Functional dependence following intensive care unit-treated sepsis: three-year follow-up results from the prospective Mid-German Sepsis Cohort (MSC).

Background: Surviving sepsis can lead to chronic physical, psychological and cognitive impairments, which affect millions of patients worldwide, including survivors after COVID-19 viral sepsis. We aimed to characterize the magnitude and trajectory of functional dependence and new impairments post-sepsis. Methods: We conducted a prospective cohort study including sepsis survivors who had been discharged from five German intensive care units (ICUs), until 36 months post-discharge. Primary outcome was functional dependence, defined as ≥1 impaired activity of daily living (ADL; 10-item ADL score <100), self-reported nursing care dependence or nursing care level. Secondary outcome was post-sepsis morbidity in the physical, psychological or cognitive domain. We used a multistate, competing risk model to address competing events in the course of dependence, and conducted multiple linear regression analyses to identify predictors associated with the ADL score. Findings: Of 3210 sepsis patients screened, 1968 survived the ICU treatment (61.3%). A total of 753 were included in the follow-up assessments of the Mid-German Sepsis cohort. Patients had a median age of 65 (Q1-Q3 56-74) years, 64.8% (488/753) were male and 76.1% (573/753) had a septic shock. Considering competing risk modelling, the probability of still being functional dependent was about 25%, while about 30% regained functional independence and 45% died within the three years post-sepsis. Patients reported a high burden of new and often overlapping impairments until three years post-sepsis. In the subgroup of three-year survivors (n = 330), new physical impairments affected 91.2% (n = 301) while new cognitive and psychological impairments were reported by 57.9% (n = 191) and 40.9% (n = 135), respectively. Patients with pre-existing functional limitations and higher age were at risk for low ADL scores three years after sepsis. Interpretation: Sepsis survivorship was associated with a broad range of new impairments and led to functional dependence in around one quarter of patients. Targeted measures are needed to mitigate the burden of this Post-Sepsis-Syndrome and increase the proportion of patients that achieve functional improvements. Funding: This work was supported by the Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC) at the Jena University Hospital funded by the German Ministry of Education and Research and by the Rudolf Presl GmbH & Co, Kreischa, Germany.

Passive leg raising test versus rapid fluid challenge in critically ill medical patients.

BACKGROUND: The passive leg raising (PLR) test is a simple test to detect preload responsiveness. However, variable fluid doses and infusion times were used in studies evaluating the effect of PLR. Studies showed that the effect of fluid challenge on hemodynamics dissipates in 10 min. This prospective study aimed to compare PLR and a rapid fluid challenge (RFC) with a 300-ml bolus infused within 5 min in adult patients with a hemodynamic compromise. MATERIALS AND METHODS: Critically ill medical patients with signs of systemic hypoperfusion were included if volume expansion was considered. Hemodynamic status was assessed with continuous measurements of cardiac output (CO), when possible, and mean arterial pressure (MAP) at baseline, during PLR, and after RFC. RESULTS: A total of 124 patients with a median age of 65.0 years were included. Their acute physiology and chronic health evaluation (APACHE) II score was 19.7 ± 6.0, with a sequential organ failure assessment (SOFA) score of 9.0 ± 4.4. Sepsis was diagnosed in 73.3%, and 79.8% of the patients were already receiving a norepinephrine infusion. Invasive MAP monitoring was established in all patients, while continuous CO recording was possible in 42 patients (33.9%). Based on CO changes, compared with those with RFC, the false positive and false negative rates with PLR were 21.7 and 36.8%, respectively, with positive and negative predictive values of 70.6 and 72.0%, respectively. Based on MAP changes, compared with those with RFC, the false positive and false negative rates with PLR compared to RFC were 38.2% and 43.3%, respectively, with positive and negative predictive values of 64.4 and 54.0%, respectively. CONCLUSION: This study demonstrated a moderate agreement between PLR and RFC in hemodynamically compromised medical patients, which should be considered when testing preload responsiveness.

Detection of direct oral anticoagulants with the diluted Russel's viper venom time.

