Abstract: The hepatic artery buffer response, which is lost during endotoxemia, plays a central role in the autoregulation of liver perfusion. A temporarily decreased synthesis of nitric oxide during early endotoxemia might be responsible for this dysfunction; hence exogenous administration of nitric oxide could reestablish the autoregulation of hepatic blood flow and help prevent hepatic damage later in septic shock. Fifteen pigs were treated with lipopolysaccharide +/- the nitric oxide donor nitroprusside-sodium via the portal vein. Hemodynamics were measured, and serum chemistry and liver biopsies for nitric oxide synthase expression were obtained. Lipopolysaccharide decreased arterial liver perfusion after 5 hours by 38% (p = .012), which was reversed by addition of nitroprusside (8%). Administration of nitroprusside preserved an increase of 28% in hepatic arterial upon portal vein flow reduction (p < .001). Nitroprusside maintained mRNA levels of constitutive nitric oxide synthase in liver tissue which were decreased by lipopolysaccharide (p = .026 vs. p = .114) and tempered the burst in inducible nitric oxide synthase expression at t = 3 hours. The early administration of the nitric oxide donor sodium nitroprusside during endotoxemia is able to reestablish the autoregulatory response of the hepatic artery following reduction of hepatic blood flow. This beneficial effect might help to prevent subsequent hepatic damage in the course of abdominal sepsis.
Abstract: INTRODUCTION: The management of patients with a laparostoma due to peritonitis is a challenge for every surgeon and intensivist. The goal of this study was to compare the different treatment strategies for the open abdomen: Abdominal Dressing (AD), the classic V.A.C. therapy (CV) and conventional open therapy (CT). METHODS: Between 2001 and 2005 we identified 62 patients in 4 surgical departments in Austria who had to be treated with a laparostoma due to peritonitis. 27 patients were conventionally treated, 16 with the Classic V.A.C. therapy and 19 patients with V.A.C. abdominal dressing. RESULTS: The mortality was 3/16 (14 %) in the AD group vs. 4/12 (21 %) patients in the CV group and 18/9 (59 %) in conventional therapy. There was no significant difference for survivors in the length of ICU stay: 26.6 +/- 23.0 days in the CT group, 34.6 +/- 30.2 days in the CV group and 38.9 +/- 27.2 days in the AD group. Apache II Score and Mannheimer Peritonitis Score showed no difference between the groups. CONCLUSION: We found a reduction of mortality in the V.A.C. Abdominal Dressing group by approximately 40 % (AD: 14 %, CT: 59 %). Although we could identify a difference in age in our retrospective study we believe that V.A.C. Abdominal Dressing is the important factor for the different clinical outcome. These first results indicate the need for further prospective evaluation of the V.A.C. Abdominal Dressing therapy, to prove if a new standard in the therapy of the open abdomen is created.
Abstract: Adenocarcinoma is the most common malignant pancreatic tumor, affecting the head in 60-70% of cases. By the time of diagnosis, approximately 80% of tumors are unresectable. Helical CT is very effective in detection and staging of adenocarcinoma, with a sensitivity of 76-92% for detection and an accuracy of 80-90% for staging, but it has limitations in the detection of small cancers (< or =2 cm). Multidetector CT (MDCT) has brought substantial improvements with its inherent 3D imaging capability. Mangafodipir-enhanced MRI is a problem-solving tool in the depiction of small cancers following an equivocal CT imaging result. Gadolinium-enhanced 3D gradient-echo MRI is helpful in the assessment of vascular invasion of cancer and in determining the etiology of cystic lesions. Serous cystadenoma is benign, has a lobulated contour and contains innumerable small cysts of 0.1-2 cm in diameter. Mucinous cystic neoplasms are unilocular or multilocular (fewer than six cysts), and the cyst diameter exceeds 2 cm. The presence of solid nodular components should alert the radiologist to suspect cystadenocarcinoma. Neuroendocrine tumors are mostly hypervascular. Diagnosis of insulinoma is a challenge: they are <2 cm in 90% of cases and mostly hypervascular at CT or MRI. A combination of contrast-enhanced MDCT, MRI, endosonography, and/or somatostatin receptor scintigraphy is used to detect these small tumors. This review summarizes the imaging features of the most common pancreatic tumors and discusses the limitations of CT, MRI and endosonography.
Abstract: OBJECTIVES: Endoscopic retrograde cholangiography is an established method for treatment of common bile duct stones as well as for palliation of patients with malignant pancreaticobiliary strictures. It may be unsuccessful in the presence of a complex peripapillary diverticulum, prior surgery, obstructing tumor, papillary stenosis, or impacted stones. Percutaneous transhepatic biliary drainage and surgery are alternative methods with a higher morbidity and mortality in these cases. Recently, endoscopic ultrasound (EUS) guided biliary stent placement has been described in patients with malignant biliary obstruction. We describe our experience with this method that was also used for the treatment of cholangiolithiasis for the first time. METHODS: The EUS guided transduodenal puncture of the common bile duct with stent placement was performed in 5 patients. In 2 of these patients, the stents were removed after several weeks and common bile duct stones were extracted. In another patient with gastrectomy, the left intrahepatic bile duct was punctured transjejunally and a metal stent was introduced transhepatically to bridge a distal common bile duct stenosis. RESULTS: Biliary decompression was successful in all 6 patients. No immediate complications occurred. One patient developed a subacute phlegmonous cholecystitis. CONCLUSIONS: Interventional EUS guided biliary drainage is a new technique that allows drainage of the biliary system in benign and malignant diseases when the bile duct is inaccessible by conventional ERCP.
Abstract: The present study was performed to evaluate the ability of fosfomycin, a broad-spectrum antibiotic, to penetrate into abscess fluid. Twelve patients scheduled for surgical or computer tomography-guided abscess drainage received a single intravenous dose of 8 g of fosfomycin. The fosfomycin concentrations in plasma over time and in pus upon drainage were determined. A pharmacokinetic model was developed to estimate the concentration-time profile of fosfomycin in pus. Individual fosfomycin concentrations in abscess fluid at drainage varied substantially, ranging from below the limit of detection up to 168 mg/liter. The fosfomycin concentrations in pus of the study population correlated neither with plasma levels nor with the individual ratios of abscess surface area to volume. This finding was attributed to highly variable abscess permeability. The average concentration in pus was calculated to be 182 +/- 64 mg/liter at steady state, exceeding the MIC(50/90)s of several bacterial species which are commonly involved in abscess formation, such as streptococci, staphylococci, and Escherichia coli. Hereby, the exceptionally long mean half-life of fosfomycin of 32 +/- 39 h in abscess fluid may favor its antimicrobial effect because fosfomycin exerts time-dependent killing. After an initial loading dose of 10 to 12 g, fosfomycin should be administered at doses of 8 g three times per day to reach sufficient concentrations in abscess fluid and plasma. Applying this dosing regimen, fosfomycin levels in abscess fluid are expected to be effective after multiple doses in most patients.
Abstract: OBJECTIVE: T1/ST2, a member of the interleukin (IL)-1 receptor superfamily, is predominantly expressed on type-2 T helper (Th2) cells but not Th1 cells, and plays a role in cell proliferation and Th2 immune response. The relation of soluble ST2, Th1-Th2 cytokine profile, and immunoglobulin (Ig) production in sepsis and trauma patients is not well known. DESIGN AND SETTING: Case-control study at a university hospital intensive care unit. PATIENTS: Fifteen patients recruited within 24-48 h of diagnosis of sepsis, 13 trauma patients recruited within 24 h after admission to the ICU, 11 patients who underwent abdominal surgery, and 15 healthy volunteers served as control. MEASUREMENTS AND RESULTS: ELISA was utilized to detect serum soluble ST2, IL-2, IFN-gamma, IL-10, and Ig production. Serum levels of soluble ST2 were significantly increased in septic patients (8420+/-2169 pg/ml) as compared with trauma (2936+/-826 pg/ml), abdominal surgery (1423+/-373 pg/ml), and healthy controls (316+/-72 pg/ml; p<0.001, respectively). These results were accompanied by an increase of IgG1 and IgG2 production, and decrease of IL-2 and IFN-gamma synthesis in septic patients. IL-10 was significantly increased in both septic and trauma patients. CONCLUSIONS: Our results demonstrate that soluble ST2, a marker for Th2 cytokine producing cells, is increased in sepsis and trauma patients, and they provide further evidence for a shift from Th1- to Th2-biased cells.
