Visceral artery aneurysms.

Visceral artery aneurysms are rare with an incidence of only 0.01-0.1% of the population. Open surgical or endovascular elimination should be performed for aneurysms greater than 2 cm in size. The risk of aneurysm rupture is then approximately 25-40%. If the aneurysm ruptures the mortality can be as high as 76%. For mycotic aneurysms or spurious aneurysms there is no lower limit to the diameter size for the need of treatment. Sudden abdominal pain during pregnancy can be caused by visceral artery aneurysms and must be further clarified. The indications for surgery during pregnancy should be made generously. The clinical symptoms (abdominal complaints) of visceral artery aneurysms are manifold. The treatment can be either an open surgical approach or endovascular treatment. In the emergency setting, if endovascular treatment is no longer possible, an open surgical treatment needs to be performed. There are so far no randomized studies which could identify one of the procedures (open surgery vs. endovascular surgery) as clearly being superior. The prognosis after treatment is satisfactory with a 5-10 year survival rate of approximately 90%.

[Management of lymphatic fistulas in the groin from a surgeon's perspective]. / Management von Lymphfisteln in der Leistenregion aus chirurgischer Sicht.

BACKGROUND: The postoperative occurrence of lymph fistulas in the groin is a complication that should be taken seriously. These fistulas cause an increase in morbidity and can support local and ascending infections. The treatment of this complication ranges from conservative procedures, such as compression dressings and bed rest to operative treatment with detection of the fistulas and ligation, negative pressure wound therapy (NPWT) or even muscle flaps. This review provides an overview of current therapeutic modalities. MATERIAL AND METHODS: On the basis of a current literature search via PubMed, we identified possible treatment options, which are described in this article. RESULTS: The conservative treatment options presented still have an importance in treating groin fistulas. A selection of safe and effective interventional and operative treatments is presented. CONCLUSION: If there are indications for an interventional or operative treatment a variety of safe and effective therapies are available, which can significantly reduce the length of hospital stay. The option of treatment using a muscle flap is of value as a last resort in the treatment of infected vascular prosthesis in the groin of Szilagyi type III and should be used when necessary.

[Scientific acquisition of knowledge in operative medicine. The importance of intensive care medicine]. / Wissenschaftlicher Erkenntnisgewinn in der operativen Medizin. Die Bedeutung der Intensivmedizin.

The forms of treatment in intensive care medicine and the medicinal and instrumental equipment for maintaining the circulation, pulmonary and renal functions as well as surveillance for recognition of life-threatening arrhythmias or multiorgan failure have experienced an enormous development in recent decades. Survival of traumatized or critically ill patients has been substantially improved. Due to these developments surgeons are confronted with new patterns of diseases which necessitate the development of new operative measures. This article gives a review of the most important changes in operative medicine (e.g. traumatology and vascular surgery) which can essentially be attributed to experience and success in intensive care medicine.

Calcineurin inhibitor-free immunosuppressive strategy in elderly recipients of renal allografts from deceased donors: 1-year results from a prospective single center trial.

Recently published data from our center have demonstrated the feasibility of a nephrotoxicity- and atherogenicity-free, mycophenolate mofetil (MMF)-based immunosuppressive protocol for elderly recipients of kidneys from elderly cadaveric donors. We investigated a therapeutic regimen of strictly monitored MMF (target mycophenolic acid [MPA] trough levels between 2-6 microg/mL) and steroids combined with a polyclonal-monoclonal induction regimen consisting of a low-dose, single shot of rabbit ATG (ATG-Fresenius) and the interleukin-2 receptor (IL-2R)-antibody basiliximab (d0 and d4). Between 1997 and 2007, we treated 175 elderly patients with an MMF-based, calcinearin inhibitor (CNI)-free immunosuppressive protocol. For the present cohort, 30 elderly recipients (67.8 +/- 3.8 years) of renal transplants from deceased donors (69.4 +/- 13.3 years) were recruited consecutively for this 5-year prospective, open, single center, pilot trial. One-year results of this clinical trial were patient and renal allograft survivals of 87% and 83%, respectively; death-censored 1-year graft survival was 97%. Mostly steroid-sensitive rejection episodes were observed in 46% of patients, with only 3 patients requiring serum antibody therapy. Renal allograft function was satisfactory, as reflected by a mean serum creatinine of 1.78 +/- 0.45 mg/dL and a Nankivell glomerular filtration rate (GFR) of 48.8 +/- 13.9 mg/dL at 6 months. Twenty-three percent of all patients demonstrated cytomegalovirus (CMV) infections; however, only 3.3% developed CMV disease. Application of a combined polyclonal-monoclonal induction regimen using a nephrotoxicity- and atherogenicity-free, MMF-based immunosuppressive maintenance protocol in elderly cadaveric kidney transplant recipients led to acceptable short-term outcomes, albeit at the expense of an increased rejection rate, comparable to that previously published for elderly (>50 years) recipients of allografts from elderly (>50 years) cadaveric donors.

