Validation of the time to attain maximal clot amplitude after reaching maximal clot formation velocity parameter as a measure of fibrinolysis using rotational thromboelastometry and its application in the assessment of fibrinolytic resistance in septic patients: a prospective observational study: communication from the ISTH SSC Subcommittee on Fibrinolysis.

BACKGROUND: In sepsis, fibrinolysis resistance correlates with worse outcomes. Practically, rotational thromboelastometry (ROTEM) is used to report residual clot amplitude relative to maximum amplitude at specified times after clot formation clot lysis indices (CLIs). However, healthy individuals can exhibit similar CLIs, thus making it challenging to solely diagnose the low fibrinolytic state. Furthermore, CLI does not include the kinetics of clot formation, which can affect overall fibrinolysis. Therefore, a more nuanced analysis, such as time to attain maximal clot amplitude after reaching maximal clot formation velocity (t-AUCi), is needed to better identify fibrinolysis resistance in sepsis. OBJECTIVES: To evaluate the correlation between the degree of fibrinolytic activation and t-AUCi in healthy or septic individuals. METHODS: Whole blood (n = 60) from septic or healthy donors was analyzed using tissue factor-activated (EXTEM) and nonactivated (NATEM) ROTEM assays. Lysis was initiated with tissue-type plasminogen activator, and CLI and t-AUCi were calculated. Standard coagulation tests and plasma fibrinolysis markers (D-dimer, plasmin-α2-antiplasmin complex, plasminogen activator inhibitor type 1, and plasminogen) were also measured. RESULTS: t-AUCi values decreased with increasing fibrinolytic activity and correlated positively with CLI for different degrees of clot lysis both in EXTEM and NATEM. t-AUCi cutoff value of 1962.0 seconds in EXTEM predicted low fibrinolytic activity with 81.8% sensitivity and 83.7% specificity. In addition, t-AUCi is not influenced by clot retraction. CONCLUSION: Whole-blood point-of-care ROTEM analyses with t-AUCi offers a more rapid and parametric evaluation of fibrinolytic potential compared with CLI, which can be used for a more rapid and accurate diagnosis of fibrinolysis resistance in sepsis.

Nociception Control of Bilateral Single-Shot Erector Spinae Plane Block Compared to No Block in Open Heart Surgery-A Post Hoc Analysis of the NESP Randomized Controlled Clinical Trial.

Background and Objectives: The erector spinae plane block (ESPB) is an analgesic adjunct demonstrated to reduce intraoperative opioid consumption within a Nociception Level (NOL) index-directed anesthetic protocol. We aimed to examine the ESPB effect on the quality of intraoperative nociception control evaluated with the NOL index. Materials and Methods: This is a post hoc analysis of the NESP (Nociception Level Index-Directed Erector Spinae Plane Block in Open Heart Surgery) randomized controlled trial. Eighty-five adult patients undergoing on-pump cardiac surgery were allocated to group 1 (Control, n = 43) and group 2 (ESPB, n = 42). Both groups received general anesthesia. Preoperatively, group 2 received bilateral single-shot ESPB (1.5 mg/kg/side 0.5% ropivacaine mixed with dexamethasone 8 mg/20 mL). Until cardiopulmonary bypass (CPB) was initiated, fentanyl administration was individualized using the NOL index. The NOL index was compared at five time points: pre-incision (T1), post-incision (T2), pre-sternotomy (T3), post-sternotomy (T4), and pre-CPB (T5). On a scale from 0 (no nociception) to 100 (extreme nociception), a NOL index > 25 was considered an inadequate response to noxious stimuli. Results: The average NOL index across the five time points in group 2 to group 1 was 12.78 ± 0.8 vs. 24.18 ± 0.79 (p < 0.001). The NOL index was significantly lower in the ESPB-to-Control group at T2 (12.95 ± 1.49 vs. 35.97 ± 1.47), T3 (13.28 ± 1.49 vs. 24.44 ± 1.47), and T4 (15.52 ± 1.49 vs. 34.39 ± 1.47) (p < 0.001) but not at T1 and T5. Compared to controls, significantly fewer ESPB patients reached a NOL index > 25 at T2 (4.7% vs. 79%), T3 (0% vs. 37.2%), and T4 (7.1% vs. 79%) (p < 0.001). Conclusions: The addition of bilateral single-shot ESPB to general anesthesia during cardiac surgery improved the quality of intraoperative nociception control according to a NOL index-based evaluation.