INTRODUCTION: The activity of direct oral anticoagulants (DOAC) is important in acute clinical situations. Recent studies have suggested a strong influence of DOAC on the diluted Russel's Viper Venom Time (dRVVT). Therefore, it may be a suitable screening parameter for antithrombotic plasma activity of different DOAC. This prospective study aims to evaluate the sensitivity and specificity of dRVVT to detect residual DOAC activity at recommended plasma level thresholds. METHODS: A total of 80 patients were recruited, with 20 each treated with one of the four approved DOAC (apixaban, edoxaban, rivaroxaban or dabigatran), respectively. Blood plasma was collected before (baseline), at plasma peak time, and 6 and 12 h after DOAC. DRVVT was measured using the screen (LA1) and confirm (LA2) assay for lupus anticoagulant and compared with DOAC plasma levels. A reference range was calculated based on the dRVVT values of 61 healthy blood donors. RESULTS: All DOAC significantly prolonged the dRVVT especially at higher DOAC plasma levels. The LA1 time ≥41 s had a sensitivity ≥98% to detect edoxaban, dabigatran and rivaroxaban plasma levels ≥30 ng/mL but it was only 87% for apixaban. Sensitivity was ≥98% for all DOAC with the LA2 assay ≥36 s. The negative predictive value of a DOAC plasma level <30 ng/mL and dRVVT LA2 <36 s was 99%. CONCLUSIONS: The dRVVT confirm assay (LA2) reliably detects residual DOAC plasma levels ≥30 ng/mL and could be useful to rapidly rule out relevant DOAC activity in emergency situations and to guide treatment decisions.

Kidney replacement and conservative therapies in rhabdomyolysis: a retrospective analysis.

BACKGROUND: Toxic renal effects of myoglobin following rhabdomyolysis can cause acute kidney injury (AKI) with the necessity of kidney replacement therapy (KRT). Fast elimination of myoglobin seems notable to save kidney function and intensify kidney repair. Clinical data regarding efficacy of KRT in critical care patients with rhabdomyolysis and AKI are limited. This retrospective analysis aimed to identify differences between conservative therapy and different modalities of KRT regarding myoglobin elimination and clinical outcome. METHODS: This systematic, retrospective, single-center study analyzed 328 critical care patients with rhabdomyolysis (myoglobin > 1000 µg/l). Median reduction rate of myoglobin after starting KRT was calculated and compared for different modalities. Multivariate logistic regression models were established to identify potential confounder on hospital mortality. Filter lifetime of the various extracorporeal circuits was analyzed by Kaplan-Meier curves. RESULTS: From 328 included patients 171 required KRT. Health condition at admission of this group was more critical compared to patient with conservative therapy. Myoglobin reduction rate did not differ between the groups (KRT 49% [30.8%; 72.2%] vs. conservative treatment (CT) 61% [38.5%; 73.5%]; p = 0.082). Comparison between various extracorporeal procedures concerning mortality showed no significant differences. Hospital mortality was 55.6% among patients with KRT and 18.5% with CT (p < 0.001). Multivariate logistic regression model identified requirement for KRT (OR: 2.163; CI: 1.061-4.407); p = 0.034) and the SOFA Score (OR: 1.111; CI: 1.004-1.228; p = 0.041) as independent predictive factors for hospital mortality. When comparing specific KRT using multivariate regression, no benefit was demonstrated for any treatment modality. Life span of the extracorporeal circuit was shorter with CVVH compared to that of others (log-Rank p = 0.017). CONCLUSIONS: This study emphasizes that AKI requiring KRT following rhabdomyolysis is accompanied by high mortality rate. Differences in myoglobin reduction rate between various KRTs could not be confirmed, but CVVH was associated with reduced filter lifetime compared to other KRTs, which enable myoglobin elimination, too.

Measurement of recombinant porcine factor VIII in patients with congenital haemophilia A and inhibitors in the presence of emicizumab.

