Antithrombin deficiency is associated with mortality and impaired organ function in septic pediatric patients: a retrospective study

Background Sepsis remains a major problem in intensive care medicine. It is often accompanied by coagulopathies, leading to thrombotic occlusion of small vessels with subsequent organ damage and even fatal multi-organ failure. Prediction of the clinical course and outcome—especially in the heterogeneous group of pediatric patients—is difficult. Antithrombin, as an endogenous anticoagulant enzyme with anti-inflammatory properties, plays a central role in controling coagulation and infections. We investigated the relationship between antithrombin levels and organ failure as well as mortality in pediatric patients with sepsis. Methods Data from 164 patients under the age of 18, diagnosed with sepsis, were retrospectively reviewed. Antithrombin levels were recorded three days before to three days after peak C-reactive protein to correlate antithrombin levels with inflammatory activity. Using the concept of developmental haemostasis, patients were divided into groups <1 yr and ≥1 yr of age. Results In both age groups, survivors had significantly higher levels of antithrombin than did deceased patients. An optimal threshold level for antithrombin was calculated by ROC analysis for survival: 41.5% (<1 yr) and 67.5% (≥1 yr). The mortality rate above this level was 3.3% (<1 yr) and 9.5% (≥1 yr), and below this level 41.7% (<1 yr) and 32.2% (≥1 yr); OR 18.8 (1.74 to 1005.02), p = 0.0047, and OR 4.46 (1.54 to 14.89), p = 0.003. In children <1 yr with antithrombin levels <41.5% the rate of respiratory failure (66.7%) was significantly higher than in patients with antithrombin levels above this threshold level (23.3%), OR 6.23 (1.23 to 37.81), p = 0.0132. In children ≥1 yr, both liver failure (20.3% vs 1.6%, OR 15.55 (2.16 to 685.01), p = 0.0008) and a dysfunctional intestinal tract (16.9% vs 4.8%, OR 4.04 (0.97 to 24.08), p = 0.0395) occurred more frequently above the antithrombin threshold level of 67.5%. Conclusion In pediatric septic patients, significantly increased mortality and levels of organ failure were found below an age-dependent antithrombin threshold level. Antithrombin could be useful as a prognostic marker for survival and occurrence of organ failure in pediatric sepsis

Effects of hemostatic interventions on coagulation and sepsis in critically ill patients : [a pilot trial to assess the efficacy of Argatroban (Argatra®) in critically ill patients with Heparin resistance : Argatroban in critically iII patients with HR]