Nociception Level Index-Directed Erector Spinae Plane Block in Open Heart Surgery: A Randomized Controlled Clinical Trial.

Background and Objectives: The erector spinae plane block (ESPB) is a multimodal opioid-sparing component, providing chest-wall analgesia of variable extent, duration, and intensity. The objective was to examine the ESPB effect on perioperative opioid usage and postoperative rehabilitation when used within a Nociception Level (NOL) index-directed anesthetic protocol. Materials and Methods: This prospective, randomized, controlled, open-label study was performed in adult patients undergoing on-pump cardiac surgery in a single tertiary hospital. Eighty-three adult patients who met eligibility criteria were randomly allocated to group 1 (Control, n = 43) and group 2 (ESPB, n = 40) and received general anesthesia with NOL index-directed fentanyl dosing. Preoperatively, group 2 also received bilateral single-shot ultrasound-guided ESPB (1.5 mg/kg/side 0.5% ropivacaine mixed with dexamethasone 8 mg/20 mL). Postoperatively, both groups received intravenous paracetamol (1 g every 6 h). Morphine (0.03 mg/kg) was administered for numeric rating scale (NRS) scores ≥4. Results: The median (IQR, 25th−75th percentiles) intraoperative fentanyl and 48 h morphine dose in group 2-to-group 1 were 1.2 (1.1−1.5) vs. 4.5 (3.8−5.5) µg·kg−1·h−1 (p < 0.001) and 22.1 (0−40.4) vs. 60.6 (40−95.7) µg/kg (p < 0.001). The median (IQR) time to extubation in group 2-to-group 1 was 90 (60−105) vs. 360 (285−510) min (p < 0.001). Two hours after ICU admission, 87.5% of ESPB patients were extubated compared to 0% of controls (p < 0.001), and 87.5% were weaned off norepinephrine compared to 46.5% of controls (p < 0.001). The median NRS scores at 0, 6, 12, 24, and 48 h after extubation were significantly decreased in group 2. There was no difference in opioid-related adverse events and length of stay. Conclusions: NOL index-directed ESPB reduced intraoperative fentanyl by 73.3% and 48 h morphine by 63.5%. It also hastened the extubation and liberation from vasopressor support and improved postoperative analgesia.

Cirrhotic Cardiomyopathy-A Veiled Threat.

Cirrhotic cardiomyopathy (CCM) is defined as cardiac dysfunction in patients with liver cirrhosis without preexisting cardiac disease. According to the definition established by the World Congress of Gasteroenterology in 2005, the diagnosis of CCM includes criteria reflecting systolic dysfunction, impaired diastolic relaxation, and electrophysiological disturbances. Because of minimal or even absent clinical symptoms and echocardiographic signs at rest according to the 2005 criteria, CCM diagnosis is often missed or delayed in most clinically stable cirrhotic patients. However, cardiac dysfunction progresses in time and contributes to the pathogenesis of hepatorenal syndrome and increased morbidity and mortality after liver transplantation, surgery, or other invasive procedures in cirrhotic patients. Therefore, a comprehensive cardiovascular assessment using newer techniques for echocardiographic evaluation of systolic and diastolic function, allowing the diagnosis of CCM in the early stage of subclinical cardiovascular dysfunction, should be included in the screening process of liver transplant candidates and patients with cirrhosis in general. The present review aims to summarize the most important pathophysiological aspects of CCM, the usefulness of contemporary cardiovascular imaging techniques and parameters in the diagnosis of CCM, the current therapeutic options, and the importance of early diagnosis of cardiovascular impairment in cirrhotic patients.