[Liver metastases from neuroendocrine tumours of the gastroenteropancreatic system--therapeutic strategies]. / Lebermetastasierung bei neuroendokrinen Karzinomen des gastro-entero-pankreatischen Systems--Therapiestrategien.

Neuroendocrine tumours (NET) differ appreciably with regard to their biological behaviour from tumours of epithelial origin. In general this leads to a better 5-year survival rate. Liver metastases per se and also in cases of NET result in a significantly poorer survival in comparison to tumours without metastases. In contrast to those with epithelial tumours, about (2/3) of the NET patients already have liver metastases at the time of diagnosis. Thus, in spite of the rarity of these tumours, the surgeon is frequently confronted with this tumour entity. Among other factors the prognosis depends on the primary localisation of the NET (pancreatic NET poorer than non-pancreatic NET) as well as the staging and grading (proliferation index Ki-67) of the tumours. In this article, we characterise the surgical and ablative therapies for liver metastases from NET of the gastrointestinal tract from both curative and palliative points of view on the basis of the recently published guidelines of the ENETS (European Neuroendocrine Tumour Society). Furthermore, the various options for conservative therapy are discussed and assessed for their relative values. For localised tumour disease, also of both liver lobes, the resection of liver metastases (single or multi-stage operation, if necessary in combination with RFA) remains the standard therapy. Liver resections as debulking operations (target: resection of > 90 % tumour volume) with good preoperative planning can also be carried out under palliative criteria. For diffuse liver metastases with more than 50 % tumour volume in the liver, orthotopic liver transplantation, if necessary even as a multivisceral transplantation, may be considered in individual cases. For inoperable metastases, depending on the tumour load in the liver, the tumour localisation (intrahepatic versus intra- and extrahepatic), the tumour grading (proliferation index Ki-67), the dynamics of tumour growth, and the primary localisation of the tumour, differentiated biotherapy with somatostatin analogues, peptide-mediated radioreceptor therapy (PRRT), transarterial chemoembolisation (TACE) and selective intraarterial radiotherapy (SIRT), chemotherapy and new molecular target-directed therapy options can be employed. The utilities of these treatment options are presented and discussed.

Treatment effects of high-dose antithrombin without concomitant heparin in patients with severe sepsis with or without disseminated intravascular coagulation.

BACKGROUND: Disseminated intravascular coagulation (DIC) is a serious complication of sepsis that is associated with a high mortality. OBJECTIVES: Using the adapted International Society on Thrombosis and Haemostasis (ISTH) diagnostic scoring algorithm for DIC, we evaluated the treatment effects of high-dose antithrombin (AT) in patients with severe sepsis with or without DIC. PATIENTS AND METHODS: From the phase III clinical trial in severe sepsis (KyberSept), 563 patients were identified (placebo, 277; AT, 286) who did not receive concomitant heparin and had sufficient data for DIC determination. RESULTS: At baseline, 40.7% of patients (229 of 563) had DIC. DIC in the placebo-treated patients was associated with an excess risk of mortality (28-day mortality: 40.0% vs. 22.2%, P < 0.01). AT-treated patients with DIC had an absolute reduction in 28-day mortality of 14.6% compared with placebo (P = 0.02) whereas in patients without DIC no effect on 28-day mortality was seen (0.1% reduction in mortality; P = 1.0). Bleeding complications in AT-treated patients with and without DIC were higher compared with placebo (major bleeding rates: 7.0% vs. 5.2% for patients with DIC, P = 0.6; 9.8% vs. 3.1% for patients without DIC, P = 0.02). CONCLUSIONS: High-dose AT without concomitant heparin in septic patients with DIC may result in a significant mortality reduction. The adapted ISTH DIC score may identify patients with severe sepsis who potentially benefit from high-dose AT treatment.

