Efficacy and Safety of the Platelet-Activating Factor Receptor Antagonist BN 52021 (Ginkgolide B) in Patients with Severe Sepsis : A Randomised, Double-Blind, Placebo-Controlled, Multicentre Trial.

OBJECTIVE: To evaluate the efficacy and safety of the natural platelet-activating factor receptor antagonist, BN 52021 (ginkgolide B) in the treatment of patients with severe sepsis related to Gram-negative and mixed bacterial infection. DESIGN AND SETTING: Prospective, randomised, double-blind, placebo-controlled, multicentre study carried out in 13 academic medical intensive care centres in Germany with up to 14 patients per centre. PATIENTS: 88 patients with severe sepsis under standard medical and surgical care: nine patients with pure Gram-positive infection, 79 patients with Gram-negative or mixed bacterial infections (subgroup for which efficacy was to be established). INTERVENTIONS: Patients were randomised to receive either placebo or BN 52021 1.25 mg/kg bodyweight intravenously every 12h over a 4-day period in addition to their standard medical and surgical care. MAIN OUTCOME MEASURES AND RESULTS: The primary efficacy variable was the 28-day all-cause mortality rate. The treatment groups were similar with respect to demographic data and prognostic factors influencing the outcome except for bodyweight and adequacy of antibiotic therapy. Analysis of patients with Gram-negative or mixed bacterial infection, for which efficacy was to be established, resulted in a 28-day all-cause mortality of 42.5% in the placebo group (n = 40; 17 deaths) versus 38.5% in the BN 52021 group (n = 39; 15 deaths). Among all randomised patients, the 28-day all-cause mortality rate was 40.9% in the placebo group (n = 44; 18 deaths) and 38.6% in the BN 52021 group (n = 44; 17 deaths). There were no differences in frequency and severity of adverse events between the two treatment groups. CONCLUSIONS: Four-day administration of BN 52021 failed to demonstrate a statistically significant reduction in mortality in patients with severe sepsis suspected or confirmed to be related to infections other than Gram-positive bacterial infection.

[Clinical results with the "open lung concept"]. / Klinische Ergebnisse bei der Anwendung des "Open-Lung-Konzepts".

Elements of the "open lung concept" are being increasingly included in clinical ventilatory strategies. Despite encouraging experimental investigations to date, relatively few studies exist that examine the clinical application of the complete concept. The aim of this study was to prove that with effective recruitment maneuvers and titrated PEEP levels this concept is applicable in clinical settings. We sought to determine if it was possible to achieve a significant improvement in oxygenation and also to examine what side-effects resulted. Twenty consecutive patients who had had an acute lung injury (ALI) for less than 72 hours, with an oxygenation index (P/F-Ratio = quotient from arterial partial pressure of oxygen [PaO2] and the inspiratory fraction of oxygen [FiO2]) of less than 200 torr, and with a PEEP > or = 10 cmH2O were treated using a recruitment manoeuvre (RM). A PEEP was titrated to keep the lung open, and the patients were kept under pressure-controlled ventilation. The P/F-Ratio increased while using a recruitment pressure of 66 +/- 13 cmH2O from 137 +/- 41 to 381 +/- 150 torr (p < 0.001). The titrated PEEP which kept the lung open after recruitment was 17 +/- 3 cmH2O. One patient developed a pneumothorax. The dose of norepinephrine was increased in ten patients from 0.24 +/- 0.12 to 0.31 +/- 0.1 microgram/kg/min. Due to elevated liver enzymes within the first 48 hours, titrated PEEP had to be decreased in three patients. The clinical application of the "open lung concept" demonstrated a quick and effective improvement in oxygenation in many patients. Side-effects in some patients limited the use of high PEEP levels.

[The effect of dopexamine and iloprost on plasma disappearance rate of indocyanine green in patients in septic shock]. / Einfluss von Dopexamin und Iloprost auf die Plasma-Disappearance-Rate von Indozyaningrün bei Patienten im septischen Schock.

