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The Potential Effect of Epidural Anesthesia on Mesenteric Injury after Supraceliac Aortic Clamping in a Rabbit Model
Basic Science Research The Potential Effect of Epidural Anesthesia on Mesenteric Injury after Supraceliac Aortic Clamping in a Rabbit Model Rasit Onoglu,1 Cuneyt Narin,2 Aysel Kiyici,3 Gamze Sarkilar,4 G€ urhan Hacibeyoglu,5 6 5 Fusun Baba, and Ali Sarigul, Bolu, Izmir and Konya, Turkey
Background: Epidural anesthesia is known to increase blood flow by producing vasodilatation on mesenteric circulation. In this experimental study, we aim to examine the effect of epidural anesthesia on mesenteric ischemic-reperfusion (IR) injury induced by supracoeliac aortic occlusion in a rabbit model. Methods: Twenty-eight male white New Zealand rabbits were assigned into 4 separate groups, with 7 rabbits in each group: group I, control group; group II, IR-only group; group III, IR plus epidural anesthesia group; group IV, epidural anesthesia-only group. IR model was produced by clamping supraceliac aorta with an atraumatic vascular clamp for 60 min, followed by reperfusion for 120 min. An epidural catheter was placed via Th12-L1 intervertebral space by using open technique before aortic clamping in those assigned to epidural anesthesia. IR injury was assessed using blood markers interleukin-6 and IMA and tissue markers superoxide dismutase and malondialdehyde. Also histopathological examination was performed to evaluate the degree of injury. Results: All biochemical markers in group II were significantly elevated in comparison with the other 3 groups (p < 0.05). This was paralleled by a more severe histopathological injury in IRonly group (group II). The group receiving IR plus epidural anesthesia (group III) had lower biochemical marker levels as compared with the IR-only group (group II). Conclusions: Mesenteric IR injury that can occur during abdominal aorta surgery can be reduced by epidural anesthesia, which is commonly used during or after major operations for pain control. Controlled clinical studies are required to evaluate these findings.
INTRODUCTION Mesenteric ischemiaereperfusion (IR) injury, which may occur after major cardiovascular surgery such as open or endovascular repair of abdominal
aorta aneurysms, aortoiliac surgery, aortic dissection surgery, or thoracic aneurysm surgery and in trauma victims, is a serious complication associated with high morbidity and mortality rates.1,2 The injury generally involves a systemic effect rather
Funding: This study was financially supported by Selcuk University Scientific Projects Office (10102007). Conflicts of Interest: None.
5 Department of Cardiovascular Surgery, University of Konya NE, Konya, Turkey. 6 Department of Pathology, University of Selcuk, Konya, Turkey.
1 Department of Cardiovascular Surgery, Bolu State Hospital, Bolu, Turkey.
Correspondence to: Rasit Onoglu, MD, Department of Cardiovascular Surgery, Bolu State Hospital, Bolu, Turkey; E-mail: drrasit@ hotmail.com
2 Department of Cardiovascular Surgery, Ege Saglik Hospital, Izmir, Turkey. 3
Department of Biochemistry, University of Mevlana, Konya, Turkey. 4 Department of Anaesthesiology, University of Konya NE, Konya, Turkey.
Ann Vasc Surg 2016; -: 1–7 http://dx.doi.org/10.1016/j.avsg.2015.11.013 Ó 2016 Elsevier Inc. All rights reserved. Manuscript received: June 28, 2015; manuscript accepted: November 10, 2015; published online: ---.
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2 Onoglu et al.
than a local one, and the reperfusion injury is often more detrimental than ischemic injury.3 The primary mechanisms responsible for the IR injury involve excessive release of free-oxygen radicals from parenchymal or endothelial cells or from infiltrating leucocytes that occurs in conjunction with reperfusion.4 Endogenous antioxidant enzymes including superoxide dismutase (SOD), catalase, and glutathione peroxidase provide cellular protection against free-radical oxygen damage, and their levels are indicative of the extent of the oxidative stress during IR injury.5 Furthermore, the concentration of malondialdehyde (MDA), an end product of the lipid peroxidation, may help assess reperfusion injury caused by free-oxygen radicals.6 Histologic examination provides direct information on injury at the tissue level. Ischemia-modified albumin (IMA), a nonspecific marker of ischemia, and interleukin-6 (IL-6), which is a proinflammatory mediator, both can be used to evaluate the extent of IR injury.4 Epidural anesthesia, a commonly used route of anesthesia in daily clinical practice, is known to exert positive effects on mesenteric circulation.7 Pathophysiologic effects, which involve endocrine, metabolic, and inflammatory changes occurring after major abdominal surgery, are collectively referred to as the ‘‘stress response’’ and have been shown to be preventable by the administration of epidural anesthesia.8 Such data suggest that epidural anesthesia, which takes place before and during the surgery, can be beneficial in the sense that it can provide a preventative effect on IR injury. The objective of this study is to assess the effect of epidural anesthesia on mesenteric IR injury occurring during and after abdominal aortic clamping at supraceliac level, in a rabbit model.
MATERIALS AND METHODS Experimental Animals The experimental protocol was approved by the Selcuk University Institutional Scientific and Ethical Committee in Turkey. All animals received humane care in compliance with the Principles of Laboratory Animal Care (National Society of Medical Research) and the Guide for the Care and Use of Laboratory Animals (National Institutes of Health Publication no. 85e23, revised 1996). Twenty-eight white male New Zealand rabbits weighing between 2,800 and 5,100 g were used for the study. All rabbits were provided with standard laboratory nutrition until the day of experiment.
Annals of Vascular Surgery
Fig. 1. Placement of epidural catheter by using open surgical technique. Arrow: epidural catheter.
