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Anesth Analg 2007; 105:1371-1378
© 2007 International Anesthesia Research Society
doi: 10.1213/01.ane.0000284696.99629.3a
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CRITICAL CARE AND TRAUMA

The Protective Effects of Intravenous Anesthetics and Verapamil in Gut Ischemia/Reperfusion-Induced Liver Injury

Necat Kaplan, MD*, Hatice Yagmurdur, MD{dagger}, Kamer Kilinc, MD, PhD{ddagger}, Bulent Baltaci, MD{dagger}, and Savas Tezel, MD*

From the Ministry of Health Ankara Research and Training Hospital, *Clinic of General Surgery, {dagger}Clinic of Anesthesiology and Reanimation, Ankara, Turkey; and {ddagger}Department of Biochemistry, Hacettepe University School of Medicine, Ankara, Turkey.

Address correspondence and reprint requests to Hatice Yagmurdur, MD, Esat Cad. 102/10, Kucukesat, Cankaya, 06660 Ankara, Turkey. Address e-mail to hyagmurdur{at}yahoo.com or hyagmurdu{at}gmail.com.


   Abstract
Top
 Abstract
Introduction
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
BACKGROUND: We investigated the protective effects of IV anesthetics and verapamil in gut ischemia/reperfusion-induced liver injury.

METHODS: Forty male Wistar Albino rats were randomly assigned to four groups of 10 rats each. Anesthesia was induced and maintained with propofol in Groups 1 and 3 and with thiopental in Groups 2 and 4 during the experiment. All animals developed intestinal ischemia after occlusion of the superior mesenteric artery for 30 min. Reperfusion was induced by removal of the microvascular clamp and was allowed to continue for 120 min. The animals in Groups 3 and 4 were given verapamil 10 min before reperfusion. Liver and ileum samples were taken for measurement of malondialdehyde (MDA) and histopathologic examination before ischemia and 30 and 120 min after reperfusion. Blood samples were also obtained for measurement of plasma tumor necrosis factor-{alpha} and interleukin-6 levels.

RESULTS: Gut ischemia/reperfusion-induced significant increases in MDA contents of liver and gut and serum cytokines, consistent with histopathologic injury scores. Propofol effectively stabilized the MDA levels and decreased the tissue injury scores of the liver and gut. Tumor necrosis factor-{alpha} and interleukin-6 levels increased less in the propofol groups than in the thiopental groups. There was no additive preventive effect of verapamil on propofol. The addition of verapamil to thiopental was effective in decreasing the serum cytokines and liver MDA content.

CONCLUSION: Propofol may offer advantages by inhibiting lipid peroxidation and inflammatory cytokine production in an animal model of gut ischemia/reperfusion-induced liver injury.


   Introduction
Top
 Abstract
 Introduction
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Intestinal ischemia and reperfusion are seen in a variety of clinical syndromes (1). Patients who suffer from mechanical obstruction, coagulopathies, vasculopathies, or severe trauma are at risk for intestinal ischemia and its complications (2). Surgical patients undergoing aortic, cardiac, or intestinal transplantation surgery are also at higher risk for this condition (3,4). Intestinal ischemia can be difficult to manage medically and surgically. Patients with sustained intestinal ischemia often suffer from the added complication of septic shock, leading to multiorgan failure (MOF) and death (5,6).

The liver is particularly vulnerable to the negative consequences of gut ischemia/reperfusion, presumably because the vasculature of this tissue is coupled in series with the intestinal circulation (7). The pathophysiology of acute liver injury is unclear; however, the prominent neutrophil sequestration and data from other related injury models suggest that oxygen radical species may be potentially important mediators of both local and remote organ injury (7).

Tissue injury after ischemia is primarily caused by reduced oxygen supply, and the injury may be worsened during the reperfusion phase via the formation of reactive oxygen radicals (molecular trigger) and the activation of phospholipase A2 by calcium influx (enzyme trigger) during ischemia (8). Malondialdehyde (MDA) is an intermediate product of lipid peroxidation and is used for assessment of tissue injury attributable to free radicals produced by ischemia/ reperfusion (9).

