M. Storck

Endovascular stent-graft placement versus conventional open surgery in infrarenal aortic aneurysm: a prospective study on acute phase response and clinical outcome

BACKGROUND For the treatment of aortic aneurysm, stent-graft implantation is an alternative method to open surgery. There is no study comparing both methods with regard to endotoxaemia, the acute phase cascade, and clinical outcome. METHODS In this prospective study, we enrolled 40 patients (34 males, 6 females; mean age 72.1+/-7.5 [58-92] years) with infrarenal abdominal aortic aneurysm who underwent aortic surgery. Comparable groups of patients were treated with open (n=20) or endovascular (n=20) stent-graft implantation. To characterize the inflammatory response, plasma levels of endotoxin, endotoxin-neutralizing capacity (ENC), interleukin-6 (IL-6), C-reactive protein (CRP), and white blood cell count were determined. In all patients, measurements were performed on admission, skin suture, 4 h and from the first to fifth postoperative day. As parameters for the clinical outcome, we assessed daily temperature, lung function, pain, duration of postoperative hospital stay, and morbidity. Wilcoxon rank test was used for statistical analysis. RESULTS In both groups, a significant increase of endotoxin plasma levels and a decrease of ENC was found already after skin incision. IL-6 levels peaked 4 h postoperatively in both groups, whereas CRP rose at the first postoperative day, reaching a maximum at day 2. Conventionally operated patients had significantly higher plasma levels of endotoxin, IL-6, and CRP and lower ENC during and after surgery than patients with stent-graft implantation. Moreover, patients with endovascular stent grafting had significant less postoperative pain, less restriction of total vital capacity, a shorter hospital stay, and a lower morbidity. CONCLUSIONS Endovascular stent grafting of infrarenal aortic aneurysm seems to be superior not only in terms of the inflammatory response but also in overall clinical outcome.

Preoperative oral application of immunoglobulin-enriched colostrum milk and mediator response during abdominal surgery.

Our objective was to evaluate the influence of pre-operative oral application of an immunoglobulin-enriched milk preparation on endotoxin translocation and mediator release during and after abdominal surgery. Forty patients who had been treated by partial (n = 4) or total gastrectomy (n = 8) or pancreatic resection (n = 28) were enrolled in a placebo-controlled pilot study. Pre-operatively, patients were randomly treated for 3 days by oral application of a bovine milk preparation (lactobin® 56g/day, n = 20) or placebo (n = 20). In both groups, endotoxin translocation and mediator release was studied pre- and intraoperatively by measuring endotoxin, endotoxin-neutralizing capacity (ENC), interleukin 6, C-reactive protein, transferrin, &agr;-2-macroglobulin, albumin, apoliprotein-A1/-B, IgG, IgA, and IgM. The clinical course was followed up by daily evaluation of the Apache-II-score. Clinical data were comparable in both groups. The lactobin group showed significantly lower levels of endotoxin and ENC compared to the placebo group. Acute phase response, endotoxin-binding proteins, and clinical outcome did not differ between both groups. We conclude that prophylactic oral application of lactobin reduces perioperative endotoxemia and prevents reduction of ENC, suggesting a stabilization of gut barrier during abdominal surgery.

Inflammatory response during abdominal and thyroid surgery: a prospective clinical trial on mediator release.