Study Groups A total of 4 experiment groups were defined with 7 rabbits in each group: In group I (control group), the aorta was encircled without clamping at supraceliac level; in group II (IR-only group), the aorta was encircled and clamped at supraceliac level to obtain IR; in group III (IR plus epidural anesthesia group), in addition to the procedure in group II, epidural anesthesia was administered during IR; in group IV (epidural anesthesia-only group), the procedure was the same as that in group II, except that clamping was not done and epidural anesthesia was performed. Surgical Procedures The surgical procedure was performed under intramuscular ketamine and xylazine anesthesia. Epidural catheterization was performed with an open technique. In the group III and IV (epidural anesthesia groups), each rabbit was placed in the prone position. The thoracolumber vertebral column was flexed by placing a cylinder transversely under the lower abdomen. The thoracal 12 and lomber 1 vertebras were exposed after small skin incision. An epidural catheter (Balton Epidural Anesthesia Set Small 19 G, Balton Ltd., Poland) was inserted between T12-L1 vertebrae and advance to T9 (Fig. 1). All catheters were sutured to the fascia and skins were approximated using simple silk sutures. After an initial bolus dose of lidocaine 0.5% (0.4 mL/kg), a maintenance infusion (0.1 mL/kg/hr) was given. A median laparotomy was performed to explore the aorta, which was encircled with vessel loop at supraceliac level. In the IR groups, 60 min clamping at this level was performed to achieve an ischemic status after which clamping was stopped and 120 min of reperfusion
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Fig. 2. Occlusion of supraceliac aorta for ischemia. Horizontal arrow: celiac artery, vertical arrow: supraceliac abdominal aorta.
was allowed9 (Fig. 2). Sodium nitroprusside and noradrenaline intravenous infusions were used to obtain 50 mm Hg mean arterial pressure during ischemia and reperfusion, respectively. In the epidural anesthesia groups, an initial bolus dose of lidocaine 0.5% (0.4 mL/kg) was given and maintained with continuous infusion (0.1 mL/kg/hr) in the all IR period. Blood and Tissue Samples Blood samples were obtained from inferior vena cava 180 min (60 min of ischemia plus 120 min of reperfusion) after supraceliac aortic clamping. A 2cm ileal segment was excised 10-cm proximal to the ileocecal junction for pathologic examination and tissue biochemistry testing. The distal part of the segment was used for the pathologic examination and the proximal part for the tissue biochemistry. The rabbits were sacrificed with intravenous ketamine after the procedures. Serum IL-6, serum IMA, tissue SOD activity, and tissue MDA level were determined. Histopathologic examinations were performed by light microscopy after preparing the specimens with hematoxylin-eosin stain. Assessments Serum IL-6 levels (pg/mL) were determined with Enzyme-Linked Immuno Sorbent Assay method using the commercial ‘‘Rabbit Interleukin 6’’ kit (Cusabio Biotech Co. Ltd, China), whereas serum IMA levels were assayed with a spectrophotometric method using the albumin-cobalt binding test and were expressed in ABSU (absorbance unit). Tissue SOD activity was assessed using a RANSOD (Randox, UK) SOD kit and was specified in terms of the percent tissue protein concentration (U/mg
Epidural anesthesia in aortic surgery 3
protein). Tissue protein measurements were performed using the Bradford’s method.10 The method developed by Ohkawa et al.11 was used for tissue MDA assays with the concentrations expressed as nmol per mg of wet tissue. Mesenteric IR injury was evaluated by a pathologist blinded to the study groups using light microscopy and was classified using the grading system proposed by Chiu et al.12 where the injury is graded on a scale; grade 0ebeing normal mucosa, grade 1ebeing subepithelial space developing at the tip of the villus, grade 2ebeing lifting of the epithelial layer from the lamina propia and moderate extension of the subepithelial space, grade 3ebeing some denuded tips of the villi and massive lifting of the epithelial layer, grade 4ebeing dilated and exposed capillaries and denuded villi, and grade 5ebeing hemorrhage, ulceration, and disintegrated lamina propia. Statistical Analyses SPSS (SPSS version 16.0, SPSS Inc., Chicago, IL, USA) software package was used for statistical analyses. Numerical variables were expressed as mean ± standard deviation. For the statistical analysis of biochemistry data, the difference between the groups were evaluated using 1-way analysis of variance (ANOVA) and the comparisons were performed with Tukey’s posthoc parametric tests. KruskaleWallis and ManneWhitney U tests were used for the comparison of the histopathologic data between the groups. A P value less than 0.05 was considered statistically significant in all analyses.
RESULTS No significant weight difference existed between the experimental groups. Results of tissue and serum testing in study groups are summarized in Table I with mean (±standard deviation) values. Animals undergoing IR without epidural anesthesia (group II) had significantly higher levels of all biochemical parameters tested in comparison with the other 3 groups. The group receiving IR plus epidural anesthesia (group III) had lower levels as compared with the IR-only group. No difference was found between the control groups (groups I and IV). The results of histopathologic evaluation are summarized in Table II with median (interquartile range) values. In the control group, all subjects were evaluated in grade 0¼, with normal mucosa, that is, with no mucosal injury according to Chiu’s classification (see Fig. 3A). The most significant mucosal injury was observed in group II. As far as the severity of
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Table I. Comparison of the groups with regard to serum and tissue measurements
Measurements
Group I (controls)
Group II (IR-only)
Serum IMA (ABSU) Serum IL-6 (pg/mL) Tissue MDA (nmol/mg protein) Tissue SOD (U/mg protein)
0.34 6.77 0.15 5.71
0.50 16.78 0.37 11.1
± ± ± ±
0.04 1.59 0.03 1.53
IMA, ischemia-modified albumin. a P < 0.05, versus all other groups. b P < 0.05, versus IR-only group.
0 1 2 3 4 5 Mean (InR)
0.40 10.91 0.21 6.46
± ± ± ±
0.03b 2.24b 0.04b 3.12b
0.35 7.56 0.15 5.36
± ± ± ±
0.05c 3.08c 0.04c 2.08
P > 0.05, versus control group.