Other potential mediators of gut ischemia/ reperfusion-induced hepatic microvascular dysfunction and liver injury are cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-{alpha}) (10).

Propofol (2,6-diisopropyl phenol), a highly lipid-soluble anesthetic, has demonstrated potent antioxidant activity against lipid peroxidation in both in vitro and in vivo studies (11,12). Propofol also attenuates ischemia/reperfusion-induced lipid peroxidation in humans (13,14). It is chemically similar to endogenous antioxidant {alpha}-tocopherol (vitamin E) (11). On the basis of this knowledge, we hypothesized that propofol could be an appropriate drug for gut ischemia/ reperfusion-inducing liver injury.

Thiopental is another highly lipid-soluble anesthetic, which has demonstrated antioxidant properties by inhibiting lipid peroxidation in vitro (15). At clinically relevant concentrations, it significantly depressed reactive oxygen species production of neutrophils (16).

Verapamil, a slow calcium channel entry blocker, also protects the liver against oxygen-derived free radical injury during ischemia/reperfusion (17).

Patients with intestinal ischemia may need anesthesia for urgent or elective surgical intervention. Whether IV anesthetics used to treat gut ischemia/ reperfusion during surgery have an effect on liver damage, and whether verapamil has an additive oxidative effect on these anesthetics, has not been investigated. This experimental study using biochemical analysis and histopathologic evaluation was conducted to investigate the protective effects of propofol and thiopental, with or without verapamil, on gut ischemia/reperfusion-induced liver injury.


   METHODS
Top
 Abstract
 Introduction
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Animals
The experimental protocol used for this study was approved by the Animal Investigation Committee of the Ministry of Health Ankara Research and Training Hospital, and adhered to the National Institutes of Health guidelines for the use of experimental animals. Animals were housed in individual cages in a cohorted temperature-controlled room with alternating 12 h light–dark cycles, and acclimated for a week before the study. Food was removed 8 h before the study, but all animals were allowed free access to water. Forty male Wistar Albino rats (mean body weight 270 ± 18 g) were randomly assigned into four groups of 10 rats per group (Table 1).


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  		Table 1. Experimental Conditions and Animal Groups

 

Anesthesia and Verapamil Administration
Anesthesia was induced with 10 mg/kg propofol (Abbott Propofol; Abbott Laboratories, Chicago, IL) in Groups 1 and 3, and 30 mg/kg thiopental (Pental Sodyum, IE Ulagay Ilac San., Istanbul, Turkey) in Groups 2 and 4 via the ventral tail vein. Animals then underwent aseptic placement of left carotid arterial and right internal jugular venous lines with polyethylene tubing to continuously monitor the mean arterial blood pressure (MAP) and to maintain anesthesia and fluid. Anesthesia was maintained with 20–30 mg · kg–1 · h–1 propofol in Groups 1 and 3 and with 40–90 mg · kg–1 · h–1 thiopental in Groups 2 and 4 until the end of the experiment. The animals in Groups 3 and 4 were given 0.3 mg/kg verapamil (Isoptin, Knoll, Germany) IV as a bolus 10 min before reperfusion of the intestine. Before surgical incision, a baseline measurement of MAP was obtained, and the pressure was monitored during the experiment.

Surgical Procedure
Before surgical preparation, a first blood sample was taken from the arterial line for the baseline (before surgical incision) measurement of TNF-{alpha} and IL-6. After shaving and application of 10% povidone-iodine to the skin, a midline laparotomy was performed and first tissue samples were obtained from terminal ileum and liver (baseline). Then, cut tissue edges were sutured using 4.0 silk.

Intestinal ischemia was achieved by occlusion of the superior mesenteric artery, with application of an atraumatic microvascular clamp for 30 min. The incision site and abdominal organs were covered with parafilm to prevent heat loss and desiccation during the ischemic period. Mesenteric ischemia was confirmed when the intestines were pale and normal peristalsis had ceased. Then, reperfusion of the superior mesenteric artery was induced by removal of the microvascular clamp. The intestines were returned to the abdominal cavity, and the laparotomy incision was closed in layers. At 30 min of reperfusion, the abdominal cavity was exposed again by removing the sutures, and a second set of tissue samples was obtained from the terminal ileum and liver. The cut edges and abdominal cavity were sutured in the same manner as before. At 120 min of reperfusion, a third set of tissue samples was taken in the same manner. After a second set of blood samples was obtained for TNF-{alpha} and IL-6 measurements, the animals were killed by cervical dislocation, and infusion of the anesthetic was stopped.