OBJECTIVES: To evaluate the effect of dopexamine and iloprost on the plasma disappearance rate (PDR) of indocyanine green (ICG) in patients in septic shock in a prospective clinical trial. METHODS: In 40 consecutive patients in septic shock, a femoral arterial fiberoptic catheter (COLD system) and a gastrotonometric probe were placed. Patients received either dopexamine infusion (0.5 microgram/kg body weight/min) or iloprost (1 ng/kg body weight/min) for 24 h i.v. PDR, intramucosal pH of stomach wall (pHi), cardiac index (HI) and intrathoracic blood volume (ITBV) were determined before, 1, 6, and 24 h after dopexamine or iloprost infusion and 1 h after end of infusion. RESULTS: PDR was significantly increased 24 h after starting dopexamine infusion from 12.2 +/- 1.8%/min to 17.8 +/- 2.2%/min (+45.9%) and 1 h after the end of infusion PDR decreased to baseline values. PDR increased to 16.4 +/- 2.1%/min, 1 h after starting iloprost infusion and increased to a maximum value of 18.6 +/- 2.2%/min (+33.8%, p < 0.05) 24 h after start of infusion compared to the baseline (13.9 +/- 1.7%/min). After the end of infusion PDR decreased to baseline values. Baseline values of pHi were in normal ranges in all groups and there was no change during the observation period. Cardiac index and ITBV were stable during the study. Dosage of norepinephrine could be reduced by dopexamine infusion. CONCLUSIONS: Dopexamine and iloprost have a positive effect on the plasma disappearance rate of ICG and therefore have a protective effect on splanchnic perfusion and liver function, respectively.

Effects of the stable prostacyclin analogue iloprost on the plasma disappearance rate of indocyanine green in human septic shock.

OBJECTIVES: To evaluate the effect of the stable prostacyclin analogue iloprost on the plasma disappearance rate of indocyanine green (PDR) in patients with septic shock. DESIGN AND SETTING: A prospective clinical study in a university hospital intensive care unit. PATIENTS AND INTERVENTIONS: 20 patients in septic shock. Patients received iloprost infusion (1 ng/kg per minute) for 24 h. MEASUREMENTS AND RESULTS: PDR was determined by a femoral arterial fiberoptic catheter before, 1, 6, and 24 h after start and 1 h after end of iloprost infusion. PDR increased significantly 24 h after start of iloprost infusion (baseline: 13.9 +/- 1.7% vs. 18.6 +/- 2.2%/min) and decreased 1 h after end of infusion (13.7 +/- 1.7%/min; p < 0.002). There was no change in pHi, cardiac index, mean arterial pressure, heart rate, central venous pressure, or intrathoracic blood volume index. CONCLUSION: Administration of the stable prostacyclin analogue iloprost significantly increases PDR, indicating improvement in liver function.

Parenteral selenium supplementation in critically ill patients--effects on antioxidant metabolism.

Decreased plasma selenium (Se) levels are common in critically ill patients. Oxidative stress is regarded as one possible cause of the Se deficiency. We investigated in 20 critically ill patients with decreased plasma selenium concentrations the antioxidant metabolism during parenteral selenium supplementation (week 1: 2 x 500 micrograms; week 2:1 x 500 micrograms, week 3:3 x 100 micrograms sodium selenite). As marker of oxidative stress we measured the plasma malondialdehyde levels on days 0, 1, 3, 7, 14, and 21. The content of reduced and oxidized glutathione as well as the leucocyte activity marker elastase were estimated on the same days. Initial plasma Se levels were considerably decreased (0.44 +/- 0.1 mumol/l, mean +/- SEM). After one day of supplementation Se concentrations were in the reference range. Plasma malondialdehyde levels and the ratio of oxidized and reduced glutathione were initially elevated and decreased beginning on day 3 of supplementation. The mean elastase level was 113 +/- 10 micrograms/l on day 0. On day 3 elastase values decreased significantly (85 +/- 13 micrograms/l, p < 0.05; day 21, 19 +/- 7 micrograms/l, p < 0.001). Antioxidant metabolism showed significant changes beginning after 72 hours of therapy. This latency may be explained with the induction of the enzyme glutathione peroxidase. The lowered plasma Se concentrations measured in the critically ill patients and the significant effects on antioxidant metabolism during supplementation emphasized the importance of selenium administration in these patients.

Management of swallowing disorders and chronic aspiration by glottic closure procedure.

We report an 18-year-old man with a posterior fossa tumor who had to undergo a partial resection of the tumor and supportive radiation therapy. Functional deficits of the lower cranial nerves, particularly the glossopharyngeal and vagal nerves, associated with severe swallowing disorders and refractory aspiration pneumonia were seen postoperatively. The admission to the intensive care unit (ICU) resulted from increasing respiratory failure accompanied by recurrent septic episodes. Nutritional support via nasogastric tube and later percutaneous endoscopic gastrostomy (PEG) were hampered by complications such as persistent sinusitis, local dermatitis surrounding the entrance of the PEG tube, and the development of duodenal ulcers. Furthermore, the use of continuous subglottic aspiration failed to prevent pulmonary infections. After a 9-week stay in the ICU due to inadequate antimicrobial therapy of aspiration pneumonia and the patient's persistent sepsis, a temporary surgical separation of airway and food passages was performed by glottic closure. Subsequently chronic aspiration stopped, and 3 months after admission to the ICU, the patient had stable vital organ function and was transferred to a surgical ward free of infections. Glottic closure was reversed successfully 7 months later. When compared with laryngeal function on admission, there was no more impairment. Thus, temporary glottic closure seems to be an efficacious treatment to prevent life-threatening septic complications in patients with refractory aspiration pneumonia.