Abstract: INTRODUCTION: Treatment of open abdomen following secondary peritonitis is a challenge for surgery and intensive care units (ICU). The aim of this study was to compare three different concurrent treatment strategies. METHODS: Patients suffering an open abdomen following surgery for secondary peritonitis at the Department of General Surgery from 01/01 to 12/03 were investigated. Factor studied: duration of open abdomen, incidence of multi-organ failure, need for surgical revisions, length of stay (LOS) in ICU, nursing requirements (change of dressing/day), survival and integrity of abdominal wall after discharge. Treatment strategies included: open packing (OP), classic vacuum assisted (V.A.C.(R))-therapy with silicone net protection for the intestine (CV) and V.A.C.(R)-therapy with "abdominal dressing" a newly developed meshed polyvinyl wrap (AD). RESULTS: 21 patients were studied: 5 patients were treated with OP, 8 patients with CV and 8 patients with AD. Mean LOS was 65 (OP) vs. 53 (CV) vs. 42 (AD) days (NS), peritonitis related death was 3 (OP) vs. 1 (CV) vs. 0 (AD) (p < 0.05 Chisquare test). Median nursing effort was 4 dressings/day (OP), 0.5 (CV) and 0.5 (AD) (p < 0.005 OP vs CV, AD Kruskal-Wallis test). CONCLUSION: The "abdominal dressing"-therapy seems to be a more efficient treatment option in patients suffering from open abdomen following secondary peritonitis. A trend towards shorter ICU-LOS, lower mortality rates and reduced nursing requirements support our hypothesis.
Abstract: Apoptosis of the epithelium is deemed to play a pivotal role in the pathogenesis of sepsis. A neoepitope in cytokeratin 18 (CK18), termed M30 neoantigen, becomes available at an early caspase cleavage event during apoptosis of epithelium-derived cells and is not detectable in vital or necrotic epithelial cells. A monoclonal antibody, M30, specifically recognizes a fragment of CK18 cleaved at Asp396 (M30 neoantigen). We used an enzyme-linked immunosorbent assay (ELISA) to measure M30 antigen levels in the sera of 15 septic patients. Healthy humans and critical ill patients suffering from severe trauma served as controls. Mann-Whitney U test was used to calculate significance, and a P value of <0.01 was considered to be statistically significant. Serum levels of the CK18 neoepitope M30 were significantly increased in septic patients (236.88 +/- 47.4 U/L) versus trauma (97.2 +/- 17.1 U/L) and healthy controls (66.9 +/- 9.2 U/L) (P < 0.01 and P < 0.008, respectively). The increased serum level of the CK18 neoepitope in septic patients indicates a heightened apoptotic turnover in epithelial cells as compared with trauma patients and healthy controls. Interestingly, nonsurviving trauma patients exhibited a significant increase in the M30 neoantigen as compared with survivors and healthy controls (P < 0.003 and P < 0.002, respectively). The detection of CK18 neoepitope M30 in the serum might be a useful marker in tracing apoptotic epithelium in septic patients.
Abstract: OBJECTIVE: To investigate whether the administration of different glutamine-containing dipeptides, glycyl-l-glutamine (GLY-GLN) and l-alanyl-l-glutamine, has a differing impact on perioperative immunomodulation. SUMMARY BACKGROUND DATA: Surgery leads to transitory immunosuppression, which is associated with decreased plasma glutamine (GLN) levels and increased susceptibility to infection and sepsis. A useful tool to detect immunocompetence is the ex vivo lipopolysaccharide (LPS)-stimulated tumor necrosis factor alpha (TNF-alpha) secretion in whole blood. METHODS: Forty-five patients undergoing major abdominal surgery were randomized prospectively to receive 0.5 g/kg/24 h GLN dipeptides administered as GLY-GLN or as ALA-GLN or isonitrogenous Vamin (a GLN-free amino acid solution; control group) as a continuous infusion over 72 hours, starting 24 hours before surgery. Blood samples were collected before infusion, at the end of surgery, and 48 hours postoperatively to determine the TNF-alpha release into whole blood stimulated with LPS. Groups were compared by analysis of variance. RESULTS: The groups were comparable in age, gender distribution, and length of operative time. At the end of surgery a significant reduction in ex vivo LPS-stimulated TNF-alpha production was observed in all groups. In patients who received GLY-GLN, the induced TNF-alpha production was restored after 48 hours. CONCLUSIONS: In this study perioperative infusion of GLY-GLN reduced immunosuppression. The effect of GLN-containing dipeptides seems to be different when administered in glycine or alanine form.
Abstract: Catecholamines play a central role in the treatment of sepsis-associated hypotension. However, these hormones have also been shown to modulate the lipopolysaccharide (LPS)-induced induction of cytokines such as tumor necrosis factor alpha, interleukin (IL)-10, and IL-6 in vitro and in human endotoxemia. We hypothesized that catecholamines applied therapeutically in septic shock also influence cytokine patterns. We studied the cytokine response in tissues of the splanchnic compartment in a porcine endotoxin shock model up to 4 h. Shock was induced by a short infusion of LPS, and animals were treated either with fluid resuscitation alone or in combination with continuous epinephrine or norepinephrine. Animals, receiving epinephrine therapy, showed a significantly prolonged upregulation of IL-6 mRNA expression at 4 h after LPS application in liver (P = 0.0014), spleen (P < 0.0001), and mesenteric lymph nodes (P = 0.0078) as compared with animals treated with norepinephrine or fluid resuscitation. Serum IL-6 increased over time in all groups. The total concentration of the cytokine (area under the curve) was significantly higher in the epinephrine group as compared with the norepinephrine and fluid resuscitation groups (P = 0.017). The peak of serum tumor necrosis factor alpha at 1 h after LPS application was already significantly reduced by epinephrine, which was only administered at a mean of less than 0.05 microg/kg/min at this time point (P < 0.01). None of the catecholamines had a significant effect on IL-10 serum levels when compared with animals receiving fluid resuscitation alone. Our data suggest that the therapeutic application of epinephrine but not of norepinephrine is associated with a profound effect on the IL-6 response of splanchnic reticuloendothelial tissues.
Abstract: BACKGROUND: In patients operated on for severe acute pancreatitis (SAP) the impact of the timing of operation on outcome is controversial. MATERIALS AND METHODS: In a retrospective analysis of a prospectively documented database, we studied 250 patients suffering from SAP, who were in need for surgical treatment during their course of disease. RESULTS: From 1982 to 1998, 250 patients with the diagnosis of SAP who required operative treatment were admitted to the intensive care unit (ICU) of a university hospital. The mean APACHE II score on the day of admission was 16.1 (8-35). One hundred eighty-five patients (74%) required reoperation, of whom 111 patients (60%) underwent reoperation on demand and 74 (40%) patients a pre-planned reoperation. Overall mortality was 38.8% (97 patients). In patients who were operated during the first three weeks after onset of disease, mortality was significantly higher than in patients who were operated after three weeks (46% vs. 25%, p < 0.01). Besides patient age (p < 0.05), APACHE II score at admission (p < 0.01), multiple organ dysfunction (p < 0.01), infection of pancreatic necrosis (p < 0.05), surgical control of pancreatic necrosis (p < 0.0001), and the time of surgical intervention (p < 0.05) determined survival significantly. CONCLUSION: Patients who were operated later than three weeks after onset of disease had a significantly better outcome. In patients suffering from SAP who required surgical treatment, the timing of operation is crucial for survival.
Abstract: Pancreatoduodenectomy (PD) has become a routine procedure. Recent series report perioperative mortality rates of 5% or less, moderate morbidity, and even improved long-term survival. Nevertheless, being one of the most complex abdominal operations, a certain number of surgical procedures (i.e., personal caseload) seems essential for acceptable results. The objectives of this retrospective study were to evaluate whether PD can be safely performed as a teaching operation, and if the personal caseload of the senior surgeon affects morbidity and mortality. A series of 128 consecutive PDs carried out at a large academic teaching hospital were analyzed. The 49 operations performed by 11 residents of the surgical department as teaching operations under supervision of an experienced (senior) surgeon (ES) were compared with operations performed by an ES (group 2, n = 79). Three patients died from non-procedure-related causes (two in group 1). Eleven patients of group 2 had to be reoperated, in contrast to three in group 1 (NS). The total number of complications and number of pancreatic fistulas were comparable in the two groups. Surgeons performing less than one PD per year had significantly more complications. Under direct supervision of an experienced surgeon PD can be performed safely as a teaching operation. A caseload of at least one resection per year seems necessary for consistently good results.
