Associations of tissue factor and tissue factor pathway inhibitor with organ dysfunctions in septic shock.

Coagulopathy, microvascular alterations and concomitant organ dysfunctions are hallmarks of sepsis. Attempts to attenuate coagulation activation with an inhibitor of tissue factor (TF), i.e. tissue factor pathway inhibitor (TFPI), revealed no survival benefit in a heterogenous group of sepsis patients, but a potential survival benefit in patients with an international normalized ratio (INR) < 1.2. Since an increased TF/TFPI ratio determines the procoagulant activity specifically on microvascular endothelial cells in vitro, we investigated whether TF/TFPI ratio in blood is associated with INR alterations, organ dysfunctions, disseminated intravascular coagulation (DIC) and outcome in septic shock. Twenty-nine healthy controls (HC) and 89 patients with septic shock admitted to a tertiary ICU were analyzed. TF and TFPI in blood was analyzed and related to organ dysfunctions, DIC and mortality. Patients with septic shock had 1.6-fold higher levels of TF and 2.9-fold higher levels of TFPI than HC. TF/TFPI ratio was lower in septic shock compared to HC (0.003 (0.002-0.005) vs. 0.006 (0.005-0.008), p < 0.001). Non-survivors had higher TFPI levels compared to survivors (43038 (29354-54023) vs. 28041 (21675-46582) pg/ml, p = 0.011). High TFPI levels were associated with acute kidney injury, liver dysfunction, DIC and disease severity. There was a positive association between TF/TFPI ratio and troponin T (b = 0.531 (0.309-0.754), p < 0.001). A high TF/TFPI ratio is exclusively associated with myocardial injury but not with other organ dysfunctions. Systemic TFPI levels seem to reflect disease severity. These findings point towards a pathophysiologic role of TF/TFPI in sepsis-induced myocardial injury.

[Recent developments in acute kidney injury : Definition, biomarkers, subphenotypes, and management]. / Neueste Entwicklungen bei der akuten Nierenschädigung : Definition, Biomarker, Subphänotypen und Management.

Acute kidney injury (AKI) is a common problem in critically ill patients and is associated with increased morbidity and mortality. Since 2012, AKI has been defined according to the KDIGO (Kidney Disease Improving Global Outcome) guidelines. As some biomarkers are now available that can provide useful clinical information, a new definition including a new stage 1S has been proposed by an expert group of the Acute Disease Quality Initiative (ADQI). At this stage, classic AKI criteria are not yet met, but biomarkers are already positive defining subclinical AKI. This stage 1S is associated with a worse patient outcome, regardless of the biomarker chosen. The PrevAKI and PrevAKI-Multicenter trial also showed that risk stratification with a biomarker and implementation of the KDIGO bundle (in the high-risk group) can reduce the rate of moderate and severe AKI. In the absence of a successful clinical trial, conservative management remains the primary focus of treatment. This mainly involves optimization of hemodynamics and an individualized (restrictive) fluid management. The STARRT-AKI trial has shown that there is no benefit from accelerated initiation of renal replacement therapy. However, delaying too long might be associated with potential harm, as shown in the AKIKI2 study. Prospective studies are needed to determine whether artificial intelligence will play a role in AKI in the future, helping to guide treatment decisions and improve outcomes.

Anticoagulation with argatroban using hemoclot™ targets is safe and effective in CARDS patients receiving venovenous extracorporeal membrane oxygenation: An exploratory bi-centric cohort study.