[The circulating adhesion molecules sICAM-1 and sP-selectin in patients with sepsis]. / Die zirkulierenden Adhäsionsmoleküle sICAM-1 und sE-Selectin bei Patienten mit Sepsis.

AIM: The aim of this study was to investigate whether the plasma levels of the circulating adhesion molecules sICAM-1 and sE-selectin could serve as early predictors of developing sepsis and its severity. METHODS: Twenty-four patients admitted to an intensive care unit with a high risk of developing septic complications were enrolled in this study. Patients were divided into three groups: group I, with infection without systemic sepsis, n = 8; group II, surviving patients with severe sepsis and multi-organ failure (MOF), n = 8; and group III, nonsurviving patients with severe sepsis and MOF, n = 8. Classification of patients was performed according to the clinical criteria defined by the Sepsis Consensus Conference in 1992. Blood samples were taken at 7 a.m. starting from the day of admission until the 7th day after diagnosis of sepsis. Plasma levels of sICAM-1 and sE-selectin were determined in all samples taken between the 3rd pre-septic day and the 7th day after the diagnosis of sepsis was made. RESULTS: In group I, both sICAM-1 (354.21 +/- 128.60 ng/ml, 86 samples) and sE-selectin (30.41 +/- 7.20 ng/ml, 86 samples) levels remained within the reference range over the whole period of observation. The sICAM-1 levels of group II (between 550.82 +/- 275.67 ng/ml and 445.08 +/- 243.63 ng/ml) tended to show values above the reference range without being significant. Mean sICAM-1 levels in group II did not differ from those of group I. From the 2nd pre-septic day onwards the sICAM-1 levels of group III increased, but not significantly. Significant differences in sICAM-1 levels between group I and group III were observed, with peaks at the samples of the 2nd preseptic day and after the 3rd day of sepsis, respectively (P < 0.05). The sE-selectin levels in group II were elevated from the 3rd preseptic day onwards, with a peak value on the 2nd day of sepsis (P < 0.05). Afterwards, levels decreased to initial values despite ongoing sepsis. Mean values of sE-selectin levels of group I and II were significantly different with the onset of sepsis (P < 0.05). Plasma levels of sE-selectin in group III were significantly elevated (66.30 +/- 9.00 ng/ml on the 3rd pre-septic day), reaching their maximal values of 106.67 +/- 21.66 ng/ml at the end of the observation period. Significant differences between sE-selectin levels of groups I and III existed from the 3rd pre-septic day onwards, and between group II and III on the 7th and 8th day of sepsis. CONCLUSION: Our results show that sICAM-1 is a relatively non-specific indicator for sepsis. In contrast, sE-selectin seems to be a good and early predictor of the beginning of severe sepsis with MOF. Furthermore, sE-selectin levels seem to have a prognostic value for the severity, possible course, and outcome of developing sepsis.

Monocyte deactivation in septic patients: restoration by IFN-gamma treatment.

Neutralization of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) or interleukin-1 (IL-1), decreases mortality in several animal models of sepsis. However, recent clinical trials did not show an unequivocal improvement in survival. In contrast to animals, which succumb to shock during the first 72 hours, we found that many patients die much later with signs of opportunistic infections accompanied by downregulation of their monocytic HLA-DR expression and reduced ability to produce lipopolysaccharide (LPS)-induced TNF-alpha in vitro. This phenomenon of monocyte deactivation in septic patients with fatal outcome shows similarities to experimental monocytic refractoriness induced by LPS desensitization or by pretreatment with its endogenous mediators IL-10 and transforming growth factor-beta (TGF-beta). In order to strengthen their antimicrobial defense, here we tested whether interferon-gamma (IFN-gamma) can improve monocytic functions in these patients and in experimental monocytic deactivation. The considerably lowered in vitro levels of LPS-induced TNF-alpha in these situations were significantly enhanced by IFN-gamma, but did not reach the extremely high levels of IFN-gamma primed naive cells from healthy donors. Moreover, IFN-gamma applied to septic patients with low monocytic HLA-DR expression restored the deficient HLA-DR expression and in vitro LPS-induced TNF-alpha secretion. Recovery of monocyte function resulted in clearance of sepsis in eight of nine patients. These data suggest that IFN-gamma treatment in carefully selected septic patients is a novel therapeutic strategy worth pursuing.

