Association of anti-factor Xa-guided anticoagulation with hemorrhage during ECMO support: A systematic review and meta-analysis.

BACKGROUND: The use of extracorporeal membrane oxygenation (ECMO) is associated with complex hemostatic changes. Systemic anticoagulation is initiated to prevent clotting in the ECMO system, but this comes with an increased risk of bleeding. Evidence on the use of anti-Xa-guided monitoring to prevent bleeding during ECMO support is limited. Therefore, we aimed to analyze the association between anti-factor Xa-guided anticoagulation and hemorrhage during ECMO. METHODS: A systematic review and meta-analysis was performed (up to August 2023). PROSPERO: CRD42023448888. RESULTS: Twenty-six studies comprising 2293 patients were included in the analysis, with six works being part of the meta-analysis. The mean anti-Xa values did not show a significant difference between patients with and without hemorrhage (standardized mean difference -0.05; 95% confidence interval [CI]: -0.19; 0.28, p = .69). We found a positive correlation between anti-Xa levels and unfractionated heparin dose (UFH; pooled estimate of correlation coefficients 0.44; 95% CI: 0.33; 0.55, p < .001). The most frequent complications were any type of hemorrhage (pooled 36%) and thrombosis (33%). Nearly half of the critically ill patients did not survive to hospital discharge (47%). CONCLUSIONS: The most appropriate tool for anticoagulation monitoring in ECMO patients is uncertain. Our analysis did not reveal a significant difference in anti-Xa levels in patients with and without hemorrhagic events. However, we found a moderate correlation between anti-Xa and the UFH dose, supporting its utilization in monitoring UFH anticoagulation. Given the limitations of time-guided monitoring methods, the role of anti-Xa is promising and further research is warranted.

Organ Donation from Patients Receiving Extracorporeal Membrane Oxygenation: A Systematic Review.

OBJECTIVE: The mismatch between the demand for and supply of organs for transplantation is steadily growing. Various strategies have been incorporated to improve the availability of organs, including organ use from patients receiving extracorporeal membrane oxygenation (ECMO) at the time of death. However, there is no systematic evidence of the outcome of grafts from these donors. DESIGN: Systematic literature review (Scopus and PubMed, up to October 11, 2023). SETTING: All study designs. PARTICIPANTS: Organ recipients from patients on ECMO at the time of death. INTERVENTION: Outcome of organ donation from ECMO donors. MEASUREMENTS AND MAIN RESULTS: The search yielded 1,692 publications, with 20 studies ultimately included, comprising 147 donors and 360 organ donations. The most frequently donated organs were kidneys (68%, 244/360), followed by liver (24%, 85/360). In total, 98% (292/299) of recipients survived with a preserved graft function (92%, 319/347) until follow-up within a variable period of up to 3 years. CONCLUSION: Organ transplantation from donors supported with ECMO at the time of death shows high graft and recipient survival. ECMO could be a suitable approach for expanding the donor pool, helping to alleviate the worldwide organ shortage.

ECMO in Myocardial Infarction-Associated Cardiogenic Shock: Blood Biomarkers as Predictors of Mortality.

BACKGROUND: Veno-arterial extracorporeal membrane oxygenation (va-ECMO) can provide circulatory and respiratory support in patients with cardiogenic shock. The main aim of this work was to investigate the association of blood biomarkers with mortality in patients with myocardial infarction needing va-ECMO support. METHODS: We retrospectively analyzed electronic medical charts from patients receiving va-ECMO support in the period from 2008 to 2021 at the Medical University Innsbruck, Department of Anesthesiology and Intensive Care Medicine. RESULTS: Of 188 patients, 57% (108/188) survived to discharge, with hemorrhage (46%) and thrombosis (27%) as the most frequent adverse events. Procalcitonin levels were markedly higher in non-survivors compared with survivors during the observation period. The multivariable model identified higher blood levels of procalcitonin (HR 1.01, p = 0.002) as a laboratory parameter associated with a higher risk of mortality. CONCLUSIONS: In our study population of patients with myocardial infarction-associated cardiogenic shock, deceased patients had increased levels of inflammatory blood biomarkers throughout the whole study period. Increased procalcitonin levels have been associated with a higher risk of mortality. Future studies are needed to show the role of procalcitonin in patients receiving ECMO support.

Loss or Dilution-A New Diagnostic Method to Assess the Impact of Dilution on Standard Laboratory Parameters.

