Erkenntnistheorie auf der Intensivstation – Welchen Zweck erfüllt eine Definition?

The adoption of the new sepsis definition in early 2016 introduced a new paradigm for the clinical picture of sepsis. Up until now, sepsis was defined as a systemic inflammatory reaction (systemic inflammatory response syndrome, SIRS) to an infection. Based on a better understanding of the molecular mechanisms, the focus of the new definition is no longer the inflammatory response, but rather the tissue damage and impairment of organ function which this induces. The paradigm thus moves away from the infection and the systemic inflammatory response, and toward that which makes sepsis so dangerous in terms of both disease dynamics and outcome: organ failure due to a dysregulated host response to an infection. This change of perspective or paradigm enables patients with an increased risk of developing sepsis to be recognized and treated earlier in clinical routine, even outside of the intensive care unit. The new definition also promotes development of new treatment strategies with improved ability to treat sepsis causally.     

Propionate induces polymorphonuclear leukocyte activation and inhibits formylmethionyl-leucyl-phenylalanine-stimulated activation.

Short-chain carboxylic acids (SCCA) are metabolic by-products of bacterial pathogens which can alter cytoplasmic pH and inhibit a variety of polymorphonuclear leukocyte (PMN) motile functions. Since cytoskeletal F-actin alterations are central to PMN mobility, in this study we examined the effects of SCCA on cytoskeletal F-actin. Initially, we tested nine SCCA (formate, acetate, propionate, butyrate, valerate, caproate, lactate, succinate, and isobutyrate). We document here that while eight altered cytoplasmic pH, only six altered cytoskeletal F-actin. We then selected one SCCA that altered both F-actin and cytoplasmic pH (propionate) and one SCCA that altered only cytoplasmic pH (lactate) for further study. Propionate, but not lactate, caused an irregular cell shape and F-actin distribution. Furthermore, propionate, but not lactate, inhibited formylmethionyl-leucyl-phenylalanine (fMLP)-stimulated PMN polarization, F-actin localization, and cytoplasmic pH oscillation. Propionate-induced changes in cytoskeletal F-actin and cytoplasmic acidification were not affected by the fMLP receptor antagonist N-t-BOC-1-methionyl-1-leucyl-1-phenylalanine; however, alkalinization was affected. Pertussis toxin treatment completely inhibited propionate-induced changes in F-actin but had no effect on propionate-induced cytoplasmic pH oscillation. These results indicate that propionate (i) bypasses the fMLP receptor and G protein(s) to induce cytoplasmic pH oscillation, (ii) operates through G protein(s) to induce actin oscillation, cell shape changes (to irregular), and F-actin localization, and (iii) inhibits fMLP-stimulated cytoplasmic pH and actin oscillation, PMN polarization, and F-actin localization.     

Effectiveness of a hospital-wide infection control programme on the incidence of healthcare-associated infections and associated severe sepsis and septic shock: a prospective interventional study

Objectives

To evaluate whether a hospital-wide infection control programme (ICP) is effective at reducing the burden of healthcare-associated infections (HAIs) and associated severe sepsis/septic shock or death (severe HAIs).

Ammonium decreases human polymorphonuclear leukocyte cytoskeletal actin.

Ammonium, a weak base produced as a metabolic by-product of urea metabolism by bacterial pathogens, inhibits a variety of motile polymorphonuclear leukocyte (PMN) functions. It was initially assumed that the mechanism of leukocyte inhibition was due to cytoplasmic alkalinization. However, while it is clear that ammonium can effect cytoplasmic alkalinization, current data indicate that alterations in chemotaxis, degranulation, and receptor recycling occur independently of cytoplasmic alkalinization. Since these are motility-related events, we examined the possibility that alterations in cytoskeletal actin may account for the effects of ammonium on PMN function. The results indicate that ammonium can inhibit degranulation, decrease cytoskeletal actin, and increase actin depolymerization rates. These findings are supported by five lines of evidence. First, formylmethionyl-leucyl-phenylalanine (fMLP)-induced elastase release was inhibited by 85% +/- 3% in the presence of ammonium, and ammonium by itself did not stimulate elastase release. Second, ammonium treatment of resting PMNs caused a rapid 38% +/- 6% decrease in cytoskeletal actin. Third, ammonium treatment accelerated the fMLP-induced depolymerization phase of the cytoskeletal actin transient by 150% +/- 12%. Fourth, in resting PMNs treated with cytochalasin B or D, ammonium induced a 21% +/- 4% and a 25% +/- 5% decrease in cytoskeletal actin, respectively. Conversely, ammonium did not affect the ability of the cytochalasins to inhibit an fMLP-induced cytoskeletal actin transient. Fifth, pertussis toxin treatment of neutrophils did not affect the ammonium-stimulated decrease in cytoskeletal actin. These results suggest that ammonium can inhibit neutrophil function by altering cytoskeletal actin and therefore provide new information regarding potential pathogenic mechanisms for bacterial pathogens.     