Interferon gamma-1b in the treatment of compensatory anti-inflammatory response syndrome. A new approach: proof of principle.

BACKGROUND: Immunoparalysis is defined as a decrease in the level of HLA-DR expression on monocytes during the course of sepsis. OBJECTIVE: To evaluate whether interferon gamma-1b has an immunoregulatory effect in patients with immunoparalysis during the compensatory anti-inflammatory response syndrome. METHODS: Of the patients admitted consecutively to the intensive care unit for the management of sepsis, 10 received interferon gamma-1b, 100 micrograms per 0.5 mL, after confirmation of HLA-DR expression of less than 30% on 2 consecutive days. The therapy was continued until HLA-DR expression remained more than 50% for 3 days. RESULTS: Interferon gamma-1b therapy resulted in the recovery of diminished levels of HLA-DR expression on monocytes. Of the 10 patients, 8 responded to treatment within 1 day. On the first day of interferon gamma-1b therapy, HLA-DR expression increased from mean (+/- SEM) pretreatment levels of 27% +/- 6% to 62% +/- 8% (P < .01) and remained high during the 28-day study period in 8 patients. The therapy was given to 2 patients a second time when HLA-DR expression on monocytes was less than 30%. The recovery of monocytic HLA-DR expression levels after administration of interferon gamma-1b was associated with restitution of monocytic function, reflected by a significant increase of plasma interleukin-6 (P < .05) and tumor necrosis factor alpha (P < .05) levels in 9 patients. CONCLUSIONS: This study shows that HLA-DR expression is a good marker of compensatory anti-inflammatory response syndrome. It also shows that interferon gamma-1b not only restored the levels of HLA-DR expression but also reestablished the ability of monocytes to secrete the cytokines interleukin-6 and tumor necrosis factor alpha.

[Effect of selenium administration on various laboratory parameters of patients at risk for sepsis syndrome]. / Einfluss einer Selensubstitution auf verschiedene Laborparameter bei sepsisgefährdeten Patienten.

BACKGROUND: Low selenium plasma levels were often measured in ICU patients with polytrauma, major surgery or various severe diseases. Activation of selenium-dependent functions of the antioxidant metabolism and the immune system is suggested to be causally. METHODS: In a prospective randomized clinical trial including 24 critically ill patients we investigated the plasma levels of selenium, malondialdehyde, glutathione, elastase, fT3, fT4, TSH, IL-2R, IL-6 and IL-8 with and without parenteral selenium supplementation for 3 weeks (study design: week 1: twice 500 micrograms daily, week 2: once 500 micrograms, week 3: three times 100 micrograms sodium selenite). RESULTS: Following 24 hours of supplementation selenium plasma levels were normalized. Malondialdehyde level decreased in the therapy group significantly beginning at day 3. In the control group we observed increased malondialdehyde values, a disturbed glutathione metabolism and an elevated elastase activity. fT3-values were diminished at day 0 in all patients. In the therapy group we measured a gradual fT3 restoration. In the control group a reactive TSH increase was observed. Selenium supplementation did not lead to an excessive stimulation of IL-2R, IL-6 or IL-8. CONCLUSIONS: 1. Rapid normalization of selenium plasma levels can be achieved with the applied selenium dosage. 2. Parameters of radical metabolism are significantly reduced following selenium administration. 3. T3 synthesis correlates closely with the selenium levels. 4. Excessive stimulation of the immune system does not appear in the applied dosage.

Monocyte deactivation--rationale for a new therapeutic strategy in sepsis.

Inflammatory cells, in particular monocytes/macrophages, release pro-inflammatory mediators in response to several infectious and non-infectious stimuli. The excessive release of these mediators, resulting in the development of whole body inflammation, may play an important role in the pathogenesis of sepsis and septic shock. TNF-alpha, acting synergistically with cytokines such as IL-1, GM-CSF and IFN-gamma, is the key mediator in the induction process of septic shock, as shown in several experimental models. Based on this concept and on the encouraging results obtained in several experimental models, a number of clinical sepsis trials targeting the production or action of TNF-alpha or IL-1 have been performed in recent years. Unfortunately, these trials have failed to demonstrate a therapeutic benefit. One reason for this may be the lack of exact immunologic analyses during the course of septic disease. Recently, we demonstrated that there is a biphasic immunologic response in sepsis: an initial hyperinflammatory phase is followed by a hypo-inflammatory one. The latter is associated with immunodeficiency which is characterized by monocytic deactivation, which we have called "immunoparalysis". While anti-inflammatory therapy (e.g. anti-TNF antibodies, IL-1 receptor antagonist, IL-10) makes sense during the initial hyperinflammatory phase, immune stimulation by removing inhibitory factors (plasmapheresis) or the administration of monocyte activating cytokines (IFN-gamma, GM-CSF) may be more useful during "immunoparalysis".