Abstract: In patients operated on for severe acute pancreatitis (SAP), the factors determining outcome remain unclear. From 1986 to 1998 a total of 340 patients with a diagnosis of SAP and in need of operative treatment were admitted to the intensive care unit (ICU) of a university hospital and a secondary care hospital. The mean APACHE II score on the day of admission was 16.1 (range 8-35). All patients required operative therapy. Among the 340 patients, 270 (79.4%) had to be reoperated: 196 patients (72.6%) underwent operative revisions on demand, and 74 (27.4%) patients had preplanned reoperation. The overall mortality was 39.1% (133 patients). Septic organ failure in 126 patients (37.1%) and myocardial infarction or pulmonary embolism in 7 patients (2%) were the causes of death. The patient's age (p < 0.0002), APACHE II scores at admission (p < 0.0001), presence or development of (single or multiple) organ failure (p < 0.002), infection (p < 0.02) and extent (p < 0.04) of pancreatic necrosis, and surgical control of local necrosis (p < 0.0001) significantly determined survival. SAP that requires surgical treatment is associated with high in-hospital mortality. Surgical control of local necrosis is the precondition for survival. Advanced age of the patient, high APACHE II score at admission, development of organ failure, and the extent and infection of pancreatic necrosis influence the outcome.
Abstract: The immunological side effects of catecholamines have recently gained specific attention in the area of sepsis related research, since stimulation of adrenergic and dopaminergic receptors can lead to a modulation of the cytokine network. Catecholamines alter the production of these immune mediators in peripheral blood cells but also in various tissues such as liver, spleen, lung, heart, kidney and the skin. The sympathetic regulation of cytokines is highly dependent on which type of receptor is stimulated. Whereas ligation of the alpha-adrenoreceptor is associated with predominantly immunostimulating effects (i.e. the induction of TNF alpha and IL-1 beta), stimulation of the beta-adrenoreceptor usually has immunosuppressive consequences (i.e. inhibition of TNF alpha and IL-1 beta, induction of IL-10). In case both receptors are stimulated (i.e. by epinephrine) the beta-adrenoreceptor mediated effects usually dominate those induced by alpha-adrenoreceptor stimulation. Moreover, the adrenergic immunostimulation can be differentially regulated depending on which type of cell or tissue is stimulated. This suggests locoregional effects. Dopaminergic immunomodulation is dominated by immunosuppressive effects, such as the induction of IL-6, the inhibition of TNF alpha, the attenuation of the chemoattractant effect of IL-8 and the inhibition of endothelial adhesion. Catecholamines also alter the number and function of neutrophils and lymphocytes. This again depends on which type of receptor is stimulated. Whereas beta-adrenergic stimulation leads to lymphocytosis, alpha-adrenoreceptors mediate lymphocyte homing. Catecholamine induced neutrophilia involves alpha 1-adrenoreceptor ligation. With respect to neutrophil function, epinephrine increases the respiratory burst. Up to now, most of the available data on catecholamine-induced immunomodulation were obtained in experimental settings. The overwhelming, clear results indicate that this system might have important implications for the pathophysiology of immunological diseases such as septic shock, which are accompanied by increased levels of catecholamines.
Abstract: BACKGROUND AND AIMS: Surgery, trauma and inflammation reduce HLA-DR expression on monocytes, which is associated with an increased susceptibility to infection and sepsis. Furthermore, surgery decreases plasma glutamine (GLN) levels. The expression of HLA-DR on human monocytes in vitro is dependent on the concentration of GLN in the culture medium. We therefore hypothesized that postoperative infusions of glutamine-dipeptides would prevent the decreased HLA-DR expression on monocytes. METHODS: Thirty patients undergoing major abdominal surgery were randomly allocated to receive either 1500 ml Vamin (control) or an isonitrogenic formulation containing Vamin and 500 ml glycyl-glutamine (35 g GLN; 0.5g/kg BW) (GLY-GLN), or Vamin and 500 ml alanyl-glutamine (35 g GLN; 0.5 g/kg BW) (ALA-GLN) as a continuous infusion over 48 h post-operatively. Immediately and 48 h after surgery blood samples were collected to determine HLA-DR expression on monocytes by flow cytometry. RESULTS: The groups were comparable with respect to age, gender distribution and operation time. In patients receiving GLY-GLN mean HLA-DR expression on monocytes at 48 h was significantly better preserved than in controls (65.0 %+/-7 % vs 42.5 %+/-4 %;P<0.05), whereas HLA-DR expression on monocytes in patients receiving ALA-GLN was not significantly different. CONCLUSION: This is the first study comparing the dipeptides GLY-GLN and ALA-GLN in the postoperative setting. The GLY-GLN induced preservation of HLA-DR on monocytes following surgery may prevent infectious complications in these patients.
Abstract: OBJECTIVE: To determine the effect of oral glutamine feeding on lymphocyte subpopulations and glutathione metabolism in Peyer's patches (PPs) of healthy and endotoxemic mice. SUMMARY BACKGROUND DATA: Recent data indicate that nutrients both maintain nitrogen and energy balances and modulate cell and organ function. In particular, glutamine has an impact on gut and immune function. This is of special importance in the perioperative phase. METHODS: Female Balb/c mice were fed a glutamine-enriched diet or a control diet for 10 days. On day 7 25 microg lipopolysaccharide (LPS) or saline was injected. On day 3 after the challenge, mice were killed, total cell yield was determined, and lymphocyte subpopulations (total T cells, CD4+, CD8+ cells, and B cells) were analyzed by flow cytometry. One experimental group was treated with buthionine sulfoximine, a specific inhibitor of glutathione synthesis. The glutathione content in PPs was measured by high-performance liquid chromatography. RESULTS: Glutamine administration led to a significant increase in total cell yield, including T and B cells, in PPs. The LPS-induced reduction of T cells (-45%) and of B cells (-30%) was significantly lower in glutamine-treated mice. Endotoxemia caused a 42% decrease of glutathione in control animals, but not in glutamine-treated animals. As with LPS, buthionine sulfoximine also lowered lymphocyte numbers and glutathione content of the PPs. CONCLUSIONS: Administration of glutamine prevents LPS-stimulated lymphocyte atrophy in PPs, possibly by increasing the glutathione content in the PPs. Therefore, oral glutamine supply seems to be a suitable approach for improving intestinal immunity in immunocompromised patients.
Abstract: The selective Kupffer cell inhibitor gadolinium chloride (GdCl3) has been demonstrated to protect animals from lethality in experimental endotoxemia and sepsis in rodent models. This study was designed to investigate the effect of Kupffer cell blockade on the early response to endotoxin in a large animal model. Using a porcine endotoxemia model, animals were randomized to receive either GdCl3 (10 mg/kg or 30 mg/kg; n = 8 in each group) or vehicle saline (n = 8) 24 h before exposure to endotoxin. Pretreatment with GdCl3 resulted in a dose dependent reduction in early hepatic oxygen consumption as well as oxygen extraction ratio in response to continuous infusion of endotoxin. At 5 h there was significant lower serum AST level in animals given 30 mg/kg of GdCl3 as compared to the two other groups. Pretreatment with GdCl3 induced a dose dependent reduction of Kupffer cells in the liver sinusoids. Despite this, all animals deteriorated with continuous infusion of endotoxin as evidenced by the progressive reduction in cardiac output, mean arterial pressure and total liver blood flow. Also, increases in pulmonary arterial pressure, portal venous pressure and systemic, pulmonary and hepatic vascular resistance were seen. This is consistent with activation of other cell populations and defense mechanisms by endotoxin, perpetuating the septic response. However, modulation of reticuloendothelial cell function seems feasible also in larger animals, and our results stimulate to further research on potential immunomodulatory tools in early sepsis.
Abstract: The catecholamine-mediated modulation of the cytokine network has primarily been demonstrated for leukocytes. Whereas catecholamines decrease the LPS-induced production of IL-6 by leukocytes, serum levels of IL-6 are dramatically increased by the catecholamine epinephrine in animal endotoxemia models. We now demonstrate that epinephrine as well as norepinephrine can induce IL-6 in an endothelial cell line (HMEC-1). Furthermore, these catecholamines could even potentiate the LPS-induced IL-6 protein production. The synergistic effect of catecholamines and LPS could be reproduced in primary human skin microvascular endothelial cells. The catecholamine-induced IL-6 stimulation is based on increased IL-6 mRNA levels. RNA stability assays revealed that this regulation is not a result of enhanced RNA stability and therefore is most likely due to an increased transcription. Treatment with cycloheximide indicated that new protein synthesis is not necessary for this transcriptional up-regulation of IL-6 mRNA. Preincubation with alpha and beta receptor antagonists showed that the effect is mediated by beta(1)- and beta(2)-adrenergic receptors. Thus, endothelial cells might be a possible source of increased IL-6 production observed in situations such as stress or septic shock, in which catecholamines are elevated due to endogenous production or exogenous application.