The effect of a viscoelastic-guided bleeding algorithm implementation on blood products use in adult liver transplant patients. A propensity score-matched before-after study.

BACKGROUND: Perioperative blood products transfusion is correlated with increased morbidity and mortality in liver transplantation (LTx). The objectives of our study are to assess the effect of a standardized viscoelastic test (VET)-guided bleeding management algorithm implementation on intraoperative bleeding, allogenic blood products and factor concentrates requirements and on early postoperative complications in LTx. METHODS: Retrospective before-after study comparing two matched cohorts of patients undergoing LTx before (control cohort) and after (intervention cohort) the implementation of a VET-based bleeding algorithm in a single center academic hospital. RESULTS: After propensity score matching, we included 94 patients in each cohort. Patients in intervention cohort received significantly less blood products, fresh frozen plasma (FFP), and cryoprecipitate (p < 0.001 for each), while the amount of fibrinogen concentrate used was significantly higher (p < 0.001). Postoperatively, intervention cohort patients had significantly lower postoperative hemoglobin and fibrinogen levels and longer prothrombin time compared to control cohort. There were no significant differences in red blood cells transfusions, intraoperative bleeding, early postoperative complications, and short term survival. CONCLUSIONS: The implementation of a VET-guided bleeding algorithm decreases allogenic blood products requirements, mainly FFP use and allows a more restrictive management of coagulopathy in patients with chronic liver disease undergoing LTx.

Lidocaine effects on coagulation assessed by whole blood rotational thromboelastometry.

Lidocaine may be beneficial when added in solutions for the preservation of vascular grafts or solid organs as it has anti-inflammatory, endothelial protective, and antithrombotic effects. However, the mechanisms of lidocaine-induced changes in hemostasis were not elucidated until now. The aim of the study was to examine the effect of increasing concentrations of lidocaine on coagulation parameters and blood-clotting kinetics using velocity curves of clot formation assessed by rotational thromboelastometry. Ex-vivo blood coagulation using whole blood from healthy volunteers was studied with rotational thromboelastometry. For each volunteer, four assays were performed: saline control and samples with lidocaine end blood concentrations of 0.3, 0.6, and 0.9%. In this in-vitro study, whole blood from 15 healthy volunteers was used. Lidocaine concentration of 0.3% prolonged the initiation phase of clotting without significant differences in the propagation phase or clot stability and inhibited clot lysis compared with the control group. Higher lidocaine concentrations (0.6 and 0.9%) resulted in prolongation of both initiation and propagation phases and decreased clot firmness compared with the control group. Lysis was significantly increased only in the 0.6% lidocaine group compared with control. Although lidocaine concentration of 0.3% only delays coagulation initiation, the 0.6% concentration inhibits all phases of hemostasis and increases clot lysis compared with control. Higher lidocaine concentration results in very weak clot formation with very low lysis visible on thromboelastometry. More research is needed to explain the effects of lidocaine on clotting kinetics.

Aggressive surgical approach in patients with adrenal-only metastases from hepatocellular carcinoma enables higher survival rates than standard systemic therapy.

BACKGROUND: Although guidelines recommend systemic therapy even in patients with limited extrahepatic metastases from hepatocellular carcinoma (HCC), a few recent studies suggested a potential benefit for resection of extrahepatic metastases. However, the benefit of adrenal resection (AR) for adrenal-only metastases (AOM) from HCC was not proved yet. This is the first study to compare long-term outcomes of AR to those of sorafenib in patients with AOM from HCC. METHODS: The patients with adrenal metastases (AM) from HCC were identified from the electronic records of the institution between January 2002 and December 2018. Those who presented AM and other sites of extrahepatic disease were excluded. Furthermore, the patients with AOM who received other therapies than AR or sorafenib were excluded. RESULTS: A total of 34 patients with AM from HCC were treated. Out of these, 22 patients had AOM, 6 receiving other treatment than AR or sorafenib. Eventually, 8 patients with AOM underwent AR (AR group), while 8 patients were treated with sorafenib (SOR group). The baseline characteristics of the two groups were not significantly different in terms of age, sex, number and size of the primary tumor, timing of AM diagnosis, Child-Pugh and ECOG status. After a median follow-up of 15.5 months, in the AR group, the 1-, 3-, and 5-year overall survival rates (85.7%, 42.9%, and 0%, respectively) were significantly higher than those achieved in the SOR group (62.5%, 0% and 0% at 1-, 3- and 5-year, respectively) (P = 0.009). The median progression-free survival after AR (14 months) was significantly longer than that after sorafenib therapy (6 months, P = 0.002). CONCLUSIONS: In patients with AOM from HCC, AR was associated with significantly higher overall and progression-free survival rates than systemic therapy with sorafenib. These results could represent a starting-point for future phase II/III clinical trials.

