Showing papers by "Eugen Faist published in 2001"

Removal of mediators by continuous hemofiltration in septic patients.

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

Interferon-gamma modifies cytokine release in vitro by monocytes from surgical patients.

Abstract: BACKGROUND Treatment with interferon-gamma (IFN-gamma), a key mediator for adequate forward-regulatory monocyte immune capability, has been advocated to overcome posttraumatic mononuclear leukocyte paralysis. Conversely, IFN-gamma also is a potent proinflammatory mediator contributing to capillary leakage in sepsis-driven organ failure. The objective of this investigation was to further define the potential of IFN-gamma as a modifier of monocyte activity before and after injury. METHODS Whole blood samples from 19 patients (7 female and 12 male patients; age, 68 +/- 5 years) before and after cardiac surgery with extracorporeal circulation were incubated under continuous rotation with lipopolysaccharide for 12 hours in the presence or absence of human recombinant IFN-gamma. Pro- and anti-inflammatory cytokines were determined in the plasma. RESULTS Lipopolysaccharide-induced release of tumor necrosis factor-alpha, interleukin (IL)-6, IL-12, and IL-1Ra, and prostaglandin E2 was clearly augmented with IFN-gamma most strikingly postoperatively (p < 0.05). There was no effect on IL-1beta, neopterin, and soluble tumor necrosis factor-R release. CONCLUSION Thus there is a wide spectrum of IFN-gamma activity on monocyte activation including anti-inflammatory properties. Since cellular preactivation facilitates monocyte reactivity toward IFN-gamma, we conclude that exogenous administration should be effective but must be carried out with great caution in patients with profound inflammation.

Perioperative treatment with human recombinant interferon-gamma: a randomized double-blind clinical trial.

Abstract: In spite of proven immunoregulatory effects in vitro of recombinant human interferon-gamma (rhIFN-gamma) in trauma, clinical trials remain inconclusive in such patients. To investigate the in vivo effect of rhIFN-gamma perioperatively in surgical patients we did a pilot study in 46 patients termed anergic by negative delayed-type hypersensitivity (DTH) skin test, who were undergoing major surgery (22 women and 24 men). They received 100 micrograms of rhIFN-gamma subcutaneously (treated [T]; n = 24) in a double-blind, placebo- (control [C]; n = 22) controlled manner on preoperative days -7, -5, and -3. Whole-blood cultures were stimulated on days -7, -1, 4, 7, and 10 for 12 h with or without LPS (1 microgram/mL). Mild side effects such as fever, headache, or chills were observed in 7/24 patients. No major complications occurred and no significant effect of rhIFN-gamma on HLA-DR, IL-1, and IL-8 was demonstrated. PGE2, TNF-alpha and IL-6 levels were elevated perioperatively in T. versus C. Neopterin, a metabolite of activated monocytes and macrophages, was significantly activated on days -1 (C: 7.6 +/- 1.2 versus T: 20.5 +/- 2.4 nmol/mL; P < 0.001), day 1 (C: 8.3 +/- 1.4 nmol/mL versus T: 24.9 +/- 2.8 nmol/mL; P < 0.001), and day 4 (C: 9.5 +/- 1.1 nmol/mL versus T: 16.0 +/- 1.8 nmol/mL; P < 0.05). Due to the overall lack of infectious complications during the investigation, no clinical effect was shown for rhIFN-gamma treatment. DTH skin testing failed to detect high-risk individuals in the patient population studied. In conclusion, we demonstrated in our pilot study that pre-operative immunomodulation with rhIFN-gamma in surgical anergic patients did not show severe side effects and modulated in vitro immunoresponse. A larger clinical trial in better-defined high-risk patients may show whether a reduction of infectious complications can be achieved.

Clinical expert round table discussion (session 5) at the Margaux Conference on Critical Illness: outcomes of clinical trials in sepsis: lessons learned.