Group I (controls)
Group III (IR-plus Group II epidural (IR-only) anesthesia)
Group IV (epidural anesthesiaonly)
7 0 0 0 0 0 0 (0)
0 0 1 2 3 1 4 (1)
6 1 0 0 0 0 0 (0)
0 4 2 1 0 0 2 (1)
0.04a 4.57a 0.06a 4.47a
Group IV (epidural anesthesia-only)
c
Table II. Results of histopathologic evaluation Degree of IR injury
± ± ± ±
Group III (IR plus epidural anesthesia)
Mean, median; InR, interquartile range.
the damage is concerned, severe loss of mucosal epithelial lining and glands with completely denuded intestinal villi, sloughing off of the epithelial cells to intestinal lumen, subepithelial gap formation at tips of the villi, and engorgement and hyperemia of submucosal vessels were observed (see Fig. 3B). However, in the IR plus epidural anesthesia group (group III), grade 3 injury was detected in only one subject, and the rest of the other subjects showed only mild damages like focal mild mucosal gland injury and formation of subepithelial gaps (see Fig. 3C). Epidural anesthesia only group (group IV) showed no mucosal injury except one subject that was classified in grade 1 injury (see Fig. 3D). Histopathologic grading of the groups was as follows: median (interquartile range); group I, 0 (0); group II, 4 (1); group III, 2 (1); and group IV, 0 (0). The comparison between the control group and the IR-only group showed more extensive injury in rabbits experiencing IR (P < 0.05). Also significant differences were observed between the IRonly and the ‘‘IR plus epidural anesthesia’’ groups (P < 0.05). The control groups (groups I and IV) did not differ significantly (P > 0.05). However, both IR-only and ‘‘IR plus epidural anesthesia’’
groups exhibited higher scores in comparison with both control groups (P < 0.05 for all pairwise comparisons).
DISCUSSION Our findings suggest that epidural anesthesia with lidocaine was able to alleviate mesenteric IR-injury in a rabbit IR model with supraceliac aortic occlusion. Detection of more prominent biochemical and histopathologic injury in IR groups also points to the suitability of the model for the assessment of such injury. A successful animal IR model requires a thorough consideration of collateral circulation. In a previous experimental study, interruption of the collateral circulation between celiac artery and superior mesenteric artery resulted in a more efficient ischemia as compared with that achieved by clamping the superior mesenteric artery.13 Also, in abdominal aorta surgery, rather than the selective occlusion of superior mesenteric artery, all collaterals originating from the abdominal aorta are completely occluded by the occlusion of aorta at the supraceliac level. Therefore, clamping to obtain mesenteric IR injury was done at supraceliac level in this study. However, mesenteric IR studies applying clamping at this level are relatively limited in number.14,15 Previously, positive effects of epidural anesthesia on mesenteric circulation have been demonstrated in a number of studies.7,16e19 Mesenteric vessel bed represents 25% of the total blood volume and 80% of the regional blood volume, receiving substantial sympathetic nervous supply that regulates the mesenteric blood distribution through tonic sympathetic neuronal activity.8 Therefore, epidural anesthesia is thought to exert its positive effects on the mesenteric perfusion and intestinal motility via the sympathetic tonus. Bedirli et al.20 stated
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Epidural anesthesia in aortic surgery 5
Fig. 3. Histopathologic results of groups. (A, D) The orderly intestinal mucosal epithelial lining and villi, lamina propria, glands along with submucosa, and muscularis propria with no observable signs of injury at any level (horizontal arrows; 5X H.E., 25X H.E.) (B) Severely damaged intestinal mucosa characterized by denuded
villi with loss of mucosal epithelium (vertical arrows) and glands (star arrow); and cellular debris in lumen (horizontal arrow; 10X H.E.), (C) denudation of surface mucosal cells to the lumen (horizontal arrow) and formation of submucosal gap at the tips of intestinal villi (vertical arrow; 10X H.E.).
that epidural bupivacain administration was found to decrease the inflammatory response and intestinal injury due to mesenteric IR. As many published studies mentioned, there are still conflicting comments on the effects of epidural anesthesia. Decreasing sympathetic activity, leading vasodilation, reducing mucosal permeability, and regulating tissue oxygenation are attributed to main effects of epidural anesthesia on mesenteric circulation after IR injury.21 A major mechanism responsible for the intestinal injury is lipid peroxidation caused by IR.22 MDA is the end product of lipid peroxidation and used to estimate the extent of tissue injury resulting from reperfusion.23 In a study by Ntinas et al.,24 oxygenated perfluorocarbon compounds have been shown to reduce MDA levels in mesenteric IR injury. Similarly, Gao et al.9 observed reduced MDA in mesenteric IR when experimental animals (rabbits) were preconditioned with hyperoxygenated solutions. In our study, significantly lower MDA levels were found in the ‘‘aortic IR plus epidural anesthesia’’ group as compared with the ‘‘aortic IR’’ group, suggesting a protective role for epidural anesthesia
against lipid peroxidation injury during the reperfusion stage. Free-oxygen radicals play a significant role in the pathogenesis of IR injury, and the most important of these are O2, OH,and H2O2. The enzyme SOD catalyzes the conversion of O2 anions to H2O2, which in turn is converted to O2 and H2O by catalase and GSH-Px. Thus, SOD is a critical intracellular enzyme for the cellular protection against free-oxygen radicals. Oxidative stress associated with IR injury may result in increased concentrations of free-oxygen radicals and a decreased breakdown of these.22 The increase in SOD levels in the aortic IR group in our study might represent an augmentation in the cellular protection response against increased free-oxygen radical production induced by IR. Also, in contrast with aortic IR group, rabbits in the aortic IR plus epidural anesthesia group had significantly lower SOD levels, suggesting an effective alleviation of the free-oxygen radical injury by epidural anesthesia. Intestinal IR injury has been shown to be caused by the activation of several cytotoxic and inflammatory cascades.25 Endotoxins released into the portal
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circulation due to the disruption of the mucosal barrier by IR-injury represent an important triggering mechanism for cytokine cascade,26 the stimulation of which is associated with the release of tumor necrosis factor (TNF). On the other hand, IL-6 production is partially controlled by TNF.27 TNF and IL-6 are released into the circulation from the area of injury. Although IL-6 has no direct hemodynamic effects, elevated levels of IL-6 are closely associated with mortality. IL-6 is formed during intestinal ischemia and released during reperfusion.26 However, maximum levels are reached on the first postoperative day and concentrations start to decline on the second postoperative day.28 In the present study, aortic IR group had significantly higher IL-6 levels as compared with other groups, whereas significantly lower levels were found in the aortic IR plus epidural anesthesia group as compared with IR-only group. In the study by Bedirli et al.,20 IL-6 levels were decreased with the treatment of epidural anesthesia after mesenteric IR injury in rats. Similarly, in our study, rabbits receiving epidural anesthesia had significantly lower IL-6 concentrations than in the IR-only group. However, in the study by Bedirli et al., markedly higher IL-6 levels were reported, probably because of the fact that blood sampling was performed after prolonged reperfusion (12 hours). The decrease in IL-6 observed with the administration of epidural anesthesia indicates that epidural anesthesia may alleviate the inflammatory process associated with mesenteric IR injury. Furthermore, since IL-6 is known to trigger distant-organ injury, lowered IL6 concentrations in conjunction with epidural anesthesia may also help prevent or diminish distant organ injury. In acute ischemia, metal binding capacity of the N-terminal of albumin is reduced, which can be indirectly estimated using the increase in serum IMA levels.29 In a comparison between patients with acute mesenteric ischemia and healthy volunteers, increased IMA concentrations were found in ischemic subjects.30 Dundar et al.31 showed a positive correlation between serum IMA levels and the duration of ischemia in a rabbit mesenteric ischemia model. A similar correlation was reported by Gunduz et al. in rats. Interestingly, in that study, a similar increase in IMA levels with time was observed also in control rabbits, which may be due to hypotension occurring in the absence of blood pressure monitoring with arterial catheterization.30 Our findings are supportive of these results and suggest that IMA can be used as a marker of mesenteric IR injury and epidural anesthesia may alleviate ischemic injury via a decrease in IMA concentrations.
