liver was determined by measuring MDA, an end-product of liver peroxidation. Tissue sampled from the liver was homogenized with a Virsonic 100 (Virtis Company Inc., Gardiner, NY) ultrasonic homogenizer. Tissue MDA levels were measured according to the method of Ohkawa et al.16 Briefly, 0.1 mL of homogenate was mixed with 0.1 mL of 8.1% sodium dodecyl sulfate, 0.75%, 0.8% thiobarbituric acid, and 0.3 mL of distilled water and kept in a boiling water bath for 60 min. After cooling, 0.5 mL of distilled water and 2.5 mL 15/1 (v/v) n-butanol/pyridine was added. After centrifugation at 4000 rpm, the absorbance of the supernatant at 532 nm was measured with spectrophotometry (Shimadzu Corp., Tokyo, Japan) using a calibration curve obtained from MDA standard. Protein concentrations of supernatant were measured using Bradford's method.17 MDA activity was expressed as nanomole per gram protein.
Determination of Tissue ATP, ADP, AMP, and Energy Charge
For the measurement of tissue ATP, ADP, and AMP concentrations, we used high-performance liquid chromatography. The tissues were homogenized in 1 mL cold 0.6 N perchloric acid and homogenates placed on ice for 1 h, followed by neutralization with 450 µL of K2HPO4 (1M), centrifugation for 15 min at 10,000g at 4°C, and filtration through a 0.2 µm syringe filter. Supernatants were stored at –80°C until analysis. ATP, ADP, and AMP were measured at a wavelength of 254 nm on a Agilent 1100 series (Agilent Technologies Inc., Palo Alto, CA), using Allsphere ODS-2, C-18 5 µm reverse-phase column with a mobile phase of 160 mM KH2PO4 with 100 mM KCl at pH 6.5.18 ATP and its catabolites were expressed as micromole per gram liver. Tissue energy charge was calculated as ([ATP] + 0.5 [ADP])/([ATP] + [ADP] + [AMP]).19
Histological Assessment Liver I/R Injury
Histological assessment was performed by a researcher blinded to the study groups. For morphometric assessment of reperfusion injury and polymorphonuclear neutrophil (PMN) adhesion, excised liver specimens were fixed in 10% formalin and embedded in paraffin. Six-micrometer thick hematoxylin- and eosin-stained sections were evaluated at x200 magnification by a point-counting method for severity of hepatic injury using an ordinal scale as follows: grade 0, minimal or no evidence of injury; grade 1, mild injury consisting of cytoplasmic vacuolation and focal nuclear pyknosis; grade 2, moderate to severe injury with extensive nuclear pyknosis, cytoplasmic hypereosinophilia, and loss of intercellular borders; and grade 3, severe necrosis with disintegration of hepatic cords, hemorrhage, and PMN infiltration.
Statistical Analysis
All values were expressed as the mean ± sd. Data were compared by analysis of variance with post hoc analysis using Newman–Keuls test. When a difference was found, specific differences were identified by using Kruskal–Wallis test. Statistical evaluation was performed by using SPSS 10.0 software (SPSS, Chicago, IL). Values of P < 0.05 were accepted as significant.
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RESULTS
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Throughout the experiment, the heart rate ranged from 370 to 480 bpm and the MABP ranged from 95 to 160 mm Hg in all groups. There were no significant differences in heart rate and MABP among groups (Fig. 2). The Paco2 levels were also compared and no differences were found within the three groups (Fig. 3).
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Figure 2. Time course of changes in mean arterial blood pressure (MABP) in three experimental groups. Data represents the mean ± sd. There was no statistical significance among the groups at the various time points.
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Figure 3. Time course of changes in arterial partial pressure of carbon dioxide (PAco2) in three experimental groups. Data represents the mean ± sd. There was no statistical significance among the groups at the various time points.
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HTBF before and after IR was measured by using a laser Doppler flowmeter. Blood flow decreased immediately after ischemia and did not change during reperfusion; it remained significantly lower in the vehicle-treated group at 5, 15, 30, and 60 min after reperfusion was initiated, compared with that before ischemia. In contrast, with sevoflurane, the impaired HTBF almost completely recovered after IR: recovery was 98% at 15 min and 102% at 60 min after reperfusion. Isoflurane did not affect the reduction of HTBF induced by IR (Fig. 4).
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Figure 4. Time course of changes in hepatic tissue blood flow (HTBF) before and after ischemia-reperfusion. Blood flow values are expressed as a percentage of the value measured before ischemia was started. *P < 0.05 versus control and isoflurane groups.
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As seen in Figure 5, enzymatic profiles were similar in all groups with a steady increase beginning at ischemia, followed by an overall increase of activities until the end of the experiment. The evolution of AST and ALT was influenced more by isoflurane than by sevoflurane. The increase of enzyme activity in the postischemic period was significantly higher in the isoflurane group than in the sevoflurane group (P < 0.01). Peak serum AST and ALT levels were measured at 4 h of reperfusion in the isoflurane group (AST = 955 U/L; ALT = 718 U/L). The lowest values were measured in the sevoflurane group, after the postischemic period (AST = 122 U/L; ALT = 94 U/L).
