|Year : 2015 | Volume
| Issue : 1 | Page : 49-54
Resuscitation with hydroxyethyl starch 130/0.4 attenuates intestinal injury in a rabbit model of sepsis
Wei-Hua Lu, Xiao-Ju Jin, Xiao-Gan Jiang, Zhen Wang, Jing-Yi Wu, Guang-Gui Shen
Department of Anesthesiology and Critical Care Medicine, Yijishan Hospital, Wannan Medical College, Wuhu, China
|Date of Submission||28-Mar-2014|
|Date of Decision||13-May-2014|
|Date of Acceptance||27-Jul-2014|
|Date of Web Publication||30-Jan-2015|
Dr. Xiao-Ju Jin
Department of Anesthesiology and Critical Care Medicine, Yijishan Hospital, Wannan Medical College, Wuhu
Source of Support: This study was supported by a grant
(WK2014ZF03) from the Cultivating fund for key research project of
Wannan Medical College., Conflict of Interest: None
Objective: Improvement of mucosal barrier function and reduction of bacterial translocation are important in the management of sepsis. The mechanisms that underlie the protective effects of colloids on the intestinal mucosal barrier are unclear. The study aims to investigate the effect of fluid resuscitation with hydroxyethyl starch (HES) 130/0.4 against intestinal mucosal barrier dysfunction in a rabbit model of sepsis.
Materials and Methods: Thirty healthy rabbits were randomly and equally divided into a sham-operated control, a sepsis model, or a sepsis + HES treatment group. The sepsis model and sepsis + HES treatment groups were subjected to a modified colon ascendens stent peritonitis (CASP) procedure to induce sepsis. Four hours after the CASP procedure, fluid resuscitation was performed with 6% HES 130/0.4. Arterial and superior mesenteric vein blood samples were collected 4 and 8 h after the CASP procedure for blood gas analysis and measuring tumor necrosis factor-α, interleukin-10, and D-lactate levels. The rabbits were euthanized 8 h after CASP, and sections of the small intestine were stained to evaluate histopathological changes.
Results: Respiratory rate and blood pressure were stable during the resuscitation period. Fluid resuscitation with 6% HES 130/0.4 alleviated pathological changes in the abdominal cavity, improved blood gas parameters and inflammatory mediator levels, decreased plasma D-lactate levels, and reduced intestinal mucosal injury compared with the non-treated sepsis model.
Conclusions: Fluid resuscitation with 6% HES 130/0.4 protects against intestinal mucosal barrier dysfunction in rabbits with sepsis, possibly via mechanisms associated with improving intestinal oxygen metabolism and reducing the release of inflammatory mediators.
Keywords: HES 130/0.4, intestinal mucosal barrier, inflammatory mediators, resuscitation, sepsis
|How to cite this article:|
Lu WH, Jin XJ, Jiang XG, Wang Z, Wu JY, Shen GG. Resuscitation with hydroxyethyl starch 130/0.4 attenuates intestinal injury in a rabbit model of sepsis. Indian J Pharmacol 2015;47:49-54
|How to cite this URL:|
Lu WH, Jin XJ, Jiang XG, Wang Z, Wu JY, Shen GG. Resuscitation with hydroxyethyl starch 130/0.4 attenuates intestinal injury in a rabbit model of sepsis. Indian J Pharmacol [serial online] 2015 [cited 2020 Jan 25];47:49-54. Available from: http://www.ijp-online.com/text.asp?2015/47/1/49/150333
| » Introduction|| |
Sepsis is the presence of infectious organisms, or the toxins they produce, as well as systemic inflammatory response syndrome leading to tissue hypoperfusion and abnormal cellular metabolism or organ dysfunction such as infection-induced hypotension, elevated lactate, or oliguria.  If not managed successfully, infection leading to sepsis can progress to septic shock, the failure of multiple organs, and even death. Severe sepsis and septic shock are major healthcare problems, affecting millions of people around the world each year. Intestinal metabolic abnormalities occur in the early stage and are considered a priming factor for multiple organ dysfunction syndrome. 