Assessment of the safety and efficacy of the monoclonal anti-tumor necrosis factor antibody-fragment, MAK 195F, in patients with sepsis and septic shock: a multicenter, randomized, placebo-controlled, dose-ranging study.

OBJECTIVE: To investigate the safety, biological effects, and efficacy of the anti-tumor necrosis factor (TNF) antibody fragment, MAK 195F, in a phase II trial in patient with severe sepsis. DESIGN: Prospective, randomized, open label, placebo-controlled, dose-ranging, multicenter, multinational clinical trial. SETTING: Sixteen academic medical centers' intensive care units in six European countries. PATIENTS: One hundred twenty-two patients with severe sepsis or septic shock who received standard supportive care and antimicrobial therapy. INTERVENTIONS: Patients received one of three different doses of the anti-TNF antibody (0.1 mg/kg, 0.3 mg/kg, or 1.0 mg/kg) or placebo; the antibody or placebo was given in nine doses at 8-hr intervals over 3 days. MEASUREMENTS AND MAIN RESULTS: There were no significant differences in mortality rates among the groups receiving various doses of the anti-TNF antibody or placebo, but patients with baseline serum interleukin (IL)-6 concentrations of > 1000 pg/mL appeared to benefit from MAK 195F in a dose-dependent fashion. Increased circulating IL-6 concentrations, but not TNF concentrations, were found to be important prognostic indicators for mortality for the patients in the placebo and the two lower dosage groups but not in the high dosage group (1 mg/kg). IL-6 concentrations decreased during the first 24 hrs of treatment in all three anti-TNF groups but not in the placebo group. MAK 195F was well tolerated by all patients. Human antimurine antibodies developed in 40% of the patients receiving the antibody. CONCLUSIONS: There was no increase in survival from sepsis for the patients receiving anti-TNF treatment in the overall study population. Retrospective stratification of patients by IL-6 concentrations suggests beneficial effects of the drug for patients with baseline circulating IL-6 concentrations of > 1000 pg/mL. This hypothesis requires validation in a larger, blinded, prospective study.

Mechanism of endotoxin desensitization: involvement of interleukin 10 and transforming growth factor beta.

Tolerance of monocytes/macrophages to endotoxin (lipopolysaccharide [LPS]) can be induced both in vivo and in vitro by LPS itself. Exposure to LPS, even at a very low dose, induces a downregulation of cytokine response to a second high dose LPS challenge. To learn more about the unknown mechanisms of this phenomenon, we studied the role of antiinflammatory cytokines in this process. Preculture of human peripheral blood monocytes for 24 hours with low concentrations of LPS induced hyporesponsiveness to high-dose LPS rechallenge with respect to tumor necrosis factor (TNF) alpha and interleukin (IL) 10 but not IL-1RA production. These results suggest that LPS tolerance reflects a functional switch of monocytes rather than a general LPS hyporesponsiveness. IL-10 and transforming growth factor (TGF) beta 1 showed additive effects in replacing LPS for induction of LPS hyporesponsiveness in vitro. Additionally, neutralizing anti-IL-10 and anti-TGF-beta monoclonal antibodies prevented induction of LPS tolerance. In vitro induced LPS tolerance looks like the ex vivo LPS hyporesponsiveness of monocytes from septic patients with fatal outcome: downregulation of LPS-induced TNF-alpha and IL-10 production but not of IL-1RA secretion. LPS hyporesponsiveness in septic patients was preceded by expression of IL-10 at both the mRNA and protein level. In summary, our data suggests that IL-10 and TGF-beta mediate the phenomenon of LPS tolerance in vitro and perhaps in vivo (septic patients), too.

[Determination of lipids in serum and erythrocytes during surgery with extracorporeal circulation]. / Lipidbestimmungen in Serum und Erythrozyten während Operationen mit der Herz-Lungen-Maschine

The changes of the lipids in serum and erythrocytes inclusively the fatty acid pattern of the phosphatids were registered at 16 patients of whose congenital heart defects were corrected with extracorporeal circulation. The differently evident changes of the lipid fractions are to relate to heparinization, hemodilution and injury of erythrocytes which is increasing in the duration of perfusion. They are discussed in their importance for clinical essential phenomenous as disturbances of the coagulation or hemolysis. From these preliminary studies is to conclude that the substitution of phosphatids is necessary at the end of or after the extracorporeal circulation.