INTRODUCTION: Recombinant porcine factor VIII (rpFVIII) is a treatment option for break-through bleeds in patients with congenital haemophilia A with inhibitors (CHAwI) on emicizumab. However, there are limited data about the measurement of rpFVIII in the presence of emicizumab. AIM: To analyse whether rpFVIII can be measured with a chromogenic assay with bovine component (bCSA) in plasma from CHAwI on emicizumab treatment. METHODS: In the first part of the study, FVIII deficient plasma was spiked with rpFVIII, in the second part, commercial plasma from CHAwI was spiked with emicizumab and rpFVIII, and in the third part, plasma from CHAwI on emicizumab treatment was spiked with rpFVIII. FVIII was then measured with bCSA and a chromogenic assay with human component (hCSA). Thrombin generation (TG) and clot-waveform analysis (CWA) were also carried out. RESULTS: The recovery of rpFVIII measured with bCSA is approximately 80% and is further influenced by the presence of an anti-porcine inhibitor. rpFVIII assessed with hCSA was influenced by emicizumab. CWA and TG showed a weak correlation with baseline emicizumab concentration, but peak thrombin and CWA correlated well with increasing emicizumab concentrations and rpFVIII activities. CONCLUSION: This study indicates that rpFVIII can be measured in the presence of emicizumab with a bCSA. A calibration curve for the measurement of rpFVIII with bCSA should be established.

[Laboratory and calorimetric monitoring of medical nutrition therapy in intensive and intermediate care units : Second position paper of the Section Metabolism and Nutrition of the German Interdisciplinary Association for Intensive Care and Emergency Medicine (DIVI)]. / Laborchemisches und kalorimetrisches Monitoring der medizinischen Ernährungstherapie auf der Intensiv- und Intermediate Care Station : Zweites Positionspapier der Sektion Metabolismus und Ernährung der Deutschen Interdisziplinären Vereinigung für Intensiv- und Notfallmedizin (DIVI).

This second position paper of the Section Metabolism and Nutrition of the German Interdisciplinary Association for Intensive Care and Emergency Medicine (DIVI) provides recommendations on the laboratory monitoring of macro- and micronutrient intake as well as the use of indirect calorimetry in the context of medical nutrition therapy of critically ill adult patients. In addition, recommendations are given for disease-related or individual (level determination) substitution and (high-dose) pharmacotherapy of vitamins and trace elements.

Weight-adjusted dosing of tinzaparin for thromboprophylaxis in obese medical patients.

Background: The optimal dose of tinzaparin for prophylaxis in obese medical patients is not well defined. Objectives: To evaluate the anti-Xa activity in obese medical patients on tinzaparin prophylaxis adjusted for actual bodyweight. Methods: Patients with a body mass index of ≥30 kg/m2 treated with 50 IU/kg tinzaparin once daily were prospectively included. Anti-Xa and anti-IIa activity; von Willebrand factor antigen and von Willebrand activity; factor VIII activity; D-dimer, prothrombin fragments; and thrombin generation were measured 4 hours after subcutaneous injection between days 1 and 14 after the initiation of tinzaparin prophylaxis. Results: We included 121 plasma samples from 66 patients (48.5% women), with a median weight of 125 kg (range, 82-300 kg) and a median body mass index of 41.9 kg/m2 (range, 30.1-88.6 kg/m2). The target anti-Xa activity of 0.2 to 0.4 IU/mL was achieved in 80 plasma samples (66.1%); 39 samples (32.2%) were below and 2 samples (1.7%) above the target range. The median anti-Xa activity was 0.25 IU/mL (IQR, 0.19-0.31 IU/mL), 0.23 IU/mL (IQR, 0.17-0.28 IU/mL), and 0.21 IU/mL (IQR, 0.17-0.25 IU/mL) on days 1 to 3, days 4 to 6, and days 7 to 14, respectively. The anti-Xa activity did not differ among the weight groups (P = .19). Injection into the upper arm compared to the abdomen resulted in a lower endogenous thrombin potential, a lower peak thrombin, and a trend to a higher anti-Xa activity. Conclusion: Dosing of tinzaparin adjusted for actual bodyweight in obese patients achieved anti-Xa activity in the target range for most patients, without accumulation or overdosing. In addition, there is a significant difference in thrombin generation depending on the injection site.

[Thrombotic thrombocytopenic purpura-a differential diagnostic challenge in an emergency]. / Thrombotisch-thrombozytopenische Purpura ­ eine differenzialdiagnostische Herausforderung im Notfall.