In the normal intestine, the mucosal barrier prevents translocation of intraluminal bacteria and toxins into the blood. When sepsis occurs, an intestinal inflammatory response and intestinal mucosal ischemia/hypoxia can compromise this function; increased intestinal mucosal permeability in turn results in translocation of endotoxins and bacteria, the systemic inflammatory response, and ultimately multiple organ dysfunction syndrome.  Thus, improvement of mucosal barrier function and reduction of bacterial translocation are important in the management of sepsis.
As sepsis is associated with tissue hypoperfusion, early adequate fluid resuscitation is a cornerstone of therapy for septic shock, to improve tissue perfusion and oxygenation and prevent progression to multiple organ dysfunction syndrome.  Both crystalloids and colloids have been successfully used for fluid resuscitation in patients with septic shock, although there has been a long-standing debate over the choice of resuscitation fluid due to different efficacies and adverse side effects. 
Although more patients resuscitated with 6% hydroxyethyl starch (HES) underwent renal-replacement therapy in the intensive care unit (ICU), there was no significant difference in 90-day mortality between those who received resuscitation with HES 130/0.4 or saline.  A multicenter study compared the hemodynamic efficacy and safety of 6% HES 130/0.4 and NaCl 0.9% for delayed hemodynamic stabilization in patients with severe sepsis, and found that there were no differences in mortality, coagulation, or pruritus up to 90 days after treatment initiation, but a significantly lower volume of HES was required to achieve hemodynamic stabilization.  Although colloid solutions are more expensive and may be harmful in some patients, they were more frequently administered to resuscitate critically ill patients than crystalloids. 
Interestingly, distinct types of HES show clear differences in pharmacokinetic, clinical efficacy, and adverse effects. HES 130/0.4 is associated with lower risk for tissue accumulation and causes fewer effects on coagulation and hemodynamics compared with other HES specifications. Best known for their use as intravascular volume expanders, HES 130/0.4 solutions are also associated with microcirculatory improvement and anti-inflammatory properties and can scavenge oxygen free radicals, stabilize the cell membrane, and attenuate endothelial cell swelling. 
Given that dysfunction of the intestinal mucosal barrier has a central role in the pathogenesis of sepsis, elucidation of the mechanisms that underlie the protective effects of colloids on the intestinal mucosal barrier is of great clinical significance. In the present study, we developed a rabbit model of sepsis to investigate whether resuscitation with 6% HES 130/0.4 is protective against intestinal mucosal barrier dysfunction, noting its effect on intestinal metabolism and intestinal inflammatory response.
| » Materials and Methods|| |
Healthy adult male New Zealand white rabbits weighing 2.5-3.0 kg were used for all experiments. All animals were purchased from Nanjing Experimental Animal Centre (Jiangsu, China). Prior to surgery, the rabbits were fasted for 24 h with free access to water. All animal experiments were performed under protocols approved by the Animal Care and Use Committee that are in accordance with the Guidance to Treat Experimental Animals established by the Chinese Council on Animal Care.
Induction of sepsis
A rabbit model of abdominal sepsis (colon ascendens stent peritonitis, or CASP) was developed as previously described  with some modifications. Briefly, a median abdominal incision, 1.5 to 2.0 cm long, was made under local anesthesia to expose the ascending colon. A 10 F catheter (~3 cm long) was stitched through the antimesenteric wall into the lumen of the ascending colon. When the catheter was ~1 cm from the ileocecal valve, the ileum was squeezed to check if stool appeared from the catheter end. After ensuring proper intraluminal positioning, the catheter was fixed using 7/0 Ethicon thread. The bowel was then put back into the abdominal cavity and the abdomen was closed. The rabbits were given free access to food and water postoperatively.
