Major Visceral Surgery Research Articles

Host Inactivation of Bacterial Lipopolysaccharide Prevents Prolonged Tolerance Following Gram-Negative Bacterial Infection

A transient state of tolerance to microbial molecules accompanies many infectious diseases. Such tolerance is thought to minimize inflammation-induced injury, but it may also alter host defenses. Here we report that recovery from the tolerant state induced by Gram-negative bacteria is greatly delayed in mice that lack acyloxyacyl hydrolase (AOAH), a lipase that partially deacylates the bacterial cell-wall lipopolysaccharide (LPS). Whereas wild-type mice regained normal responsiveness within 14 days after they received an intraperitoneal injection of LPS or Gram-negative bacteria, AOAH-deficient mice had greatly reduced proinflammatory responses to a second LPS injection for at least 3 weeks. In contrast, LPS-primed Aoah- knockout mice maintained an anti-inflammatory response, evident from their plasma levels of interleukin-10 (IL-10). LPS-primed Aoah-knockout mice experiencing prolonged tolerance were highly susceptible to virulent E. coli challenge. Inactivating LPS, an immunostimulatory microbial molecule, is thus important for restoring effective host defenses following Gram-negative bacterial infection in animals.

Use of procalcitonin for early prediction of lethal outcome of postoperative sepsis

Background To develop strategies for the prediction of sepsis outcome systemic procalcitonin (PCT) levels were correlated with various clinical parameters. Methods PCT levels and Acute Physiology and Chronic Health Evaluation (APACHE) II scores were assessed on the day of sepsis diagnosis in a large series (n = 160) of patients developing sepsis after major visceral surgery. Results In multivariate analysis, systemic PCT and the APACHE II score could be identified as independent early predictive indicators of lethal sepsis. Combining both indicators at sepsis onset, a prognosis score could be calculated using binary logistic regression analysis allowing the identification of high- and low-risk groups. While 71% of the high-risk patients died of sepsis, 77% of patients assigned to the low-risk group survived the septic complication (sensitivity 71%, specificity 77%). Conclusion Calculation of the prognosis-score allowed for an early prediction of the septic course with high sensitivity and specificity. This information could aid in deciding on adequate treatment strategies.

Effects of functional Toll-like receptor-4 mutations on the immune response to human and experimental sepsis.

Genetically determined responsiveness to microbial stimuli such as lipopolysaccharide (LPS) may affect the pathophysiology of human sepsis. The D299G mutation in human Toll-like receptor-4 (TLR4) impairs LPS signalling in homozygous and heterozygous individuals. To investigate whether the presence of the TLR4(D299G) mutation may correlate with the development or outcome of sepsis following major visceral surgery the presence of TLR4(D299G) mutation was analysed in 307 Caucasian patients (154 without and 153 with sepsis). Sepsis was caused in 84% of patients by polymicrobial infection. The presence of the mutant TLR4 did not significantly correlate with development or outcome of sepsis. Serum levels of tumour necrosis factor, interleukin (IL)-10, and IL-6 at sepsis onset did not significantly differ between patients carrying wild-type and mutant TLR4. Moreover, studies in a murine model of polymicrobial septic peritonitis demonstrated that TLR4-deficiency did neither influence the systemic cytokine response nor the development of organ injury. The results suggest that the signalling capacity of TLR4 as affected by loss-of-function mutations does not influence human or experimental sepsis caused by polymicrobial infection. Thus, in polymicrobial infection, other innate immune receptors may compensate for TLR4 defects.

Impaired monocyte IL-12 production before surgery as a predictive factor for the lethal outcome of postoperative sepsis.

To investigate whether monocyte paralysis resistant to interferon-gamma (IFN-gamma) costimulation may exist before surgery and postoperative infection and may correlate with the outcome of postoperative sepsis. Several studies have correlated monocyte paralysis during the course of sepsis with lethal outcome. Although the authors' previous work indicated that preoperative defects in monocyte interleukin (IL)-12 production are associated with the development of severe postoperative sepsis, the functional state of monocytes before surgery and infection and its significance for sepsis requires further analysis. In a prospective study, monocyte functions of 1,113 consecutive patients were examined before major visceral surgery. Monocytes were isolated from peripheral blood and were stimulated in vitro with IFN-gamma and lipopolysaccharide. The secretion of IL-12 p70, IL-12 p40, IL-10, and tumor necrosis factor was measured. Preoperative monocyte secretion of IL-12 p70 and IL-12 p40 was significantly reduced in patients who developed lethal postoperative sepsis compared with sepsis survivors and patients with uneventful postoperative recovery. Moreover, preoperative monocyte IL-12 production was an independent predictive factor for the lethal outcome of postoperative sepsis by multivariate analysis. Preoperative monocyte IL-10 production was impaired in the sepsis group but did not correlate with death from sepsis. Preoperative monocyte tumor necrosis factor secretion was comparable between patients with uneventful recovery, sepsis survivors, and nonsurvivors. Thus, impaired preoperative monocyte IL-12 secretion in patients developing lethal postoperative sepsis did not result from an overproduction of IL-10 or from a generalized monocyte paralysis. The association between impaired preoperative monocyte IL-12 production and death from sepsis was also not explained by gender differences, underlying malignant disease, tumor type, neoadjuvant therapy, or age. These results identify a selective preoperative defect in monocyte IL-12 production as a predictive factor for the lethal outcome of postoperative sepsis. These data suggest that a partial preoperative monocyte paralysis severely impairs the host defense against postoperative infection, resulting in an increased risk of lethal sepsis.

