Most animal models of sepsis induced high mortality or early recovery and do not mimic the long-lasting catabolic state observed in patients. The purpose of this study is to develop a model of sepsis which reproduces these disorders, especially the long-lasting muscle wasting. This report summarizes our observations in a series of seven experiments using this model with rats to study the route of live Escherichia coli administration, dose of bacteria, reproducibility of the model, bacterial count in tissues, comparison of injection of live or dead bacteria, metabolic perturbations linked to infection, and potential role of tumor necrosis factor alpha (TNF-α) in muscle wasting. After intravenous infection, animals were anorexic and the catabolic state was long-lasting: body weight loss for 2 to 3 days followed by a chronic wasting state for several days. Liver, spleen, lung protein content, and plasma concentration of α2-macroglobulin were increased 2 and 6 days after infection. At 6 days, muscle protein content was substantially (−40%) reduced. The plasma TNF-α level measured 1.5 h after infection correlated with body weight loss observed 9 days later. The inhibition of TNF-α secretion by administration of pentoxifylline 1 h before infection reduced muscle wasting and activation of proteolysis at day 2 and abolished them at day 6. This septic model mimics in rats the prolonged protein metabolism alterations and muscle atrophy characteristics of infected patients and thus is useful for studying the impact of nutritional support on outcome.

A Sustained Rat Model for Studying the Long-Lasting Catabolic State of Sepsis

Objectives: To describe the postoperative course of patients who underwent hyperthermic isolated limb perfusion with recombinant tumor necrosis factor (TNF)-alpha and melphalan after pretreat ment with recombinant interferon-gamma as treatment for recurrent melanoma, primary nonresectable soft-tissue tumors, planocellular carcinoma, or metastatic carcinoma. To measure systemic TNF-alpha concentrations and relate these values with indices of disease severity. Setting: A 12-bed surgical intensive care unit (ICU) in a university referral hospital. Design: Prospective, descriptive study. Patients: Consecutive patients (n = 25) treated with hyperthermic isolated limb perfusion. Interventions: Blood samples were taken at regular intervals to determine TNF-alpha concentrations during and after hyperthermic isolated limb perfusion with recombinant TNF-alpha. Hemodynamic variables were obtained with a Swan-Ganz pulmonary artery catheter. Measurements and Main Results: All patients developed features of sepsis syndrome and required intensive care treatment. Most patients recovered quickly, with a median ICU stay of 2 days (range 1 to 25). Maximum systemic TNF-alpha concentrations ranged from 2284 to 83,000 ng/L (median 25,409) and returned to baseline values within 8 hrs. Despite these high concentrations of TNF-alpha, no patient died in the ICU, although the patient with the highest TNF-alpha concentration developed multiple organ failure and required continuous venovenous hemofiltration for 16 days. Linear regression analysis showed positive correlations between maximum TNF-alpha concentrations and systemic vascular resistance (p <.01), cardiac index (p <.02), Lung Injury Score (p <.02), prothrombin time (p <.02), and activated partial thromboplastin time (p <.05). Conclusions: Hyperthermic isolated limb perfusion with recombinant TNF-alpha leads to high systemic concentrations of TNF-alpha, probably due to leakage of recombinant TNF-alpha from the perfusion circuit, mainly through collateral blood flow. A sepsis-like syndrome is seen in all patients. Despite high concentrations of systemic TNF-alpha, this sepsis syndrome is short-lived and recovery is rapid and complete in most patients.

High plasma tumor necrosis factor (TNF)-alpha concentrations and a sepsis-like syndrome in patients undergoing hyperthermic isolated limb perfusion with recombinant TNF-alpha, interferon-gamma, and melphalan

Elevated concentrations of interleukin-1 (IL-1) were found in tissue surrounding biomaterials infected with Staphylococcus epidermidis. To determine the role of IL-1 in biomaterial-associated infection (BAI), IL-1 receptor type I-deficient (IL-1R(-/-)) and wild-type mice received subcutaneous implants of silicon elastomer (SE) or polyvinylpyrrolidone-grafted SE (SEpvp), combined with an injection of 10(6) CFU of S. epidermidis or sterile saline. Neither mouse strain was susceptible to BAI around SE. IL-1R(-/-) mice with SEpvp implants had a no abscess formation and a reduced susceptibility to persistent S. epidermidis infection. The normal foreign body response, characterized by giant-cell formation and encapsulation, was delayed around SEpvp in wild-type mice but not in IL-1R(-/-) mice. This coincided with enhanced local IL-4 production in IL-1R(-/-) mice. These data suggest that inhibition of local IL-1 activity may be beneficial for the outcome of BAI.