Annals of Vascular Surgery
Ischemic changes of the intestinal mucosal cells initially involve the tips of the villi and approximately 15 min of ischemia suffices to result in that effect. After this period, Grunhagen areas can be observed in the same location. Ischemia duration of 60 min causes complete erosion of the villi and enterocytes are observed in the lumen.32 Irreversible cell death occurs when mesenteric ischemia exceeds 1 hour.12 Reperfusion before the development of necrosis is a prerequisite for the maintenance of cellular viability. On the other hand, an obvious worsening occurs in ischemic injury with reperfusion.3 A study evaluating the effect of epidural anesthesia on mesenteric IR injury reported decreased rate of apoptosis in intestinal mucosa cells with the administration of epidural bupivacaine.20 In our samples, ileal tissue examination showed less severe histopathologic injury in aortic IR plus epidural anesthesia group as compared with the aortic IR group, suggesting a beneficial effect of epidural anesthesia on IR injury. Our study had several limitations. First, we did not examine the effect of epidural anesthesia on mesenteric injury after supraceliac IR at later time points such as 12 or 24 hours after reperfusion. Therefore, usage of epidural anesthesia for 180 min might have been insufficient to elicit further effects of epidural anesthesia on mesenteric IR injury. Second, serum IL-6 and serum IMA levels are nonspecific markers of mesenteric IR injury. Limb ischemia secondary to aortic occlusion might have influenced these markers levels. But, tissue SOD activity and tissue MDA level are specific markers for mesenteric ischemia because of measured from ileal specimens. Moreover, histopathologic examination might have been helpful for bringing out specific mesenteric IR injury. Third, the systemic inflammatory response might have been increased by traumatic effect of open surgical technique for replacement of epidural catheter. Group IVeonly epidural control group was included in the study for presenting of the effect of epidural anesthesia and all groups were compared each other for statically analysis. In this way, the systemic inflammatory response to open surgical technique was evaluated and did not show any increasing for inflammatory markers. In conclusion, the results of this experimental study suggest a possible role for epidural anesthesia, which is frequently used during and after a variety of surgical procedures for pain control, in reducing the severity of mesenteric IR injury that may develop after major cardiovascular surgery including abdominal aorta surgery. Furthermore, comparative clinical studies are warranted in human subjects undergoing
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abdominal aortic surgery with supraceliac clamping to better define the therapeutic targets based on similar protective mechanisms conferred by epidural anesthesia against IR injury.
REFERENCES 1. Najibi S, Terramani TT, Weiss VJ, et al. Endoluminal versus open treatment of descending thoracic aortic aneurysms. J Vasc Surg 2002;36:732e7. 2. Koike K, Moore FA, Moore EE, et al. Gut ischemia mediates lung injury by a xanthine oxidase-dependent neutrophil mechanism. J Surg Res 1993;54:469e73. 3. Stallion A, Kou TD, Miller KA, et al. IL-10 is not protective in intestinal ischemia reperfusion injury. J Surg Res 2002;105:145e52. 4. Cotran RS. Ischemia-reperfusion damage. In: Robbins SL, Kumar V eds. Basic Pathology. Philadelphia: Saunders Company, 2000. pp 1e9. 5. Singh D, Chander V, Chopra K. Protective effect of catechin on ischemia-reperfusion-induced renal injury in rats. Pharmacol Rep 2005;57:70e6. 6. Mallick IH, Yang W, Winslet MC, et al. Ischemia-reperfusion injury of the intestine and protective strategies against injury. Dig Dis Sci 2004;49:1359e77. 7. Hogan QH, Stadnicka A, Stekiel TA, et al. Effects of epidural and systemic lidocaine on sympathetic activity and mesenteric circulation in rabbits. Anesthesiology 1993;79:1250e60. 8. Kapral S, Gollmann G, Bachmann D, et al. The effects of thoracic epidural anesthesia on intraoperative visceral perfusion and metabolism. Anesth Analg 1999;88:402e6. 9. Gao C, Chai W, Xu L, et al. Protective effects of hyperoxygenated solution preconditioning on intestinal ischemiareperfusion injury in rabbits. J Surg Res 2006;135:268e74. 10. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976;72:248e54. 11. Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 1979;95:351e8. 12. Chiu CJ, McArdle AH, Brown R, et al. Intestinal mucosal lesion in low-flow states. I. A morphological, hemodynamic, and metabolic reappraisal. Arch Surg 1970;101:478e83. 13. Gomes OM, Brasileiro Filho G, Porto LA, et al. Ischemiareperfusion histopathology alterations of the rabbit intestinal wall with and without exclusion of the collateral mesenteric circulation supply. Acta Cir Bras 2010;25:318e21. 14. Kotake Y, Yamamoto M, Matsumoto M, et al. Sivelestat, a neutrophil elastase inhibitor, attenuates neutrophil priming after hepatoenteric ischemia in rabbits. Shock 2005;23: 156e60. 15. Studer W, Wu X. Supraceliac aortic cross-clamping and declamping. Effects of dopexamine and dopamine on systemic and mesenteric hemodynamics, metabolism and intestinal tonometry in a rat model. Acta Anaesthesiol Scand 2000;44:241e8.
