Thomas Sautner

Surgical treatment for severe acute pancreatitis: extent and surgical control of necrosis determine outcome.

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.

Oral Feeding With Glutamine Prevents Lymphocyte and Glutathione Depletion of Peyer’s Patches in Endotoxemic Mice

ObjectiveTo 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 DataRecent 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. MethodsFemale Balb/c mice were fed a glutamine-enriched diet or a control diet for 10 days. On day 7 25 &mgr;g 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. ResultsGlutamine 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. ConclusionsAdministration 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.

Attenuation of catecholamine-induced immunosuppression in whole blood from patients with sepsis.

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.

Candida infection of local necrosis in severe acute pancreatitis is associated with increased mortality.

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.

Catecholamines up-regulate lipopolysaccharide-induced IL-6 production in human microvascular endothelial cells

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 epi‐nephrine 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 cat‐echolamines and LPS could be reproduced in primary human skin microvascular endothelial cells. The cate‐cholamine‐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. Prein‐cubation with α and β receptor antagonists showed that the effect is mediated by β1‐ and β2‐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.—Gornikiewicz, A., Sautner, T., Brostjan, C., Schmierer, B., Függer, R., Roth, E., Muhlbacher, F., Bergmann, M. Catecholamines up‐regu‐late lipopolysaccharide‐induced IL‐6 production in human microvascular endothelial cells. FASEB J. 14, 1093–1100 (2000)

Elevated serum levels of epithelial cell apoptosis-specific cytokeratin 18 neoepitope m30 in critically ill patients.

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.

Early effects of catecholamine therapy on mucosal integrity, intestinal blood flow, and oxygen metabolism in porcine endotoxin shock.

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.

Surgical Treatment of Severe Acute Pancreatitis: Timing of Operation is Crucial for Survival

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.

Severe acute pancreatitis causes alterations in HLA-DR and CD14 expression on peripheral blood monocytes independently of surgical treatment

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.

Continuous therapeutic epinephrine but not norepinephrine prolongs splanchnic IL-6 production in porcine endotoxic shock.

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 &mgr;g/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.