https://iai.asm.org/content/iai/68/12/6924.full.pdf

Interleukin-1 receptor type I gene-deficient mice are less susceptible to Staphylococcus epidermidis biomaterial-associated infection than are wild-type mice.

A persistent Staphylococcus epidermidis infection in mice around a subcutaneous polyvinylpyrrolidone-grafted silicon elastomer catheter (SEpvp) but not around a conventional silicon elastomer catheter was observed. With SEpvp pericatheter tissue, protracted and exaggerated interleukin-1β (IL-1β) production was found. Apparently, sustained levels of IL-1β are associated with enhanced susceptibility to biomaterial-associated S. epidermidis infection.

Enhanced susceptibility to subcutaneous abscess formation and persistent infection around catheters is associated with sustained interleukin-1beta levels.

Background In this study, we have evaluated hepatotoxicity, secondary cytokine production and hepatic acute-phase response (APR) in patients who underwent isolated hepatic perfusion (IHP) with tumour necrosis factor (TNF) a and melphalan for irresectable colorectal liver metastases. Design An extracorporeal veno-venous bypass was used to shunt blood from the lower body and intestines to the heart. Inflow catheters were placed in the hepatic artery and portal vein, and an outflow catheter in the inferior caval vein. The liver was perfused for 60 min with 0·4 mg of TNF-a plus 1 mg kg π1 melphalan (IHPTM group, n o 6) or 1 mg kg π1 melphalan (IHPM group, n o 3). The liver was washed with macrodex before restoring vascular continuity. Results After the washout procedure, a TNF-a peak (169 6 38 pg mL π1 ) was demonstrated in the IHPTM group only. Both groups demonstrated peak levels of interleukin 6 (IL-6) in the perfusate as well as systemically. These were significantly higher in the IHPTM group. Acute-phase protein (APP) levels followed a similar pattern as has been demonstrated after major surgery, with no significant differences between both groups. The addition of TNF-a to the perfusate did not lead to a significant difference in APP levels and the time course between groups. Conclusions IHP with TNF and melphalan is followed by a transient systemic peak of TNF directly after liver washout. Secondary IL-6 induction was seen in the present study after IHP with and without TNF, which was highest when TNF was added. This phenomenon cannot be extrapolated to APP induction, which appeared unaffected by the addition of TNF, presumably because the surgical procedure itself already causes maximal stimulation of APP production.

https://repub.eur.nl/pub/60695/Vries_et_al-1999-European_Journal_of_Clinical_Investigation.pdf

Acute-phase response patterns in isolated hepatic perfusion with tumour necrosis factor α (TNF-α) and melphalan in patients with colorectal liver metastases

• We tested the hypothesis that long-term intravascular cannulation exacerbates the harmful effects of an infectious challenge. Four groups of rats were initially studied: rats without intravascular catheters or infection (group 1), rats without catheters with a polymicrobial infection (group 2), rats with catheters but no infection (group 3), and rats with catheters and infection (group 4). Infected animals had an increased mortality and generated a significantly increased tumor necrosis factor response compared with noninfected animals. Animals with catheters and infection generated far less cardiac output than animals from the other three groups. No histologic changes differentiated the four groups. Therefore, the presence of a sterile intravascular catheter significantly increases cardiac dysfunction and mortality rates in rats with chronic bacteremia. These results suggest that intravascular plastic catheters potentiate the destructive cascade of events produced by the host in response to bacteremia. ( Arch Surg . 1991;126:1087-1093)

Intravascular plastic catheters. How they potentiate tumor necrosis factor release and exacerbate complications associated with sepsis.

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Intravascular plastic catheters. How they potentiate tumor necrosis factor release and exacerbate complications associated with sepsis.