[Development, state of the art and perspectives of transplantation medicine, exemplified by kidney transplantation]. / Trotz grosser Fortschritte bei der Nierentransplantation: Warum steht nur jeder fünfte Dialysepatient auf der Warteliste?

In particular the knowledge of the immunological aspects of organ rejection represented a giant step forward in the field of transplantation medicine. However, despite the fact that, in the absence of a contraindication, every dialysis-requiring preterminal/terminal renal insufficiency is an indication for transplantation, fewer than 20% of 50,000 candidate patients in Germany are earmarked for a new kidney. Furthermore, the fate of the patients on the waiting list is determined in particular by the dearth of donor organs. As a rule, the source of a transplantable kidney continues to be a brain-dead donor. If, however, no such organ is likely to be available in the foreseeable future, a kidney from a living donor is an alternative option. The proportion of organs from living donors in Germany is currently between 10 and 20%.

Antithrombin: a new look at the actions of a serine protease inhibitor.

Antithrombin (AT) is a plasma-derived, single-chain glycoprotein with a molecular weight of 58 kDa. It is a serine protease inhibitor (serpin), sharing about 30% homology in amino acid sequence with other serpins. AT is a complex molecule with multiple biologically important properties. It is a potent anticoagulant that has been demonstrated to provide benefit in animal models and small cohorts of patients with coagulation disorders. AT also has remarkable anti-inflammatory properties, several of which result from its actions in the coagulation cascade. Activated coagulation proteases like activated factor X and thrombin contribute to inflammation; for instance, by the release of pro-inflammatory mediators. Inhibition of these proteases by AT prevents their specific interaction with cells and subsequent reactions. Anti-inflammatory properties of AT independent of coagulation involve direct interactions with cells leading to the release of, for instance, prostacyclin. Binding of AT to a recently identified cellular receptor, syndecan-4, leads to the interference with the intracellular signal induced by mediators like lipopolysaccharides and, thereby, to a down-modulation of the inflammatory response. AT has been shown to be effective in prospective and well-controlled small-scale studies of patients with inflammatory conditions, including sepsis. Although AT did not decrease overall patient mortality in a double-blind, placebo-controlled, phase III trial of patients with sepsis, it is important to note that AT improved the survival of individuals in this study not receiving heparin as a prophylactic regimen, which can be explained by the impaired interaction of AT with its cellular receptor in the presence of heparin, resulting in the reduction of the anti-inflammatory properties. Accordingly, the supplementation of AT without concomitant heparin may be beneficial in disorders with inflammatory characteristics, which has to be demonstrated in further clinical studies. Finally, recent results suggest that latent AT can induce apoptosis of endothelial cells by disrupting cell-matrix interactions. Further investigations will have to demonstrate whether latent and/or cleaved AT are physiological means to control angiogenesis. A potential prophylactic or therapeutic use as an anti-angiogenic and antitumor agent merits further exploration, including whether the growth of vessels in tumor tissues or close to tumors can be controlled by latent AT without affecting the formation of blood vessels during wound healing processes.

Removal of mediators by continuous hemofiltration in septic patients.

Continuous hemofiltration currently represents standard renal replacement therapy in critically ill patients. Because higher ultrafiltration rates are related to better survival rates in experimental and clinical studies and hemofiltration results in fewer cardiovascular side effects than does conventional hemodialysis, the use of inflammatory mediator removal by this extracorporeal procedure has emerged. This article reviews clinically relevant principles of compound transport and the experimental and clinical effects of hemofiltration during sepsis. Hemofiltration did not have a major impact on plasma concentrations of prominent inflammatory cytokines (tumor necrosis factor-a and interleukins 1b, 6, and 8) and seems therefore not to be able to counterbalance endogenous cytokine production despite considerable cytokine removal in the filtrate. Contradictory results in the literature are discussed under the viewpoint of membrane-related sieving coefficients and plasma cytokine measurement. A significant reduction in plasma anaphylatoxin concentrations by hemofiltration is associated with impressive immunomodulatory and cardiodepressive ultrafiltrate effects. Thus far, however, the use of hemofiltration for nonrenal indications remains experimental and is not supported by controlled clinical trials. Modern strategies of blood purification that may be associated with a high degree of effectiveness for mediator removal (high-volume hemofiltration and heparin-induced extracorporeal lipoprotein-fibrinogen precipitation) are discussed.