Hintergrund: Thromboembolismus ist eine häufige und schwerwiegende Komplikation bei kritisch kranken Patienten mit einer Inzidenz von 40-80%. Daher ist eine effektive Antikoagulation unerlässlich. Die Standardtherapie für eine kontinuierlich intravenös verabreichte Gabe ist das Unfraktionierte Heparin (UFH). Allerdings entwickeln manche Patienten eine sogenannte Heparinresistenz (HR). HR ist so definiert, dass trotz hoher Dosen von UFH (1.200 IE/h) keine ausreichende Antikoagulation, welche anhand der aktivierten partiellen Thromboplastinzeit (aPTT) gemessen wird, erreicht werden kann. Es gibt keine alternative Medikation, die für diese Indikation registriert ist. Das Ziel dieser Studie ist herauszufinden, ob eine Gabe von Argatroban (Argatra®) besser wirkt als die maximale Dosis von Heparin, auch in Hinblick auf die Zeit bis zu einer adäquaten Antikoagulation. Methode: In die klinische Prüfung wurden 42 auswertbare kritisch kranke Patienten mit einer Heparinresistenz, welche an den Intensivstationen der Allgemeinen und Chirurgischen Intensivmedizin der Medizinischen Universität Innsbruck, Österreich, behandelt wurden, eingeschlossen und entweder in den Behandlungsarm mit der weiteren Gabe der Standardtherapie in Form einer Erhöhung von Heparin bis zur Maximaldosis (Gruppe H) oder in den Behandlungsarm mit dem Wechsel zu Argatroban (Gruppe A) randomisiert. 20 Patienten wurden in die Gruppe H und 22 in die Gruppe A randomisiert. Als Endpunkte waren das Erreichen des aPTT-Zielbereichs von 45-60 Sekunden innerhalb von 8 Stunden (Primärer Endpunkt) und von 24 Stunden (Sekundärer Endpunkt) definiert. Ergebnis: 60% der Patienten in der Gruppe H erreichten den aPTT-Zielbereich nach 8 Stunden, wobei nur 44% die angestrebte aPTT bis 24 Stunden halten konnten. In der Gruppe A konnten 64% den Zielbereich der aPTT innerhalb von 8 Stunden erreichen, nach 24 Stunden waren sogar 91% der Patienten mit einer Argatrobangabe im aPTT-Zielbereich. Der Behandlungserfolg (Primärer Endpunkt) unterschied sich zwischen den beiden Gruppen nicht (p=0.1000, zweiseitiger Exakter Fisher-Test), während nach 24 Stunden (Sekundärer Endpunkt) Argatroban klar im Vorteil war (p=0.0021, zweiseitiger Exakter Fisher-Test). Im Hinblick auf die Häufigkeit von Blutungsereignissen und thromboembolische Komplikationen gab es keinen Unterschied zwischen den beiden Behandlungsarmen. Schlussfolgerung: Die Argatrobangabe erwies sich im Hinblick auf eine ausreichende Antikoagulation innerhalb von 24 Stunden als signifikant überlegen. Die Dauer von 8 Stunden zeigte sich in der klinikspezifischen Routine als zu kurz, um eine bessere Wirksamkeit von Argatroban zu demonstrieren. Dennoch ist Argatroban bei kritisch kranken Pateinten mit einer Heparinresistenz, welche eine Thromboseprophylaxe von mehr als 8 Stunden benötigen, einer weiteren Heparingabe vorzuziehen.Background: Thromboembolism frequently occurs (incidence 40-80%) in critically ill patients. Therefore, a sufficient anticoagulation is crucial. The standard therapy for a continuous intravenous administration of anticoagulants is unfractionated heparin (UFH). However, some critically ill patients develop a so called heparin resistance (HR). HR is present, when, despite a high dose of heparin (1,200 IU/h), a sufficient anticoagulation, measured with the activated partial thromboplastin time (aPTT), cannot be achieved. There is no available anticoagulant registered for this indication. The aim of this study is to investigate, whether the administration of argatroban (Argatra®) is a superior antithrombotic therapy in comparison to a maximum dose of heparin regarding the elapsed time until sufficient anticoagulation. Methods: 42 evaluable critically ill patients with heparin resistance, treated at the General and Surgical Intensive Care Units of the Medical University Innsbruck, Austria, were included and randomized into either treatment with the standard therapy, which is increasing heparin to a maximum dose (group H), or with argatroban (group A). 20 patients were allocated to group H and 22 patients to group A. The endpoints were defined as achieving an aPTT-target range of 45 60 sec within 8 hours (primary endpoint) and 24 hours (secondary endpoint). Results: 60% of group H reached the target aPTT-level within 8 hours, whereas only 44% could maintain the target aPTT for 24 hours. 64% of group A achieved the target aPTT-range within 8 hours and after 24 hours 91% of the argatroban patients reached the target aPTT-level. The treatment success at 8 hours (primary endpoint) did not differ between groups (p=0.1000, two-sided Fishers exact test) whereas at 24 hours (secondary endpoint) group A was significantly superior (p=0.0021, two-sided Fishers exact test) to group H. There was no difference in the occurrence of bleeding events or thromboembolic complications between the treatment arms. Conclusion: Argatroban was superior to heparin in providing an adequate anticoagulation within 24 hours. However, in the clinical setting 8 hours proved to be too short to demonstrate an advantage of argatroban to heparin in achieving the target aPTT-range. Nonetheless, the administration of argatroban is clearly preferable for thromboprophylaxis in critically ill patients with heparin resistance who are in need of anticoagulation for more than 24 hours.Bakk. Biol. Mirjam Bachler, MA. rer.nat.Zusammenfassung in deutscher SpraheAbweichender Titel laut Übersetzung der Verfasserin/des VerfassersMedizinische Universität Innsbruck, Dissertation, 2017OeBB(VLID)221508

