Ursula Müller-Werdan

Score-based immunoglobulin G therapy of patients with sepsis : The SBITS study

Objective: Intravenous immunoglobulin as an adjunctive treatment in sepsis was regarded as promising by a Cochrane meta‐analysis of smaller trials. In this phase III multicenter trial, we assessed whether intravenous immunoglobulin G (ivIgG) reduced 28‐day mortality and improved morbidity in patients with score‐defined severe sepsis. Design: Randomized, double‐blind, placebo‐controlled, multicenter trial. Setting: Twenty‐three medical and surgical intensive care units in university centers and large teaching hospitals. Patients: Patients (n = 653) with score‐defined sepsis (sepsis score 12–27) and score‐defined sepsis‐induced severity of disease (Acute Physiology and Chronic Health Evaluation II score 20–35). Interventions: Patients were assigned to receive either placebo or ivIgG (day 0, 0.6 g/kg body weight; day 1, 0.3 g/kg body weight). Measurements and Main Results: The prospectively defined primary end point was death from any cause after 28 days. Prospectively defined secondary end points were 7‐day all‐cause mortality, short‐term change in morbidity, and pulmonary function at day 4. Six hundred fifty‐three patients from 23 active centers formed the intention‐to‐treat group, 624 patients the per‐protocol group (placebo group, n = 303; ivIgG group, n = 321). The 28‐day mortality rate was 37.3% in the placebo group and 39.3% in the ivIgG group and thus not significantly different (p = .6695). Seven‐day mortality was not reduced, and 4‐day pulmonary function was not improved. Drug‐related adverse events were rare in both groups. Exploratory findings revealed a 3‐day shortening of mechanical ventilation in the surviving patients and no effect of ivIgG on plasma levels of interleukin‐6 and tumor necrosis factor receptors I and II. Conclusions: In patients with score‐defined severe sepsis, ivIgG with a total dose of 0.9 g/kg body weight does not reduce mortality.

Impaired energy metabolism in hearts of septic baboons: diminished activities of Complex I and Complex II of the mitochondrial respiratory chain.

Recent findings support the view that the bioenergetic part of septic organ failure is not caused by insufficient supply of oxygen but by disturbances of the mitochondrial function. Therefore, the aim of the present study was to investigate key enzymes of energy metabolism in septic hearts to answer the question whether or not impairment of mitochondrial or glycolytic enzymes occur under these conditions. For this purpose the well established model of septic baboons was used. Baboons under general anesthesia were made septic by infusion of Escherichia coli. Single challenge with infusion of high amounts of bacteria was compared with a multiple challenge protocol (less bacteria infused). Some animals obtained no E. coli (sham). The hearts of the baboons were removed after 72 h (survival: yes) or after death (survival: no) of the animals, frozen in liquid nitrogen, and stored at -80 degrees C until spectrophotometrical measurement of nine mitochondrial and glycolytic enzymes. A reduction of the activity of NADH:cytochrome-c-reductase (Complex I + III) to 67% and succinate:cytochrome-c-reductase (Complex II + III) to 45% was found in the hearts of surviving animals after infusion of high amounts of bacteria. After multiple challenge with lesser amounts of bacteria, no significant changes in enzyme activity were detectable. After lethal septic shock, activities of Complex I + III (12%) and Complex II + III (13%) as well as of phosphofructokinase (16%) were found to be strongly diminished. Decylubiquinol:cytochrome-c-reductase (Complex III, 59%), cytochrome-c-oxidase (51%), succinate dehydrogenase (60%), glucosephosphate isomerase (61%), lactate dehydrogenase (61%), and citrate synthase (120%) were less or unaffected. Similar but less pronounced effects were found after infusion of lesser amounts of bacteria. By means of inhibitor titrations of succinate: cytochrome-c-reductase, it was shown that the loss of activity is not caused by Complex III but by disturbances in Complex II. It is concluded that E. coli-induced sepsis causes decreased activities of Complex I and Complex II in baboon heart mitochondria in a dose-dependent manner.