The thrombin antagonist hirudin fails to inhibit endotoxin-induced leukocyte/endothelial cell interaction and microvascular perfusion failure.

Besides its central role in coagulatory pathways, thrombin is known to be a key mediator of macrophage and granulocyte activation in vitro. During recent years the concept of thrombin inhibition by the specific thrombin inhibitor, hirudin, has been established to treat septic disorders. Since basic mechanisms of sepsis include leukocyte/endothelial cell interaction and deterioration of capillary perfusion, we hypothesized that hirudin modulates leukocyte activation and microvascular injury. Severe endotoxemia was induced in Syrian hamsters by intravenous administration of endotoxin (lipopolysaccharide [LPS], E. coli, 2mg/kg) at 0 h. Hirudin (0.25 mg/kg/h) was substituted intravenously during the 4 h after the induction of endotoxemia (n = 7, hirudin). In control animals (n = 6, control) LPS was given without hirudin substitution. In skinfold chamber preparations leukocyte/endothelial cell interaction and functional capillary density (FCD, measure of capillary perfusion) were analyzed during a 24-h period after LPS injection using intravital fluorescence microscopy. Hirudin effectively normalized thromboplastin time and antithrombin activity when compared to controls (P < 0.05, ANOVA). However, hirudin did not attenuate LPS-induced arteriolar and venular leukocyte adherence, and even tended to increase leukocyte adherence after 24 h (P > 0.05, MANOVA). In parallel, addition of hirudin led to a significant deterioration of FCD over time when compared to controls (hirudin: baseline = 171 +/- 19 cm(-1) versus 16 +/- 9 at 24 h; control: baseline = 150 +/- 20 cm(-1) versus 62 +/- 18 at 24 h; P < 0.05). The fall in FCD in hirudin animals was associated with a significant increase of wet-to-dry weight ratios in lung, kidney, muscle, and small intestine (P < 0.05 versus control, ANOVA). Thus our study does not indicate a protective effect of hirudin on microcirculation during endotoxemia, despite an improvement of coagulatory parameters. This result may at least in part explain the lack of efficacy of hirudin on lethality during endotoxemia and sepsis.

Antithrombin reduces leukocyte adhesion during chronic endotoxemia by modulation of the cyclooxygenase pathway.

Antithrombin (AT) is known as the most important natural inhibitor of thrombin activity and has been shown to improve distinct clinical parameters during the course of septic (endotoxin)-induced multiple organ dysfunction. We hypothesized that AT acts by inhibiting leukocyte activation and microvascular injury via the promotion of endothelial release of PGI(2), and therefore, we studied the effects of AT on leukocyte/endothelial cell interaction and microvascular perfusion during endotoxemia. In a skinfold preparation of Syrian hamsters, severe endotoxemia was induced by repeated administration of endotoxin intravenously [lipopolysaccharide (LPS), Escherichia coli, 2 mg/kg] at 0 and 48 h. AT (250 IU/kg) was administered intravenously at 0, 24, and 48 h (n = 6, AT group). In control animals (n = 5, control), LPS was given without AT supplementation. By intravital fluorescence microscopy, leukocyte-endothelial cell interaction and functional capillary density (FCD; measure of capillary perfusion) were analyzed during a 72-h period after the first LPS injection. AT significantly attenuated LPS-induced arteriolar and venular leukocyte adherence after both the first and the second LPS injection [P < 0.01, measures analysis of variance (MANOVA)]. In parallel, AT was effective in preventing LPS-induced depression of FCD after the first and the second LPS administration (P < 0.05, MANOVA). By pretreatment with the cyclooxygenase inhibitor indomethacin (n = 6), effects of AT on leukocyte adherence and FCD were found completely abolished. Thus our study indicates that AT exerts its beneficial effects in endotoxemia by reducing leukocyte-endothelial cell interaction and microvascular perfusion failure probably via liberation of prostacyclin from endothelial cells.

[Virtual coloscopy with multi-slice computerized tomography. Preliminary results]. / Virtuelle Koloskopie mit der Mehrschichtcomputertomographie. Vorläufige Ergebnisse.