The acbH gene of Actinoplanes sp. encodes a solute receptor with binding activities for acarbose and longer homologs

Acarbose, a pseudomaltotetraose, is produced by strains of the genus Actinoplanes and is a potent inhibitor of alpha-glucosidases, including those from the human intestine. Therefore, it is used in the treatment of patients suffering from type 2 diabetes. The benefits of acarbose for the producer are not known; however, besides acting as an inhibitor of alpha-amylases secreted by competitors, a role as a 'carbophor' has been proposed. This would require a transport system mediating its uptake into the cytoplasm of Actinoplanes sp. A putative sugar ATP binding cassette (ABC) transport system, the genes of which are included within the biosynthetic gene cluster for acarbose, was suggested to be a possible candidate. The genes acbHFG encode a possible sugar binding protein (AcbH) and two membrane integral subunits (AcbFG). A gene coding for an ATPase component is missing. Since Actinoplanes sp. cannot yet be genetically manipulated we performed experiments to identify the substrate(s) of the putative transporter by assessing the substrate specificity of AcbH. The protein was overproduced in Escherichia coli as His10-fusion protein, purified under denaturating conditions and renatured. Refolding was verified by circular dichroism spectroscopy. Surface plasmon resonance studies revealed that AcbH binds acarbose and longer derivatives, but not maltodextrins, maltose or sucrose. Immunoblot analysis revealed the association of AcbH with the membrane fraction of Actinoplanes cells that were grown in the presence of maltose, maltodextrins or acarbose. Together, these findings suggest that the AcbHFG complex might be involved in the uptake of acarbose and are consistent with a role for acarbose as a 'carbophor'.     

Procalcitonin, C-reactive protein and APACHE II score for risk evaluation in patients with severe pneumonia

Objective   Procalcitonin (PCT) is a peptide that is found elevated in patients with sepsis and severe infections. In healthy persons PCT serum levels are below 0.1 ng/mL. The aim of this study was to investigate the value of serum PCT determination for risk evaluation in patients with pneumonia.
Methods   We focused on the correlation of PCT with the clinical status of the patient and prognosis of the disease. In a prospective study, in a nonsurgical intensive care unit the following parameters were assessed regularly in 93 patients with documented pneumonia: C-reactive protein (CRP), white blood cell count (WBC), body temperature, PCT and Acute Physiology and Chronic Health Evaluation (APACHE) II score.
Results   At the onset of infection 50% of the patients had elevated PCT levels above 2 ng/mL. The model of multivariate analysis of all tested parameters on days 0–5 stratified for clinical outcome (change in clinical classification or death) showed local significance for APACHE II score only. None of the other parameters in this model serves as an isolated indicator for change of clinical status or death. An intra-individual change of body temperature or CRP was never significantly associated with a change in the clinical status of the patient.
Conclusion   Change in PCT on admission and at the end of the observation period significantly indicated a clinical change.     

Regulation of the in vitro monoclonal immunoglobulin production in cultures of peripheral blood mononuclear cells and bone marrow cells from myeloma patients mediated by T cell dependent mitogens

In vitro monoclonal immunoglobulin (mIg) production of cultured tumour cells--prepared from the bone marrow (BM) or from the peripheral blood (PB) of 40 multiple myeloma (MM) patients, 16 patients with monoclonal gammopathy of undetermined significance and two patients with M. Waldenström--was measured with an enzyme-linked immunosorbent assay (ELISA) using anti-idiotype and anti-class specific antisera. After in vitro stimulation with pokeweed mitogen (PWM) or OKT3 antibody, mIg production was regularly suppressed in BM cell cultures, whereas enhanced, unaltered or suppressed production was observed in PB cell cultures. These observations show that the expanded clone in MM can still be regulated in vitro. Separation experiments demonstrated the involvement of T cells in this in vitro system. The results could be explained by the hypothesis that activated T cells can suppress mature cells of B cell differentiation, as found in BM of the patients, but stimulate earlier B cells from the peripheral blood towards differentiation into Ig secreting cells.     

Aktuelle Aspekte zur Definition und Diagnostik der Sepsis und Antibiotikaresistenz

Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz - Die Krankenhaussterblichkeit von Patienten mit sekundärer Sepsis ist mit ca. 40 % unverändert hoch....     

Procalcitonin in patients undergoing cardiopulmonary bypass in open heart surgery - first results of the Procalcitonin in Heart Surgery study (ProHearts)

Objective: To investigate procalcitonin (PCT) levels in patients undergoing cardiopulmonary bypass (CPB) in order to assess the prevalence and prognostic capacity of elevated PCT levels following CPB in open heart surgery.¶Design: prospective observational study in consecutive patients.¶Setting: Twenty-four-bed ICU, department of thoracic and cardiovascular surgery, university hospital.¶Patients: Seven hundred and twenty two patients, 691 of whom underwent CPB, i. e., 476 had coronary bypass surgery (CABG), 130 valve replacement, 34 combined CABG and valve replacement, and 23 thoracic aortic surgery.¶Interventions: Standard perfusion techniques were used with cardioplegic arrest and mild hypothermia (28-32 °C). With the exception of thoracic aortic procedures, full-flow perfusion was performed.¶Measurements and results: PCT was measured prior to surgery and daily thereafter until ICU discharge or death. PCT significantly increased at day 1 postoperatively compared to baseline values (0.25 - 1.65 vs 6.49 - 22.0 ng/ml, p < 0.005). However, in 55.1 % of patients PCT was below 1.0 ng/ml. In 12.8 % of CABG patients PCT was increased to > 5.0 ng/ml, compared to 39 % in valve patients and 35 % of patients with aortic surgery. An elevated PCT level > 1.0-5.0 ng/ml at day 1 was highly predictive of mortality (P < 0.03, vs < 1.0 ng/ml), with an additional accuracy when levels > 5.0 ng/ml were measured (P < 0.002 vs < 1.0 ng/ml).¶Conclusions: These results provide evidence that PCT might serve as an early prognostic marker in patients undergoing CPB in open heart surgery. It may be worth considering immunomodulating approaches in patients presenting elevated PCT levels in the early phase after CPB.