Impaired regulation of cardiac function in sepsis, SIRS, and MODS.

In sepsis, systemic inflammatory response syndrome (SIRS), and multiorgan dysfunction syndrome (MODS), a severe prognostically relevant cardiac autonomic dysfunction exists, as manifested by a strong attenuation of sympathetically and vagally mediated heart rate variability (HRV). The mechanisms underlying this attenuation are not limited to the nervous system. They also include alterations of the cardiac pacemaker cells on a cellular level. As shown in human atrial cardiomyocytes, endotoxin interacts with cardiac hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels, which mediate the pacemaker current If and play an important role in transmitting sympathetic and vagal signals on heart rate and HRV. Moreover, endotoxin sensitizes cardiac HCN channels to sympathetic signals. These findings identify endotoxin as a pertinent modulator of the autonomic nervous regulation of heart function. In MODS, the vagal pathway of the autonomic nervous system is particularly compromised, leading to an attenuation of the cholinergic antiinflammatory reflex. An amelioration of the blunted vagal activity appears to be a promising novel therapeutic target to achieve a suppression of the inflammatory state and thereby an improvement of prognosis in MODS patients. Preliminary data revealed therapeutic benefits (increased survival rates and improvements of the depressed vagal activity) of the administration of statins, beta-blockers, and angiotensin-converting enzyme inhibitors in patients with MODS.

Autonomic dysfunction in the ICU patient.

The sympathetic-parasympathetic balance may be altered in critically ill patients. Assessment of autonomic function provides information concerning prognosis, pathogenesis, and treatment strategies in ICU-relevant disorders. Proven tools are heart rate variability, baroreflex sensitivity, and, with limitations, cardiac chemoreflex sensitivity. New nonlinear methods are being evaluated that may predict risk more precisely in critically ill patients. This article summarizes application of these tools in the ICU. In addition, a model is introduced for investigating the impaired autonomic function in multiple organ dysfunction syndrome and sepsis, integrating extrinsic mechanisms and factors that are intrinsic to the cardiac tissue. By this combined approach, the authors hope to gain insight into the pathogenesis of multiple organ dysfunction syndrome. New pathophysiologic concepts are needed for the development of treatment strategies for this life-threatening disease.

Endotoxin impairs the human pacemaker current If.

LPSs trigger the development of sepsis by gram-negative bacteria and cause a variety of biological effects on host cells, including alterations on ionic channels. Because heart rate variability is reduced in human sepsis and endotoxemia, we hypothesized that LPS affects the pacemaker current If in human heart, which might-at least in part-explain this phenomenon. Isolated human myocytes from right atrial appendages were incubated for 6 to 10 h with LPS (1 and 10 μg/mL) and afterwards used to investigate the pacemaker current If. If was measured with the whole-cell patch-clamp technique (at 37°C). Incubation of atrial myocytes with 10 μg/mL LPS was found to significantly impair If by suppressing the current at membrane potentials positive to −80 mV and slowing down current activation, but without effecting maximal current conductance. Furthermore, in incubated cells (10 μg/mL), the response of If to β-adrenergic stimulation (1 μM isoproterenol) was significantly larger compared with control cells (shift of half-maximal activation voltage to more positive potentials amounted to −10 and −14 mV in untreated and treated cells, respectively). Simulations using a spontaneously active sinoatrial cell model demonstrated that LPS-induced If impairment reduced the responsiveness of the model cell to fluctuations of autonomic input. This study showed a direct impact of LPS on the cardiac pacemaker current If. The LPS-induced If impairment may contribute to the clinically observed reduction in heart rate variability under septic conditions and in cardiac diseases such as heart failure, where endotoxin can be of pathophysiological relevance.