SUBJECT: Using multi-slice computed tomography (MSCT) large body areas can scanned with high spatial resolution. In this study, MSCT was employed for virtual colonoscopy in various pathologies of the colon. MATERIALS AND METHODS: For MSCT a Somatom Plus 4, Volume Zoom scanner, (Siemens, Forchheim) was employed, equipped with four parallel detector rows. Twenty-five patients were included in this trial, prior to colonoscopy or partial colon resection. After cleaning the colon, distension was achieved by insufflation of room air using a rectal tube. The parameters of acquisition and reconstruction were as follows: collimation 4 x 1 mm and 4 x 2.5 mm respectively; tube charge per slice: 140-160 mAs; pitch 5-6; i.v. contrast medium: 120 ml Ultravist 300 (Schering) with a flow rate of 3 ml/s; delay: 35 s. For 3D reconstruction we used edge-enhanced volume rendering, virtual colonoscopy and extraluminal views of volume-rendered images. RESULTS: Nine polyps and four of five colon carcinomas were detected using MSCT virtual colonoscopy. In three patients with ulcerative colitis virtual coloscopy revealed morphological alterations compatible with this disease. In two of four patients with multiple diverticula of the colon the true extent of the disorder could be assessed in virtual colonoscopy. CONCLUSION: Utilizing virtual MSCT colonoscopy polyps and cancer of the colon can be reliably detected, if proper cleaning and distension is provided. On axial images alone smaller polyps may be assessed. The high z-axis resolution of MSCT offers superior conditions for CT-based virtual colonoscopy.

A chronic model for intravital microscopic study of microcirculatory disorders and leukocyte/endothelial cell interaction during normotensive endotoxemia.

Sepsis-induced microvascular leukocyte/endothelial cell interaction may result in a deterioration of capillary perfusion that finally leads to septic organ dysfunction. The aim of the present study was to characterize a novel, sublethal, two-hit model of chronic systemic sepsis that allows the repeated analysis of microcirculation by intravital microscopy. In Syrian golden hamsters the effect of a single i.v. endotoxin (LPS, 2 mg/kg, E. coli) injection (SH-LPS group, n = 5 animals) vs. a double LPS injection (DH-LPS group, n = 6 animals) was analyzed. After monitoring baseline parameters (t1), measurements were performed at 30 min (t2), 3 h (t3), 8 h (t4), 24 h (t5), 48 h (t6), 56 h (t7) and 72 h (t8) (both groups) after initial LPS exposure. In DH-LPS animals, a second LPS injection (2 mg/kg) was given at t6 (48 h). Intravital fluorescence microscopy was performed in a dorsal skin fold chamber preparation and allowed determination of leukocyte-endothelial cell interaction (leukocyte rolling and sticking), and measurement of functional capillary density (FCD), which served as a measure of capillary perfusion. The first LPS injection comparably altered leukocyte/endothelial cell interaction and capillary perfusion in both groups (t1-t6, P > 0.05, MANOVA). Between t6 and t8 leukocyte adherence decreased in SH-LPS animals, whereas in DH-LPS animals adherence remained constantly elevated (SH-LPS: -53.0 +/- 6.2% between t6 and t8 vs. DH-LPS: -3 +/- 5; P < 0.05). The ongoing inflammatory response in DH-LPS animals was associated with a progressive deterioration of FCD, whereas FCD remained constant in SH-LPS animals (DH-LPS: -71.5 +/- 17% between t6 and t8 vs. SH-LPS: 3.0 +/- 13%; P < 0.05). In parallel, coagulatory parameters were found significantly altered only in DH-LPS animals but not in SH-LPS animals. We conclude that "double hit" LPS exposure is an appropriate model (i) to analyze repeatedly over time microcirculatory disorders under conditions of persistent endotoxemia-induced inflammatory response, and (ii) to prove the effectiveness of novel anti-inflammatory strategies.

Hemofiltrate from patients with severe sepsis and depressed left ventricular contractility contains cardiotoxic compounds.

