COVID-19 associated coagulopathy: Mechanisms and host-directed treatment.

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is associated with specific coagulopathy that frequently occurs during the different phases of coronavirus disease 2019 (COVID-19) and can result in thrombotic complications and/or death. This COVID-19-associated coagulopathy (CAC) exhibits some of the features associated with thrombotic microangiopathy, particularly complement-mediated hemolytic-uremic syndrome. In some cases, due to the anti-phospholipid antibodies, CAC resembles catastrophic anti-phospholipid syndrome. In other patients, it exhibits features of hemophagocytic syndrome. CAC is mainly identified by: increases in fibrinogen, D-dimers, and von Willebrand factor (released from activated endothelial cells), consumption of a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13 (ADAMTS13), over activated and dysregulated complement, and elevated plasma cytokine levels. CAC manifests as both major cardiovascular and/or cerebrovascular events and dysfunctional microcirculation, which leads to multiple organ damage. It is not clear whether the mainstay of COVID-19 is complement overactivation, cytokine/chemokine activation, or a combination of these activities. Available data have suggested that non-critically ill hospitalized patients should be administered full-dose heparin. In critically ill, full dose heparin treatment is discouraged due to higher mortality rate. In addition to anti-coagulation, four different host-directed therapeutic pathways have recently emerged that influence CAC: (1) Anti-von Willebrand factor monoclonal antibodies; (2) activated complement C5a inhibitors; (3) recombinant ADAMTS13; and (4) Interleukin (IL)-1 and IL-6 antibodies. Moreover, neutralizing monoclonal antibodies against the virus surface protein have been tested. However, the role of antiplatelet treatment remains unclear for patients with COVID-19.

Physiologic risk factors for early acute kidney injury in severely injured patients.

BACKGROUND: The evaluation of the predictive value of the neutrophil gelatinase-associated lipocalin (NGAL) for an early acute kidney injury (AKI) development in severely injured patients. Determination of the time-dependent roles of trauma-related physiologic markers of tissue hypoxia, systemic inflammation and rhabdomyolysis in AKI development. METHODS: 81 adult patients were screened for the presence of AKI for eight consecutive days following the injury. Arterial levels of plasma NGAL, lactate, interleukin-6, procalcitonin, and myoglobin were investigated at 24 hours (T1), 48 hours (T2), and 96 hours (T3) after the injury. RESULTS: The incidence of AKI was 32.1 %. Patients with AKI were older, but no significant difference in injury severity was observed. NGAL levels were significantly higher in the AKI group at T1, T2, and T3 when compared to the non-AKI group. Lactate levels were significantly higher in the AKI group at T2 only, and IL-6 levels were significantly higher in the AKI group at T2 and T3. Procalcitonin and myoglobin levels were significantly higher in the AKI group at T1, T2, and T3, when compared to the non-AKI group. Positive correlations were found between plasma NGAL and all screened physiological factors at all defined time points. CONCLUSION: Development of AKI after blunt trauma is very complex and multifactorial. Activation of the systemic inflammatory response and rhabdomyolysis (high concentration of myoglobin) were strongly involved in AKI development. Blood NGAL levels after injury were significantly higher in patients, who developed posttraumatic AKI. Plasma NGAL, lactate, procalcitonin, interleukin-6, and myoglobin had potential to be useful parameters for risk stratification and prediction of AKI after trauma (Tab. 6, Ref. 40).

A new definition of sepsis (Sepsis-3) - aims, advantages, and controversies.

Sepsis is a life-threatening condition caused by a dysregulated host response to infection. Over the last decades, the approach to sepsis is evolving dramatically, mainly as a result of a rapid increase in the knowledge of its epidemiology, physiopathology, and management. In this context, the new international criteria and definition for sepsis, The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3), were introduced in 2016. The criteria were established consensually by the Task Force which consisted of experts from the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. The main goal is the expansion of awareness of the professional public about this medical condition with a high fatality rate, particularly when not diagnosed and treated early. Sepsis-3 should also serve as a benchmark for future preclinical and clinical research, development of new diagnostic methods, and the terapy of patients with sepsis and septic shock.

[Alarmins and surgical injury]. / Alarminy a chirurgické trauma.

Surgical intervention is an inseparable part of the management of serious surgical disease. However, surgery also presents a potential risk related to the so-called surgical injury causing immune response. When dysregulated the immune activation is able to cause local complications (i.e. wound dehiscence, impaired healing). Systemic decompartmentization of the immunologic disturbance can negatively influence long-term outcomes (i.e. hospital length of stay, mortality). Due to aseptic conditions in the operating room, such an immune activation is almost always of sterile nature. This involves the release of alarmins, protein-based molecules of the damage-associated molecular patterns family. The group includes e.g. high-mobility group box 1, heat-shock proteins, proteins S100A, and more. Under normal conditions, alarmins fulfil their physiologic intracellular functions. When the cell is stressed and/or damaged, alarmins are released into the extracellular space where they probably play their cytokine-like roles activating preferably the innate immune system. A number of experimental and clinical publications have been published concerning the role of alarmins in various acute and chronic diseases. However, to date a potential relationship between alarmins and surgical injury has not been extensively studied. Identification of alarmins that influence the pathological physiology of surgical trauma might play a role in the improvement of monitoring and predicting outcomes after major surgery.Key words: alarmins immune response major surgery sterile injury.