Abstract: OBJECTIVE: To find out if the severity of acute pancreatitis or the surgical treatment of severe acute pancreatitis influences HLA-DR and CD14 expression on peripheral blood monocytes. DESIGN: Prospective open study. SETTING: University hospital, Austria. SUBJECTS: 9 consecutive patients with severe acute pancreatitis in need of operative treatment, 5 patients with mild acute pancreatitis, and 7 healthy volunteers. INTERVENTIONS: Samples of 5 ml blood were taken daily into endotoxin free tubes at same time points. Surgical treatment for severe acute pancreatitis consisted of blunt necrosectomy, operative lavage, laparostomy, and open drainage. MAIN OUTCOME MEASURES: Correlation between HLA-DR and CD14 expression on peripheral blood monocytes on the one hand and the severity of acute pancreatitis and operative treatment of severe acute pancreatitis, on the other. RESULTS: In patients with severe acute pancreatitis expression of HLA-DR and CD14 was significantly downregulated both before and after operation (p < 0.0001; ANOVA), compared with patients with mild acute pancreatitis or healthy controls. However the expression of the two cell surface markers was not affected either by the first operation, or by the reoperations. CONCLUSION: These findings suggest that in acute pancreatitis the expression of cell surface markers on peripheral blood monocytes is related to the severity of disease but is not influenced by operative treatment.
Abstract: Intestinal mucosal dysfunction appears to contribute to infectious complications in critically ill patients. The current study was undertaken to investigate whether endotoxin affects lymphocyte subpopulations and the expression of costimulatory signals in Peyer's patches (PP). Female Balb/c mice were given an intraperitoneal injection of 25 microg LPS and sacrified 24 h or 72 h later to determine total cell yield, lymphocyte subpopulations (B-cells, total T-cells, CD4+- and CD8+-cells), the costimulatory molecules CD28, B7.1 (CD80) and B7.2 (CD86) and the percentage of apoptotic cells in PP and in the spleen as well as small intestinal IgA concentration. Lipopolysaccharide (LPS) challenge caused a significant decrease of total cell yield in PP at both time-points (-50+/-28% and -43+/-25%, respectively; P < 0.001). This decrease was significant for all measured lymphocyte subpopulations. In contrast, total cell yield was increased (P < 0.001) in the spleen 24 h (+52+/-13%) and 72 h (+130+/-22%) after LPS. The decrease of lymphocyte numbers in the PP was accompanied by an increased percentage of lymphocytes expressing costimulatory molecules. In this respect, an increased percentage of CD40+CD80+, CD40+CD86+, and of CD4+CD28+ could be demonstrated after LPS administration. In the spleen, the percentage of CD4+CD28+ was also elevated after LPS bolus, however, the percentage of CD40+CD80+ was reduced, and that of CD40+CD86+ was unaltered. The influence of LPS on apoptosis of lymphocytes was time-dependent. The percentage of apoptotic cells 24 h after LPS was increased in PP (P < 0.01), but was unchanged in the spleen. Seventy-two hours after LPS injection, the percentage of apoptotic cells returned to normal in PP. Luminal IgA levels remained unchanged after LPS challenge. In conclusion, our data show that LPS causes atrophy of PP which seems to be counterregulated by an enhanced expression of costimulatory molecules.
Abstract: The aim of this study was to evaluate the frequency of Candida infection of pancreatic necrosis in patients suffering from severe acute pancreatitis (SAP) and to analyze its impact on the outcome. Two-hundred and fifty consecutive patients with SAP from January 1986 to December 1998 were studied retrospectively. Their mean APACHE II score at the day of admission was in 16.1 (range 8-35). All patients were in need of operative therapy. Overall mortality was 38.8% (97 patients). One-hundred and eighty-two patients (72.8%) suffered from local infected necrosis. Among these patients, local Candida infection was observed in 31 patients, whereof 23 patients (74%) suffered from local fungal infection detected at first operation. During the course of disease, 12 patients (39%) also revealed fungemia. Local Candida infection as compared to no Candida infection was associated with an increased mortality rate (84% vs. 32%; P 0.0001). Multivariate logistic regression analysis identified APACHE II score (P < 0.0001), age of the patient (P < 0.003), extent of pancreatic necrosis (P < 0.002), and local bacterial (P < 0.04) and fungal infection (P < 0.004) as independent factors significantly contributing to mortality. SAP, requiring surgical treatment, is associated with high in-hospital mortality. Patients suffering from local Candida infection are at high risk of fatal outcome.
Abstract: Sepsis and related syndromes account for a high morbidity and mortality caused by the development of multiorgan failure. Pathogenesis of sepsis is complex, involving humoral as well as cellular factors. Since the role of platelets is still undefined in this concern, we investigated CD63, CD62P, CD36, and CD31 expression on platelets of patients in septic shock (n = 18) using a flow cytometric assay in whole blood. Samples were drawn within 24 hours of onset. We found thrombocytopenia accompanied by a significantly higher expression of CD63, CD62P, and CD31 and a significant downregulation of CD36 in comparison to healthy volunteers (n = 18). Changes in CD63 and CD62P expression indicates platelet activation. Because CD62P, CD36, and CD31 mediate interaction of platelets with leukocytes, subendothelial matrix and probably endothelial cells as well as platelet adhesion/aggregation, our findings suggest an involvement of platelets in leukocyte/endothelial cell interaction in septic shock. We suspect that thrombocytopenia is not due to bone marrow depression, but rather is due to consumption of highly activated platelets in the microcirculation. We feel that our observations may offer a rationale for potentially beneficial effects of antiplatelet therapy in sepsis; however, further studies have to evaluate its beneficial impact as well as its potential risk for bleeding complications.
Abstract: Studies performed on healthy volunteers have revealed that catecholamines down-regulate the lipopolysaccharide (LPS)-induced production of tumor necrosis factor (TNF)alpha, interleukin (IL)-6, and IL-1beta. We extended this observation and show that this effect is based on changes in the mRNA concentration of these cytokines. Catecholamines are increased in severe sepsis due to endogenous production and have to be administered exogenously when the disease has proceeded to the state of prolonged hypotension. We here investigated whether the immunomodulating effect of catecholamines could also be demonstrated in the blood of patients with prolonged severe sepsis and of those in prolonged septic shock. Blood was stimulated ex vivo with LPS in the presence and absence of epinephrine and the cytokine protein concentration was determined. In blood of healthy volunteers, epinephrine reduced the LPS-stimulated synthesis of TNFalpha by 62.5% (P< 0.0001), of IL-6 by 39% (P< 0.0001), and of IL-1beta by 40% (P= 0.015), and increased the LPS-stimulated IL-10 production by 77.8% (P < 0.0001). Correspondingly, in blood of patients with prolonged severe sepsis, TNFalpha was reduced by 67.2% (P < 0.0001) and IL-6 was reduced by 32.9% (P < 0.0001); IL-1beta and IL-10 were not modulated by catecholamines in these patients. In blood samples of patients in prolonged septic shock, epinephrine did not modulate cytokine levels of IL-6 and IL-10, and decreased TNFalpha only by 36.4% (P < 0.0001). Interestingly, epinephrine suppressed the IL-1beta production by 73% (P < 0.0001) in blood of patients in prolonged septic shock, which was twice as much as in blood samples of healthy volunteers. The altered response of septic blood to catecholamines might be due to an altered reactivity of leukocytes in the prolonged disease although an additional role of preexisting catecholamines cannot be completely excluded.
Abstract: OBJECTIVES: To evaluate and compare outcomes and complications in patients having undergone gastrostomy by surgical (SG), percutaneous endoscopic (PEG), or percutaneous radiological (PRG) procedure. DESIGN: Retrospective analysis. SETTING: University-based tertiary care center. PATIENTS: Of 82 patients who met inclusion criteria, 14 patients (median age, 40 years) received a surgical tube placement (SG), in 24 patients (median age, 55 years) a PEG procedure was performed, and in 44 patients (median age, 57 years) the tube was placed under fluoroscopic guidance (PRG). Indications for gastrostomy were similar in all groups, representing mainly cancer of the oropharyngeal, head and neck region (51 [61%]) as well as the upper gastrointestinal tract (6 [8%]), neurological disorders (15 [18%]), and others (10 [13%]). MAIN OUTCOME MEASURES: Catheter function rates, major and minor procedure-related complications, and survival. RESULTS: Median follow-up was 17.2 months. Ten patients (71%) died in the SG group 7 to 855 days (median, 67 days) after the procedure, 7 patients (29%) died 5 to 263 days (median, 103 days) after PEG placement, and 30 patients (68%) died within 3 to 621 days (median, 112 days) after PRG, of their underlying disease or disease-related complications; 1 procedure-related death occurred 6 days after radiological tube placement. We observed a rate of minor complications of 43% (6 patients), 33% (8), and 36% (16) and a major complication rate of 14% (2 patients), 17% (4), and 11% (5) in the SG, PEG, and PRG groups, respectively. Tube function rates at 1 year were 67% (9 patients) and 68% (20) in the SG and PEG groups, respectively, and 10% lower (39) in the PRG group, although the difference was not statistically significant. CONCLUSIONS: There is no major difference between SG, PEG, and PRG concerning procedure-related complications. Tube function tends to be inferior after radiological tube placement.