Antithrombin and Its Role in Host Defense and Inflammation

Antithrombin (AT) is a natural anticoagulant that interacts with activated proteases of the coagulation system and with heparan sulfate proteoglycans (HSPG) on the surface of cells. The protein, which is synthesized in the liver, is also essential to confer the effects of therapeutic heparin. However, AT levels drop in systemic inflammatory diseases. The reason for this decline is consumption by the coagulation system but also by immunological processes. Aside from the primarily known anticoagulant effects, AT elicits distinct anti-inflammatory signaling responses. It binds to structures of the glycocalyx (syndecan-4) and further modulates the inflammatory response of endothelial cells and leukocytes by interacting with surface receptors. Additionally, AT exerts direct antimicrobial effects: depending on AT glycosylation it can bind to and perforate bacterial cell walls. Peptide fragments derived from proteolytic degradation of AT exert antibacterial properties. Despite these promising characteristics, therapeutic supplementation in inflammatory conditions has not proven to be effective in randomized control trials. Nevertheless, new insights provided by subgroup analyses and retrospective trials suggest that a recommendation be made to identify the patient population that would benefit most from AT substitution. Recent experiment findings place the role of various AT isoforms in the spotlight. This review provides an overview of new insights into a supposedly well-known molecule

Diagnostic Modalities in Critical Care: Point-of-Care Approach

The concept of intensive care units (ICU) has existed for almost 70 years, with outstanding development progress in the last decades. Multidisciplinary care of critically ill patients has become an integral part of every modern health care system, ensuing improved care and reduced mortality. Early recognition of severe medical and surgical illnesses, advanced prehospital care and organized immediate care in trauma centres led to a rise of ICU patients. Due to the underlying disease and its need for complex mechanical support for monitoring and treatment, it is often necessary to facilitate bed-side diagnostics. Immediate diagnostics are essential for a successful treatment of life threatening conditions, early recognition of complications and good quality of care. Management of ICU patients is incomprehensible without continuous and sophisticated monitoring, bedside ultrasonography, diverse radiologic diagnostics, blood gas analysis, coagulation and blood management, laboratory and other point-of-care (POC) diagnostic modalities. Moreover, in the time of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, particular attention is given to the POC diagnostic techniques due to additional concerns related to the risk of infection transmission, patient and healthcare workers safety and potential adverse events due to patient relocation. This review summarizes the most actual information on possible diagnostic modalities in critical care, with a special focus on the importance of point-of-care approach in the laboratory monitoring and imaging procedures