The criteria for a successful model included decreased blood pressure, increased heart rate and respiratory rate (~2 × the normal value for both), raised blood glucose, and acutely elevated levels of tumor necrosis factor-α (TNF-α).  For the sham operation, the CASP surgical procedure was performed, except for the catheterization.
Thirty rabbits were randomly divided into a sham-operated control group, a sepsis model group, and a sepsis + HES treatment group (n = 10, each). The sham-operated control group underwent a sham surgery, while the sepsis model and sepsis + HES treatment groups underwent the CASP surgery.
Fluid resuscitation with HES 130/0.4 was given to the sepsis + HES treatment group 4 h after the CASP procedure. A median abdominal incision (~6 cm long) was made to open the abdominal cavity. After observing gross pathological changes in the abdominal cavity, the superior mesenteric vein was identified for administering 6% HES 130/0.4 (Fresenius Kabi, Germany), at an infusion rate of 1 mL·kg -1·min -1 for 30 minutes in the sepsis + HES treatment group, and the same amount of Ringer's fluid infusion in the sepsis model group. BES (N, N-bis[2-hydroxyethyl]-2-aminoethanesulfonic acid)-buffered saline was administered at an infusion rate of 10 mL/kg -1·h -1 for animals in the three groups for supplementing physiological amounts. All animals were monitored to record respiratory rate and urine output during the experiment.
Four hours after the CASP procedure, a 24-gauge catheter needle was inserted percutaneously into the marginal ear vein of animals and connected to an intravenous infusion system. After the animals were anesthetized by intravenously infusing 3% sodium pentobarbital via the marginal ear vein, the right carotid artery was cannulated and connected to a biotic signal collection and processing system (MedLab-U/4cs, MeiYi, Nanjing, China) for continuous recording of the mean arterial pressure (MAP) and heart rate.
Blood gas, lactate, blood glucose and D-lactate
Blood samples were collected from the carotid artery (1 mL) and superior mesenteric vein (2 mL) 4 and 8 h after the CASP procedure to conduct blood gas analysis and measure blood lactate with an i-STAT blood gas analyzer (Abbott, USA). The oxygen extraction ratio (O 2 ER) was calculated using the formula: O 2 ER = (SaO 2 -SvO 2 )/SaO 2 , where SaO 2 is the arterial oxygen saturation and SvO 2 is the venous oxygen saturation. Blood samples collected from the superior mesenteric vein were centrifuged at 3000 rpm at 4°C for 10 min to separate the plasma. The optical density of the mixture was measured at 340 nm. The concentration of D-lactate was determined using a standard curve. Values were expressed in μg/mL.
TNF-α and interleukin (IL) 10 levels
Blood samples collected from the superior mesenteric vein were centrifuged at 3000 rpm at 4°C for 10 min to separate out the plasma. Plasma TNF-α and IL-10 were determined using ELISA kits (R and D systems, USA) in accordance with the manufacturer's instructions.
Intestinal water content
Rabbits were euthanized 8 h after the CASP procedure. Two centimeters of intestinal segments that were ~ 5 cm away from the ileocecal valve were excised, weighed for wet weight, dried in a vacuum oven at 70°C for 24 h, and weighed again for dry weight. Intestinal water content was determined from the wet weight/dry weight (W/D) ratio.
Rabbits were euthanized 8 h after the CASP procedure. Intestinal samples were taken, fixed in 10% neutral buffered formalin, and processed routinely for hematoxylin and eosin (H and E) staining. Stained sections were examined under a light microscope. A five-point scoring system was applied to assess the severity of intestinal mucosal injury, as previsouly decscribed by Chiu et al.  The scoring criteria were: 0, normal intestinal mucosa; 1, presence of subepithelial detachments at the tip of the villi with capillary congestion; 2, presence of subepithelial detachments at the tip of the villi, moderate edema of the lamina propria, and expansion of central lacteals; 3, obvious edema of the lamina propria, degeneration and necrosis of epithelial cells, and the presence of few denuded villus tips; 4, degeneration, necrosis, and shedding of epithelial cells, shedding of some villi, exposure of the lamina propria, and capillary expansion and congestion; and 5, shedding of villi, disintegration of lamina propria, and bleeding or ulceration.