Thrombotic thrombocytopenic purpura (TTP), which comprises thrombocytopenia, elevated lactate dehydrogenase levels, and anemia in the combination of organ involvement, is a rare but life-threatening condition associated with an extremely high lethality in the acute phase if left untreated. Using the example of a 49-year-old woman admitted to the hospital with unexplained abdominal symptoms and subfebrile temperatures, recommendations for the emergency situation are presented. Increased awareness of the disease and targeted further diagnostics with determination of the PLASMIC score or ADAMTS13 activity may lead directly to diagnosis of TTP; delayed diagnosis is usually associated with secondary complications.

[Fluid and vasopressor therapy in sepsis]. / Volumen- und vasoaktive Therapie bei Sepsis.

Sepsis is one of the most common and lethal conditions in intensive care medicine. Besides adequate treatment of the infection, timely hemodynamic management is essential to treat tissue hypoperfusion due to sepsis. Adequate fluid resuscitation plays a central role, and this should be carried out with dynamic monitoring of the hemodynamic response. However, a positive fluid balance is associated with poor outcome. Vasopressor therapy is required in case of inadequate response to fluid resuscitation, with norepinephrine considered the first choice. With increasing norepinephrine dose, addition of hydrocortisone or vasopressin may contribute to maintaining the hemodynamic state, although the prognostic advantage of these drugs has not been demonstrated. While dobutamine may be considered in patients with septic cardiomyopathy, the evidence for inotropic therapy in sepsis is limited.

[Coagulation diagnostics in the clinical routine-Part 1 : Evaluation of the risk of bleeding before surgery, interventions and diagnostics in bleeding diathesis]. / Gerinnungsdiagnostik im klinischen Alltag ­ Teil 1 : Evaluation des Blutungsrisikos vor Operationen, Interventionen und Diagnostik bei Blutungsneigung.

This article on coagulation diagnostics is published in two parts covering five common clinical scenarios for coagulation diagnostics. Part 1 deals with the diagnostics prior to invasive interventions and coagulation diagnostics to clarify a tendency to bleeding. The global parameters Quick and activated partial thromboplastin time are established for monitoring certain anticoagulants; however, they are not predictive with respect to the risk of bleeding prior to elective invasive interventions. In this context, disorders of primary hemostasis are frequent, which are insufficiently detected by the global parameters. Most clinical bleeding tendencies are due to acquired causes. These include anticoagulants and diseases which can be accompanied by tendency to bleeding. For coagulation tests preanalytical issues are essential in order to avoid false results. The interpretation should always be made in the context of the current physiological state.

[Coagulation diagnostics in the clinical routine-part 2 : Monitoring of anticoagulation treatment, new-onset thrombocytopenia and thrombophilia]. / Gerinnungsdiagnostik im klinischen Alltag ­ Teil 2 : Überwachung von Antikoagulanzientherapien, neu aufgetretene Thrombozytopenie und Thrombophilie.

Monitoring of vitamin K antagonist treatment with the international normalized ratio (INR) is obligatory, whereas this only applies to direct oral anticoagulants (DOAC) or low molecular weight heparin in the context of selected clinical scenarios. For DOAC the focus is on the determination of trough and peak plasma levels of the drug but for low molecular weight heparins the focus is on anti-Xa activity. The timing of blood sampling in relation to drug intake is essential for the interpretation of the results. A new-onset thrombocytopenia during hospitalization is common. The cause can frequently be identified based on the classification of the underlying disease, the day of onset and documentation of the dynamics of thrombocytopenia as well as the medication history. The importance of thrombophilia testing following a venous thromboembolism has decreased in the absence of clear therapeutic consequences; however, antiphospholipid antibody syndrome must not be overlooked as both the duration of treatment and the choice of anticoagulant depend on this.