Determination of Tissue Lipid Peroxidation (MDA)
Terminal ileum and liver samples were weighed and immediately frozen and stored at –70°C until analysis within 2 wk. Samples were subsequently homogenized in buffer and assayed for MDA content using the thiobarbituric acid (TBA) reaction, as described by Uchiyama and Mihara (18). Briefly, 0.5 mL of homogenate (10% concentration) was mixed with 3 mL of 1% H3PO4. After addition of 1 mL of 0.67% TBA reagent, the tubes were heated in boiling water for 45 min. The color was formed with 4 mL of n-butanol and centrifuged. The color intensity of the butanol layer was estimated by spectrophotometric absorbance at 532 nm. MDA content was then expressed as nanomoles per gram of tissue (nmol/g).

Plasma TNF-{alpha} and IL-6 Levels
The plasma levels of these proinflammatory cytokines in each rat were measured by enzyme-linked immunosorbent assay (Biosource International, Camarillo, CA) and expressed as picograms per milliliter (pg/mL).

Histopathologic Evaluation
Histopathologic examination of liver and ileum samples was performed twice: before surgical incision (baseline) and at 120 min of reperfusion. Double-blind analysis was applied to all liver and ileum samples. For the light microscopy process, the specimens were fixed in 10% neutral buffered formalin, embedded in paraffin, cut in sections of 5 µm thickness, and stained with hematoxylin–eosin. Mucosal lesions of intestine were graded on a scale from 0 to 5 as described by Chiu et al. (19) according to the following criteria: grade 0 = normal mucosa; grade 1 = development of subepithelial space at the apex of the villus; grade 2 = extension of subepithelial space with moderate separation of mucosa; grade 3 = extensive epithelial separation with a few denuded villi; grade 4 = denuded villi with exposed dilated capillaries, and grade 5 = disintegration of lamina propria with hemorrhagic ulceration. Histopathologic changes observed in representative liver sections were assigned histologic scores (HS) based on the extent of hepatocellular injury as follows: HS 0 = normal liver architecture; HS 1 = reactive changes only (swelling, congestion, single cell dropout, and glycogen depletion); HS 2 = mild injury, one or more minute foci of necrosis, the largest involving approximately <1% of the examined sectional area of the lobule; HS 3 = moderate injury, as in 2, but the necrotic foci are approximately 1%–5% of the lobule; HS4 = severe injury, as above, but >5% of the lobule (20).

Statistical Analysis
Where appropriate, the data were expressed as the mean ± sd. Analysis of MDA, TNF-{alpha}, and IL-6 were made with the Kruskall–Wallis one-way analysis of variance test among groups. Paired comparisons of groups were made with the Mann–Whitney U-test for assessment of which group or groups were the reasons for the difference. Then, the {alpha} = 0.05 error level was divided into the number of comparisons and Bonferroni's corrections were made. Histopathologic findings were evaluated qualitatively by nonparametric {chi}2 analysis with Yates' correction factor. P values <0.05 were considered significant.


   RESULTS
Top
 Abstract
 Introduction
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
MAP was 92 ± 10 mm Hg in Group 1, 89 ± 12 mm Hg in Group 2, 93 ± 11 mm Hg in Group 3, and 90 ± 13 mm Hg in Group 4. There were no significant differences in baseline (before surgical incision) measurement of MAP among the groups (P > 0.05). The volume of fluid needed to keep MAP within 10% of baseline levels was not different among the groups (P > 0.05).