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16. Hogan QH, Stekiel TA, Stadnicka A, et al. Region of epidural blockade determines sympathetic and mesenteric capacitance effects in rabbits. Anesthesiology 1995;83:604e10. 17. Ai K, Kotake Y, Satoh T, et al. Epidural anesthesia retards intestinal acidosis and reduces portal vein endotoxin concentrations during progressive hypoxia in rabbits. Anesthesiology 2001;94:263e9. 18. Kosugi S, Morisaki H, Satoh T, et al. Epidural analgesia prevents endotoxin-induced gut mucosal injury in rabbits. Anesth Analg 2005;101:265e72. table of contents. 19. Daudel F, Freise H, Westphal M, et al. Continuous thoracic epidural anesthesia improves gut mucosal microcirculation in rats with sepsis. Shock 2007;28:610e4. 20. Bedirli N, Akyurek N, Kurtipek O, et al. Thoracic epidural bupivacaine attenuates inflammatory response, intestinal lipid peroxidation, oxidative injury, and mucosal apoptosis induced by mesenteric ischemia/reperfusion. Anesth Analg 2011;113:1226e32. 21. Siniscalchi A, Gamberini L, Laici C, et al. Thoracic epidural anesthesia: effects on splanchnic circulation and implications in Anesthesia and Intensive care. World J Crit Care Med 2015;4:89e104. 22. Requena JR, Fu MX, Ahmed MU, et al. Lipoxidation products as biomarkers of oxidative damage to proteins during lipid peroxidation reactions. Nephrol Dial Transplant 1996;11: 48e53. 23. Guan L, Gong D, Tian N, et al. Uncoupling protein 2 involved in protection of glucagon-like peptide 2 in small intestine with ischemia-reperfusion injury in mice. Dig Dis Sci 2005;50:554e60. 24. Ntinas A, Iliadis S, Alvanou Achparaki A, et al. The protective effect of oxygenated perfluorocarbons (PFCs) on intestinal ischemia reperfusion injury (I/R) in rabbits. Vasc Endovascular Surg 2010;44:81e8. 25. Yao YM, Bahrami S, Redl H, et al. IL-6 release after intestinal ischemia/reperfusion in rats is under partial control of TNF. J Surg Res 1997;70:21e6. 26. Bathe OF, Chow AW, Phang PT. Splanchnic origin of cytokines in a porcine model of mesenteric ischemia-reperfusion. Surgery 1998;123:79e88. 27. Deitch EA. Multiple organ failure. Pathophysiology and potential future therapy. Ann Surg 1992;216:117e34. 28. Holzheimer RG, Gross J, Schein M. Pro- and antiinflammatory cytokine-response in abdominal aortic aneurysm repair: a clinical model of ischemia-reperfusion. Shock 1999;11:305e10. 29. Bar-Or D, Lau E, Winkler JV. A novel assay for cobalt-albumin binding and its potential as a marker for myocardial ischemia-a preliminary report. J Emerg Med 2000;19:311e5. 30. Gunduz A, Turkmen S, Turedi S, et al. Time-dependent variations in ischemia-modified albumin levels in mesenteric ischemia. Acad Emerg Med 2009;16:539e43. 31. Dundar ZD, Cander B, Gul M, et al. Serum ischemiamodified albumin levels in an experimental acute mesenteric ischemia model. Acad Emerg Med 2010;17:1233e8. 32. Ikeda H, Suzuki Y, Suzuki M, et al. Apoptosis is a major mode of cell death caused by ischaemia and ischaemia/ reperfusion injury to the rat intestinal epithelium. Gut 1998;42:530e7.
Background: Epidural anesthesia is known to increase blood flow by producing vasodilatation on mesenteric circulation. In this experimental study, we aim to examine the effect of epidural anesthesia on mesenteric ischemic-reperfusion (IR) injury induced by supracoeliac aortic occlusion in a rabbit model. Methods: Twenty-eight male white New Zealand rabbits were assigned into 4 separate groups, with 7 rabbits in each group: group I, control group; group II, IR-only group; group III, IR plus epidural anesthesia group; group IV, epidural anesthesia-only group. IR model was produced by clamping supraceliac aorta with an atraumatic vascular clamp for 60 min, followed by reperfusion for 120 min. An epidural catheter was placed via Th12-L1 intervertebral space by using open technique before aortic clamping in those assigned to epidural anesthesia. IR injury was assessed using blood markers interleukin-6 and IMA and tissue markers superoxide dismutase and malondialdehyde. Also histopathological examination was performed to evaluate the degree of injury. Results: All biochemical markers in group II were significantly elevated in comparison with the other 3 groups (p < 0.05). This was paralleled by a more severe histopathological injury in IRonly group (group II). The group receiving IR plus epidural anesthesia (group III) had lower biochemical marker levels as compared with the IR-only group (group II). Conclusions: Mesenteric IR injury that can occur during abdominal aorta surgery can be reduced by epidural anesthesia, which is commonly used during or after major operations for pain control. Controlled clinical studies are required to evaluate these findings.
INTRODUCTION Mesenteric ischemiaereperfusion (IR) injury, which may occur after major cardiovascular surgery such as open or endovascular repair of abdominal
aorta aneurysms, aortoiliac surgery, aortic dissection surgery, or thoracic aneurysm surgery and in trauma victims, is a serious complication associated with high morbidity and mortality rates.1,2 The injury generally involves a systemic effect rather
Funding: This study was financially supported by Selcuk University Scientific Projects Office (10102007). Conflicts of Interest: None.
5 Department of Cardiovascular Surgery, University of Konya NE, Konya, Turkey. 6 Department of Pathology, University of Selcuk, Konya, Turkey.
1 Department of Cardiovascular Surgery, Bolu State Hospital, Bolu, Turkey.
Correspondence to: Rasit Onoglu, MD, Department of Cardiovascular Surgery, Bolu State Hospital, Bolu, Turkey; E-mail: drrasit@ hotmail.com
2 Department of Cardiovascular Surgery, Ege Saglik Hospital, Izmir, Turkey. 3
Department of Biochemistry, University of Mevlana, Konya, Turkey. 4 Department of Anaesthesiology, University of Konya NE, Konya, Turkey.
Ann Vasc Surg 2016; -: 1–7 http://dx.doi.org/10.1016/j.avsg.2015.11.013 Ó 2016 Elsevier Inc. All rights reserved. Manuscript received: June 28, 2015; manuscript accepted: November 10, 2015; published online: ---.