Abstract: OBJECTIVE: To determine the early effects of therapy of endotoxin (ET) shock with epinephrine, norepinephrine, or dopexamine on splanchnic circulation, oxygen metabolism, sigmoid mucosal pHi, bacterial translocation, and morphologic integrity of the ileal, colonic, and sigmoid mucosa. SUMMARY BACKGROUND DATA: Conflicting concepts exist concerning the catecholamine therapy of septic shock, but little is known about the effects of catecholamine treatment on splanchnic circulation and mucosal integrity. METHODS: ET shock was induced in pigs by ET infusion over 30 minutes, and animals were studied for 4 hours. All animals were resuscitated with fluid. To mimic the treatment of septic shock in humans, mean arterial pressure was maintained in two groups at >70 mm Hg with the administration of epinephrine or norepinephrine. A third group of animals received dopexamine at 7 microg/kg per minute. Systemic and splanchnic blood flow and oxygen metabolism were studied, sigmoid colon mucosal pHi was obtained tonometrically, and bacterial translocation was determined by culture of portal venous blood, mesenteric lymph nodes, liver, spleen, and lung specimens. Histologic sections of ileal, colonic, and sigmoid mucosa were morphometrically examined for therapy effects. RESULTS: All investigated catecholamines increased cardiac output and systemic oxygen delivery, whereas intestinal blood flow and oxygen delivery remained unchanged. Sigmoid mucosal pHi decreased in all study animals, but the decrease was most pronounced in the epinephrine group. Pigs receiving epinephrine also showed >40% damage of the mucosa of the ileum and colon, whereas animals receiving ET alone, norepinephrine, or dopexamine showed only moderate lesions with signs of restitution. No animal showed bacterial translocation. CONCLUSIONS: Systemic hemodynamics and oxygen metabolism data do not reflect intestinal perfusion. Norepinephrine or dopexamine administration in ET shock causes no additional impairment of intestinal integrity. Epinephrine therapy, in contrast, is associated with a significant reduction of mucosal pHi and considerable early mucosal damage. Its application in septic shock is hazardous.
Abstract: The role of endotoxin (lipopolysaccharide, LPS) and nitric oxide in hepatic oxygen metabolism was investigated in 36 pigs receiving 1) LPS (1.7 microgram. kg-1. h-1) for 7 h and NG-nitro-L-arginine methyl ester (L-NAME; 25 mg/kg) after 3 h, 2) LPS, 3) NaCl and L-NAME, and 4) NaCl. Infusion of LPS reduced hepatic oxygen delivery (DO2H) from 60 +/- 4 to 30 +/- 5 ml/min (P < 0.05) and increased the oxygen extraction ratio from 0.29 +/- 0.07 to 0.68 +/- 0.04 after 3 h (P < 0.05). Hepatic oxygen consumption (VO2H) was maintained (18 +/- 4 and 21 +/- 4 ml/min, change not significant), but acidosis developed. Administration of L-NAME during endotoxemia caused further reduction of DO2H from 30 +/- 3 to 13 +/- 2 ml/min (P < 0.05) and increased hepatic oxygen extraction ratio from 0.46 +/- 0.04 to 0.80 +/- 0.03 (P < 0.05). There was a decrease in VO2H from 13 +/- 2 to 9 +/- 2 ml/min that did not reach statistical significance, probably representing a type II error. Acidosis was aggravated. Administration of L-NAME in the absence of endotoxin also increased the hepatic oxygen extraction ratio, but no acidosis developed. In a different experiment, liver blood flow was mechanically reduced in the presence and absence of endotoxin, comparable to the flow reductions caused by L-NAME. The increase in hepatic oxygen extraction ratio (0.34) and maximum hepatic oxygen extraction ratio (approximately 0.90) was similar whether DO2H was reduced by occlusion or by L-NAME. We concluded that L-NAME has detrimental circulatory effects in this model. However, neither endotoxin nor L-NAME seemed to prevent the ability of the still circulated parts of the liver to increase hepatic oxygen extraction ratio to almost maximum when oxygen delivery was reduced. The effect of L-NAME on oxygen transport thus seems to be caused by a reduction in DO2H rather than by alterations in oxygen extraction capabilities.
Abstract: Generation of reactive oxygen intermediates (ROI) has been implicated in tissue damage in a variety of disease states including sepsis and trauma. On the other hand, generation of ROI in polymorphonuclear granulocytes (PMN) presents a crucial element in the defence of the host against invading microorganisms. In the present study we investigated the generation of superoxide anions (O2-) and hydrogen peroxide (H2O2) by neutrophils (PMN)5 of 17 critically ill patients treated at a intensive care unit (ICU) after polytrauma (n = 6), heart operation (n = 6) or during septic shock (n = 5) using flow cytometry. O2- production of PMN from ICU patients was significantly lower (p < 0.01) than that in healthy volunteers (HV) during non-receptor mediated stimulation with phorbol-myristate-acetate (PMA) but higher (p < 0.001) during receptor mediated stimulation with formylmethionine-leucine-phenylalanine (FMLP). H2O2 generation of PMN from ICU patients was increased after stimulation with FMLP (p < 0.01) and remained unchanged after stimulation with PMA. Patients in septic shock had lower O2(-)-generation of PMN than did injured patients and patients after heart operations. We conclude that receptor mediated formation of O2- and H2O2 is stimulated in ICU patients. However, in patients in septic shock O2(-)-generation decreases, which potentially might contribute to the immunoparalysis present in septic shock.
Abstract: OBJECTIVE: To determine the effect of reoperation for severe abdominal sepsis on the course of proinflammatory mediators and hemodynamic factors. DESIGN: Inception cohort. SETTING: A university hospital and a secondary care hospital. PATIENTS AND METHODS: Fifteen patients suffering from severe peritonitis due to intestinal perforation or infected necrotizing pancreatitis were studied following 19 subsequent operations. Plasma samples were obtained immediately before and after reoperation, as well as at 1, 3, 6, 12, and 24 hours after operation to determine endotoxin, tumor necrosis factor alpha, and interleukin-6 levels. Clinical factors and therapeutic support were recorded at the corresponding times. MAIN OUTCOME MEASURES: Postoperative hemodynamic instability as defined by changes of the mean arterial pressure, pulmonary capillary wedge pressure, and vasopressor support. Courses of proinflammatory mediators were correlated to the hemodynamic findings. RESULTS: Mean arterial pressure decreased from 94 mm Hg postoperatively to 80 mm Hg at 3 hours (P = .006) and 81 mm Hg at 6 hours postoperatively (P = .005). Pulmonary capillary wedge pressure dropped from 14 mm Hg postoperatively to 12 mm Hg at 1 hour (P = .05). Vasopressor support significantly increased from 1 to 6 hours postoperatively (P = .02). Neither endotoxin nor tumor necrosis factor alpha levels showed significant changes in the postoperative course. Interleukin-6 levels continously increased from 586 pg/mL preoperatively to 910 pg/mL at 1 hour (P = .02) and 931 pg/mL at 3 hours postoperatively (P = .04). Overall interleukin-6 levels (R = -0.38, P = .003) and especially early postoperative interleukin-6 levels inversely correlated with postoperative mean arterial pressure. CONCLUSIONS: Reoperation for abdominal sepsis frequently causes substantial hypotension, and is, thus, potentially harmful to the patient. Reoperative trauma may induce an early postoperative increase in interleukin-6 levels. Because this increase occurs before the development of hypotension, a relationship between the kinetics of this cytokine and the observed hemodynamic instability may be present.
Abstract: Several studies have shown that exogenous human growth hormone (HGH) exerts an anabolic effect on protein metabolism in surgical patients with mild or moderate catabolism. However, contradictory results have been demonstrated in polytrauma patients where HGH did not improve protein metabolism. Aim of this study was to evaluate whether the pharmacokinetics of recombinant biosynthetic human GH (r-HGH) are altered in critically ill patients. After an overnight fast, r-HGH was infused at a rate of 460 micrograms/h/kg/bw during 120 min to five intensive care unit (ICU) patients. The patients were catabolic (nitrogen balance -11 +/- 0.5), showed normal liver function, and only one patient had a slightly impaired kidney function (creatinine > 1.5 mg/dl). Endogenous GH secretion was suppressed by continuous infusion of 50 micrograms/m2/h somatostatin. From plasma GH curves, elimination half life (t1/2kle), whole body clearance (Cltot) and steady state distribution space (DS) were calculated in an open two compartment model. Additionally, the effects of r-HGH infusion on plasma insulin, glucagon and amino acid concentrations were evaluated. T1/2kle was 19.6 +/- 2.3 min, Cltot 2.9 +/- 0.4 ml/kg/bw/min and DS 76.4 +/- 3.8 ml/kg/bw for 90 min. The plasma levels of total amino acids including the branched chain amino acids valine, leucine and isoleucine and of glutamine were significantly higher during r-HGH infusion than during the basal and somatostatin periods. In conclusion, the elimination of r-HGH in catabolic ICU patients is not different from that of healthy volunteers.