Myocardial dysfunction due to sepsis is common in patients with multiple organ dysfunction syndrome and is believed to be produced by inflammatory mediators. Some of these mediators may be eliminated by continuous hemofiltration, which is a standard procedure in an ICU for renal replacement therapy. This study was designed to directly compare the effects of ultrafiltrates from patients with sepsis (UFs) with ultrafiltrates from healthy volunteers (UFh) in well-characterized cardiomyocyte culture systems. Isovolemic hemofiltration (filtration rate: 2 L/h, polyamide membrane) was performed during 12 hours in 5 patients with severe sepsis (Elebute Score >20) and simultaneously reduced left ventricular contractility (left ventricular stroke work index [LVSWI] <30 g m/m2) and in 5 healthy volunteers. Inflammatory mediator concentrations (interleukin [IL]-1beta, IL-6, IL-8, tumor necrosis factor [TNF] alpha, C3a, and C5a) were measured in plasma and ultrafiltrate samples taken shortly after the beginning of the hemofiltration procedure. Cell culture experiments were done comparing UFs with UFh by using spontaneously beating or electrically driven neonatal rat cardiomyocyte cultures. UFs contained significantly higher amounts of IL-1, IL-8, and C3a when compared to UFh. Simultaneously, UFs induced a decrease in the contraction frequency of electrically-stimulated cardiomyocytes, whereas UFh had no effect. The cardiotoxic effect could be reversed by the addition of a high concentration (2.4 mM) of Ca++. Hemofiltration did not alter parameters of cardiac performance during 12 hours in patients with sepsis. UFs induced significant cardiotoxic effects in rat cardiomyocytes, whereas UFh showed no cardiotoxicity. Contact of blood with the hemofiltration membrane did not induce activation of cardiotoxic mediators. Significantly higher filtration rates may be required to improve left ventricular contractility in patients with sepsis by hemofiltration.

Liposuction technique and lymphatic lesions in lower legs: anatomic study to reduce risks.

Liposuction is a standard procedure in plastic surgery. Especially, lipectomy with suction of the lower extremities has been of greater interest in recent years. Until now, however, there was no definite information about the integrity of epifascial lymph collectors during this procedure. To study the effect of liposuction devices on lymph vessel injury, postmortem lymphatic preparations were done in five human cadavers (10 lower extremities). Conventional liposuction with a blunt 4-mm cannula and a dry technique was used. Adiposuction was performed either in parallel to the extremity axis and, therefore, in parallel to the superfascial lymph vessels or transversally in an 80- to 90-degree angle to the extremity. Careful surgical preparation of the regions followed. A specific macroscopic lymph vessel injury score was applied to differentiate 3 degrees of lymph vessel lesions according to the extravasation of patent blue. In all lower extremities, postmortem lymph flow occurred as indicated by patent blue staining of the lymph vessels. Lymph vessel injury was more severe in areas where liposuction was performed transversally, vertical to the extremity's axis, than in those after a longitudinal procedure. The difference was statistically significant (p < 0.01). The volumes of adipoaspirate and of the compared regions were comparable between both groups, verified by circumference measurements. Longitudinal liposuction of the lower extremities is unlikely to cause major lesions of epifascial lymph vessels and, therefore, should be preferred in comparison to liposuction vertical to the extremity.

Effect of antithrombin III supplementation on inflammatory response in patients with severe sepsis.

Antithrombin III (AT III) is an important inhibitor of thrombin activity, as well as of many other proteases of the coagulation system. AT III administration showed beneficial effects on septic multiple organ dysfunction in clinical and experimental studies. It was the aim of this study to determine whether continuous long-term AT III supplementation alters the systemic inflammatory response in patients with severe sepsis. In a prospective study, 29 surgical patients with severe sepsis were randomly assigned to receive either conventional intensive care treatment (n = 15, control group) or additional AT III supplementation to achieve a plasma AT III activity >120% during a 14 day study period (n = 14, AT III group). Plasma concentrations of interleukin (IL)-6 and IL-8 and of the circulating soluble adhesion molecules sICAM-1 and sE-selectin, as well as of PMN elastase, were determined daily. Additionally, total leukocyte count and C-reactive protein (CRP) were measured daily, and body temperature was registered. Compared to control patients, a down-regulation of plasma IL-6 was observed in the AT III group (p < or = .01). AT III supplementation prevented the continuous increase in sICAM-1 plasma concentration observed in control patients and led to a significant fall in soluble sE-selectin and CRP concentration (p < or = .01). This fall corresponded to a down-regulation of body temperature over time (p < or = .01). There was no AT III effect on IL-8, PMN-elastase concentration, or total leukocyte count. Our results show that long-term AT III supplementation attenuates the systemic inflammatory response in patients with severe sepsis. The down-regulation of IL-6 may also explain the fall in endothelium-derived adhesion molecules and may represent the molecular basis by which AT III exerts its beneficial effects on organ function.