Liver and ileal contents of the lipid peroxidation by-product MDA are shown in Table 2. There were no significant differences in baseline liver and ileal MDA contents in all groups (P > 0.05). Liver and ileal MDA levels increased significantly in Groups 2 and 4 at 30 and 120 min after reperfusion (AR) compared with baseline. The liver MDA content of Group 2 was significantly higher than that of Groups 1, 3, and 4 both at 30 and 120 min AR. Although ileal MDA levels were significantly increasing in Groups 2 and 4, these levels were unchanged in Groups 1 and 3 at 30 and 120 min AR. Liver and ileal MDA differences between Groups 3 and 4 were also significant at 30 and 120 min AR.


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  		Table 2. Malondialdehyde (MDA) Contents of Tissues (nmol/g)

 

The plasma TNF-{alpha} and IL-6 findings in all groups are shown in Figures 1 and 2, respectively. There were no significant differences in baseline (before surgical incision) levels among the groups (P > 0.05). The mean TNF-{alpha} and IL-6 levels were increased significantly in all groups compared with baseline at 120 min AR. But the measurements at 120 min AR showed that gut ischemia/reperfusion caused significantly higher TNF-{alpha} and IL-6 levels in Group 2 than in Groups 1, 3, and 4 (P < 0.05). However, the addition of verapamil to thiopental in Group 4 caused lower TNF-{alpha} and IL-6 levels compared with Group 2 (P < 0.05).


Figure 132
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  		Figure 1. Plasma levels of tumor necrosis factor-alpha (TNF-{alpha}) (pg/mL) (mean ± sd). Baseline: before surgical incision. AR: after reperfusion. *P < 0.05 versus baseline, {dagger}Group 2 versus Groups 1, 3, and 4 (P < 0.05), {ddagger}Group 4 versus Groups 1 and 3 (P < 0.05).

 


Figure 232
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  		Figure 2. Plasma levels of interleukin-6 (IL-6) (pg/mL) (mean ± sd). Baseline: before surgical incision. AR: after reperfusion. *P < 0.05 versus baseline, {dagger}Group 2 versus Groups 1, 3, and 4 (P < 0.05), {ddagger}Group 4 versus Groups 1 and 3 (P < 0.05).

 
In the baseline situations, the histopathologic examinations of all groups' samples showed similar architecture of liver and ileum (Table 3, Figs. 3A and 4A). There were no significant differences between Groups 1 and 3 with respect to histopathologic injury scores for liver and ileum (P > 0.05). Also, the median injury scores in Groups 2 and 4 were statistically similar (P > 0.05) (Table 3). Light microscopy showed that the gut ischemia/reperfusion caused significantly greater injury in Groups 2 and 4 than in Groups 1 and 3, both in liver and ileum (P < 0.05) (Figs. 3B and 4B). Propofol administration with or without verapamil in Groups 1 and 3 markedly reduced lesions and improved the histologic appearance of the liver and ileum (P < 0.05) (Figs. 3C and 4C).


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  		Table 3. Histopathologic Evaluation of Liver (HS) and Ileum (G)

 

Figure 332
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  		Figure 3. A, Histology of a representative liver collected from a rat at baseline (before surgical incision). Normal liver architecture with reactive changes only. Hematoxylin–eosin stain, original magnification x20. B, Histology of a representative liver collected from a rat that had undergone gut ischemia/reperfusion with thiopental anesthesia (Groups 2 and 4). Severe injury with necrotic foci seen in >5% of the lobule. Hematoxylin–eosin stain, original magnification x20. C, Histology of a representative liver collected from a rat that had undergone gut ischemia/reperfusion with propofol anesthesia (Groups 1 and 3). Mild to moderate injury with necrotic foci seen in <5% of the lobule. Hematoxylin–eosin stain, original magnification x20.

 


Figure 432
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  		Figure 4. A, Histology of a representative ileum collected from a rat at baseline (before surgical incision). Normal mucosa with occasional development of subepithelial space at the apex of the villus. Hematoxylin–eosin stain, original magnification x20. B, Histology of a representative ileum collected from a rat that had undergone gut ischemia/reperfusion with thiopental anesthesia (Groups 2 and 4). Denuded villi and disintegration of lamina propria with hemorrhagic ulceration. Hematoxylin–eosin stain, original magnification x20. C, Histology of a representative ileum collected from a rat that had undergone gut ischemia/reperfusion with propofol anesthesia (Groups 1 and 3). Extension of subepithelial space, with moderate separation of mucosa and a few denuded villi. Hematoxylin–eosin stain, original magnification x20.