Critical role of Kupffer cell-derived IL-10 for host defense in septic peritonitis.

Intra-abdominal infection in patients following major visceral surgery is associated with high mortality. Using a macrophage depletion technique, we demonstrate that in murine septic peritonitis, Kupffer cells are a major source of systemic IL-10 levels. Kupffer cell-depleted mice were highly susceptible to the lethal effects of septic peritonitis and exhibited an increased bacterial load. Kupffer cell-depleted mice were protected by the administration of an IL-10-Fc fusion protein. Loss of Kupffer cell-derived IL-10 was associated with a weak increase in serum IL-12 levels, whereas TNF, IL-1alpha, and IL-18 levels were not significantly elevated, suggesting that the loss of Kupffer cell-derived IL-10 did not result in a toxic cytokine release syndrome. Instead, loss of Kupffer cell-derived IL-10 was associated with a reduced splenocyte production of IFN-gamma that is required for immune protection in murine septic peritonitis. Therefore, the results suggest that the protective function of IL-10 in septic peritonitis may not be restricted to the anti-inflammatory activities of IL-10.

Sympathoadrenerge, Kreislauf- und Streß-Reaktionen bei Co-Induktion mit Propofol und Midazolam*

This study was undertaken to investigate simultaneously the influence of coinduction with propofol and midazolam on sympathoadrenergic and hemodynamic reactions and stress response during the extended induction period of TIVA. 2 x 20 patients over the 60th year of life with major visceral surgery were investigated in a prospective randomized design. All patients received about 0.1 mg/kg BW midazolam for oral premedication. In the midazolam-group, induction of TIVA was undertaken with 0.05 mg/kg BW midazolam, 2.5 micrograms/kg BW fentanyl and 1.0 mg/kg BW propofol (1 min later). Controls received 2.5 micrograms/kg BW fentanyl and 2.0 mg/kg BW propofol. After muscle relaxation with 0.1 mg/kg BW vecuronium, TIVA was conducted in both groups with 8-5 mg/kg BW/h propofol and bolus injections of fentanyl with respect to clinical demands. Beyond consumption of anesthetics and recovery, sympathoadrenergic and hemodynamic reactions and SEF90 were investigated at 6 time points before induction of anesthesia and at skin incision. Plasma levels of ADH, ACTH and cortisol were measured twice before induction and at skin incision. Biometric data of both groups were comparable, and mean age was over 65 years. In the midazolam-group, co-induction with a mean dosage of 3.8 mg midazolam halved the induction dose of propofol and reduced the propofol demand during the following course of anesthesia as well, achieving a significant over all reduction of 200 mg propofol (p = 0.04). With respect to recovery from anesthesia more than 90 min later, no significant differences were found. Plasma concentrations of noradrenaline and adrenaline dropped significantly in both groups (p < 0.0001), as well as mean arterial pressure and heart rate (Fig. 1 and 2). For ADH, ACTH, cortisol and SEF90, no statistical differences were observed. Plasma-concentrations of midazolam were significantly higher in the midazolam-group. In elderly patients, co-induction with 0.05 mg/kg BW midazolam halved the induction dose of propofol and led to a further dose reduction with maintained hypnotic potency. However, the halvage of propofol induction dose had no effect on the reduction of the sympathoadrenergic tone with decrease of blood pressure and heart rate. The overall moderation of the stress response was comparable as well. Thus, both induction regimens investigated in this study cannot be recommended in patients with severe hemodynamic disorders like hemorrhagic or cardiac shock. The propofol reduction should be primarily considered under economic aspects.

