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Sildenafil (Viagra), the first approved and widely used oral drug for the treatment of erectile dysfunction, was occasionally associated with life-threatening ventricular arrhythmias in patients. Since inward rectifier potassium current (IK1) may considerably contribute to this arrhythmogenesis, we investigated the effect of sildenafil on the human Kir2.1 and Kir2.2, the prevailing subunits forming the ventricular IK1 channels. Experiments were performed by the whole-cell patch clamp technique at 37°C using Chinese hamster ovary cells transiently expressing the human Kir2.1 and Kir2.2 channels. Changes of both the inward and outward current components (at -110 and -50 mV, respectively) were tested to be able to consider the physiological relevance of the sildenafil effect (changes at -110 and -50 mV did not significantly differ, results at -50 mV are listed below). A significant Kir2.1 inhibition was observed at all applied sildenafil concentrations (16.1% ± 3.7%, 20.0% ± 2.6%, and 15.0% ± 3.0% at 0.1, 1, and 10 µM, respectively). The inhibitory effect of 0.1 µM sildenafil was potentiated by the presence of a low concentration of Ba2+ (0.1 µM) which induced only a slight Kir2.1 inhibition by 5.95% ± 0.75% alone (the combined effect was 35.5% ± 3.4%). The subtherapeutic and therapeutic sildenafil concentrations (0.1 and 1 µM) caused a dual effect on Kir2.2 channels whereas a significant Kir2.2 activation was observed at the supratherapeutic sildenafil concentration (10 µM: 34.1% ± 5.6%). All effects were fully reversible. This is the first study demonstrating that sildenafil at clinically relevant concentrations inhibits both the inward and outward current components of the main human ventricular IK1 subunit Kir2.1. This inhibitory effect was significantly potentiated by a low concentration of environmental contaminant Ba2+ in agreement with recently reported data on rat ventricular IK1 which additionally showed a significant repolarization delay. Considering the similar subunit composition of the human and rat ventricular IK1 channels, the observed effects might contribute to sildenafil-associated arrhythmogenesis in clinical practice. [ABSTRACT FROM AUTHOR]

SepsEast is an enthusiastic intensivists group initiative launched in 2012, with the aim to facilitate clinical and research activities in the region. Through its actions and with the motto «Together we win, divided we are slow!» several joint research projects in the fields of perioperative medicine, fluid therapy, cardiovascular monitoring and support have been conducted. In the light of the COVID-19 pandemic, the SepsEast community is aware of its mission and is ready to take the challenge. This is mirrored by several educational, clinical and research activities including the development of a COVID-19 Registry; and an observational clinical study on cytokine adsorption in COVID-19 patients. The current pandemic should be our lesson on how to manage the global threat of infectious disease and to develop strategies for effective diagnostic and therapeutic procedures. Hopefully, the SepsEast community will contribute to these developments and scientific advances in general. [ABSTRACT FROM AUTHOR]

Background and Aims: The effect in smokers of nicotine withdrawal following surgery may contribute to the development of postoperative delirium. Nicotine is known to increase myocardial oxygen demand, coronary vasoconstriction, and may cause platelet activation leading to thrombosis. All of this can negatively impact postoperative recovery. The aim of this study was to determine whether nicotine replacement therapy can overweigh its negative effects, reduce the incidence of delirium, reduce the need for sedatives/analgesics, and/or shorten the duration of artificial pulmonary ventilation., Methods: This prospective randomized single-blind study was performed in a 21-bed ICU. Fifty-two patients (26 intervention/ 26 control) met the inclusion criteria. Patients in the intervention group received a 21mg nicotine patch daily until discharged from the ICU (up to 7 days), patients in the control group received a placebo patch. The incidence of delirium was monitored with the CAM-ICU test. Sedatives/analgesics used in the ICU, and the duration of both artificial ventilation as well as total ICU stay were recorded for both groups., Results: Nicotine replacement in smokers did not reduce the incidence of delirium in patients who had undergone surgery. Neither did it statistically significantly affect the length of hospitalization, sedation, analgesia, or vasopressors., Conclusion: This study did not confirm the effect of nicotine replacement therapy in reducing the incidence of delirium, it did not shorten the total duration of ICU stay or artificial ventilation and there was no reduced sedation requirement. We therefore saw no beneficial effect in patients receiving nicotine replacement therapy following elective surgery.

The aim of this mini-review is to draw attention to the risk aspects associated with antibiotic treatment in critically ill patients. These include antibiotic underdosing in the early phase of sepsis if treatment is governed by pharmacopoeia and unnecessarily long exposure to antibiotics if treatment is guided by traditional recommendations for the length of antibiotic administration. The need for discussing the loading dose of antibiotics and routine monitoring of serum antibiotic concentrations during treatment is stated. Antibiotic-induced mitochondrial dysfunction and oxidative stress are also discussed. Indeed, both of these mechanisms, otherwise effective in inhibiting the growth of tumor cells, may play an important role in the prolonged course of multiorgan failure if antibiotic treatment is too long.

Therapy of haemorrhagic shock presents a huge challenge nowadays. Changes in circulation and metabolism are preceded with changes in cells, vessels and extracellular fluid. The main disorder takes place in microcirculation. Monitoring of extracellular fluid is possible with microdialysis. This method was verified on animal models and a became base of many clinical examinations in the world. First of all it is monitoring of lactate, pyruvate, glucose and glycerole as main markers of cell metabolism. Tissue condition can be described not only with absolute values but also as relations between individual parameters e.g. lactate/pyruvate and lactate/glucose. These values do not only inform us about forthcoming change from aerobic to anaerobic metabolism but also about the degree of reperfusion. Precious information about mitochondrial dysfunction which is the essence of multiorgan dysfunction in intensive care is collected as well. Based on changes we can asses the quality of resuscitation care together with speed of shock elimination, increasing oxygen delivery and mitochondrial dysfunction treatment.

Anticytokine therapy in sepsis belongs to a subgroup of therapeutic interventions referred to as antiinflammatory or immunomodulatory strategies in the intensive care literature. Between the mid-1980s and the late 1990s, this approach was considered very promising. Against all expectations, it proved ineffective or even harmful in many cases. However, the recent literature is suggestive of a renewed interest in the topic. Therefore, we attempted at a retrospective search for causes of the failure.

Severe sepsis is at present serious medical and social problem. In contrast to many other diseases its incidence shows an upward tendency and so does mortality due to sepsis. From the point of view of pathogenesis the cause of this complaint is a disturbed response to infection. The basis of this disruption is either a huge local inflammation that goes hand in hand with the penetration of proinflammatory cytokines into systemic circulation or an excessive proinflammatory systemic response. In the first instance the consequence is a systemic proinflammatory response accompanied by a disruption of macrocirculation, later also of microcirculation and finally mitochondrial failure. These mechanisms are responsible for the gradual failure of distant organs. In the second instance the consequence is a deactivation of systemic and local immunocompetent cells accompanied by the risk of uncontrolled proliferation of microorganisms. Affected are organs with a disturbed antimicrobial barrier, especially the lungs du ring mechanical ventilation, the bloodstream or the urinary system during catheterization. A large group of selectively acting preparations has been clinically tested in the management of this disorder, but only very few of these preparations were efficacious. We may postulate that the great diversity of the investigated population of patients was responsible for this lack of success.