Statistical analyses were performed using a DAS1.0 software program. Numerical data are expressed as mean ± standard deviation. The means of two variables were compared using the paired t-test, while comparison of multiple variables was performed using analysis of variance. P values < 0.05 were considered statistically significant.
| » Results|| |
General status of the animals
Four hours after induction of sepsis, the rabbits in the sepsis model group showed varying degrees of shortness of breath, abdominal breathing, and decreased activity. At 8 h, the rabbits in the sepsis model group showed varying degrees of dyspnea, and some animals exhibited sighing, increased heart rate, decreased blood pressure, oliguria, and even anuria. In contrast, the rabbits in the sham-operated control group and sepsis + HES treatment group had stable respiration and blood pressure, and normal urine output.
Four hours after the initial surgery to induce sepsis, there were no significant differences in MAP or heart rate among the three groups [Figure 1]. From 4-8 h after induction of sepsis, MAP gradually declined and heart rate increased in the rabbits of the sepsis model group (P < 0.05 for all). In contrast, MAP and heart rate were relatively stable in the sham-operated control group and sepsis + HES treatment group.
|Figure 1: Dynamic changes in (a) MAP and (b) heart rate (n = 10). Data shown are mean ± standard deviation. *P < 0.05 compared with 4 h|
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Gross pathological changes in the abdominal cavity
Eight hours after induction of sepsis, continuous outflow of a large volume of intestinal contents from the catheter opening was seen in rabbits of the sepsis model group. The abdominal cavity contained much turbid purulent fluid that had a thick stench, which is the typical feature of generalized infectious peritonitis. The serosa of the small intestine showed severe congestion, edema, inflammatory adhesion, and scattered ecchymosis and bleeding points. Some rabbits had expansion and paralysis of the intestinal canal, vascular dilation and congestion, obvious lymph node swelling, and mild ascites. Rabbits of the sepsis + HES treatment group developed only mild peritonitis, and intestinal congestion and adhesion were observed only in the areas near the catheter. Rabbits of the sham-operated control group showed no obvious abnormalities.
Changes in intestinal mucosal barrier function
Four hours after induction of sepsis, blood glucose, pH, and base excess were all within the normal range in the three groups [Table 1]. Compared to the sham-operated control group, the intestinal O 2 ER decreased and blood D-lactate levels increased in the sepsis model and sepsis + HES treatment groups (P < 0.05 for all) [Table 1] and [Table 2]. Eight hours after induction of sepsis, the sepsis model group had decreased intestinal O 2 ER, base excess, and pH, and increased blood lactic acid, blood glucose, and blood D-lactate levels compared with the sham-operated control group (P < 0.05 for all). At 8 h after induction of sepsis, the sepsis model group had lower base excess and higher blood D-lactate levels, and the sepsis + HES treatment group had lower blood D-lactate levels and higher intestinal O 2 ER, compared with these levels at 4 h (P < 0.05 for all). There was no significant difference in the intestinal W/D ratio among the three groups.
|Table 1: Effcet of Hydroxyethyl starch 130/0.4 on intestinal injury in a rabbit model of sepsis - Changes in intestinal parameters (n=10)|
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|Table 2: Effcet of hydroxyethyl starch 130/0.4 on intestinal injury in a rabbit model of sepsis - changes in intestinal W/D ratio and D-lactate (n=10)|
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Changes in plasma TNF-α and IL-10 levels
Four hours after induction of sepsis, plasma TNF-α levels increased in the sepsis model and sepsis + HES treatment group compared to the sham-operated group (P < 0.05 for both) [[Figure 2]a]. However, plasma IL10 levels showed no significant differences among the three groups [[Figure 2]b]. Eight hours after induction of sepsis, both plasma TNF-α and IL-10 levels increased in the sepsis model group compared to the sham-operated. Plasma IL10 levels at 8 h were significantly higher in the sepsis model group than in the sepsis + HES treatment group (P < 0.05).