Abstract: Planned and "on-demand' reoperations are well-established concepts in the management of severe diffuse peritonitis. Both concepts were applied at our surgical department and reviewed with regard to specific complications and lethality. In the period between 1 January 1989 and 31 May 1994, 62 patients with the diagnosis of diffuse peritonitis underwent operative treatment at our surgical department. The mean age of the 29 female and 33 male patients was 58.2 years (range 17-93 years). The origin of peritonitis was the stomach in 8.1%, duodenum in 16.1%, small intestine in 12.9%, large intestine in 41.9% and the pancreas in 16.1%. Among these 62 patients, 15 were reoperated upon according to plan and 47 were reoperated upon on demand. The intraoperatively gained Mannheim peritonitis index and the Apache II score were similar in both groups. The average number of reoperations was five in the group of planned revisions and three in the group of on-demand revisions. Also lethality was similar in both groups. Regarding lethality, only the age of the patient (P < 0.03) and the preoperative Apache II score (P < 0.01) reached statistical significance. As expected, eradication of the infectious source was the precondition of survival regardless of the type of reoperation. Regarding our results, we conclude that planned or on-demand reoperations lead to similar results in the treatment of diffuse peritonitis. The crucial point for success is that elimination of the infection source take place as soon as possible.
Abstract: Infections occurring during the early postoperative phase after liver transplantation result in a significant rise in morbidity and mortality. The records of 279 orthoptic transplantations performed in 248 patients were analyzed retrospectively. 55.6% of all patients suffered from one or more episodes of bacterial and/or fungal infection during their postoperative hospitalisation. The median onset of bacterial/fungal infection was on day 7 after transplantation. Enterococci (42 episodes), Pseudomonas aeruginosa (38 episodes), staphylococci (37 episodes), Escherichia coli (17 episodes) and Candida albicans (11 episodes) were the most frequently detected organisms. 74 (29.8%) patients developed viral infections. 20 patients (8.1%) showed infection with cytomegalovirus (CMV), 32 patients (12.9%) with herpes simplex virus (HSV) and 6 patients (2.4%) with varicella zoster virus (VZV). 14 patients (5.6%) developed infection with both CMV and VZV. Triple infection with CMV, HSV and VZV occurred in one patient. Statistical analysis of potential risk factors showed a significant influence of blood volume replacement (p < 0.001) and occurrence of at least one rejection period (p < 0.02) for major bacterial/fungal infection and immunosuppression (p < 0.001), cold ischemic time (p < 0.04), occurrence of at least one rejection period (p < 0.005) and blood volume replacement (p < 0.04) for viral infection.
Abstract: OBJECTIVE: To present our experience with laparostomy and necrosectomy in the treatment of acute necrotising pancreatitis, and to show how refinements in our treatment regimen improved mortality over the years despite no reduction in the severity of the disease. DESIGN: Retrospective study. SETTING: University hospital, Austria. SUBJECTS: 125 patients treated by laparostomy/necrosectomy with repeated revisions during the period January 1983 to December 1991. INTERVENTIONS: Laparostomy, blunt necrosectomy, operative lavage, and open drainage. MAIN OUTCOME MEASURES: Mortality and morbidity. RESULTS: The severity of disease was assessed by the APACHE II score (median 15, range 4-30). In 106 of the 125 patients (85%) the necrotic pancreatic tissue was infected. Patients were operated on if they deteriorated clinically or if organ failure was suspected. A change in the protocol from revisions on demand (1983/4) to planned re-exploration at 48 hour intervals (1985/8) was associated with a reduction in mortality from 53% (16/30) to 28% (20/72). This was further reduced in 1989/91 to 17% (4/23) when a protocol of revisions planned for individual patients was introduced (p = 0.02). The incidence of gastrointestinal fistulas during the three periods was 6/30 (20%); 24/72 (33%); and 1/23 (4%); (p = 0.022), whereas that of intraabdominal bleeding remained much the same (7/23, 23%; 13/72, 18%; and 4/23, 17%; p = 0.56). The median (range) APACHE II scores for the three periods were 12 (4-27), 15 (5-30), and 14 (4-25). CONCLUSION: By continual revision of our protocol, together with accompanying improvements in intensive care, our mortality decreased significantly during the nine year period.
Abstract: OBJECTIVE: To see if it was possible to predict the development of infection after liver transplantation from concentrations of endotoxin, tumour necrosis factor-alpha (TNF-alpha), or interleukin-6 (IL-6) in plasma. DESIGN: Prospective open study. SETTING: University hospital, Austria. SUBJECTS: 46 Consecutive patients who underwent liver transplantation for end stage liver disease, 1989-90. INTERVENTIONS: Samples of 4 ml blood were taken in endotoxin free tubes, and of 10 ml into heparinised tubes at the beginning of the operation, during hepatectomy, at the beginning and end of the anhepatic phase, 10 minutes after reperfusion, and at the end of the operation. MAIN OUTCOME MEASURES: Correlation between development of infections postoperatively and operative release of endotoxin, TNF-alpha, and IL-6. RESULTS: There was no correlation between development of postoperative infections and operative concentrations of endotoxin, and of TNF-alpha and IL-6 up to the end of the anhepatic phase. There was, however, a sixfold increase in TNF-alpha and IL-6 concentrations between the end of the anhepatic phase and the end of the operation in patients who subsequently developed infections (p = 0.01). CONCLUSION: The increase in the concentrations of these two cytokines in the blood after reperfusion of the transplanted liver seems to predict the development of subsequent bacterial infection.
Abstract: Insulin-like growth factor-I (IGF-I) is a potent protein-anabolic hormone with a glucose-lowering effect and is therefore a possible agent for treating catabolic patients. In this study we investigated the effect of recombinant human (rh) IGF-I on the interorgan flux of glucose under hypo- and normoglycemic conditions in catabolic, anaesthetized, and catheterized dogs. We administered a primed (40 micrograms/kg) continuous (1.5 micrograms.kg-1.min-1) infusion of rhIGF-I (Kabi Biopharma, Stockholm, Sweden) for 180 min together with either a saline (0.9% NaCl) or an amino acid solution (2.2 mg AA.kg-1.min-1 solution of Vamin, Kabi Nutrition, Stockholm, Sweden). RhIGF-I administration lowered plasma glucose levels for approximately 50% of the baseline (P < 0.001) and stimulated glucose uptake from skeletal muscle about twofold (P < 0.01), but did not modify glucose balances across the gut and liver. The same effects were found when infusing rhIGF-I together with AA. A co-infusion of rhIGF-I and glucose to maintain normoglycemic conditions stimulated glucose uptake from skeletal muscle by about fivefold (P < 0.001) and glucose uptake across the gut by about 50%, but reduced the hepatic glucose liberation (-65%; P < 0.01). The rhIGF-I infusion did not alter arterial lactate levels, but stimulated lactate release from skeletal muscle (P < 0.05) and lactate uptake across the liver (P < 0.05). We conclude that rhIGF-I reduces plasma glucose levels mainly by stimulating glucose uptake across skeletal muscle.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Evaluation of graft quality remains a major problem in liver transplantation. The aim of this retrospective analysis was to examine the impact of donor criteria on postoperative graft function. Between June 1986 and September 1993 324 liver transplantations were performed at our institution. Criteria for exclusion from analysis were postoperative thrombosis of graft vessels, retransplantation, death prior to the 5th postoperative day or missing donor criteria. For the eligible 255 transplantations the impact of the following donor criteria were examined: age (range 1-62 years, median 28 years), size/body weigt index, duration of intensive care, cause of death, circulatory condition, need for vasopressive support and liver function tests (bilirubin, GOT, GPT, GGT, LDH, ALP, prothrombin time (PT), creatinine, sodium). The following intraoperative factors were also assessed: type of protective solution, cold ischaemic time (CIT), anhepatic period and blood transfusions. Graft function during the first 5 postoperative days was categorized into four groups: (1) good function (GOT max < 1000 U/l, spontaneous PT > 50%, bile production > 100 ml/day); (2) fair function (GOT 1000-2500 U/l, clotting factor support < 2 days, bile < 100 ml/day); (3) poor function (GOT > 2500 U/l, clotting factor support > 2 days, bile < 20 ml/day); (4) primary non-function (retransplantation required within 7 days). A univariate analysis revealed duration of intensive care (P = 0.001), circulatory condition (P = 0.005), anhepatic period (P = 0.0004), blood transfusions (P = 0.03) and CIT (P = 0.039) as significant risk factors for postoperative graft function. Entering these factors in a multivariate regression model we identified creatinine (P = 0.007), duration of intensive care (P = 0.009) and the size/body weight index (P = 0.03) as donor-related factors of high significance. Analysis of the intraoperative data revealed the anhepatic period as the factor of highest significance (P = 0.0004) together with CIT (P = 0.02) and intraoperative blood transfusions (P = 0.008). A doubling of the number of days of intensive care resulted in a threefold increased risk of postoperative graft failure. Prolonged intensive care is a variable representing multiple risk factors. Accepting donors with a longer history of hypotension or who show signs such as elevated creatinine should be carefully considered. In patients with expected surgical difficulties resulting in an extended anhepatic period and a higher blood loss, transplantation of organs retrieved from donors with a long duration of intensive care and a long CIT should be avoided.