Direct thrombin inhibitors, including argatroban, are increasingly used for anticoagulation during venovenous extracorporeal membrane oxygenation (VV ECMO). In many centers activated partial thromboplastin time (aPTT) is used for monitoring, but it can be affected by several confounders. The aim of this study was to evaluate the safety and efficacy of anticoagulation with argatroban titrated according to diluted thrombin time targets (hemoclot™ assay) compared to anti-Xa guided anticoagulation with unfractionated heparin (UFH). METHODS: This cohort study included adults at two tertiary care centers who required VV ECMO for severe COVID-19-related acute respiratory distress syndrome (CARDS). Patients received center-dependent argatroban or UFH for anticoagulation during ECMO. Argatroban was guided following a hemoclot™ target range of 0.4-0.6 µg/ml. UFH was guided by anti-factor Xa (antiXa) levels (0.2-0.3 IU/ml). The primary outcome was safety of argatroban compared to UFH, assessed by time to first clinically relevant bleeding event or death during ECMO. Secondary outcomes included efficacy (time to thromboembolism) and feasibility (proportion of anticoagulation targets within range). RESULTS: From 2019 to 2021 57 patients were included in the study with 27 patients (47 %) receiving argatroban and 30 patients (53 %) receiving UFH. The time to the first clinically relevant bleeding or death during ECMO was similar between groups (HR (argatroban vs. UFH): 1.012, 95 % CI 0.44-2.35, p = 0.978). Argatroban was associated with a decreased risk for thromboembolism compared to UFH (HR 0.494 (95 % CI 0.26-0.95; p = 0.034)). The overall proportion of anticoagulation within target ranges was not different between groups (46 % (23-54 %) vs. 46 % (37 %-57 %), p = 0.45). CONCLUSION: Anticoagulation with argatroban according to hemoclot™ targets (0.4-0.6 µg/ml) compared to antiXa guided UFH (0.2-0.3 IU/ml) is safe and may prolong thromboembolism-free time in patients with severe ARDS requiring VV ECMO.

[Artificial intelligence and acute kidney injury]. / Künstliche Intelligenz und akute Nierenschädigung.

Digitalization is increasingly finding its way into intensive care units and with it artificial intelligence (AI) for critically ill patients. One promising area for the use of AI is in the field of acute kidney injury (AKI). The use of AI is primarily focused on the prediction of AKI, but further approaches are also being used to classify existing AKI into different phenotypes. Different AI models are used for prediction. The area under the receiver operating characteristic curve values (AUROC) achieved with these models vary and are influenced by several factors, such as the prediction time and the definition of AKI. Most models have an AUROC between 0.650 and 0.900, with lower values for predictions further into the future and when applying Acute Kidney Injury Network (AKIN) instead of KDIGO criteria. Classification into phenotypes already makes it possible to categorize patients into groups with different risks of mortality or requirement of renal replacement therapy (RRT), but the etiologies or therapeutic consequences derived from this are still lacking. However, all the models suffer from AI-specific shortcomings. The use of large databases does not make it possible to promptly include recent changes in therapy and the implementation of new biomarkers in a relevant proportion. For this reason, serum creatinine and urinary output, with their known limitations, dominate current AI models for prediction impairing the performance of the current models. On the other hand, the increasingly complex models no longer allow physicians to understand the basis on which the warning of a threatening AKI is calculated and subsequent initiation of therapy should take place. The successful use of AIs in routine clinical practice will be highly determined by the trust of the physicians in the systems and overcoming the aforementioned weaknesses. However, the clinician will remain irreplaceable as the decisive authority for critically ill patients by combining measurable and nonmeasurable parameters.

Outcome of COVID-19 patients treated with VV-ECMO in Tyrol during the pandemic.