|Figure 2: Changes in plasma levels of (a) TNF-β and (b) IL-10 at 4 and 8 h after induction of sepsis among the different groups (n = 10). *P < 0.05 compared with the sham-operated control group; #P < 0.05 compared with the sepsis + HES treatment group|
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Histopathological changes in the intestinal mucosa
In the sepsis model group, histopathology revealed obvious atrophy of the intestinal mucosa, shedding of villi, degeneration, necrosis, and shedding of epithelial cells. Exposure, edema, and lymphocyte and neutrophil infiltration of the lamina propria were also evident, and lymphocyte and neutrophil infiltration, submucosal capillary congestion, and purulent mossy exudate on the serosal surface were visible [[Figure 3]a]. Compared to the sepsis model group, the sepsis + HES treatment group showed mild atrophy of the intestinal mucosa, regularly arranged villi, grossly intact epithelium, increased number of goblet cells, cystic space below the upper villous epithelium, and mild edema and lymphocyte infiltration of the lamina propria [[Figure 3]b]. The sham-operated control group had intestinal mucosa that was of an even thickness, regularly arranged villi, intact epithelium, and mild lymphocyte infiltration of the lamina propria [[Figure 3]c].
|Figure 3: Histopathological changes in the small intestinal mucosa of rats of different groups 8 h after induction of sepsis. (a) sepsis model; (b) sepsis + HES treatment; C, sham-operated control (H and E,x100 staining)|
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Chiu's scores for the sham-operated, sepsis model, and sepsis + HES treatment groups were 0.5 ± 0.5, 4.3 ± 0.9, and 2.0 ± 0.7, respectively, and the mean score of the sham-operated group was significantly higher than either of the other two groups (P < 0.05 for both). However, Chiu's score of the sepsis + HES treatment group was significantly lower than that of the sepsis model group (P < 0.05).
| » Discussion|| |
Several previous studies indicated that fluid resuscitation can ameliorate intestinal mucosal injury in sepsis. , In the present study, we developed a rabbit model of sepsis and investigated the effect of resuscitation with HES 130/0.4 on dysfunction of the intestinal mucosal barrier. Because HES 130/0.4 quickly expands to twice its initial volume, reaching a plateau at 4 to 6 h,  we observed its effect beginning at 4 h after resuscitation. We found that respiratory rate and blood pressure were stable during the resuscitation period, and that HES 130/0.4 could alleviate pathological changes in the abdominal cavity, improve blood gas parameters, decrease plasma D-lactate levels, and reduce intestinal mucosal injury in septic rabbits. These data suggest that fluid resuscitation with HES 130/0.4 protects against intestinal mucosal barrier dysfunction in septic rabbits.
Most of the present knowledge regarding the pathophysiology of sepsis was gained from animal models that were developed to mimic human sepsis. There are two major means of developing an animal model to mimic pathological changes in sepsis: 1) the injection of bacteria, microbial components or toxins; and 2) surgical injury to liberate endogenous microbial flora from a septic focus. Cecal ligation and puncture is the most widely used injury-type model. However, it is associated with high mortality and only reveals intra-abdominal abscess formation with minor signs of systemic inflammation. In contrast, the CASP model closely replicates the clinical course of diffuse peritonitis with early and steadily increasing systemic infection and inflammation (that is, systemic inflammatory response syndrome).  For this reason, a CASP model was developed in our study. We noted that our sepsis-model rabbits developed typical symptoms of peritonitis-induced sepsis. This indicates that the CASP model is a satisfactory means of reproducing the features of sepsis and is highly suitable for the study of the pathophysiology of abdominal sepsis.