ECMO Predictors of Mortality: A 10-Year Referral Centre Experience

Background: Extracorporeal membrane oxygenation (ECMO) is a specialised life support modality for patients with refractory cardiac or respiratory failure. Multiple studies strived to evaluate the benefits of ECMO support, but its efficacy remains controversial with still inconsistent and sparse information. Methods: This retrospective analysis included patients with ECMO support, admitted between January 2010 and December 2019 at a tertiary university ECMO referral centre in Austria. The primary endpoint of the study was overall all-cause three-month mortality with risk factors and predictors of mortality. Secondary endpoints covered the analysis of demographic and clinical characteristics of patients needing ECMO, including incidence and type of adverse events during support. Results: In total, 358 patients fulfilled inclusion criteria and received ECMO support due to cardiogenic shock (258, 72%), respiratory failure (88, 25%) or hypothermia (12, 3%). In total, 41% (145) of patients died within the first three months, with the median time to death of 9 (1&ndash;87) days. The multivariate analysis identified hypothermia (HR 3.8, p &lt; 0.001), the Simplified Acute Physiology Score III (HR 1.0, p &lt; 0.001), ECMO initiation on weekends (HR 1.6, p = 0.016) and haemorrhage during ECMO support (HR 1.7, p = 0.001) as factors with higher risk for mortality. Finally, the most frequent adverse event was haemorrhage (160, 45%) followed by thrombosis. Conclusions: ECMO is an invasive advanced support system with a high risk of complications. Nevertheless, well-selected patients can be successfully rescued from life-threatening conditions by prolonging the therapeutic window to either solve the underlying problem or install a long-term assist device. Hypothermia, disease severity, initiation on weekends and haemorrhage during ECMO support increase the risk for mortality. In the case of decision making in a setting of limited (ICU) resources, the reported risk factors for mortality may be contemplable, especially when judging a possible ECMO support termination

ICU-Acquired Hypernatremia Is Associated with Persistent Inflammation, Immunosuppression and Catabolism Syndrome

Developing hypernatremia while on intensive care unit (ICU) is a common problem with various undesirable effects. A link to persistent inflammation, immunosuppression and catabolism syndrome (PICS) can be established in two ways. On the one hand, hypernatremia can lead to inflammation and catabolism via hyperosmolar cell stress, and on the other, profound catabolism can lead to hypernatremia via urea-induced osmotic diuresis. In this retrospective single-center study, we examined 115 patients with prolonged ICU stays (&ge;14 days) and sufficient renal function. Depending on their serum sodium concentrations between ICU day 7 and 21, allocation to a hypernatremic (high) and a nonhypernatremic group (low) took place. Distinct signs of PICS were detectable within the complete cohort. Thirty-three of them (28.7%) suffered from ICU-acquired hypernatremia, which was associated with explicitly higher signs of inflammation and ongoing catabolism as well as a prolonged ICU length of stay. Catabolism was discriminated better by the urea generation rate and the urea-to-creatinine ratio than by serum albumin concentration. An assignable cause for hypernatremia was the urea-induced osmotic diuresis. When dealing with ICU patients requiring prolonged treatment, hypernatremia should at least trigger thoughts on PICS as a contributing factor. In this regard, the urea-to-creatinine ratio is an easily accessible biomarker for catabolism

Inflammatory and coagulatory parameters linked to survival in critically ill children with sepsis

Abstract Background Sepsis is associated with a deflection of inflammatory and coagulative parameters, since some clotting factors are known to be involved in the host’s defense against infection and inflammation. These parameters could play a crucial role in the course of sepsis and be used as prognostic markers in critically ill children. Methods A total of 250 critically ill pediatric patients diagnosed with sepsis were retrospectively analyzed to identify routinely measured predictors for in-hospital mortality at the peak level of C-reactive protein. Those parameters entered multivariate logistic regression analysis as well as a decision tree for survival. Results Multivariate logistic regression analysis revealed fibrinogen, platelets and activated partial thromboplastin time (aPTT) at the peak level of C-reactive protein to be predictors for survival (p = 0.03, p = 0.01 and p = 0.02, respectively). An increase in fibrinogen and platelets is linked to survival, whereas an aPTT prolongation is associated with higher mortality; adjusted odds ratios (95% CI) for an increase of 100 mg/dl in fibrinogen are 1.35 (1.04–1.82) per 50 G/l platelets 1.94 (1.3–3.29) and 0.83 (0.69–0.96) for an aPTT prolongation of 10 s. Decision tree analysis shows that a fibrinogen level below 192 mg/dl (90.9% vs. 13% mortality) is most distinctive in non-survivors. Conclusions High levels of fibrinogen and platelets as well as a non-overshooting aPTT are associated with a higher survival rate in pediatric patients with diagnosed sepsis. In particular, hypofibrinogenemia is distinctive for a high mortality rate in septic critically ill children