Intraoperative fluid therapy is regularly used in patients undergoing cardiac surgery procedures with cardiopulmonary bypass (CPB). Although fluid administration has several advantages, it unavoidably leads to hemodilution. The hemodilution may further influence the interpretation of concentration-based laboratory parameters like hemoglobin (Hgb), platelet count (PLT) or prothrombin time (PT). These all parameters are commonly used to guide blood product substitution. To assess the impact of dilution on these values, we performed a prospective observational study in 174 patients undergoing elective cardiac surgery. We calculated the total blood volume according to Nadler's formula, and fluid therapy was correlated with a newly developed dilution coefficient formula at the end of CPB. Intravenously applied fluids were measured from the beginning of the anesthesia (baseline, T0) and 15 min after the end of protamine infusion (end of CPB, T1). The amount of the administered volume (crystalloids or colloids) was calculated according to the percentage of the intravascular fluid effect, and intraoperative diuresis was further subtracted. The median blood volume increased by 148% in all patients at T1 compared to the calculated total blood volume at T0. This led to a dilution-dependent decrease of 38% in all three parameters (Hgb 24%, corrCoeff = 0.53; PLT 41%, corrCoeff = 0.68; PT 44%, corrCoeff = 0.54). The dilution-correlated decrease was significant for all parameters (p < 0.001), and the effect was independent from the duration of CPB. We conclude that the presented calculation-based approach could provide important information regarding actual laboratory parameters and may help in the guidance of the blood product substitution and potential transfusion thresholds. Further research on the impact of dilution and related decision-making for blood product substitution, including its impact on morbidity and mortality, is warranted.

Cytomegalovirus Disease as a Risk Factor for Invasive Fungal Infections in Liver Transplant Recipients under Targeted Antiviral and Antimycotic Prophylaxis.

Cytomegalovirus (CMV) infection is the most common opportunistic infection that occurs following orthotopic liver transplantation (OLT). In addition to the direct infection-related symptoms, it also triggers an immunological response that may contribute to adverse clinical outcomes. CMV disease has been described as a predictor of invasive fungal infections (IFIs) but its role under an antiviral prophylaxis regimen is unclear. METHODS: We retrospectively analyzed the medical records of 214 adult liver transplant recipients (LTRs). Universal antiviral prophylaxis was utilized in recipients with CMV mismatch; intermediate- and low-risk patients received pre-emptive treatment. RESULTS: Six percent of patients developed CMV disease independent of their serostatus. The occurrence of CMV disease was associated with elevated virus load and increased incidence of leucopenia and IFIs. Furthermore, CMV disease was associated with higher one-year mortality and increased relapse rates within the first year of OLT. CONCLUSIONS: CMV disease causes significant morbidity and mortality in LTRs, directly affecting transplant outcomes. Due to the increased risk of IFIs, antifungal prophylaxis for CMV disease may be appropriate. Postoperative CMV monitoring should be considered after massive transfusion, even in low-risk serostatus constellations. In case of biliary complications, biliary CMV monitoring may be appropriate in the case of CMV-DNA blood-negative patients.

Invasive Fungal Infections: The Early Killer after Liver Transplantation.

BACKGROUND: Liver transplantation is a standard of care and a life-saving procedure for end-stage liver diseases and certain malignancies. The evidence on predictors and risk factors for poor outcomes is lacking. Therefore, we aimed to identify potential risk factors for mortality and to report on overall 90-day mortality after orthotopic liver transplantation (OLT), especially focusing on the role of fungal infections. METHODS: We retrospectively reviewed medical charts of all patients undergoing OLT at a tertiary university center in Europe. RESULTS: From 299 patients, 214 adult patients who received a first-time OLT were included. The OLT indication was mainly due to tumors (42%, 89/214) and cirrhosis (32%, 68/214), including acute liver failure in 4.7% (10/214) of patients. In total, 8% (17/214) of patients died within the first three months, with a median time to death of 15 (1-80) days. Despite a targeted antimycotic prophylaxis using echinocandins, invasive fungal infections occurred in 12% (26/214) of the patients. In the multivariate analysis, patients with invasive fungal infections had an almost five times higher chance of death (HR 4.6, 95% CI 1.1-18.8; p = 0.032). CONCLUSIONS: Short-term mortality after OLT is mainly determined by infectious and procedural complications. Fungal breakthrough infections are becoming a growing concern. Procedural, host, and fungal factors can contribute to a failure of prophylaxis. Finally, invasive fungal infections may be a potentially modifiable risk factor, but the ideal perioperative antimycotic prophylaxis has yet to be determined.