Abstract: Primary non-function (PNF) of renal allografts has been attributed to various risk factors, among them immunological ones, as well as unfavourable preservation conditions. To investigate the impact of these risk factory on the occurrence of PNF, 1335 consecutive kidney transplants performed at a single centre over a 10-year period were analysed. All patients received immunosuppression based on cyclosporine. As the method of analysis a conditional stepwise logistic regression model was chosen, comparing each graft suffering PNF with its partner kidney retrieved from the same donor. Thus, all donor-related variables could be omitted from the analysis, as they are the same in every pair of grafts. Risk factors analysed included panel-reactive antibodies, number of pretransplant transfusions, pregnancies, number of prior transplants, cold and second warm ischaemia time, mismatches on HLA loci A, B and DR and recipient age. The overall incidence of PNF was 87 grafts (6.5%). One patient suffered immediate rejection due to transplantation of an ABO incompatible graft. This case was excluded from further analysis. PNF occurred three times in recipients of living related grafts, twice in recipients of en-bloc grafts and four times in grafts, in which the paired kidney was either not transplanted or shipped outside the Eurotransplant region, so that no paired graft was available for matched case-control analysis. Of the remaining 77 pairs, twice both organs of one donor failed immediately. The remaining 73 complete pairs were analysed. Two of the investigated risk factors have independently a significant impact on the occurrence of PNF. Increasing the number of pretransplant transfusions raises the relative risk of graft failure up to six fold (P=0.02), while a history of prior transplants bears a relative risk of 0.21E05 (P=0.005). Ischaemia has no significant impact on the occurrence of PNF. Our data strongly suggest that immunological rather than donor risk factors are responsible for the non-function of kidney grafts.
Abstract: OBJECTIVE: To review the value of obturator canal bypass with respect to long-term results. DESIGN: Case series and literature review. SETTING: University of Vienna Medical School in Austria. PATIENTS/METHODS: Personal experience with 34 consecutive patients and 125 cases published since 1982 with respect to patient data, patency, and survival are compared and jointly analyzed retrospectively. INTERVENTIONS: Patients received obturator canal bypass for lesions of the pelvic or common femoral vessels precluding orthotopic reconstruction. MAIN OUTCOME MEASURES: The rates of patient survival, limb salvage, and graft patency were analyzed. RESULTS: The postoperative mortality rate in the present series was 14.7%. The limb salvage rate after 5 years was 76.5%. One- and 5-year secondary patency rates were 75.3% and 54.9%, respectively. All grafts in patients without atherosclerosis were patent at a median of 34 months. For 57 cases documented in the literature, 1- and 5-year patency rates were 70.8% and 59.7%, respectively. Combined analysis of 90 obturator canal bypasses revealed rates of 72.7% and 56.9% of patent grafts at 1- and 5-years, respectively. CONCLUSIONS: The use of obturator canal bypass is recommended in deep groin infections and especially in patients with lesions of the pelvic vessels due to other occlusive vascular disease.
Abstract: Several studies have shown that the postoperative course of cytokines such as TNF-alpha or IL-6 is predictive of rejection and infection after human orthotopic liver transplantation (OLT). The aim of this prospective clinical trial was to evaluate the impact of transhepatic metabolism of endotoxin (ET), tumor necrosis-factor-alpha (TNF-alpha), and interleukin-6 (IL-6) after hepatic ischemia/reperfusion on the postoperative graft function. In 13 consecutive elective adult OLT patients with primary grafts, we determined concentrations of ET, TNF-alpha, and IL-6 in the radial artery, portal vein, and right hepatic vein at 1, 4, 7, 10, and 13 min after reperfusion. Of the 13 patients, four had ET levels below the detection limit (< 10 ng/L), and one patient had extremely high ET concentrations (151 ng/L in the hepatic vein). In the remaining patients the mean ET levels were 26 +/- 14, 26 +/- 15, and 24 +/- 14 ng/L in the portal vein, hepatic vein, and in the radial artery, respectively. These values indicate that in patients with a moderately elevated ET level, no transhepatic concentration differences of ET exist. However, in the patient with severe endotoxemia, the liver was apparently an ET-producing organ (HV-P: 29 +/- 13 ng/L). TNF-alpha levels were not measurable in four patients, and varied between 15 and 72 pg/ml (portal vein) in the remaining patients. The transhepatic concentration differences (HV-P and HV-A, respectively) of patients with PNF or dysfunction were higher than in those with "good" or "excellent" graft function (HV-P: 160 +/- 122 pg/ml vs. 7.3 +/- 9.7 pg/ml; P < 0.01 and HV-A: 137 +/- 101 pg/ml vs. 3.9 +/- 12 pg/ml; P < 0.01, respectively). Arterial IL-6 levels were below 88 pg/ml (mean value: 31 +/- 20 pg/ml) at the beginning of the operation, and increased considerably in three patients during the anhepatic phase and after reperfusion. No clinical correlation was found with the transhepatic concentration differences of IL-6. We conclude that in OLT patients without infection no transhepatic ET exchange was documented. However, a stimulated hepatic TNF-alpha release seems to be predictive of the beginning of liver dysfunction.
Abstract: PURPOSE: The long-term survival probability of patients who undergo surgery for stage 3 and 4 gastric cancer is poor, predominantly due to metastatic spread of the tumor. Depending on the type of tumor histology, the pathway of metastases is mainly peritoneal or hepatic dissemination. Interruption of this mechanism may be possible by intraperitoneal chemotherapy (IPT). PATIENTS AND METHODS: In a prospective randomized trial of 67 patients undergoing surgery for stage 3 and 4 gastric cancer, 33 patients underwent adjuvant postoperative IPT with cisplatin, while 34 control subjects remained untreated. RESULTS: Patients in the treatment group received a median of four IPT perfusions. Apart from frequent nausea, no adverse reactions or complications were noted. The median disease-free survival durations were 12.7 months and 9.7 months in treated patients and controls, respectively (P = .8). After a median follow-up duration of 72 months, 54 patients (80%) had died of primary disease or related complications. The median survival duration for IPT patients was 17.3 months as compared with 16.0 months for controls (P = .6). Autopsies were performed on 12 (18%) of 54 patients who died, and showed tumor spread to the peritoneal cavity and/or to the liver, irrespective of the application of IPT. CONCLUSION: IPT with cisplatin monotherapy does not improve survival probability after surgery for stage 3 and 4 gastric cancer. The reasons for ineffectiveness of IPT may be the choice of an unsuitable chemotherapeutic agent, an inefficient modus of application, or a lack of sufficient drug penetration into the serosa or peritoneal metastasis.
Abstract: The technique of Laparoscopic resection of the colon sigmoideum was practised in an experimental model before starting a clinical program of laparoscopic colonic surgery. Until now, two resections of the colon sigmoideum, one ileocecal resection, one right colectomy, one Hartmann's procedure and one transversostomy have been performed laparoscopically. Three patients had colonic carcinoma. One sigmoid resection had to be converted to open surgery and this patient underwent relaparotomy because of postoperative ileus. The postoperative course of the other patients was uncomplicated. The promising initial experience demonstrates that laparoscopic colonic surgery is feasible, although further studies have to prove advantages and indications, especially with respect to oncology.