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Figure 5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in serum. Each bar represents the mean ± sd *P < 0.01 versus control and isoflurane groups.
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As shown in Figure 6, very high hepatic MDA levels were detected in ischemic rats. However, after reperfusion, the MDA levels decreased significantly. Tissue MDA levels reached their maximum value in the postischemic period in the control group and the lowest value in the sevoflurane group at the 4 h of reperfusion. At all measurement times, in the isoflurane group, MDA levels were high compared with the sevoflurane group. However, they were only significantly high in the isoflurane group compared with that in the sevoflurane group at 2 h of reperfusion (P < 0.05).
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Figure 6. Malondialdehyde (MDA) levels in liver. Each bar represents the mean ± sd. *P < 0.05 versus control and isoflurane groups.
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TNF- concentrations after ischemia, 2 and 4 h of reperfusion are displayed in Figure 7. TNF- was globally higher in the isoflurane group but no significant difference was observed among the groups (P > 0.05). TNF- levels reached their highest value at 2 h of reperfusion in the isoflurane group. Similarly, increased IL-1β expression was detected in the isoflurane group and reached its highest level at 2 h of reperfusion.
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Figure 7. Serum tumor necrosis factor (TNF)- and interleukin (IL)-1β concentrations in rats postischemia, 2 and 4 h after reperfusion. Each bar represents the mean ± sd.
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Changes in adenine nucleotide contents in ischemic liver are shown in Table 1. The ATP levels in the liver were low after ischemia, whereas a concomitant transient increase in the AMP level was observed. At 4 h after reperfusion, the hepatic ATP levels were higher than in the postischemic period. The hepatic energy charge was significantly lower in the isoflurane group than in the sevoflurane group at all measurement times. The energy charge was low after ischemia; however, it increased 4 h after reperfusion.
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Table 1. Changes in Adenosine 5'-Triphosphate (ATP), Adenosine 5'-Diphosphate (ADP), Adenosine 5'-Monophosphate (AMP), and Energy Charge in Livers
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Liver biopsy specimens were obtained after ischemia, 2 and 4 h of reperfusion for morphometric assessment of liver injury. After 45 min of warm ischemia, both isoflurane and sevoflurane administration resulted in a reduction grade of hepatocyte injury compared with the control group, this reduction was also higher in the sevoflurane group but the difference was not significant (Fig. 8). None of the rats had a high degree of hepatocyte necrosis (grade 3). After 2 h of reperfusion, the sevoflurane group (13%, grade 2) showed markedly reduced hepatocytic degeneration compared with the isoflurane group (38%, grade 2) and control group (50%, grade 2). After 4 h of reperfusion, the percentage of grade 3 necrosis in livers from the sevoflurane, isoflurane, and control groups were 13%, 13%, and 25%, respectively (Table 2).
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Figure 8. Liver sections of rats in control and isoflurane groups after 4 h reperfusion showed cytoplasmic hypereosinophilia, loss of intercellular borders and extensive nuclear pyknosis (A and B). On the contrary, livers of sevoflurane-pretreated rats showed mild injury consisting of cytoplasmic vacuolation and focal nuclear pyknosis (C) (hematoxylin and eosin, x400).
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DISCUSSION
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The development of strategies to counteract the manifestation of IR injury of the liver is a major challenge in liver surgery. Ischemic preconditioning refers to a phenomenon in which tissues are rendered resistant to the deleterious effects of IR by previous exposure to brief periods of vascular occlusion. The protective effect of ischemic preconditioning was first described in myocardium,20 but a considerable number of studies have documented that ischemic preconditioning is also a powerful tool to increase ischemic tolerance in the liver.21,22 Evidence has shown the protective effects of volatile anesthetic pretreatment against IR injury in the heart similar to the phenomenon of ischemic preconditioning.10 Both isoflurane and sevoflurane have been reported to mimic ischemia preconditioning effects in the heart, suggesting that the preischemic administration of these anesthetics may be protective against liver IR injury.23 In isolated perfused rat liver, isoflurane, sevoflurane, and halothane reduced IR injury when administered during the reperfusion phase; however, they did not reduce injury when administered only during ischemia.24 Heindl et al.5 showed that both sevoflurane and isoflurane reduced the adhesion of PMNs in the reperfused coronary system, and thereby helped to preserve cardiac function; the effects of these two drugs were not significantly different from each other. However, Preckel et al. suggested that sevoflurane had more prominent protective effects than isoflurane on myocardial reperfusion injury.25 In addition to these studies, to clarify the significance of hepatic tissue perfusion for the protective effects of sevoflurane and isoflurane, we evaluated HTBF and hepatic energy metabolism before, during and after hepatic ischemia and reperfusion. To use a clinically relevant amount of anesthetics, the rats inhaled 2% sevoflurane or 1.5% isoflurane (approximately 1 MAC). We have demonstrated that only sevoflurane provided significant hepatic protection against IR injury. Although it is not appropriate to directly apply these data to humans, the administration of sevoflurane rather than isoflurane for general anesthesia for hepatic surgery might be considered.