Association of aPTT-Guided Anticoagulation Monitoring with Thromboembolic Events in Patients Receiving V-A ECMO Support: A Systematic Review and Meta-Analysis.

BACKGROUND: The initiation of extracorporeal membrane oxygenation (ECMO) is associated with complex inflammatory and coagulatory processes, raising the need for systemic anticoagulation. The balance of anticoagulatory and procoagulant factors is essential, as therapeutic anticoagulation confers a further risk of potentially life-threatening bleeding. Therefore, our study aims to systematize and analyze the most recent evidence regarding anticoagulation monitoring and the thromboembolic events in patients receiving veno-arterial ECMO support. METHODS: Using the PRISMA guidelines, we systematically searched the Scopus and PubMed databases up to October 2022. A weighted effects model was employed for the meta-analytic portion of the study. RESULTS: Six studies comprising 1728 patients were included in the final analysis. Unfractionated heparin was used for anticoagulation, with an activated partial thromboplastin time (aPTT) monitoring goal set between 45 and 80 s. The majority of studies aimed to investigate the incidence of adverse events and potential risk factors for thromboembolic and bleeding events. None of the authors found any association of aPTT levels with the occurrence of thromboembolic events. Finally, the most frequent adverse events were hemorrhage (pooled 43%, 95% CI 28.4; 59.5) and any kind of thrombosis (pooled 36%, 95% CI 21.7; 53.7), and more than one-half of patients did not survive to discharge (pooled 54%). CONCLUSIONS: Despite the tremendous development of critical care, aPTT-guided systemic anticoagulation is still the standard monitoring tool. We did not find any association of aPTT levels with thrombosis. Further evidence and new trials should clarify the true incidence of thromboembolic events, along with the best anticoagulation and monitoring strategy in veno-arterial ECMO patients.

First-Line Administration of Fibrinogen Concentrate in the Bleeding Trauma Patient: Searching for Effective Dosages and Optimal Post-Treatment Levels Limiting Massive Transfusion-Further Results of the RETIC Study.

Fibrinogen supplementation is recommended for treatment of severe trauma hemorrhage. However, required dosages and aimed for post-treatment fibrinogen levels remain a matter of discussion. Within the published RETIC study, adult patients suffering trauma-induced coagulopathy were randomly assigned to receive fibrinogen concentrate (FC) as first-line (n = 50) or crossover rescue (n = 20) therapy. Depending on bodyweight, a single dose of 3, 4, 5, or 6 g FC was administered and repeated if necessary (FibA10 < 9 mm). The dose-dependent response (changes in plasma fibrinogen and FibA10) was analyzed. Receiver operating characteristics (ROC) analysis regarding the need for massive transfusion and correlation analyses regarding fibrinogen concentrations and polymerization were performed. Median FC single doses amounted to 62.5 (57 to 66.66) mg.kg-1. One FC single-dose sufficiently corrected fibrinogen and FibA10 (median fibrinogen 213 mg.dL-1, median FibA10 11 mm) only in patients with baseline fibrinogen above 100 mg.dL-1 and FibA10 above 5 mm, repeated dosing was required in patients with lower baseline fibrinogen/FibA10. Fibrinogen increased by 83 or 107 mg.dL-1 and FibA10 by 4 or 4.5 mm after single or double dose of FC, respectively. ROC curve analysis revealed post-treatment fibrinogen levels under 204.5 mg.dL-1 to predict the need for massive transfusion (AUC 0.652; specificity: 0.667; sensitivity: 0.688). Baseline fibrinogen/FibA10 levels should be considered for FC dosing as only sufficiently corrected post-treatment levels limit transfusion requirements.

Hemoadsorption with CytoSorb in Septic Shock Reduces Catecholamine Requirements and In-Hospital Mortality: A Single-Center Retrospective 'Genetic' Matched Analysis.