Individual goal-directed intraoperative fluid management of initially hypovolemic patients for elective major urological surgery.

BACKGROUND: The impact of different approaches to fluid management during intraoperative volume resuscitation in patients undergoing major elective surgery is poorly defined. We compared volume effectiveness of crystalloid and colloid substitution aimed to maintain the cardiac index (CI) between 2.6 and 3.8 l/min/m(2) as measured by transesophageal Doppler (TED). METHODS: A total of 115 urological patients were enrolled in the prospective randomized trial and then randomized into 2 groups, one with volume therapy based on crystalloids (n = 57) and the other with colloids (n = 58). A TED probe was inserted and then hemodynamic optimization (therapy with Ringer's solution or hydroxyethyl starch 6 % 130/0.4 and administration of vasoactive drugs) was started according to TED variables to maintain the CI between 2.6 and 3.8 l/min/m(2). RESULTS: We observed high incidence of CI < 2.6 l/min/m(2) after induction of anesthesia (75 %) in both groups. There were no significant differences in demographic characteristics, ASA classification, length of surgery, estimated blood loss and the CI during surgery. To maintain the CI within the requested interval, significantly different amounts of crystalloids were needed as compared to colloid (median: 5000 ml vs 1500 ml). In the CRY group, more patients were treated by vasodilatators (40.4 vs 20.7 %). CONCLUSIONS: The study confirmed that crystalloids and colloids are effective in correcting flow-related perfusion abnormalities. The significant difference between volumes of crystalloids and colloids proved their different characteristics such as unequal distribution between compartments. The expansion of therapeutic algorithm by using vasoactive drugs allows us to avoid adverse events resulting from fluid overload (Tab. 1, Fig. 5, Ref. 35).

[Serious sepsis treatment in intensive care departments in the Czech Republic -  EPOSS Project pilot results]. / Lécba tezké sepse na pracovistích intenzivní péce v Ceské republice -  pilotní výsledky projektu EPOSS.

INTRODUCTION: Severe sepsis is still associated with significant morbidity and mortality, which is however different, as well as its management, depending on the region. What is the situation in the Czech Republic and what is the character of patients with severe sepsis is currently not known. The aim of the project is to describe the processes of care, outcome and characteristics of patients with severe sepsis admitted to the intensive care department of the Czech Republic. METHODS: This is a multicentre and observational project with retrospective enrollment of patients who meet the criteria for severe sepsis before or within 24 hours after admission to selected intensive care units (ICU EPOSS). RESULTS: 394 patients were analyzed. Median age at admission was 66 (56- 76) years, males predominated (58.9%) and the median APACHE II score on admission was 25 (19- 32). Patients were predominantly medical (56.9%) and most were secondary admitted from other ICU (53.6%). Meeting the criteria of severe sepsis was most frequently within the period (± 4 hours) of admission the EPOSS ICU (77.6%). Median total fluid intake during the first 24 hours was 6,680 (4,840- 9,450) ml. Most patients required mechanical ventilation (58.4%). Compliance with the resuscitation bundle of severe sepsis in our group was very good and was associated with lower mortality of patients. Most frequently, the EPOSS ICU length of stay (LOS) was 7 (3- 15) days and median hospital LOS was 13 (8- 28) days. Hospital mortality in our cohort was 35.8%. CONCLUSION: Introducing the project, which in its first stage obtained valuable and internationally comparable data about patients with severe sepsis admitted to the involved ICU in the Czech Republic.

Exogenous surfactant as a component of complex non-ECMO therapy of ARDS caused by influenza A virus (2009 H1N1).

During the pandemy caused by novel influenza A virus (subgroup H1N1), a significant number of patients became critically ill from respiratory failure. In the most severe cases of primary pneumonia, patients develop refractory hypoxemic acute respiratory distress syndrome (ARDS) with typical computed tomographic findings of multi-lobar alveolar opacities and extremely reduced pulmonary airspace. To reduce the risk of injurious ventilation and promote survival, some authors recommend the use of extracorporeal membrane oxygenation (ECMO). Unfortunately, ECMO is expensive, associated with serious complications, and available at very few centers. Other therapeutic options are clearly needed. Here we report three patients with severe influenza pneumonia who recovered following treatment with porcine surfactant (Tab. 1, Fig. 3, Ref. 6). Full Text in free PDF www.bmj.sk.