Standard and derived rotational thromboelastometry parameters for prediction of disseminated intravascular coagulation in septic patients.

: Waiting for lab tests results for the calculation of disseminated intravascular coagulation (DIC) scores leads to unwanted delays in diagnosis. The use of rotational thromboelastometry (ROTEM) for this purpose would allow for a more rapid DIC diagnosis at the bedside. The aim of this study was to assess the ability of standard ROTEM parameters and calculated parameters from the ROTEM velocity curve to predict DIC. The retrospective observational study included 97 septic patients. Japanese Association for Acute Medicine score was used for DIC diagnosis and whole-blood ROTEM was performed at study inclusion. Univariate analysis revealed delayed coagulation initiation and propagation and reduced clot firmness and maximum elasticity in DIC patients compared with patients without DIC. To adjust for confounders, multivariable logistic regression models were created and fibrinogen levels, prothrombin time and ROTEM parameters such as maximum clot firmness, maximum clot elasticity (MCE) and total thrombus formation [area under the curve (AUC)] were identified as significant predictors of DIC. According to receiver operating characteristics analysis, MCE and total thrombus formation (AUC) were the most useful ROTEM parameters for DIC prediction. MCE less than 158 (73% sensitive, 80% specific) and AUC less than 6175 mm × 100 (73% sensitive, 76% specific) predicted DIC in septic patients. Both standard and derived ROTEM parameters are useful for rapid DIC prediction in septic patients, allowing the timely identification of patients with higher mortality risk which might benefit from additional therapies. Further studies are needed to assess the clinical relevance of these findings.

Can goal-directed fluid therapy decrease the use of blood and hemoderivates in surgical patients?

The purpose of goal-directed therapy (GDT) is to improve patient outcome by the optimization of hemodynamic status, as it is considered that many perioperative complications are related to microcirculatory disturbance due to an imbalance between oxygen delivery and consumption. The application of GDT protocols incorporating the assessment and optimization of patients' intravascular status should theoretically lead to a reduction in perioperative bleeding and transfusion requirements, as both hypervolemia and hypovolemia and their consequences such as dilutional coagulopathy, anemia and inadequate oxygen delivery to the tissues are avoided. However, the research reporting decreased usage of blood products in patients which received targeted fluid management is sparse; decreased blood loss and transfusion requirements were reported in spine surgery using GDT, while studies in abdominal or cardiac surgery did not consistently report significant decreases in blood products transfusion when GDT were applied. These heterogenous results reported can be explained by the differences between the GDT protocols used, as the differences in therapeutic goals can impact on blood transfusion requirements. In the future, the GDT protocols should include not only the prediction of fluid responsiveness and optimization of hemodynamic status, but also the assessment of microcirculation and measures to improve tissue oxygenation, parameters which can also guide the decision for blood product transfusion. A better standardization of GDT algorithms is also required in order to perform a more accurate assessment of the effects of applying GDT on the consumption of blood products.

Thromboelastometric prediction of mortality using the kinetics of clot growth in critically ill septic patients.