Septic shock is a major burden to healthcare with mortality rates remaining high. Blood purification techniques aim to reduce cytokine levels and resultant organ failure. Regarding septic shock, hemoadsorption via CytoSorb seems promising, but the main effects on organ failure and mortality remain unclear. In this retrospective single-center study, septic shock patients receiving CytoSorb in addition to renal replacement therapy (n = 42) were analyzed and compared to matched controls (n = 42). A generalized propensity-score and Mahalanobis distance matching method ('genetic' matching) was applied. Baseline comparability was high. Differences were merely present in higher initial Sequential Organ Failure Assessment (SOFA) scores (median and interquartile range: 13.0 (12.0-14.75) vs. 12.0 (9.0-14.0)) and requirements of norepinephrine equivalents (0.54 (0.25-0.81) vs. 0.25 (0.05-0.54) µg/kg/min) in the CytoSorb group. While remaining fairly constant in the controls, the catecholamines decreased to 0.26 (0.11-0.40) µg/kg/min within 24 h after initiation of CytoSorb therapy. In-hospital mortality was significantly lower in the CytoSorb group (35.7% vs. 61.9%; p = 0.015). Risk factors for mortality within the CytoSorb group were high lactate levels and low thrombocyte counts prior to initiation. Hereby, a cut-off value of 7.5 mmol/L lactate predicted mortality with high specificity (88.9%). Thus, high lactate levels may indicate absent benefits when confronted with septic shock patients considered eligible for CytoSorb therapy.

Dynamics of Platelet Counts in Major Trauma: The Impact of Haemostatic Resuscitation and Effects of Platelet Transfusion-A Sub-Study of the Randomized Controlled RETIC Trial.

Although platelets play a central role in haemostasis, the dynamics of platelet counts during haemostatic resuscitation, the response to platelet transfusion, and effects on clinical outcome are poorly described for trauma patients. As a sub-study of the already published randomized controlled RETIC Study "Reversal of Trauma-induced Coagulopathy using First-line Coagulation Factor Concentrates or Fresh-Frozen Plasma" trial, we here analysed whether the type of first-line haemostatic resuscitation influences the frequency of platelet transfusion and determined the effects of platelet transfusion in coagulopathic patients with major trauma. Patients randomly received first-line plasma (FFP) or coagulation factor concentrates (CFC), mainly fibrinogen concentrate. In both groups, platelets were transfused to maintain platelet counts between 50 and 100 × 109 /L. Transfusion rates were significantly higher in the FFP (n = 44) vs. CFC (n = 50) group (FFP 47.7% vs. CFC 26%); p = 0.0335. Logistic regression analysis adjusted for the stratification variables injury severity score (ISS) and brain injury confirmed that first-line FFP therapy increases the odds for platelet transfusion (odds ratio (OR) 5.79 (1.89 to 20.62), p = 0.0036) and this effect was larger than a 16-point increase in ISS (OR 4.33 (2.17 to 9.74), p =0.0001). In conclusion, early fibrinogen supplementation exerted a platelet-saving effect while platelet transfusions did not substantially improve platelet count and might contribute to poor clinical outcome.

Reversal of trauma-induced coagulopathy using first-line coagulation factor concentrates or fresh frozen plasma (RETIC): a single-centre, parallel-group, open-label, randomised trial.

BACKGROUND: Effective treatment of trauma-induced coagulopathy is important; however, the optimal therapy is still not known. We aimed to compare the efficacy of first-line therapy using fresh frozen plasma (FFP) or coagulation factor concentrates (CFC) for the reversal of trauma-induced coagulopathy, the arising transfusion requirements, and consequently the development of multiple organ failure. METHODS: This single-centre, parallel-group, open-label, randomised trial was done at the Level 1 Trauma Center in Innsbruck Medical University Hospital (Innsbruck, Austria). Patients with trauma aged 18-80 years, with an Injury Severity Score (ISS) greater than 15, bleeding signs, and plasmatic coagulopathy identified by abnormal fibrin polymerisation or prolonged coagulation time using rotational thromboelastometry (ROTEM) were eligible. Patients with injuries that were judged incompatible with survival, cardiopulmonary resuscitation on the scene, isolated brain injury, burn injury, avalanche injury, or prehospital coagulation therapy other than tranexamic acid were excluded. We used a computer-generated randomisation list, stratification for brain injury and ISS, and closed opaque envelopes to randomly allocate patients to treatment with FFP (15 mL/kg of bodyweight) or CFC (primarily fibrinogen concentrate [50 mg/kg of bodyweight]). Bleeding management began immediately after randomisation and continued until 24 h after admission to the intensive care unit. The primary clinical endpoint was multiple organ failure in the modified intention-to-treat population (excluding patients who discontinued treatment). Reversal of coagulopathy and need for massive transfusions were important secondary efficacy endpoints that were the reason for deciding the continuation or termination of the trial. This trial is registered with ClinicalTrials.gov, number NCT01545635. FINDINGS: Between March 3, 2012, and Feb 20, 2016, 100 out of 292 screened patients were included and randomly allocated to FFP (n=48) and CFC (n=52). Six patients (four in the FFP group and two in the CFC group) discontinued treatment because of overlooked exclusion criteria or a major protocol deviation with loss of follow-up. 44 patients in the FFP group and 50 patients in the CFC group were included in the final interim analysis. The study was terminated early for futility and safety reasons because of the high proportion of patients in the FFP group who required rescue therapy compared with those in the CFC group (23 [52%] in the FFP group vs two [4%] in the CFC group; odds ratio [OR] 25·34 [95% CI 5·47-240·03], p<0·0001) and increased needed for massive transfusion (13 [30%] in the FFP group vs six [12%] in the CFC group; OR 3·04 [0·95-10·87], p=0·042) in the FFP group. Multiple organ failure occurred in 29 (66%) patients in the FFP group and in 25 (50%) patients in the CFC group (OR 1·92 [95% CI 0·78-4·86], p=0·15). INTERPRETATION: Our results underline the importance of early and effective fibrinogen supplementation for severe clotting failure in multiple trauma. The available sample size in our study appears sufficient to make some conclusions that first-line CFC is superior to FFP. FUNDING: None.