Antithrombin III supplementation in severe sepsis: beneficial effects on organ dysfunction.

Activation of thrombin and of the coagulation system plays an important role in the pathophysiology of sepsis-associated organ dysfunction. Antithrombin III (AT III) is a natural inhibitor of thrombin, a central procoagulatory factor with pleiotropic activities. Experimental supplementation of AT III improved coagulation parameters and ameliorated organ dysfunction. To determine whether long-term AT III supplementation has beneficial effects on organ function, we conducted a randomized, prospective study in surgical patients with severe sepsis. The study evaluated the long-term effect of AT III supplementation (duration of treatment: 14 days). After randomization (AT III vs. control group), AT III was infused continuously over 14 days to obtain plasma AT III activities > 120%. Forty consecutive patients were recruited (20 AT III/20 control group). Eleven patients had a rapid fatal course and did not met the criterion of a 14 day treatment period. From these 11 patients, 8 patients (5 AT III/3 control group) died within 72 h due to septic shock. The remaining 14 AT III patients and 15 controls survived 14 days and showed no differences in baseline parameters of organ function. AT III caused a disappearance of disseminated intravascular coagulation (DIC) in all patients with DIC, whereas in control patients, the frequency of DIC remained constant (p < .05). In AT III patients a progressive increase in oxygenation index (PaO2/FiO2 ratio) and a continuous decrease in pulmonary hypertension index (mean pulmonary artery pressure/mean arterial pressure (PAP/MAP) ratio) indicated an improvement of lung function (p < .05 vs. control). AT III prevented the continuous rise in total serum bilirubin concentration observed in control patients and diminished the frequency of artificial renal support therapy (p < .05). Long-term supplementation with AT III may improve lung function and prevent the development of septic liver and kidney failure in patients with severe sepsis.

Tumor necrosis factor measurement and use of different anticoagulants: possible interference in plasma samples and supernatants from endotoxin-stimulated monocytes.

OBJECTIVE AND DESIGN: Unfractionated heparin is frequently used as an anticoagulant during blood sampling and in cell culture experiments. In the present study we investigated whether heparin and other anticoagulants (citrate and EDTA) interfered with measurements of plasma tumor necrosis factor alpha (TNF alpha) concentrations or with TNF alpha release from endotoxin-stimulated monocytes. MATERIAL AND METHODS: TNF alpha was measured by a WEHI 164 bioassay in the plasma of 16 septic patients anticoagulated with heparin, citrate, or EDTA. Anticoagulants were incubated with the bioassay cell line and cell lysis was monitored. To exclude falsely low TNF alpha concentrations, anticoagulants were incubated in increasing amounts with human recombinant TNF alpha/saline solution, and rTNF alpha recovery was measured either with the WEHI 164 bioassay or an ELISA test. Further, anticoagulants were incubated with monocytes isolated from healthy volunteers and stimulated with endotoxin. Supernatants were analyzed for TNF alpha with both test systems. RESULTS: No biologically active TNF alpha was detected in the plasma with heparin anticoagulation, whereas with citrate, reproducible, TNF alpha-induced cytotoxicity was detectable in blood samples of 13 of the 16 patients. Anticoagulation with EDTA resulted in fairly high, variable and poorly reproducible TNF alpha values. Only EDTA produced falsely high values by unspecific lysis of WEHI cells. Only heparin at a concentration of 20 I.U./ml or more was found to produce falsely low values by interaction with the TNF alpha bioassay, but also with the ELISA test. In monocyte culture experiments, heparin significantly attenuated the stimulatory effect of endotoxin on TNF alpha release already at the lowest concentration tested (25 I.U./ml). CONCLUSIONS: Heparin and EDTA may have significant adverse effects on TNF alpha measurement when used for blood sampling. Citrate does not interfere with the TNF alpha bioassay or ELISA, and seems, therefore, to be the anticoagulant of choice. Due to intrinsic interactions with various cell systems (including the WEHI cell and monocytes), one should be careful in using heparin in cell culture studies in which effects of TNF alpha or of endotoxin are being studied.