1
2 Onoglu et al.
than a local one, and the reperfusion injury is often more detrimental than ischemic injury.3 The primary mechanisms responsible for the IR injury involve excessive release of free-oxygen radicals from parenchymal or endothelial cells or from infiltrating leucocytes that occurs in conjunction with reperfusion.4 Endogenous antioxidant enzymes including superoxide dismutase (SOD), catalase, and glutathione peroxidase provide cellular protection against free-radical oxygen damage, and their levels are indicative of the extent of the oxidative stress during IR injury.5 Furthermore, the concentration of malondialdehyde (MDA), an end product of the lipid peroxidation, may help assess reperfusion injury caused by free-oxygen radicals.6 Histologic examination provides direct information on injury at the tissue level. Ischemia-modified albumin (IMA), a nonspecific marker of ischemia, and interleukin-6 (IL-6), which is a proinflammatory mediator, both can be used to evaluate the extent of IR injury.4 Epidural anesthesia, a commonly used route of anesthesia in daily clinical practice, is known to exert positive effects on mesenteric circulation.7 Pathophysiologic effects, which involve endocrine, metabolic, and inflammatory changes occurring after major abdominal surgery, are collectively referred to as the ‘‘stress response’’ and have been shown to be preventable by the administration of epidural anesthesia.8 Such data suggest that epidural anesthesia, which takes place before and during the surgery, can be beneficial in the sense that it can provide a preventative effect on IR injury. The objective of this study is to assess the effect of epidural anesthesia on mesenteric IR injury occurring during and after abdominal aortic clamping at supraceliac level, in a rabbit model.
MATERIALS AND METHODS Experimental Animals The experimental protocol was approved by the Selcuk University Institutional Scientific and Ethical Committee in Turkey. All animals received humane care in compliance with the Principles of Laboratory Animal Care (National Society of Medical Research) and the Guide for the Care and Use of Laboratory Animals (National Institutes of Health Publication no. 85e23, revised 1996). Twenty-eight white male New Zealand rabbits weighing between 2,800 and 5,100 g were used for the study. All rabbits were provided with standard laboratory nutrition until the day of experiment.
Annals of Vascular Surgery
Fig. 1. Placement of epidural catheter by using open surgical technique. Arrow: epidural catheter.
Study Groups A total of 4 experiment groups were defined with 7 rabbits in each group: In group I (control group), the aorta was encircled without clamping at supraceliac level; in group II (IR-only group), the aorta was encircled and clamped at supraceliac level to obtain IR; in group III (IR plus epidural anesthesia group), in addition to the procedure in group II, epidural anesthesia was administered during IR; in group IV (epidural anesthesia-only group), the procedure was the same as that in group II, except that clamping was not done and epidural anesthesia was performed. Surgical Procedures The surgical procedure was performed under intramuscular ketamine and xylazine anesthesia. Epidural catheterization was performed with an open technique. In the group III and IV (epidural anesthesia groups), each rabbit was placed in the prone position. The thoracolumber vertebral column was flexed by placing a cylinder transversely under the lower abdomen. The thoracal 12 and lomber 1 vertebras were exposed after small skin incision. An epidural catheter (Balton Epidural Anesthesia Set Small 19 G, Balton Ltd., Poland) was inserted between T12-L1 vertebrae and advance to T9 (Fig. 1). All catheters were sutured to the fascia and skins were approximated using simple silk sutures. After an initial bolus dose of lidocaine 0.5% (0.4 mL/kg), a maintenance infusion (0.1 mL/kg/hr) was given. A median laparotomy was performed to explore the aorta, which was encircled with vessel loop at supraceliac level. In the IR groups, 60 min clamping at this level was performed to achieve an ischemic status after which clamping was stopped and 120 min of reperfusion
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Fig. 2. Occlusion of supraceliac aorta for ischemia. Horizontal arrow: celiac artery, vertical arrow: supraceliac abdominal aorta.
was allowed9 (Fig. 2). Sodium nitroprusside and noradrenaline intravenous infusions were used to obtain 50 mm Hg mean arterial pressure during ischemia and reperfusion, respectively. In the epidural anesthesia groups, an initial bolus dose of lidocaine 0.5% (0.4 mL/kg) was given and maintained with continuous infusion (0.1 mL/kg/hr) in the all IR period. Blood and Tissue Samples Blood samples were obtained from inferior vena cava 180 min (60 min of ischemia plus 120 min of reperfusion) after supraceliac aortic clamping. A 2cm ileal segment was excised 10-cm proximal to the ileocecal junction for pathologic examination and tissue biochemistry testing. The distal part of the segment was used for the pathologic examination and the proximal part for the tissue biochemistry. The rabbits were sacrificed with intravenous ketamine after the procedures. Serum IL-6, serum IMA, tissue SOD activity, and tissue MDA level were determined. Histopathologic examinations were performed by light microscopy after preparing the specimens with hematoxylin-eosin stain. Assessments Serum IL-6 levels (pg/mL) were determined with Enzyme-Linked Immuno Sorbent Assay method using the commercial ‘‘Rabbit Interleukin 6’’ kit (Cusabio Biotech Co. Ltd, China), whereas serum IMA levels were assayed with a spectrophotometric method using the albumin-cobalt binding test and were expressed in ABSU (absorbance unit). Tissue SOD activity was assessed using a RANSOD (Randox, UK) SOD kit and was specified in terms of the percent tissue protein concentration (U/mg
Epidural anesthesia in aortic surgery 3
protein). Tissue protein measurements were performed using the Bradford’s method.10 The method developed by Ohkawa et al.11 was used for tissue MDA assays with the concentrations expressed as nmol per mg of wet tissue. Mesenteric IR injury was evaluated by a pathologist blinded to the study groups using light microscopy and was classified using the grading system proposed by Chiu et al.12 where the injury is graded on a scale; grade 0ebeing normal mucosa, grade 1ebeing subepithelial space developing at the tip of the villus, grade 2ebeing lifting of the epithelial layer from the lamina propia and moderate extension of the subepithelial space, grade 3ebeing some denuded tips of the villi and massive lifting of the epithelial layer, grade 4ebeing dilated and exposed capillaries and denuded villi, and grade 5ebeing hemorrhage, ulceration, and disintegrated lamina propia. Statistical Analyses SPSS (SPSS version 16.0, SPSS Inc., Chicago, IL, USA) software package was used for statistical analyses. Numerical variables were expressed as mean ± standard deviation. For the statistical analysis of biochemistry data, the difference between the groups were evaluated using 1-way analysis of variance (ANOVA) and the comparisons were performed with Tukey’s posthoc parametric tests. KruskaleWallis and ManneWhitney U tests were used for the comparison of the histopathologic data between the groups. A P value less than 0.05 was considered statistically significant in all analyses.