Several studies have been demonstrated that endotoxin is a potent stimulus of the acute inflammatory response following traumatic injury. Although numerous studies have indicated that the extent of surgical intervention correlates well with the inflammatory response, the potential role of endotoxin as a trigger under those conditions still remains unknown. Therefore, the aim of this study was to elucidate whether or not the up-regulated inflammatory mediators are paralleled by increased endotoxin plasma levels during and following surgery, and whether the extent of surgical intervention represents a crucial factor under those conditions. To study this, plasma was collected at various time points during and after surgery from 52 patients subjected to abdominal surgery (i.e., major surgery) and 25 patients subjected to thyroid surgery (i.e., minor surgery). Plasma was assessed for endotoxin, endotoxin neutralizing capacity (ENC), and inflammatory mediators (leucotriene-C4 [LTC4]-, 6-keto-prostaglandin-F-1-alpha [PGF]-, thromboxane-B2 [TxB2], interleukin-6 [IL-6], and C-reactive protein [CRP]). Furthermore, splanchnic blood circulation was measured by determination of the intraluminal pH of the stomach and sigma (pHi) by intraluminal tonometry. Mesenteric lymph nodes were also collected at the time point of organ mobilization in the major surgery group and were assessed for bacterial translocation. Among all parameters investigated, endotoxin showed the most rapid changes. A significant increase in plasma levels of endotoxin and a decrease of ENC were found in the major surgery groups following induction of anesthesia and in the minor surgery groups after skin incision. Moreover, the incidence of elevated endotoxin levels was significantly higher (89% with elevated endotoxin levels) than the incidence of bacterial translocation (35% with gram-negative bacteria) in mesenterial lymph nodes of the major surgery group. pHi decreased significantly in both groups after skin incision, but no difference was observed between the major and minor surgery groups. Plasma mediators of the arachidonic acid cascade (LTC4, PGF, and TxB2) were only elevated in individual patients during and following surgery in both groups. Conversely, the post-operative increase in the acute phase mediators was significantly different in the major and minor surgery groups. IL-6 plasma levels peaked higher and earlier after major surgery than after minor surgery and the delayed increase of CRP was significantly greater in the major surgery group. In conclusion, the results indicate that plasma levels of endotoxin significantly correlate with the severity of the surgical intervention and may play an important role in inducing mediators of the acute phase reaction under such conditions.

Endotoxin release and endotoxin neutralizing capacity during colonoscopy

In 38 patients who underwent elective colonoscopy, endotoxin and endotoxin neutralizing capacity (ENC) were determined by use of the limulus--amebocyte--lysate test. A control group of 10 patients, prepared for colonoscopy, were sampled in the same manner as the study group prior to endoscopy. Elevated endotoxin plasma levels were only found when comparing the plasma levels before endoscopy with the highest levels available during endoscopy. The timed endotoxin plasma levels did not change significantly by use of the conventional limulus amebocyte test. However, ENC was found to decrease significantly 5 min after the onset of endoscopy. Maximal values were reached at the end of colonoscopy which recovered completely 24 h later. These results, obtained in a population which did not receive any infusions, demonstrate that the half life of endotoxin in the circulation seems to be very short and therefore endotoxin cannot itself be detected. On the other hand, small amounts of endotoxin reaching the blood stream are able to reduce ENC which can be analyzed by a modified limulus--amebocyte--lysate test. With the use of ENC and plasma endotoxin determinations, we are able to show significant endotoxemia during a minimal invasive procedure such as colonoscopy.

Production of proinflammatory cytokines and adhesion molecules in ex-vivo xenogeneic kidney perfusion

Abstract Xenogeneic transplantation of solid organs is limited due to hyperacute rejection. In concordant systems, the mechanisms of rejection can be studied due to cross‐reactivity of mediators with anti‐human monoclonal antibodies. The aim of this study was to obtain information about the kinetics of proinflammatory cytokines and production of soluble adhesion molecules in the acute phase of reperfusion, eight kidneys from rhesus monkeys were perfused ex‐vivo with human blood (group B/0) for 1 hour in a closed system. Blood levels of IL‐1b, IL‐6, TNFα, soluble ICAM, and E‐electin were measured using an ELISA technique under steady‐tate conditions. Cytokine levels rose significantly within the 60‐min interval (IL‐1b, 6.1 ± 2.6–161.1 + 98.5 pg/ml; IL‐6, 30.2 ± 7.7–274.2 ± 75.8 pg/ml; TNFα, 544.2 ± 363.6–1651.0±25.7 pg/ml; P < 0.05). Immediately after the beginning of reperfusion, soluble ICAM‐1 and selectin levels were abnormally high and rose constantly throughout the observation period, reaching significance at 60 min. High levels of proinflammatory cytokines may lead to an induction of adhesion molecules, thus, upregulating the leukocyte‐endothelial interaction in a complement‐independent mechanism. Specific pretreatment with monoclonal antibodies against ICAM‐1, LFA‐1, or other soluble mediators may be useful in down‐regulating hyperacute rejection in trans‐pecies transplantation.