D-lactic acid is a metabolic product of bacteria found in the intestinal tract. When intestinal mucosal permeability increases, D-lactic acid enters into the bloodstream via the damaged mucosa. Therefore, the level of D-lactate in the blood can sensitively reflect bacterial overgrowth in the intestinal tract and the degree of mucosal damage.  In this study, we found that induction of sepsis in rabbits increased blood D-lactic acid levels, and fluid resuscitation with HES 130/0.4 decreased these levels. This suggests that fluid resuscitation with HES 130/0.4 alleviated dysfunction of the intestinal mucosal barrier induced by sepsis.
The O 2 ER is the fraction of oxygen delivered to the microcirculation that is taken up by the tissues. In sepsis, intestinal tissue enters a state of hypermetabolism and hypoperfusion, which could result in intestinal hypoxia/ischemia. As a result, the body has a compensatory increase in O 2 ER to maintain oxygen consumption. However, as sepsis progresses and oxygen supply further decreases, the increase in O 2 ER is not adequate to meet the oxygen demand. At that point, the O 2 ER decreases and an elevation in glycolysis causes overproduction of lactate. Lactate accumulation results in cellular acidosis, which in turn leads to mitochondrial respiratory dysfunction, intestinal mucosal injury, and mucosal barrier dysfunction.  Consistent with this, we found that rabbits with sepsis had lower O 2 ERs and increased lactic acid. The observation that HES 130/0.4 could reverse these alterations indicates that fluid resuscitation with HES 130/0.4 could improve intestinal oxygen metabolism in sepsis.
There are several possible mechanisms which might explain why fluid resuscitation with HES 130/0.4 improves intestinal oxygen metabolism and alleviates intestinal mucosal barrier dysfunction in septic rabbits. First, fluid resuscitation increases the effective circulating blood volume, maintains intestinal tissue perfusion, improves the oxygen supply, and increases the O 2 ER. Previous studies have clearly shown that fluid resuscitation with HES 130/0.4 can improve microcirculatory perfusion. , Second, we found that fluid resuscitation with HES 130/0.4 reduced the hematocrit by 20% in this study. When the hematocrit is ≥ 20%, the oxygen supply to tissues is not obviously affected. However, a decrease in the hematocrit can optimize oxygen delivery, thereby promoting intestinal mucosal repair and regeneration, and maintaining intestinal epithelial cell morphology, structure and function.  Finally, a previous study showed that resuscitation with crystalloids such as lactated Ringer's solution might cause an intestinal inflammatory response and bacterial translocation,  while fluid resuscitation with HES 130/0.4 can reduce the inflammatory response and increase the O 2 ER. 
Intestinal microbial components activate a strong immune response and lead to an overproduction of harmful immune mediators that are crucially involved in the pathogenesis of sepsis.  Among these inflammatory mediators, TNF-α has a central role in initiating proinflammatory signalling cascades, and IL-10 is significantly associated with the prognosis of sepsis.  Many previous studies have indicated that HES 130/0.4 could control the release of inflammatory mediators and thereby reduce the inflammatory response. , In our study, we discovered that plasma levels of both TNF-α and IL-10 in septic rabbits resuscitated with HES 130/0.4 returned to normal 8 h after sepsis induction, indicating that HES 130/0.4 could modulate the release of cytokines. Consistent with our finding, a previous study showed that HES 130/0.4 reduced intestinal permeability by modulating inflammatory response. 
In conclusion, herein we provide evidence that fluid resuscitation with HES 130/0.4 protects against intestinal mucosal barrier dysfunction in a rabbit model of sepsis, possibly via mechanisms associated with improving intestinal oxygen metabolism and reducing the release of inflammatory mediators. Early resuscitation with HES 130/0.4 in patients with sepsis may reduce intestinal mucosal injury and therefore prevent multiple organ dysfunction syndrome.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]