[Assessment and technical monitoring of nutritional status of patients in intensive and intermediate care units : Position paper of the Section Metabolism and Nutrition of the German Interdisciplinary Association for Intensive and Emergency Medicine (DIVI)]. / Erfassung und apparatives Monitoring des Ernährungsstatus von Patient*innen auf der Intensiv- und Intermediate Care Station : Positionspapier der Sektion Metabolismus und Ernährung der Deutschen Interdisziplinären Vereinigung für Intensiv- und Notfallmedizin (DIVI).

At the time of admission to an intensive or intermediate care unit, assessment of the patients' nutritional status may have both prognostic and therapeutic relevance with regard to the planning of individualized medical nutrition therapy (MNT). MNT has definitely no priority in the initial treatment of a critically ill patient, but is often also neglected during the course of the disease. Especially with prolonged length of stay, there is an increasing risk of malnutrition with considerable prognostic macro- and/or micronutrient deficit. So far, there are no structured, evidence-based recommendations for assessing nutritional status in intensive or intermediate care patients. This position paper of the Section Metabolism and Nutrition of the German Interdisciplinary Association for Intensive and Emergency Medicine (DIVI) presents consensus-based recommendations for the assessment and technical monitoring of nutritional status of patients in intensive and intermediate care units. These recommendations supplement the current S2k guideline "Clinical Nutrition in Intensive Care Medicine" of the German Society for Nutritional Medicine (DGEM) and the DIVI.

Chest Compression-Related Flail Chest Is Associated with Prolonged Ventilator Weaning in Cardiac Arrest Survivors.

Chest compressions during cardiopulmonary resuscitation (CPR) may be associated with iatrogenic chest wall injuries. The extent to which these CPR-associated chest wall injuries contribute to a delay in the respiratory recovery of cardiac arrest survivors has not been sufficiently explored. In a single-center retrospective cohort study, surviving intensive care unit (ICU) patients, who had undergone CPR due to medical reasons between 1 January 2018 and 30 June 2019, were analyzed regarding CPR-associated chest wall injuries, detected by chest radiography and computed tomography. Among 109 included patients, 38 (34.8%) presented with chest wall injuries, including 10 (9.2%) with flail chest. The multivariable logistic regression analysis identified flail chest to be independently associated with the need for tracheostomy (OR 15.5; 95% CI 2.77−86.27; p = 0.002). The linear regression analysis identified pneumonia (ß 11.34; 95% CI 6.70−15.99; p < 0.001) and the presence of rib fractures (ß 5.97; 95% CI 1.01−10.93; p = 0.019) to be associated with an increase in the length of ICU stay, whereas flail chest (ß 10.45; 95% CI 3.57−17.33; p = 0.003) and pneumonia (ß 6.12; 95% CI 0.94−11.31; p = 0.021) were associated with a prolonged duration of mechanical ventilation. Four patients with flail chest underwent surgical rib stabilization and were successfully weaned from the ventilator. The results of this study suggest that CPR-associated chest wall injuries, flail chest in particular, may impair the respiratory recovery of cardiac arrest survivors in the ICU. A multidisciplinary assessment may help to identify patients who could benefit from a surgical treatment approach.

Outcome After Thrombolysis in Patients With Intermediate High-Risk Pulmonary Embolism: A Propensity Score Analysis.

BACKGROUND: The role of thrombolytic treatment in patients with intermediate high-risk pulmonary embolism (IHR-PE) remains controversial. OBJECTIVES: In this study, we assessed whether systemic thrombolysis decreases hemodynamic decompensation and mortality in a cohort of unselected patients with IHR compared with patients with conventional anticoagulation. METHODS: Between January 2014 and December 2018, 137 patients with IHR-PE were identified among 539 consecutive patients treated for symptomatic PE. In 35 patients (25.5%), systemic thrombolysis was used. Propensity score matching was performed based on 17 pretreatment variables. The primary outcome was hemodynamic decompensation, defined by systolic hypotension, need for catecholamines or signs of end-organ hypoperfusion, and all-cause mortality during hospitalization. Secondary outcomes, such as 1-year survival, and safety outcomes, such as bleeding events, were analyzed. RESULTS: The effects of systemic thrombolysis and anticoagulation were compared in 55 matched patients with IHR-PE (systemic thrombolysis n = 21; anticoagulation n = 34). Thrombolysis was associated with a reduction (0% vs. 31%; p = 0.004) of the primary outcome during hospitalization and a 1-year survival benefit (100% vs. 83.2%; p = 0.036). Severe bleeding events occurred in 4.8% vs. 0% (p = 0.382) and moderate bleeding was observed in 14.3% vs. 7.1% (p = 0.359) in patients with thrombolysis compared with anticoagulation, respectively. CONCLUSIONS: Thrombolysis was associated with a significant reduction of the combined endpoint of hemodynamic decompensation and death during hospitalization and lower all-cause mortality after 1 year in an unselected group of patients with IHR-PE. Further studies are required to improve the therapy of IHR-PE and to identify the subgroup of patients that might benefit from thrombolytic therapy.