INTRODUCTION: A small percentage of patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV­2) showed severe respiratory deterioration requiring treatment with extracorporeal membrane oxygenation (ECMO). During the pandemic surges availability of ECMO devices was limited and resources had to be used wisely. The aim of this analysis was to determine the incidence and outcome of venovenous (VV) ECMO patients in Tyrol, when criteria based on the Extracorporeal Life Support Organization (ELSO) guidelines for VV-ECMO initiation were established. METHODS: This is a secondary analysis of the Tyrol-CoV-ICU-Reg, which includes all patients admitted to an intensive care unit (ICU) during the coronavirus disease 2019 (COVID-19) pandemic in Tyrol. Of the 13 participating departments, VV-ECMO was performed at 4 units at the University Hospital Innsbruck. RESULTS: Overall, 37 (3.4%) of 1101 patients were treated with VV-ECMO during their ICU stay. The hospital mortality rate was approximately 40% (n = 15). Multiorgan failure due to sepsis was the most common cause of death. No significant difference in survival rates between newly initiated and experienced centers was observed. The median survival time of nonsurvivors was 27 days (interquartile range, IQR: 22-36 days) after initiation of VV-ECMO. Acute kidney injury meeting the Kidney Disease: Improving Global Outcomes (KDIGO) criteria occurred in 48.6%. Renal replacement therapy (RRT) was initiated in 12 (32.4%) patients after a median of 18 days (IQR: 1-26 days) after VV-ECMO start. The median length of ICU and hospital stays were 38 days (IQR: 30-55 days) and 50 days (IQR: 37-83 days), respectively. DISCUSSION: Despite a rapidly increased demand and the resulting requirement to initiate an additional ECMO center, we could demonstrate that a structured approach with interdisciplinary collaboration resulted in favorable survival rates similar to multinational reports.

Incidence, risk factors and outcome of acute kidney injury in critically ill COVID-19 patients in Tyrol, Austria: a prospective multicenter registry study.

INTRODUCTION: Acute kidney injury is a frequent complication in critically ill patients with and without COVID-19. The aim of this study was to evaluate the incidence of, and risk factors for, acute kidney injury and its effect on clinical outcomes of critically ill COVID-19 patients in Tyrol, Austria. METHODS: This multicenter prospective registry study included adult patients with a SARS-CoV-2 infection confirmed by polymerase chain reaction, who were treated in one of the 12 dedicated intensive care units during the COVID-19 pandemic from February 2020 until May 2022. RESULTS: In total, 1042 patients were included during the study period. The median age of the overall cohort was 66 years. Of the included patients, 267 (26%) developed acute kidney injury during their intensive care unit stay. In total, 12.3% (n = 126) required renal replacement therapy with a median duration of 9 (IQR 3-18) days. In patients with acute kidney injury the rate of invasive mechanical ventilation was significantly higher with 85% (n = 227) compared to 41% (n = 312) in the no acute kidney injury group (p < 0.001). The most important risk factors for acute kidney injury were invasive mechanical ventilation (OR = 4.19, p < 0.001), vasopressor use (OR = 3.17, p < 0.001) and chronic kidney disease (OR = 2.30, p < 0.001) in a multivariable logistic regression analysis. Hospital and intensive care unit mortality were significantly higher in patients with acute kidney injury compared to patients without acute kidney injury (Hospital mortality: 52.1% vs. 17.2%, p < 0.001, ICU-mortality: 47.2% vs. 14.7%, p < 0.001). CONCLUSION: As in non-COVID-19 patients, acute kidney injury is clearly associated with increased mortality in critically ill COVID-19 patients. Among known risk factors, invasive mechanical ventilation has been identified as an independent and strong predictor of acute kidney injury.

Renal function in very old critically ill patients.

PURPOSE OF REVIEW: Current demographic change leads to higher number of elderly patients admitted to an ICU. Among other organs also the kidneys show age-related changes, which are associated with a decline in various aspects of renal function. The purpose of this review is to provide an overview of structural and functional changes in elderly and also to specifically address the increased risk of acute kidney injury (AKI) in this population. RECENT FINDINGS: Ageing in the kidneys is affected by many different factors, such as low grade chronic inflammation, called inflammageing, and various comorbidities. Nevertheless, a decrease of glomerular filtration rate (GFR) occurs independent of the presence of comorbidities and a steady decline of GFR has been reported in both healthy men and women. Pharmacodynamic of many drugs is altered by these changes. Additionally the rate of diuretic resistance appears to be increased. The cause of AKI occurrence in older age is, multifactorial and includes preventable triggers (hypovolemia, hypotension, nephrotoxins) as well as changes associated with aging. SUMMARY: Age-related alterations of the kidneys were found at microscopic and macroscopic levels of the cell. These changes lead to a reduced renal reserve and subsequently to an increased vulnerability of aged kidneys when an additional stressor is added. Age is an independent risk factor for developing AKI. Physicians should take into account the altered renal function in elderly patients and take renal protective measures at an early stage.