Na-K/2Cl transporter inhibition for reduction of postis-chemic kidney failure tested in autologous reperfusion

Abstract  Postischemic kidney function may be influenced by donor conditioning. The sulfamoyl‐benzoate “piretanide” (P) is a diuretic agent with an inhibitory effect on the luminal Na‐K‐2CL‐transporter system in the ascending part of the loop of Henle. A clinical pilot study demonstrated a lower rate of organ dysfunction following transplantation in humans when the donor organs were pretreated with piretanide. In an experimental ex vivo model the effect of piretanide on immediate organ function following long or short cold ischemia was studied. Porcine kidneys (n = 36) were removed after in situ transaortal hypothermic flushing with 21 Eurocollins solution. Following short storage (1 h, n= 18) or long storage (24 h, n= 18) the kidneys were reperfused with intraoperatively drawn heparinized autologous blood diluted with Ringers lactate to a hematocrit of 25 %. Urine flow was higher in the piretanide‐pretreated group (p), especially after long storage. The electrolyte loss was comparable in both groups. Postischemic endogenous creatinine clearance was significantly elevated in the treatment group (4.45 ± 0.6 ml/min per 100 mg in P vs 1.91 ± 0.4 ml/min per 100 mg, in control, P < 0.05 Mann‐Whitney test). Renal hemodynamics were improved by piretanide, resulting in significantly lower resistance and allowing higher flow during pressure‐controlled perfusion. O2 consumption, representing general metabolic activity, was higher after long storage, indicating an earlier recovery from cold ischemia. In this ex vivo model, autologous reperfusion of porcine kidneys could be improved by piretanide pretreatment. Auto‐regulation of kidney vasculature was maintained as well as functional parameters such as creatinine clearance or gluconeogenesis. Therefore, piretanide may be used in larger clinical trials to further improve organ quality in times of donor shortage.

The function of transgenic human DAF‐expressing porcine livers during hemoperfusion with human blood

Abstract  Extracorporal pig liver perfusion could bridge the deadly problem of acute human liver failure. However, preformed natural antibodies and complement activation (CA) are the predominant mechanisms of hyperacute xenoge‐neic rejection. The blockade of both pathways of CA in the xenograft, using transgenic livers expressing human decay accelerating factor on the endothelial surface results in prolonged graft survival and lower release of mediators.

Expression of human decay accelerating factor (hDAF) in transgenic pigs regulates complement activation during ex vivo liver perfusion — immunopathological findings

Abstract  Ex vivo perfusions of human decay accelerating factor‐ex pressing transgenic (n = 3), and nontransgenic (n = 6) porcine livers with human blood revealed a higher degree of organ damage in non transgenic pig livers. Transgenic livers were protected from immuno‐histologically detectable complement deposition, despite corresponding IgM and IgG deposits in both groups. Complement activation and consumption of C3 and C4 turned out to be lower in transgenic pig livers. In contrast to livers of normal landrace pigs, livers from genetically manipulated pigs showed no morphological alterations after perfusion.

A Prospective Randomised Study on Endotoxaemia, Mediator Release and Morbidity in Conventional, Compared with Laparoscopic Cholecystectomy

Surgical procedures usually result in elevation of body temperature and changes of blood cell count or electrolyte levels, commonly known as the postoperative acute phase reaction. The present prospective randomised study compares the intensity of the postoperative acute phase reaction and postoperative morbidity in groups of patients who underwent either laparoscopic or conventional cholecystectomy. Conventionally-operated patients had significantly higher endotoxin plasma levels and a lower endotoxin-neutralisation capacity in the plasma 20 min after skin incision. This difference persisted until 6 h postoperatively. The plasma levels of interleukin-6 (IL-6) increased postoperatively, but did not differ between the two groups. C-reactive protein (CRP) increased postoperatively, with a maximum at 48 h after surgery. When comparing both groups, laparoscopically-operated patients had lower CRP-levels. The postoperatively elevated body temperature decreased significantly earlier in laparoscopically-operated patients, whereas there was no statistically relevant difference in the leukocyte count of the two groups. Contrary to studies from other authors, we did not find a significant increase of tumour necrosis factor (TNF-α). Patients with conventional cholecystectorny experienced significantly more postoperative pain, more restriction of total vital capacity and a longer postoperative hospital stay. In conclusion, patients who underwent laparoscopic rather than conventional cholecystectomy had a lower intensity postoperative acute phase reaction, as indicated by lower plasma endotoxin, CRP and body temperature, and a higher endotoxin-neutralisation capacity.