Abstract: T hese are thrilling times for intensivists, as we are finally beginning to see positive results from clinical trials of new therapeutic agents in patients with severe sepsis. The results of the recently completed recombinant human activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial using activated protein C (APC) (1) are particularly exciting, and studies involving tissue factor pathway inhibitor, low-dose corticosteroids, platelet activating factor acetylhydrolase, extracorporeal systems, and others are under way. The key outcome measure in all clinical trials in septic patients has always been mortality, but, increasingly, investigators are being called on to include morbidity in their trial design (2). Improved survival without improved morbidity may be challenged as a positive outcome; merely postponing mortality may just increase the numbers of futile patients in our intensive care units, and may also result in higher costs. Such a situation could not really be said to be “positive”; for example, decompressive craniotomy in severe brain injury may indeed increase survival, but at what expense in terms of long-term outcome and quality of life? Indeed, one may believe that these two end points should go hand in hand, that is, that a reduction in mortality should be accompanied by improved morbidity. How could a drug reduce mortality without reducing morbidity? Is it possible for a therapy to reduce mortality but not reduce length of stay, duration of ventilation, frequency of complications, and so forth? Clinical trial analysis is certainly simplified if mortality is reduced and the survivors in the treatment group also show signs of improved morbidity, but should one be surprised if improved morbidity is not shown? What if, in fact, there is no apparent difference between the survivors in the treatment and the placebo groups? If a treatment improves mortality, there will be a certain percentage of survivors in the treatment group who would not have survived and who are presumably very sick. Carrying this thought through, one could expect there to be a shift in the severity of the disease process in the whole treatment population, with more patients in each severity category—severe, moderate, or mild—in the treatment group. The problem then comes in defining these groups and making statistical comparisons between them as the numbers become too small for relevant analysis. In fact, if a treatment improves mortality, it stands to reason that it must also improve morbidity; the problem is in our methods of measuring morbidity. Quantifying morbidity has always been difficult, but recently developed organ dysfunction scores such as the Sequential Organ Function Assessment (SOFA) (3) enable us to describe the development and course of individual organ (dys)function during a patient’s illness and, hence, perhaps, to monitor response to treatment. Such scoring systems can provide valid information about morbidity, which, although not replacing mortality as an end point, can complement it. Focusing in on APC as a potential therapy for severe sepsis, the positive results of the recent PROWESS study (1) are exciting, but questions remain about the exact mode of action of the drug. APC has anticoagulant and profibrinolytic effects. Severe sepsis is associated with activation of coagulation, and APC could thus be of benefit merely by its anticoagulant effects. However, the procoagulant and proinflammatory responses to infection are intricately linked, and it is therefore likely that APC also shows antiinflammatory effects, with reduced levels of cytokines such as interleukin-6. Again, problems arise with our means of measuring the degree of inflammatory response. Levels of many of the key cytokines, e.g., tumor necrosis factor, are notoriously unreliable markers of the inflammatory response, varying between individuals and within the same individual over time. What is becoming increasingly apparent is that the tools available for monitoring the degree of immune response and hence for assessing which patients may benefit most from which therapy, and for monitoring response to therapy, are far from adequate. With the complexities of the immune response, it is unlikely that all agents will benefit all septic patients all of the time. It may be that certain treatments can be used in combination, e.g., bactericidal permeabilityincreasing protein in the very early “endotoxin” stage, followed soon after by APC, which may have an effect further down the inflammatory cascade and which is more safely administered after major risks of bleeding have been eliminated. In addition, other questions need to be answered, including those of dose and duration of treatment. For example, if a patient responds very rapidly to treatment, should the drug be withdrawn early, or conversely, if a patient is not responding or is responding very slowly, Proceedings of the Margaux Conference on Critical Illness, Margaux, France, November 8–12, 2000. Copyright © 2001 by Lippincott Williams & Wilkins

Männliche und weibliche Sexualhormone: Gegensätzliche Effekte auf die Immunantwort nach traumatisch-hämorrhagischem Schock

Abstract: Studies indicate that androgens are responsible for the depressed splenocyte Th1 cytokine release in males following trauma-hemorrhage. In contrast, female mice maintain their Th1 cytokine release capacity following trauma-hemorrhage. Nonetheless, the effect of male and female sex steroids on Th1 and Th2 cytokine release following trauma-hemorrhage remains unknown. Male C3H/HeN mice were castrated and treated with pellets containing either vehicle, 50α-dihydrotestosterone (DHT), 17β-estradiol (estradiol), or a combination of both steroid hormones, for 14 days prior to soft-tissue trauma (i.e. laparotomy) and hemorrhagic shock (35 ± 5 mmHg for 90 min followed by adequate fluid resuscitation) or sham operation. The animals were sacrificed 24 h later plasma was obtained and splenocytes harvested. Plasma DHT and estradiol levels in treated animals were comparable with intact male and female mice, respectively. A significant depression of splenocyte Th1 cytokines, i.e. IL-2, IFN-γ, was observed in DHT-treated castrated animals, as opposed to maintained Th1 cytokine release in vehicle, estradiol and estradiol/ DHT-treated castrated animals. The release of the anti-inflammatory cytokine IL-10 was markedly increased in vehicle and DHT-treated mice following trauma-hemorrhage, but decreased in estrogen-treated mice. These results suggest that male and female sex steroids differentially affect the release of Th1 and Th2 cytokines following trauma-hemorrhage and should be further studied for their potential to modulate splenocyte function in trauma victims.