Abstract: The effects of acute administration of human recombinant insulin-like growth factor-I (rhIGF-I) on amino acid (AA) flux between hindlimbs, liver and gut were investigated in anaesthetized post-operative dogs. rhIGF-I produced about a 10-fold increase in plasma IGF-I concentrations above baseline values (P < 0.001), increased the plasma levels of glucagon and adrenaline (P < 0.05), and evoked a fall in plasma glucose (-55 +/- 8%; (P < 0.001) and plasma total AA levels (-23 +/- 8%; P < 0.05). AA flux in post-absorptive dogs under NaCl infusions was characterized by an efflux of AA from the hindlimbs (as a result of the protein-catabolic situation), an equal AA balance across the gut and an AA uptake by the liver. The administration of rhIGF-I increased hepatic AA uptake in the NaCl group from 3.51 +/- 0.8 to 7.5 +/- 0.4 mumol/min per kg (P < 0.01) and in the AA-infused group from 16.8 +/- 0.6 to 22.4 +/- 1.5 mumol/min per kg (P < 0.05), but did not influence the AA balance across hindlimbs and gut. Glucose infusions normalized the plasma concentrations of counter-regulatory hormones without influencing the inter-organ AA balances. We conclude that hypoaminoacidaemia caused by rhIGF-I infusions is the result of a stimulated AA uptake by the liver, but is unrelated to alterations of AA exchange across the hindlimbs.
Abstract: The purpose of this study was to investigate the impact of prenephrectomy donor tissue typing on tissue typing quality and transplantation outcome in human kidney transplantation. We report on 680 consecutive kidney transplantations performed at the Vienna Transplantation Center from 1986 to June 1991. In 343 of them, HLA typing was performed using donor lymph node cells obtained in a small surgical procedure several hours before organ retrieval. The mean cold ischemia time (CIT) could be reduced to 17.7 h in these patients compared with 21.9 h in the control group (n = 337, conventional tissue typing using spleen lymphocytes obtained during the organ removal, P = 0.0001). There was a trend towards better initial and long-term function in the lymph node group; however, this did not reach statistical significance. The clarity of tissue typing results was significantly better when lymph nodes were used as the lymphocyte source. We conclude that prenephrectomy tissue typing is a feasable and inexpensive method of shortening CIT in renal transplantation and favors HLA typing, both likely to benefit transplantation outcome particularly within organ exchange programs.
Abstract: The impact of high donor age on transplantation outcome was analysed in 1180 consecutive cadaveric grafts transplanted in adult recipients. Grafts were divided into three groups acording to donor age (< 55 years (n = 1073, group 1), 55-59 years (n = 51, group 2), > or = 60 years (n = 56, group 3)) and transplantation outcome was compared for these groups. Criteria investigated were the incidence of primary non-function (PNF), initial function (IF) (urine production first 24 h) and long-term function (LTF). The impact of donor age on LTF was analysed among other potential donor, graft and recipient risk factors by the multivariate proportional hazardous model analysis (Cox model). The incidence of PNF was 5.8% (group 1), 11.8% (group 2), and 16.1% (group 3) (P = 0.002). Analysis of paired kidneys of PNF grafts in group 2 and group 3 revealed good function for all paired grafts except for one in each group. IF was anuria in 19.7% of group 1, 29.4% group 2 and 21.5% of group 3, oliguria in 18.2% of group 1, 23.5% of group 2 and 32% of group 3. Normal diuresis was found in 62.1% of group, 47.1% of group 2 and 47.3% of group 3 (P = 0.05). Independent risk factors for graft survival were year of transplantation, recipient age, panel reactive antibodies, donor age group and number of transplantation. After the exclusion of PNF grafts from the analysis, recipient age, year of transplantation and level of panel reactive antibodies remained as independent risk factors.
Abstract: The impact of potential risk factors for development of panel reactive antibodies (PRA) in 1078 cadaveric kidney graft recipients was investigated in a multivariate analysis. Multiple transplantation, transfusion of more than five blood units and more than two pregnancies were revealed as factors with a significant independent impact on the formation of high levels of PRA. Multiple transplantation and polytransfusion also affected primary non-function, initial function and long-term graft survival at 1, 3 and 5 years. Incidence of early rejection (within 30 days) was significantly increased with repeated transplantation and decreased with a full-house HLA match. However, these effects on transplantation outcome could only be observed when risk factors lead to the formation of antibodies. In patients with risk factors present, but without subsequent sensitization, the graft survival expectation was the same as in patients in whom risk factors were absent.
Abstract: In a prospective study 54 patients with 62 saphenous vein arterial bypass grafts were examined by colour-coded Doppler sonography and angiography. Five cases of graft occlusion were diagnosed by colour-coded Doppler sonography and confirmed by angiography. In comparison with angiography, colour-coded Doppler sonography showed a sensitivity of 92% and a specificity of 100% in the detection of focal graft stenosis. Only two stenoses in the region of the distal anastomosis could not be detected by colour-coded Doppler sonography. In 28 cases a marked dilatation of the proximal anastomosis was found corresponding to the surgically used patch angioplasty. Within this dilated bypass segment, turbulence and flow reversal zones were demonstrated, which might be predisposing factors for graft stenosis. Colour-coded Doppler sonography can accurately detect saphenous vein arterial bypass graft stenoses and should be routinely used in postoperative screening.
Abstract: To determine whether long-term oral anticoagulant treatment was effective in improving graft performance and preventing major amputation following vein bypass surgery for femoropopliteal atherosclerosis, a clinical trial was conducted in one single center and continued during 10 years. After 130 patients had electively received a femoropopliteal vein graft, they were randomly assigned to a therapy group (treatment with phenprocoumon [n = 66]) or to a control group (n = 64) that remained without any anticoagulant treatment. Primary end points of the study were graft reocclusion and limb loss. The median durations of primary patency and limb salvage were significantly longer for treated patients than that for controls. In addition, survival in the therapy group was longer. Following autologous vein bypass surgery in the treated group, the results were superior in terms of graft patency, limb salvage, and survival.
Abstract: Common carotid artery occlusion is not necessarily associated with thrombosis of the ipsilateral internal carotid artery. Noninvasive imaging of the carotid bifurcation with colour-coded Doppler sonography demonstrated patency of the external and internal carotid arteries distal to a common carotid occlusion in 4 patients which could be proven surgically. Identification of internal carotid artery patency could be demonstrated by angiography in two of the patients while in the other two cases angiography was inconclusive. Thus, CCDS provided a correct diagnosis of the internal carotid patency in these patients with common carotid occlusion.
Abstract: From 1982 to January 1991 228 orthotopic liver transplantations (OLT) were performed in 213 patients with end-stage disease at the Vienna transplantation centre, 1st University Department of Surgery. 14 patients were serum HBV surface antigen (HBsAg) positive at the time of transplantation. In the first 4 patients only OLT was performed; postoperatively all grafts became reinfected and the patients developed chronic hepatitis. In a further series, immunoprophylaxis against hepatitis B virus reinfection was carried out with hyperimmuneglobulin. In 4 patients short-term immunoprophylaxis was performed; all of them were seronegative after OLT, but HBsAg ++reoccurred in the serum within 3-16 weeks after transplantation and all patients experienced reinfection of their graft. The 2 patients, who had been transplanted in a replicative state (HBeAg positive) showed a fatal course of hepatitis in the graft. Out of 6 patients given long-term immunoprophylaxis 3 cases showed stable liver function, without any signs of reinfection, and the HBsAg negative status remained for up to 19 months after transplantation. Since two patients displayed a HBV replicate status prior to transplantation, alpha interferon was administered preoperatively, which resulted in decreased serum HBV-DNA levels.
Abstract: 99 living related kidney transplantations were performed between January 1967 and December 1988. At the time of observation 4 of 94 organ donors had died; there was no correlation between unilateral nephrectomy and the patient's death. Intraoperative (2.9%) and postoperative (25%) complications did not result in severe physical consequences for the organ donors. Hypertension was found in 2 donors. There was no decrease in function of the remaining kidneys. The 3-year organ survival of the transplanted kidney was 60% with "conventional immunosuppression" and 93% with cyclosporin. No association was found between HLA DR-matching and graft survival. Rejection episodes occurred significantly more often in the HLA DR-mismatched grafts.
Abstract: In the years 1965 to 1988 one or more organs were harvested for the purpose of transplantation from 649 brain dead organ donors reported to the Vienna transplantation centre. Based on a 1982 law regulating organ donation a large number of initiatives aiming at the improvement of the organ procurement system have taken place. In particular, the introduction of a decentralized donor guidance and organ retrieval system, a few information campaigns, as well as the introduction of full-time transplantation coordinators have significantly increased the number of organ donors. This development has made the Vienna transplantation centre one of the largest centres in Europe and has recently resulted in the achievement of a virtual balance between the increase of patients on the waiting list and the growth of the rate of transplantations performed. If this organ procurement policy is consistently continued in the years to come, there is a good chance of ensuring sufficient supply of organs for all patients on waiting lists, at least within the Viennese area.