Additional file 1: Table S1. of Four-factor prothrombin complex concentrate improves thrombin generation and prothrombin time in patients with bleeding complications related to rivaroxaban: a single-center pilot trial

Data are indicated as means (+/−standard deviation). Abbreviations: CRP, C-reactive protein; FI, fibrinogen; immun, immunologic method; ATIII, anti-thrombin III; FIIa, activated blood coagulation factor IIa; FXa, activated blood coagulation factor Xa; FII, blood coagulation factor II; FV, blood coagulation factor V, etc.; vWF, Von Willebrand factor. (DOCX 23 kbr

Comparison of pediatric scoring systems for mortality in septic patients and the impact of missing information on their predictive power: a retrospective analysis

Background Scores can assess the severity and course of disease and predict outcome in an objective manner. This information is needed for proper risk assessment and stratification. Furthermore, scoring systems support optimal patient care, resource management and are gaining in importance in terms of artificial intelligence. Objective This study evaluated and compared the prognostic ability of various common pediatric scoring systems (PRISM, PRISM III, PRISM IV, PIM, PIM2, PIM3, PELOD, PELOD 2) in order to determine which is the most applicable score for pediatric sepsis patients in terms of timing of disease survey and insensitivity to missing data. Methods We retrospectively examined data from 398 patients under 18 years of age, who were diagnosed with sepsis. Scores were assessed at ICU admission and re-evaluated on the day of peak C-reactive protein. The scores were compared for their ability to predict mortality in this specific patient population and for their impairment due to missing data. Results PIM (AUC 0.76 (0.68–0.76)), PIM2 (AUC 0.78 (0.72–0.78)) and PIM3 (AUC 0.76 (0.68–0.76)) scores together with PRSIM III (AUC 0.75 (0.68–0.75)) and PELOD 2 (AUC 0.75 (0.66–0.75)) are the most suitable scores for determining patient prognosis at ICU admission. Once sepsis is pronounced, PELOD 2 (AUC 0.84 (0.77–0.91)) and PRISM IV (AUC 0.8 (0.72–0.88)) become significantly better in their performance and count among the best prognostic scores for use at this time together with PRISM III (AUC 0.81 (0.73–0.89)). PELOD 2 is good for monitoring and, like the PIM scores, is also largely insensitive to missing values. Conclusion Overall, PIM scores show comparatively good performance, are stable as far as timing of the disease survey is concerned, and they are also relatively stable in terms of missing parameters. PELOD 2 is best suitable for monitoring clinical course

Oceanic fronts in the Sargasso Sea control the early life and drift of Atlantic eels

Anguillid freshwater eels show remarkable life histories. In the Atlantic, the European eel (Anguilla anguilla) and American eel (Anguilla rostrata) undertake extensive migrations to spawn in the oceanic Sargasso Sea, and subsequently the offspring drift to foraging areas in Europe and North America, first as leaf-like leptocephali larvae that later metamorphose into glass eels. Since recruitment of European and American glass eels has declined drastically during past decades, there is a strong demand for further understanding of the early, oceanic phase of their life cycle. Consequently, during a field expedition to the eel spawning sites in the Sargasso Sea, we carried out a wide range of dedicated bio-physical studies across areas of eel larval distribution. Our findings suggest a key role of oceanic frontal processes, retaining eel larvae within a zone of enhanced feeding conditions and steering their drift. The majority of the more westerly distributed American eel larvae are likely to follow a westerly/northerly drift route entrained in the Antilles/Florida Currents. European eel larvae are generally believed to initially follow the same route, but their more easterly distribution close to the eastward flowing Subtropical Counter Current indicates that these larvae could follow a shorter, eastward route towards the Azores and Europe. The findings emphasize the significance of oceanic physical–biological linkages in the life-cycle completion of Atlantic eels