RESULTS No significant weight difference existed between the experimental groups. Results of tissue and serum testing in study groups are summarized in Table I with mean (±standard deviation) values. Animals undergoing IR without epidural anesthesia (group II) had significantly higher levels of all biochemical parameters tested in comparison with the other 3 groups. The group receiving IR plus epidural anesthesia (group III) had lower levels as compared with the IR-only group. No difference was found between the control groups (groups I and IV). The results of histopathologic evaluation are summarized in Table II with median (interquartile range) values. In the control group, all subjects were evaluated in grade 0¼, with normal mucosa, that is, with no mucosal injury according to Chiu’s classification (see Fig. 3A). The most significant mucosal injury was observed in group II. As far as the severity of
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Table I. Comparison of the groups with regard to serum and tissue measurements
Measurements
Group I (controls)
Group II (IR-only)
Serum IMA (ABSU) Serum IL-6 (pg/mL) Tissue MDA (nmol/mg protein) Tissue SOD (U/mg protein)
0.34 6.77 0.15 5.71
0.50 16.78 0.37 11.1
± ± ± ±
0.04 1.59 0.03 1.53
IMA, ischemia-modified albumin. a P < 0.05, versus all other groups. b P < 0.05, versus IR-only group.
0 1 2 3 4 5 Mean (InR)
0.40 10.91 0.21 6.46
± ± ± ±
0.03b 2.24b 0.04b 3.12b
0.35 7.56 0.15 5.36
± ± ± ±
0.05c 3.08c 0.04c 2.08
P > 0.05, versus control group.
Group I (controls)
Group III (IR-plus Group II epidural (IR-only) anesthesia)
Group IV (epidural anesthesiaonly)
7 0 0 0 0 0 0 (0)
0 0 1 2 3 1 4 (1)
6 1 0 0 0 0 0 (0)
0 4 2 1 0 0 2 (1)
0.04a 4.57a 0.06a 4.47a
Group IV (epidural anesthesia-only)
c
Table II. Results of histopathologic evaluation Degree of IR injury
± ± ± ±
Group III (IR plus epidural anesthesia)
Mean, median; InR, interquartile range.
the damage is concerned, severe loss of mucosal epithelial lining and glands with completely denuded intestinal villi, sloughing off of the epithelial cells to intestinal lumen, subepithelial gap formation at tips of the villi, and engorgement and hyperemia of submucosal vessels were observed (see Fig. 3B). However, in the IR plus epidural anesthesia group (group III), grade 3 injury was detected in only one subject, and the rest of the other subjects showed only mild damages like focal mild mucosal gland injury and formation of subepithelial gaps (see Fig. 3C). Epidural anesthesia only group (group IV) showed no mucosal injury except one subject that was classified in grade 1 injury (see Fig. 3D). Histopathologic grading of the groups was as follows: median (interquartile range); group I, 0 (0); group II, 4 (1); group III, 2 (1); and group IV, 0 (0). The comparison between the control group and the IR-only group showed more extensive injury in rabbits experiencing IR (P < 0.05). Also significant differences were observed between the IRonly and the ‘‘IR plus epidural anesthesia’’ groups (P < 0.05). The control groups (groups I and IV) did not differ significantly (P > 0.05). However, both IR-only and ‘‘IR plus epidural anesthesia’’
groups exhibited higher scores in comparison with both control groups (P < 0.05 for all pairwise comparisons).
DISCUSSION Our findings suggest that epidural anesthesia with lidocaine was able to alleviate mesenteric IR-injury in a rabbit IR model with supraceliac aortic occlusion. Detection of more prominent biochemical and histopathologic injury in IR groups also points to the suitability of the model for the assessment of such injury. A successful animal IR model requires a thorough consideration of collateral circulation. In a previous experimental study, interruption of the collateral circulation between celiac artery and superior mesenteric artery resulted in a more efficient ischemia as compared with that achieved by clamping the superior mesenteric artery.13 Also, in abdominal aorta surgery, rather than the selective occlusion of superior mesenteric artery, all collaterals originating from the abdominal aorta are completely occluded by the occlusion of aorta at the supraceliac level. Therefore, clamping to obtain mesenteric IR injury was done at supraceliac level in this study. However, mesenteric IR studies applying clamping at this level are relatively limited in number.14,15 Previously, positive effects of epidural anesthesia on mesenteric circulation have been demonstrated in a number of studies.7,16e19 Mesenteric vessel bed represents 25% of the total blood volume and 80% of the regional blood volume, receiving substantial sympathetic nervous supply that regulates the mesenteric blood distribution through tonic sympathetic neuronal activity.8 Therefore, epidural anesthesia is thought to exert its positive effects on the mesenteric perfusion and intestinal motility via the sympathetic tonus. Bedirli et al.20 stated
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Fig. 3. Histopathologic results of groups. (A, D) The orderly intestinal mucosal epithelial lining and villi, lamina propria, glands along with submucosa, and muscularis propria with no observable signs of injury at any level (horizontal arrows; 5X H.E., 25X H.E.) (B) Severely damaged intestinal mucosa characterized by denuded
villi with loss of mucosal epithelium (vertical arrows) and glands (star arrow); and cellular debris in lumen (horizontal arrow; 10X H.E.), (C) denudation of surface mucosal cells to the lumen (horizontal arrow) and formation of submucosal gap at the tips of intestinal villi (vertical arrow; 10X H.E.).