: Sepsis induces alterations in blood coagulation which are associated with mortality. Using rotational thromboelastometry (ROTEM), these states are often characterized by changes in parameters representing terminal clot lysis. However, the ROTEM changes are often subtle, making them difficult to recognize and interpret. The objective of this study is to evaluate a new ROTEM clot velocity parameter representing clot formation kinetics in septic ICU patients. We hypothesized that this time-based parameter was significantly different in critically ill septic survivors vs. nonsurvivors. This retrospective observational study included severe sepsis and septic shock patients having a minimum of two organ dysfunctions by Sequential Organ Failure Assessment criteria (study group), and a control group of healthy adults without infection . ROTEM with EXTEM activation was performed in all groups. The time from maximal clot formation velocity to zero velocity, representing the latter portion of time during active clot formation prior to achieving maximal clot firmness (t-AUCi) was calculated along with other ROTEM parameters and compared between septic survivors, nonsurvivors and healthy controls. A total of 76 septic patients, of which 26.3%, survived, were included in the study group, and 26 healthy control individuals were included in the control group. t-AUCi correlated with terminal clot lysis (P < 0.001), and was significantly prolonged in septic nonsurvivors compared with survivors and healthy controls (P < 0.001). t-AUCi also differentiated nonsurvivors vs. survivors among those patients having similar ROTEM lysis indices. t-AUCi was useful to differentiate critically ill septic patients, and could be useful to identify septic patients with high-risk of ICU mortality.

Effects of malignancy on blood coagulation in septic intensive care patients.

: The objectives of the study are to examine the effect of sepsis on the coagulation profile of patients having solid cancer and to test the hypothesis that septic patients with cancer have normal or increased hemostatic capacity despite prolonged standard coagulation tests (SCTs) compared with noninfected cancer patients. Patients with solid cancer were included in the study forming two groups: study group included patients with sepsis with minimum two organ dysfunctions and control group formed by noninfected cancer patients. SCTs, platelet count, plasma levels of coagulation factors and rotation thromboelastometry (TEM International GmbH, Munich, Germany) were determined in both groups. Study group patients (n = 35) showed prolonged SCTs, thrombocytopenia, decreased coagulation factor levels and increased D-dimer compared with control group (n = 35). However, fibrinogen levels and clot firmness assessed by rotation thromboelastometry were not different between groups and clot lysis indexes at 45 and 60 min were increased in study group compared with control group. The first derivative of the clot firmness curve revealed an increased time to the maximum velocity of clot formation for study group, without differences in the maximum velocity of clot formation, or in total thrombus formation. Sepsis with organ dysfunction in cancer patients is associated with delayed initiation of coagulation and reduced fibrinolysis compared with control patients, but overall clot formation and stabilization is not different. For septic cancer patients, SCTs and plasmatic indicators of fibrinolysis do not translate well to whole blood clot formation and may be misleading indicators of thrombotic or bleeding risk.

First report of cytokine removal using CytoSorb® in severe noninfectious inflammatory syndrome after liver transplantation.

INTRODUCTION: Emergency transplantation of a donor liver that is not matched for the major blood antigens can produce marked immune-mediated cytokine release that can cause donor graft loss. Control of the inflammatory response may be a key element in treatment. METHODS: We present the case of a 46-year-old man with primary graft nonfunction after liver transplantation who underwent emergency retransplantation with an ABO-incompatible graft. A severe inflammatory response syndrome (SIRS) was noted in the perioperioperative period of retransplantation. The patient was successfully treated for this condition with a new hemoadsorption column (CytoSorb®), in combination with continuous venovenous hemofiltration (CVVH) throughout the intraoperative and early postoperative period. RESULTS: During and after each treatment a significant and rapid decrease of pro- and anti-inflammatory cytokines was observed, especially for interleukin-6 (IL-6), IL-10 and monocyte chemotactic protein 1 (MCP-1). Reduction of cytokines was associated with normalization of cardiac output and systemic vascular resistance, and improved liver function. CONCLUSIONS: We believe this is the first case in which hemoadsorptionin combination with CVVH has been used to manage SIRS in a patient with primary graft nonfunction undergoing emergency retransplantation.