 

   DISCUSSION
Top
 Abstract
 Introduction
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Gut ischemia/reperfusion has been implicated as a prime mechanism in the pathogenesis of MOF as an initiator of remote organ injury (6). Understanding the cascade of events that leads to remote organ injury and a fatal outcome may provide insight into the pathophysiology of MOF syndrome and into clinical manipulation of these mechanisms to improve survival in critically ill patients. The liver seems to be the first organ affected by gut ischemia/reperfusion, other than the gut per se (21). Hepatic dysfunction often presages death in patients with MOF, and is the subject of this investigation.

Gut ischemia/reperfusion-induced accumulation of leukocytes in the liver, both neutrophils and lymphocytes, results in an oxidative stress in sinusoids that contributes to subsequent hepatocellular injury. Kupffer's cells (KC), the resident macrophages of the liver, also play an important role in the modulation of acute inflammatory responses in the liver (10,22). It has been proposed that activated KC producing oxygen radicals and chemical inflammatory mediators such as TNF-{alpha} and IL-6 are involved in the gut ischemia/reperfusion-induced neutrophil accumulation in the liver (23,24). Besides the activated KC, infiltrating neutrophils also produce increased quantities of free oxygen radicals (25).

TNF-{alpha} is regarded as the most important proinflammatory cytokine, and is released early after an inflammatory stimulus (21). IL-6, which increases after TNF-{alpha} release, contributes to both morbidity and mortality in conditions of "uncontrolled" inflammation (26). On the basis of the literature, we considered that of the cytokines produced in the liver during inflammation, TNF-{alpha} and IL-6 are particularly important because of their many biological effects both in the liver and elsewhere. Consequently, we used these proinflammatory cytokines as indicators of liver injury.

Oxygen radicals generated in response to ischemia/ reperfusion have been implicated in the microvascular dysfunction and parenchymal cell injury of the intestine and liver (27). The TBA assay, which measures MDA, is a simple and easy-to-use method for assessment of the degree of injury attributable to the free radicals produced by ischemia/reperfusion, and is frequently used in our laboratory (28).

Therefore, in our experimental model investigating the effects of IV anesthetics, with or without verapamil, on gut ischemia/reperfusion-induced liver injury, we examined both the tissues' MDA contents and serum cytokine levels in relation to histopathology. Because of substantial hepatic reserves and lack of an early discriminating hepatic function test, we did not use serum transaminases for the assessment of liver injury in our study design.

The effects of IV anesthetics used during surgical intervention on gut ischemia/reperfusion-induced liver injury have not been investigated. It is also of clinical importance to know the preventive effects of these anesthetics on gut ischemia/reperfusion-induced liver injury.

The results of the present study indicate that gut ischemia/reperfusion-induced significant increases in MDA contents of liver and gut and in serum cytokines, consistent with histopathologic injury scores. Propofol effectively stabilized the MDA levels and decreased the tissue injury scores in the liver and gut. Also, TNF-{alpha} and IL-6 levels increased less in the propofol groups than in the thiopental groups. There was no additive preventive effect of verapamil on propofol, either biochemically or histopathologically. MDA, cytokine levels, and tissue injury scores were increased most prominently in the thiopental group. Systemic administration of verapamil to animals under thiopental anesthesia may be effective in decreasing the serum proinflammatory cytokine levels and liver MDA content.

Propofol appears to inhibit lipid peroxidation, either by reacting with lipid peroxyl radicals (29) or by scavenging peroxynitrite (30), or both. Propofol is chemically similar to phenol-based free-radical scavengers, such as butylated hydroxytoluene and endogenous antioxidant {alpha}-tocopherol (vitamin E), and each molecule of propofol reacts with two radical species to form a less reactive phenoxyl radical (11). Previous studies have revealed that {alpha}-tocopherol reduces liver damage associated with oxidative stress caused by gut ischemia/reperfusion (31–33). Thus, according to our results, it can be speculated that propofol as an anesthetic may prevent the tissue injury similarly to {alpha}-tocopherol, especially in gut ischemia/reperfusion-induced liver injury.