[Ventilator-associated pneumonia]. / Ventilátorová pneumonie.

Ventilator-associated pneumonia (VAP) is defined as pneumonia occurring in a patient after intubation with an endotracheal tube or tracheostomy tube lasting for 48 hours or more. It is also one of the most common and fatal infections of patients in ICUs. The diagnostic process in VAP is still underestimated and precise criteria for diagnosis are inconsistent. Delayed diagnosis and subsequent delay in starting appropriate therapy are associated with worse outcomes in patients with VAP. Appropriate dose, adequate route of administration and reasonable length of antibiotic therapy together with de-escalation are the fundamental principles of therapy. Supportive care is also an integral part of the treatment. Implementing preventive procedures according to the local ICU standards is needed for reducing the incidence of VAP effectively.

Thrombolysis and cardiac arrest.

Cardiac arrest (CA) is a serious clinical condition that might be responsible in many cases for death, in other at least for development of irreversible multiple organ dysfunctions. During and after the CA a significant coagulopathy develops causing a decrease in proper tissue perfusion even if an early return of spontaneous circulation (ROSC) is achieved (no-reflow phenomenon). Administration of thrombolytics can solve the problem by destructing the blood clot in both macrocirculation and microcirculation. Results of some clinical trials proving an effectiveness of thrombolysis were published in the literature. Generally, it was done by describing its positive influence on some important clinical outcome measures (24hour survival, number of hospital admissions, better neurological status etc.) without significant increase in the number of bleeding complications. However, recent pivotal evidence based medicine (EBM) trial represented by TROICA study did not confirm the expected positive results. Because of that and also for other reasons (cost, fear of adverse effects, little practice etc.) thrombolysis, although theoretically promising therapeutical intervention, is not overly recommended and used in routine clinical practice in both out-of-hospital and in-hospital settings (Fig. 2, Tab. 4, Ref. 24). Full Text in free PDF www.bmj.sk.

A response to infection in patients with severe sepsis--do we need a "stage-directed therapy concept"?

Excessive forms of the response of organism to infection play an important role in the pathogenesis of severe sepsis. They may consist of either local pro-inflammatory response with a massive release of cytokines into the systemic circulation, or may be presented as an excessive systemic anti-inflammatory response. In the first case, the result is a systemic pro-inflammatory state, characterised by natural stages of the inflammatory response, in which dysfunction of macrocirculation is followed by microcirculation derangement and mitochondrial alteration at the end. These mechanisms are responsible for the development of remote organs failure. The result in the second case is a deactivation of local immunocompetent cells, which results in the risk of uncontrollable growth of microorganisms, especially in organs with an impaired antimicrobial barrier. This may explain the clinically observed recurrence of septic episodes, when a resolution of infection at one site is later replaced with an outbreak of sepsis from another site. A number of therapeutic interventions aimed on the management of causes and consequences of systemic pro-inflammatory state was clinically tested (e.g. antibiotics, goal directed hemodynamic support and inhibitors of coagulation) with surprisingly different effectiveness. The cause of this difference may lie, apart from the frequently discussed inhomogeneity of the studied patient population, also in an incorrect timing of the therapeutic interventions, which does not respect natural stages of the inflammatory response (Fig. 1, Ref. 40).

[Influencing hemostasis in substitute solution treatment]. / Ovlivnení hemostázy pri terapii náhradními roztoky.

Hemostasis is an important intricately regulated homeostatic process. During the hospitalization a critically ill patient is often subjected to various external and internal stimuli which have abilities to influence the hemostasis. Administration of substitute solutions could be related to such an adverse effect. This paper tries to describe main mechanisms leading to impair the hemostatic balance during the fluid therapy and outline possibilities of their monitoring. The work also deals with every basic arteficial substitute solutions individually in term of their influence on coagulation. The goal was as well to point out certain controversial conclusions and problems emerging from the effort of synthesis of all information acquired from clinical publications related to the main topic. Generally it is possible to conclude that all substitutes have a potential to disturb coagulation. Tromboelastography belongs between the most accurate ways to measure coagulation disturbances and has several substantial advantages compared to classic examination. Character and degree of the influence depends on quantity, velocity of administration and type of used solution.

Use of microaerobic conditions for the improvement of anaerobic digestion of solid wastes.

The treatment of solid wastes containing slowly biodegradable compounds or high level of sulphur compounds was carried out. In both cases the application of microaerobic conditions (that means controlled dosing of small amount of air or oxygen into digester) was an efficient tool to increase the biodegradability of treated material and/or to increase the activity of methanogenic bacteria by removal of their inhibitor.

Molecular characterization and phylogenesis of Steganinae (Diptera, Drosophilidae) inferred by the mitochondrial cytochrome c oxidase subunit 1.