Divergent Siblings E2F2 and E2F4 but not E2F1 and E2F3 Induce DNA Synthesis in Cardiomyocytes Without Activation of Apoptosis

Proliferation of mammalian cardiomyocytes ceases around birth when a transition from hyperplastic to hypertrophic myocardial growth occurs. Previous studies demonstrated that directed expression of the transcription factor E2F1 induces S-phase entry in cardiomyocytes along with stimulation of programmed cell death. Here, we show that directed expression of E2F2 and E2F4 by adenovirus mediated gene transfer in neonatal cardiomyocytes induced S-phase entry but did not result in an onset of apoptosis whereas directed expression of E2F1 and E2F3 strongly evoked programmed cell death concomitant with cell cycle progression. Although both E2F2 and E2F4 induced S-phase entry only directed expression of E2F2 resulted in mitotic cell division of cardiomyocytes. Expression of E2F5 or a control LacZ-Adenovirus had no effects on cell cycle progression. Quantitative real time PCR revealed that E2F1, E2F2, E2F3, and E2F4 alleviate G0 arrest by induction of cyclinA and E cyclins. Furthermore, directed expression of E2F1, E2F3, and E2F5 led to a transcriptional activation of several proapoptotic genes, which were mitigated by E2F2 and E2F4. Our finding that expression of E2F2 induces cell division of cardiomyocytes along with a suppression of proapoptotic genes might open a new access to improve the regenerative capacity of cardiomyocytes.

Mechanisms of infective endocarditis: pathogen–host interaction and risk states

Patients with infective endocarditis (IE) form a heterogeneous group, ranging from those who are successfully treated with no adverse events, to those with severe complications and a high mortality. In this Review, we highlight pathogen–host interactions and the mechanisms underlying various risk factors for patients with IE. A temporal trend in the pattern of IE has been observed in high-income countries within the past 5 decades, with patients contracting IE at an increasingly old age, and a growing incidence of health-care-associated staphylococcal IE. Consequently, prevention strategies should no longer focus on prophylaxis of streptococcal bacteraemia during dental procedures, but instead encourage a more-general approach to reduce the incidence of health-care-associated IE. Much knowledge has been gained about the mechanisms of vegetation formation, growth, and embolization on damaged or inflamed cardiac valves, and on cardiac devices. Improved understanding of these mechanisms will help to combat the increasing problem of antimicrobial resistance. Two mechanisms of IE should increasingly be the focus of future research: the role of immunosenescence in elderly patients with IE, particularly after transcatheter aortic valve implantation, and the mechanisms that trigger septic shock, a condition that leads to a substantial increase in the risk of death in patients with IE.

Autonomic dysfunction predicts both 1- and 2-month mortality in middle-aged patients with multiple organ dysfunction syndrome.

Objective:Multiple organ dysfunction syndrome (MODS) is a disease entity that carries a high mortality rate. It is characterized by a sequential failure of several organ systems after a trigger event, most commonly sepsis. There is increasing evidence that autonomic dysfunction may substantially contribute to the development of MODS. We recently characterized the spectrum of autonomic dysfunction by using heart rate variability in critically ill MODS patients and were able to show that autonomic dysfunction predicts 28-day mortality in MODS. The aim of the present study was evaluate whether autonomic dysfunction is also a predictor of 180-day and 365-day mortalities. Design:Prospective cohort study. Setting:Twelve-bed medical intensive care unit in a university center. Patients:Ninety consecutively admitted score-defined MODS patients. Interventions:We assessed heart rate variability as a marker of autonomic dysfunction. The patients were followed for 180- and 365-day mortalities. Measurements and Main Results:We prospectively used the heart rate variability variable lnVLF, which predicted 28-day mortality best in the entire cohort of patients, for analysis of longer term mortality. The variable lnVLF was found to be useful for risk prediction for about 60 days, and then the survival curves became nearly parallel. Conclusions:Autonomic function of critically ill MODS patients is blunted, and this attenuation has prognostic implications not merely concerning 28-day mortality but also concerning longer term (about 2-month) mortality.