that epidural bupivacain administration was found to decrease the inflammatory response and intestinal injury due to mesenteric IR. As many published studies mentioned, there are still conflicting comments on the effects of epidural anesthesia. Decreasing sympathetic activity, leading vasodilation, reducing mucosal permeability, and regulating tissue oxygenation are attributed to main effects of epidural anesthesia on mesenteric circulation after IR injury.21 A major mechanism responsible for the intestinal injury is lipid peroxidation caused by IR.22 MDA is the end product of lipid peroxidation and used to estimate the extent of tissue injury resulting from reperfusion.23 In a study by Ntinas et al.,24 oxygenated perfluorocarbon compounds have been shown to reduce MDA levels in mesenteric IR injury. Similarly, Gao et al.9 observed reduced MDA in mesenteric IR when experimental animals (rabbits) were preconditioned with hyperoxygenated solutions. In our study, significantly lower MDA levels were found in the ‘‘aortic IR plus epidural anesthesia’’ group as compared with the ‘‘aortic IR’’ group, suggesting a protective role for epidural anesthesia
against lipid peroxidation injury during the reperfusion stage. Free-oxygen radicals play a significant role in the pathogenesis of IR injury, and the most important of these are O2, OH,and H2O2. The enzyme SOD catalyzes the conversion of O2 anions to H2O2, which in turn is converted to O2 and H2O by catalase and GSH-Px. Thus, SOD is a critical intracellular enzyme for the cellular protection against free-oxygen radicals. Oxidative stress associated with IR injury may result in increased concentrations of free-oxygen radicals and a decreased breakdown of these.22 The increase in SOD levels in the aortic IR group in our study might represent an augmentation in the cellular protection response against increased free-oxygen radical production induced by IR. Also, in contrast with aortic IR group, rabbits in the aortic IR plus epidural anesthesia group had significantly lower SOD levels, suggesting an effective alleviation of the free-oxygen radical injury by epidural anesthesia. Intestinal IR injury has been shown to be caused by the activation of several cytotoxic and inflammatory cascades.25 Endotoxins released into the portal
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circulation due to the disruption of the mucosal barrier by IR-injury represent an important triggering mechanism for cytokine cascade,26 the stimulation of which is associated with the release of tumor necrosis factor (TNF). On the other hand, IL-6 production is partially controlled by TNF.27 TNF and IL-6 are released into the circulation from the area of injury. Although IL-6 has no direct hemodynamic effects, elevated levels of IL-6 are closely associated with mortality. IL-6 is formed during intestinal ischemia and released during reperfusion.26 However, maximum levels are reached on the first postoperative day and concentrations start to decline on the second postoperative day.28 In the present study, aortic IR group had significantly higher IL-6 levels as compared with other groups, whereas significantly lower levels were found in the aortic IR plus epidural anesthesia group as compared with IR-only group. In the study by Bedirli et al.,20 IL-6 levels were decreased with the treatment of epidural anesthesia after mesenteric IR injury in rats. Similarly, in our study, rabbits receiving epidural anesthesia had significantly lower IL-6 concentrations than in the IR-only group. However, in the study by Bedirli et al., markedly higher IL-6 levels were reported, probably because of the fact that blood sampling was performed after prolonged reperfusion (12 hours). The decrease in IL-6 observed with the administration of epidural anesthesia indicates that epidural anesthesia may alleviate the inflammatory process associated with mesenteric IR injury. Furthermore, since IL-6 is known to trigger distant-organ injury, lowered IL6 concentrations in conjunction with epidural anesthesia may also help prevent or diminish distant organ injury. In acute ischemia, metal binding capacity of the N-terminal of albumin is reduced, which can be indirectly estimated using the increase in serum IMA levels.29 In a comparison between patients with acute mesenteric ischemia and healthy volunteers, increased IMA concentrations were found in ischemic subjects.30 Dundar et al.31 showed a positive correlation between serum IMA levels and the duration of ischemia in a rabbit mesenteric ischemia model. A similar correlation was reported by Gunduz et al. in rats. Interestingly, in that study, a similar increase in IMA levels with time was observed also in control rabbits, which may be due to hypotension occurring in the absence of blood pressure monitoring with arterial catheterization.30 Our findings are supportive of these results and suggest that IMA can be used as a marker of mesenteric IR injury and epidural anesthesia may alleviate ischemic injury via a decrease in IMA concentrations.
Annals of Vascular Surgery
Ischemic changes of the intestinal mucosal cells initially involve the tips of the villi and approximately 15 min of ischemia suffices to result in that effect. After this period, Grunhagen areas can be observed in the same location. Ischemia duration of 60 min causes complete erosion of the villi and enterocytes are observed in the lumen.32 Irreversible cell death occurs when mesenteric ischemia exceeds 1 hour.12 Reperfusion before the development of necrosis is a prerequisite for the maintenance of cellular viability. On the other hand, an obvious worsening occurs in ischemic injury with reperfusion.3 A study evaluating the effect of epidural anesthesia on mesenteric IR injury reported decreased rate of apoptosis in intestinal mucosa cells with the administration of epidural bupivacaine.20 In our samples, ileal tissue examination showed less severe histopathologic injury in aortic IR plus epidural anesthesia group as compared with the aortic IR group, suggesting a beneficial effect of epidural anesthesia on IR injury. Our study had several limitations. First, we did not examine the effect of epidural anesthesia on mesenteric injury after supraceliac IR at later time points such as 12 or 24 hours after reperfusion. Therefore, usage of epidural anesthesia for 180 min might have been insufficient to elicit further effects of epidural anesthesia on mesenteric IR injury. Second, serum IL-6 and serum IMA levels are nonspecific markers of mesenteric IR injury. Limb ischemia secondary to aortic occlusion might have influenced these markers levels. But, tissue SOD activity and tissue MDA level are specific markers for mesenteric ischemia because of measured from ileal specimens. Moreover, histopathologic examination might have been helpful for bringing out specific mesenteric IR injury. Third, the systemic inflammatory response might have been increased by traumatic effect of open surgical technique for replacement of epidural catheter. Group IVeonly epidural control group was included in the study for presenting of the effect of epidural anesthesia and all groups were compared each other for statically analysis. In this way, the systemic inflammatory response to open surgical technique was evaluated and did not show any increasing for inflammatory markers. In conclusion, the results of this experimental study suggest a possible role for epidural anesthesia, which is frequently used during and after a variety of surgical procedures for pain control, in reducing the severity of mesenteric IR injury that may develop after major cardiovascular surgery including abdominal aorta surgery. Furthermore, comparative clinical studies are warranted in human subjects undergoing
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abdominal aortic surgery with supraceliac clamping to better define the therapeutic targets based on similar protective mechanisms conferred by epidural anesthesia against IR injury.
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