Influence of direct oral anticoagulants on thrombin generation on Ceveron TGA.

INTRODUCTION: Monitoring of direct oral anticoagulants (DOACs) with calibrated anti-Xa assay is limited by the high intra- and interindividual variations of the test results. Thrombin generation (TG) is a global hemostatic assay that reflects the patient´s individual coagulation status. The aim of this study was to investigate the influence of DOACs on TG measured with a fully automated assay system. METHODS: All consecutive patients under apixaban and rivaroxaban coming to the outpatient coagulation center MVZ Limbach, Magdeburg, Germany between October 2017 and April 2020 were included. DOAC plasma levels were correlated with TG assessed using the fully automated Ceveron TG analyzer. RESULTS: A total of 703 rivaroxaban and 252 apixaban containing plasma samples were included. There was a significant correlation between DOAC plasma levels and all TG parameters except for lag time regarding apixaban. Time to peak and peak thrombin followed an exponential regression curve, while this was linear for the endogenous thrombin potential (ETP). Apixaban showed a lower correlation coefficient for all TG parameters compared with rivaroxaban, and thrombin generation was less influenced by apixaban than rivaroxaban at plasma levels >100 ng/ml. The sensitivity and negative predictive value of normal TG parameters for the prediction of DOAC plasma levels <30 ng/ml was >85%. CONCLUSION: The present data show a moderate predominantly nonlinear correlation between TG parameters and plasma levels of apixaban and rivaroxaban. Rivaroxaban has a stronger effect on TG than apixaban.

Sepsis Mortality Is high in Patients With Connective Tissue Diseases Admitted to the Intensive Care Unit (ICU).

OBJECTIVES: Patients with connective tissue diseases (CTD) such as systemic lupus erythematosus (SLE) have an increased risk for infections. This study investigated the outcome and characteristics of CTD patients under intensive care unit (ICU) treatment for sepsis. METHODS: A single-center retrospective analysis was conducted and reviewed all patients with a CTD diagnosis admitted to the ICU of a university hospital for sepsis between 2006 and 2019. Mortality was computed and multivariate logistic regression was used to detect independent risk factors for sepsis mortality. Furthermore, the positive predictive value of ICU scores such as Sequential Organ Failure Assessment (SOFA) score was evaluated. RESULTS: This study included 44 patients with CTD (mean age 59.8 ± 16.1 years, 68.2% females), most of them with a diagnosed SLE (61.4%) followed by systemic sclerosis (15.9%). 56.8% (n = 25) were treated with immunosuppressives and 81.8% (n = 36) received glucocorticoids. Rituximab was used in 3 patients (6.8%). The hospital mortality of septic CTD patients was high with 40.9%. It was highest among systemic sclerosis (SSc) patients (85.7%). SOFA score and diagnosis of SSc were independently associated with mortality in multivariate logistic regression (P = 0.004 and 0.03, respectively). The Simplified Acute Physiology Score II (SAPS II), SOFA and Acute Physiology and Chronic Health Evaluation II (APACHE II) scores were good predictors of sepsis mortality in the investigated cohort (SAPS II AUC 0.772, P = 0.002; SOFA AUC 0.756, P = 0.004; APACHE II AUC 0.741, P = 0.007). CONCLUSIONS: In-hospital sepsis mortality is high in CTD patients. SSc diagnoses and SOFA were independently associated with mortality. Additionally, common ICU scores were good predictors for mortality.