Statins potently reduce the cytokine‐mediated IL‐6 release in SMC/MNC cocultures

Inflammatory pathways are involved in the development of atherosclerosis. Interaction of vessel wall cells and invading monocytes by cytokines may trigger local inflammatory processes. 3‐Hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors (statins) are standard medications used in cardiovascular diseases. They are thought to have anti‐inflammatory capacities, in addition to their lipid‐lowering effects. We investigated the anti‐inflammatory effect of statins in the cytokine‐mediated‐interaction‐model of human vascular smooth muscle cells (SMC) and human mononuclear cells (MNC). In this atherosclerosis‐related inflammatory model LPS (lipopolysaccharide, endotoxin), as well as high mobility group box 1 stimulation resulted in synergistic (i.e. over‐additive) IL‐6 (interleukin‐6) production as measured in ELISA. Recombinant IL‐1, tumour necrosis factor‐α and IL‐6 mediated the synergistic IL‐6 production. The standard anti‐inflammatory drugs aspirin and indomethacin (Indo) reduced the synergistic IL‐6 production by 60%. Simvastatin, atorvastatin, fluvastatin or pravastatin reduced the IL‐6 production by 53%, 50%, 64% and 60%, respectively. The inhibition by the statins was dose dependent. Combination of statins with aspirin and/or Indo resulted in complete inhibition of the synergistic IL‐6 production. The same inhibitors blocked STAT3 phosphorylation, providing evidence for an autocrine role of IL‐6 in the synergism. MNC from volunteers after 5 day aspirin or simvastatin administration showed no decreased IL‐6 production, probably due to drug removal during MNC isolation. Taken together, the data show that anti‐inflammatory functions (here shown for statins) can be sensitively and reproducibly determined in this novel SMC/MNC coculture model. These data implicate that statins have the capacity to affect atherosclerosis by regulating cytokine‐mediated innate inflammatory pathways in the vessel wall.

Immunoglobulin G treatment of postcardiac surgery patients with score-identified severe systemic inflammatory response syndrome—the Essics study*

Objective:A minority of patients develop severe systemic inflammatory response syndrome (SIRS) with high mortality following cardiopulmonary bypass-assisted cardiac surgery. We assessed whether intravenous immunoglobulin G (ivIgG) improves postoperative short-term (5-day) morbidity and reduces 28-day mortality in these patients. Design:Randomized, double-blind, placebo-controlled, multicenter trial. Setting:Intensive care units of 11 cardiothoracic centers. Patients and interventions:Of 6,984 patients screened, we identified 244 with severe SIRS (Acute Physiology and Chronic Health Evaluation II score ≥28 on the first postoperative day). Interventions:The 244 patients with severe SIRS were randomly assigned to receive an intravenous infusion of either albumin 0.1% (placebo group, 6 mL [6 mg]/kg of body weight on day 1 and 3 mL [3 mg]/kg of body weight on day 2) or immunoglobulin G 10% (ivIgG group, 6 mL [600 mg]/kg of body weight on day 1 and 3 mL [300 mg]/kg of body weight on day 2). Measurements and Main Results:The prospectively defined primary end points were improvement in morbidity on day 5 and death from any cause assessed on day 28. A total of 218 patients received both doses of the study drug (placebo n = 108, ivIgG n = 110). Acute Physiology and Chronic Health Evaluation II scores in the placebo group decreased from 31.8 ± 4.0 (day 1) to 25.8 ± 9.3 (day 5) and in the ivIgG group from 31.8 ± 3.4 (day 1) to 25.9 ± 10.3 (day 5), with no significant difference between the groups (p = .56). The 28-day mortality rate was not significantly different between the groups (per protocol population, placebo group 31.5%, ivIgG group 39.1%; intent-to-treat population, placebo group 37.2%, ivIgG group: 44.7%). No effect of ivIgG on plasma levels of interleukin-6, tumor necrosis factor, and tumor necrosis factor receptor I/II was observed. Drug-related adverse events were rare in both groups. Conclusions:Patients undergoing cardiac surgery (involving cardiopulmonary bypass) who develop severe SIRS derive no improvement in short-term morbidity or 28-day mortality from ivIgG.