[Hyponatremia : Etiology, diagnosis and acute therapy]. / Hyponatriämie : Ätiologie, Diagnostik und Akuttherapie.

Hyponatremia is one of the most common electrolyte disorders in emergency departments and hospitalized patients. Serum sodium concentration is controlled by osmoregulation and volume regulation. Both pathways are regulated via the release of antidiuretic hormone (ADH). Syndrome of inappropriate release of ADH (SIADH) may be caused by neoplasms or pneumonia but may also be triggered by drug use or drug abuse. Excessive fluid intake may also result in a decrease in serum sodium concentration. Rapid alteration in serum sodium concentration leads to cell swelling or cell shrinkage, which primarily causes neurological symptoms. The dynamics of development of hyponatremia and its duration are crucial. In addition to blood testing, a clinical examination and urine analysis are essential in the differential diagnosis of hyponatremia.

[Acute kidney injury and COVID-19: lung-kidney crosstalk during severe inflammation]. / Akute Nierenschädigung und COVID-19: pulmorenaler Crosstalk unter massiver Inflammation.

Coronavirus disease 2019 (COVID-19)-associated acute kidney injury (AKI) is common in critically ill patients. Renal tropism of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) appears to play only a minor role, whereas the pathological inflammatory response associated with severe COVID-19 is highly relevant. Both the consequences of invasive ventilation and acute respiratory distress syndrome (ARDS) caused by COVID-19 have a significant impact on the pathogenesis of AKI. High ventilation pressures compromise renal perfusion and, thus, may contribute to the development of AKI. The inflammatory response caused by ARDS, as well as the endothelial dysfunction typical of COVID-19 in combination with hypercoagulability are further factors that affect the kidney.

Changes in characteristics and outcomes of critically ill COVID-19 patients in Tyrol (Austria) over 1 year.

BACKGROUND: Widely varying mortality rates of critically ill Coronavirus disease 19 (COVID-19) patients in the world highlighted the need for local surveillance of baseline characteristics, treatment strategies and outcome. We compared two periods of the COVID-19 pandemic to identify important differences in characteristics and therapeutic measures and their influence on the outcome of critically ill COVID-19 patients. METHODS: This multicenter prospective register study included all patients with a SARS-CoV­2 infection confirmed by polymerase chain reaction, who were treated in 1 of the 12 intensive care units (ICU) from 8 hospitals in Tyrol, Austria during 2 defined periods (1 February 2020 until 17 July: first wave and 18 July 2020 until 22 February 2021: second wave) of the COVID-19 pandemic. RESULTS: Overall, 508 patients were analyzed. The majority (n = 401) presented during the second wave, where the median age was significantly higher (64 years, IQR 54-74 years vs. 72 years, IQR 62-78 years, p < 0.001). Invasive mechanical ventilation was less frequent during the second period (50.5% vs 67.3%, p = 0.003), as was the use of vasopressors (50.3% vs. 69.2%, p = 0.001) and renal replacement therapy (12.0% vs. 19.6%, p = 0.061), which resulted in shorter ICU length of stay (10 days, IQR 5-18 days vs. 18 days, IQR 5-31 days, p < 0.001). Nonetheless, ICU mortality did not change (28.9% vs. 21.5%, p = 0.159) and hospital mortality even increased (22.4% vs. 33.4%, p = 0.039) in the second period. Age, frailty and the number of comorbidities were significant predictors of hospital mortality in a multivariate logistic regression analysis of the overall cohort. CONCLUSION: Advanced treatment strategies and learning effects over time resulted in reduced rates of mechanical ventilation and vasopressor use in the second wave associated with shorter ICU length of stay. Despite these improvements, age appears to be a dominant factor for hospital mortality in critically ill COVID-19 patients.