Disseminated Intravascular Coagulation in Secondary Glioblastoma due to Excessive Intraoperative Bleeding: Case Report and Review of the Literature.

BACKGROUND: Disseminated intravascular coagulation (DIC) describes a pathologic activation of coagulation mechanisms, leading to thrombi in various organs with contribution to multiple organ failure. In clinical practice, diagnosis of DIC can often be made by laboratory values, including prolonged coagulation times, thrombocytopenia, or high levels of fibrin degradation products. DIC is frequently observed after neurotrauma, but rarely occurs in patients with primary brain tumors. There are only few case reports of DIC in patients with primary brain tumors, all sharing the highly elevated mortality. We report the case of a young patient presenting with secondary glioblastoma, who developed multiorgan failure induced by DIC after extensive intraoperative bleeding. CASE DESCRIPTION: A 30-year-old patient was admitted in poor general condition with insomnia, severe headache, and vomiting. She had undergone surgery for secondary glioblastoma twice. Magnetic resonance imaging revealed a left temporoparietal mass lesion with indication for resection. Surgery then was complicated by diffuse intraoperative bleeding due to a high content of microvascular proliferation as shown in the histopathologic workup. Subsequently, an uncontrollable multiorgan failure developed, causing the patient's death 4 days after surgery. CONCLUSIONS: Although a rare complication, excessive intraoperative bleeding, especially in surgery for brain tumors located next to the ventricular system, DIC should be kept in mind as a possible diagnosis.

Comparison of arterial versus venous parameters of Rotational thromboelastometry and multiple platelet function analyzer: results of a pilot study.

BACKGROUND: In the operating room and at the ICU, Rotational thromboelastometry (ROTEM) and multiple platelet function analyzer (Multiplate) are frequently performed on arterial blood samples while known reference ranges refer to venous blood only. To evaluate whether there are clinical important differences between parameters measured in arterial and venous blood, we performed a prospective study in patients undergoing orthopedic surgery. METHODS: Arterial and venous blood samples were drawn simultaneously after line insertion (T0), intraoperatively (T1), at the end of surgery (T2) and the INTEM, EXTEM and FIBTEM ROTEM assays, as well as the ASPI, ADP and TRAP assays were performed in arterial and venous samples using the ROTEM and the Multiplate device, respectively. RESULTS: After informed consent, 52 patients were enrolled and data of 50 patients remained for final analysis. Venous and arterial measurement results correlated significantly with a coefficient of 0.519-0.977. At the three measurement points only a few statistically significant deviations were detected for some of the ROTEM and Multiplate parameters. The magnitude of differences was small and most likely without clinical relevance. Pathological conditions were detected with similar frequency regardless of the sampling site. Only Multiplate TRAP at T0 indicated low platelet aggregation more frequently in venous than in arterial samples (p = 0.0455); however, values were only narrow below reference range. CONCLUSION: The observed differences between arterial and venous results were within the range of variability of the methods reported for venous blood. Pathological values that might be clinically relevant could be detected at similar rates regardless of the sampling site.