The subfamily Steganinae (Diptera, Drosophilidae) includes flies which display zoophilic feeding behaviour in the larval and/or adult stages, some of which act as vectors of Spirurida eyeworms, which infect both carnivores and humans. To date, the taxonomy and phylogeny of the subfamily Steganinae has been studied only superficially and many aspects of their systematics remain unresolved. Thus, the present study aimed to provide a molecular dataset to facilitate the identification and phylogenetic analysis of Steganinae species based on partial ( approximately 700 basepairs) mitochondrial cytochrome c oxidase subunit 1 (cox1) sequences. A total of 134 flies belonging to 13 species and eight genera of Steganinae were subjected to molecular and phylogenetic analyses. The mean nucleotide variation within the Steganinae subfamily was 8.1%, with a variation within genera for which more than one species was examined ranging from 1.6% (in Phortica spp.) to 21.8% (in Amiota spp.). Interspecific pairwise divergence ranged from 1.6% (Phortica variegata vs. Phortica semivirgo) to 24.8% (Cacoxenus indagator vs. Amiota alboguttata) and intraspecific variation ranged from 0% to 1%. Seventy of the 233 amino acids were variable, including 26 parsimony informative sites and 44 singleton sites, with some highly conserved residues identified within the genera Stegana and Amiota. Parsimony and maximum likelihood-based phylogenetic analyses provided strong support for the genus Phortica, phylogenetically distinct from the genus Amiota. Gitona distigma was placed in an unresolved position adjacent to the outgroup taxa, Drosophila yakuba and Drosophila melanogaster. The molecular data reported here represent the first molecular dataset based on cox1 of Steganinae flies and provide a base for further investigations into the evolutionary relationships among this little-studied subfamily.

The zoophilic fruitfly Phortica variegata: morphology, ecology and biological niche.

Flies belonging to the subfamily Steganinae (Drosophilidae) display unusual zoophilic feeding habits at the adult and/or larval stage. Phortica variegata (Fallén) feeds on tears or eye liquid around the eyes of humans and carnivores. When feeding it is a potential vector of Thelazia callipaeda (Railliet and Henry) eyeworms. Adult and larval stages of this fly may be easily confused with other species belonging to the same genus, and little is known on the biology and ecology of P. variegata. In April-November 2005, a total of 969 P. variegata were collected in an area with a high prevalence of canine thelaziosis. The number of flies collected weekly was then related to climatic and environmental parameters (e.g. temperature, relative humidity and total rainfall) recorded daily at the collection site. The highest number of Phortica were collected during July-August. The sex ratio (number of males : females) rose from approximately 0.5 during May-July, to approximately 3.0 in August and 181 during September-October. Distributional data, representing 242 sites at which P. variegata has been collected in Europe, were analysed using a desktop implementation of the genetic algorithm for rule-set prediction (GARP) to model ecological requirements across Europe, as well as in Italy. P. variegata is shown to be mainly active at 20-25 degrees C and 50-75% RH. The ecological niche model suggests with a high degree of confidence that large areas of Europe are likely to represent suitable habitat for this species, mostly concentrated in central Europe. The results reported here contribute basic knowledge on the ecology and geographical distribution of P. variegata flies, which will be fundamental to gaining a better understanding of their role as vectors of human and animal pathogens.

Reconsidering some aspects of the two-trials paradigm.

A common standard for the demonstration of efficacy in a clinical submission is a statistically significant outcome in at least two pivotal trials ("two-trials convention"). When the data structures in different trials are sufficiently similar to allow pooling of the data across trials for a combined analysis, we argue here that such an analysis is a more logical and efficient basis for a judgment regarding efficacy. Criteria for combined analyses may be established, which ensure the same false positive rate protection as the two-trials convention. A combined analysis will generally have much more power than the corresponding application of the two-trials approach that has the same false positive rate protection. In addition, we describe the behavior of modified versions of pure combined analysis, which incorporate a formal standard for reproducibility of trial results by limiting the larger of the individual trial p-values. These modifications are shown to maintain the desirable behavior of the pure combined analysis, namely, higher power compared to the two-trials convention.

Sodium lactate and storage temperature effects on shelf life of vacuum packaged beef top rounds.

Cooked, vacuum-packaged beef top rounds containing up to 4% sodium lactate (NaL) in the final product were stored at 0, 4, 10 or 16°C for 1, 7, 14 or 21 days. Aerobic plate counts (APCs) were lower for roasts containing 3 or 4% NaL and stored at 10°C for 7 days. At higher temperatures and longer storage times, only those treated with 4% NaL were lower than controls. Lipid oxidation, Hunter L* and b* values decreased and Hunter a* values, cooked yields and Ph increased with NaL addition. Beefy odor decreased with storage but was higher in roasts containing NaL. Roasts with added NaL had lower rancid odor scores.