Several studies on the cytokine effects of propofol have been reported. Taniguchi et al. (34,35) have shown that propofol attenuates cytokine responses (TNF-{alpha}, IL-6, and IL-10) to endotoxemia. In a previous study investigating the effects of IV anesthetics on IL-6 and IL-10 production, it was shown that propofol, but not thiopental, appears to inhibit IL-6 production in vitro (36). Takemoto (37) also found that propofol inhibited an increase in concentrations of both TNF-{alpha} and IL-6 during endotoxemia in vivo. In this context, our results seemed to be in line with the literature. However, we show here for the first time that propofol administration may inhibit inflammatory cytokine responses in liver during gut ischemia/reperfusion in vivo.

Thiopental has been shown to act as an antioxidant by inhibiting iron-stimulated but not peroxynitrite-stimulated MDA formation in vitro (15). The effect of thiopental on lipid peroxidation and free radicals in vivo may thus be a result of additional mechanisms than those suggested by in vitro experiments. Furthermore, peroxynitrite-stimulated MDA formation seemed to be a more prominent mechanism after gut ischemia/ reperfusion (38).

Calcium is involved in various mechanisms that ultimately result in oxygen radical injury to cell components after intestinal ischemia (8,39). Kimura et al. (40) showed that verapamil had protective effects on intestinal ischemia/reperfusion injury when administered as a bolus 10 min before reperfusion. Therefore, we used this time point to study the role of verapamil. It is possible that the mechanism of action of verapamil after gut ischemia/reperfusion is due to primary effects, including inhibition of xanthine oxidase and mitochondrial calcium loading, or to secondary effects, including inhibition of KC production of cytokines, or both (41–43). On the basis of these findings, a question arose about our study model regarding the protective action of verapamil on ischemia/ reperfusion in relation to its antiapoptotic effect (41–43). This requires further confirmation.

The potential additive effect of combining verapamil with {alpha}-tocopherol for prevention of reperfusion injury is controversial (44). It has been demonstrated that verapamil, when used together with {alpha}-tocopherol, does not increase the preventive effect of {alpha}-tocopherol in gut ischemia/reperfusion-induced liver injury (31,45,46). Although our results did not reveal any additive effect of verapamil on propofol, verapamil seemed to be a promising drug for combatting gut ischemia/ reperfusion-induced liver injury in animals under thiopental anesthesia. This should be confirmed in future experimental studies.

It has also been shown that morphologic damage to the rat intestinal epithelium and liver occurs through apoptosis induced by an increase in free radicals after gut ischemia/reperfusion injury (47–49). However, administration of propofol as an anesthetic decreased the grade of histopathologic injury compared with the thiopental anesthesia. Thus, propofol may have some beneficial effects in liver and gut by decreasing apoptosis after gut ischemia/reperfusion. This hypothesis also should be clarified with further studies.

Although our findings suggest that propofol is a promising anesthetic in cases of gut ischemia/ reperfusion-induced liver injury, our study had limitations. First, because of the impossibility of performing this type of surgical intervention in rats without anesthesia, we did not have a negative control group. Second, because of our limited laboratory facilities, we did not evaluate the possible benefits of propofol and verapamil with more specific measurements, such as tissue nitrotyrosine and the enzyme poly(ADP-ribose) polymerase levels, and apoptosis, respectively.

In conclusion, although the mechanisms responsible for the beneficial effects of propofol require further investigation, our results suggest that propofol as an anesthetic may offer advantages in an animal model of gut ischemia/reperfusion-induced liver injury by scavenging reactive oxygen species and peroxynitrite and inhibiting lipid peroxidation. If propofol can indeed inhibit increased inflammatory cytokine production during surgical intervention for anticipated gut ischemia/reperfusion, it may provide an important therapeutic tool for preventing the complications of surgery. The clinical significance of these results must be elucidated in further studies.


   Footnotes
 
Accepted for publication July 19, 2007.


   REFERENCES
Top
 Abstract
 Introduction
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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