Sepsis after major visceral surgery is associated with sustained and interferon-γ–resistant defects of monocyte cytokine production

Background: Recent clinical trials failed to demonstrate beneficial effects of anti-inflammatory sepsis therapy. The present study therefore asked the following questions: Is there evidence for immunosuppression during postoperative sepsis? When, during the septic course, may immunosuppression develop? Can defective cellular functions be restored by in vitro treatment with interferon-γ (IFN-γ)? Methods: The study included 35 patients with sepsis after major visceral surgery and 85 control patients. Monocyte secretion of interleukin (IL)-1β, IL-12 p40 and p70, IL-18, tumor necrosing factor, and IL-10 with or without IFN-γ treatment and its correlation with the course and outcome of postoperative sepsis were determined. Results: Postoperative sepsis was associated with an immediate defect of endotoxin-stimulated monocyte production of IL-12 p40, IL-1β, and IL-10 in both surviving and nonsurviving patients. During the final phase of postoperative sepsis, a significant recovery of IL-12 p40 and IL-1β secretion, but not of IL-10 production, correlated with survival. Despite the exposure of monocytes in vitro to IFN-γ for 16 hours, the production of the biologically active IL-12 p70 heterodimer was severely suppressed both in survivors and nonsurvivors, although the secretion of the p40 subunit was restored. In contrast, IFN-γ treatment resulted in a significant suppression of monocyte IL-1β production in all patient subgroups. Alterations of monocyte tumor necrosing factor secretion were not observed. The production of IL-18 was below the limits of detection in all samples. Conclusions: Postoperative sepsis was associated with immediate monocyte defects that affected both pro- and anti-inflammatory cytokine secretion, which suggests that immunosuppression is a primary rather than a compensatory response to a septic challenge. Sepsis survival correlated with the recovery of the proinflammatory, but not the anti-inflammatory, response. The treatment of monocytes with IFN-γ did not reconstitute defective proinflammatory cytokine production. (Surgery 2000;127:309-15.)

Immune paralysis of T-lymphocytes and monocytes in postoperative abdominal sepsis. Correlation of immune function with survival

In vitro functions of stimulated peripheral T cells and monocytes were investigate in patients experiencing sepsis following major visceral surgery. Cell culture supernatants were analyzed by ELISA for IL-2, IFN-gamma, IL-4, IL-10, TNF-alpha, IL-1 beta, and IL-12p40. In addition, monocyte HLA class II expression was determined by flow cytometry. T cell secretion of IL-2, TNF-alpha, and in part IFN-gamma (but not IL-4) was significantly diminished in non-survivors throughout the entire course of sepsis, compared to controls and sepsis survivors. Production of IL-1 beta and IL-12 p40 by monocytes was strongly reduced in both survivors and non-survivors at the onset of sepsis. Persistence of depressed monocyte cytokine secretion correlated with lethality. Thus, overall suppression of cytokine production by T cells and monocytes was already observed at the beginning of postoperative sepsis. HLA class II expression by monocytes exhibited a strong and sustained down-regulation with no significant differences between sepsis survivors and non-survivors. In summary, suppression of both T cell and monocyte functions develops early during postoperative sepsis. Recovery of immune functions and severity of immune defects are associated with outcome.

Hypophosphorémie postopératoire en chirurgie digestive. Influence du régime d'alimentation parentérale

Twenty-seven non emaciated patients undergoing major visceral surgery were randomly divided into two different groups according to the postoperative parenteral diet (100% glucose versus 50% fat 50% glucose). All patients received the same anaesthetic protocol and, peroperatively, none received any glucose. In the postoperative phase, parenteral feeding was started on the day of operation (18.5–21.8 kcal · kg −1) and was continued for a minimum of four days (37–44 kcal · kg −1 · 24 h −1). All patients received intravenous insulin and phosphorus (0.15 mmol · kg −1 · 24 h −1). During five days, daily measurements of serum phosphate and glucose levels were made and nitrogen balance was studied. For all these parameters, there was no evidence of any significant difference between the two groups. A significant fall in plasma phosphate occurred in each group on the first postoperative day, was maximum on the second and lasted until the fourth. This fall was not influenced by parenteral diet. No patients in this study developed symptoms of phosphate depletion. The glucose levels increased significantly and the nitrogen sparing effect was similar in both groups. The mechanism of hypophosphataemia seemed to be an intracellular transfer under the influence of hyperglycaemia and high plasma insulin levels rather than an increase in urinary phosphate excretion. The advantage of using lipid solutions did not appear under the dietary conditions studied. Indeed a glucose supply ⩾3 mg · kg −1 · min −1 seemed to induce a maximum intracellular transfer of phosphorus. Because of this, phosphate supplementation and frequent measurement of serum phosphate are recommended for patients undergoing major visceral surgery and postoperative intravenous feeding.

Influence de l'anesthésie péridurale sur l'épargne azotée postopératoire en chirurgie viscérale majeure

In order to determine the role of epidural anaesthesia on protein sparing, eighteen patients undergoing major visceral surgery were randomly divided into three different groups according to the mode of anaesthesia used (general anaesthesia, epidural anaesthesia, continuous epidural anaesthesia for 24 h). These patients were intravenously fed for five days postoperatively; their nitrogen balance was studied. Compared with the « general anaesthesiagroup, only the daily averages of nitrogen balance of the « continuous epiduralgroup were significantly better. In order to correlate stress with nitrogen saving, the early evolution of several parameters (cortisol, glucose, prolactin) used as « stress markerswas studied : there was no evidence of any significant difference between the three groups.