In humans, about 2%–4% of sevoflurane undergoes hepatic metabolism, compared with 0.1%–0.2% of isoflurane. Indeed, hepatic injury from the metabolism of sevoflurane may result. Thus, conventional wisdom has suggested that isoflurane is less likely to result in hepatic injury, as it better preserves the balance of hepatic oxygen supply and demand. However, in critical situations, such as IR, hemorrhage, and cirrhosis, the effects of anesthetics might be changed. Nishiyama et al.26 compared sevoflurane and isoflurane in cirrhotic patients and found that patients anesthetized with isoflurane had more enzymatic evidence of hepatocellular damage than patients anesthetized with sevoflurane. Nevertheless, no patients in that study developed hepatic failure. All increases in liver enzymes were small and of questionable clinical relevance.
The hepatic inflammatory response to IR comprises of two distinct phases. In the acute phase, the ischemic insult induces oxidant stress within the liver resulting in Kupffer cells activation and oxidant-mediated injury to hepatocytes.3 The activation of Kupffer cells results in their production of the early response cytokines TNF- and IL-1β. These potent proinflammatory cytokines are generally thought to have similar overlapping functions. Accordingly, administration of drugs that reduce the effects of TNF- has resulted in amelioration of liver IR injury. Previous studies demonstrated that some volatile anesthetics has antiinflammatory properties.27,28 Liu et al.6 reported that sevoflurane administered at 1 MAC before ischemia inhibited an increase in TNF- during IR-induced injury in isolated rat lungs. In this regard, sevoflurane suppressed the proinflammatory effects of TNF- under conditions of renal IR.29 Although it was not significant, we observed more than 40% decrease in both TNF- and IL-1β release after reperfusion in animals treated with sevoflurane, compared with controls; these results correlated with decreased lipid peroxidation, as demonstrated by lower content of liver MDA.
Studies showed that the increase of blood flow in the liver can contribute to a good prognosis in liver disease when the liver has been injured ischemically.1 When oxygen supply to hepatocytes becomes insufficient as result of reduced or absent blood flow, there is inhibition of the mitochondrial oxidative phosphorylation, with the subsequent reduction in ATP synthesis.30 Depletion of cellular ATP store induces alterations in transmembrane ion transport by inhibition of the ATP-dependent Na+/K+ ATPase, leading to sodium and chloride influx changes, intracellular sodium accumulation, secondary alterations in cellular calcium homeostasis, and particularly, cell swelling and death.31 Subsequent reperfusion results in plasma membrane injury due to the production of superoxide radicals. An excessive acute inflammatory response, which takes place promptly after blood flow restoration, has been recognized as the key mechanism of liver injury during the reperfusion period. Therefore, it is important to control the hepatic microcirculatory state after ischemic insult to the liver. We measured HTBF to determine whether volatile anesthetic pretreatment improves hepatic microcirculation and attenuates IR injury of the liver. Isoflurane did not affect the reduction of HTBF induced by IR. In contrast, with sevoflurane, the impaired HTBF almost completely recovered after IR.
The hepatic ATP concentration has been used extensively in several studies as an indicator of liver function.21 A marked decrease of hepatic ATP level was observed in nontreated ischemic livers, confirming that oxidative phosphorylation is rapidly and seriously affected by ischemia.28 Sevoflurane partially restored the ATP content in the liver, regardless of whether the time after reperfusion was 2 or 4 h. In this study, the increased ATP level and tissue blood flow was a clear indication of increased cell viability and improved microcirculatory perfusion. It is generally accepted that there is an ischemic period during which the tissue is vulnerable to reperfusion injury. In this study, sevoflurane treatment attenuated parenchymal hepatocyte injury with respect to ATP concentration in liver homogenates. These data suggest that sevoflurane treatment can alleviate IR-related injury of the liver.
In our study, organ protection was indicated by a decrease in plasma liver enzymes during the postischemic period, increased HTBF during the reperfusion period, decreased tissue MDA levels at 2 h of reperfusion. Increased hepatic ATP and energy levels also decreased hepatocyte injury in the sevoflurane group. The maintenance of microvascular perfusion after hepatic ischemia plays a crucial role in prevention of liver injury. As shown by Chun et al.,32 early restoration of liver blood flow after ischemia is of particular importance to prevent hepatocellular death. We showed that HTBF almost completely recovered after IR in the sevoflurane group. Although the longest time point presented by this study is 4 h (which does not necessarily constitute long-term protection or any change in ischemic outcome) by evaluation of microcirculatory alterations, estimating tissue MDA and ATP content in liver homogenates, measuring proinflammatory cytokine level, and histologic evaluation, we concluded that treatment with sevoflurane may ameliorate IR injury of the liver.
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Footnotes
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Accepted for publication November 1, 2007.
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Abstract
Introduction
