Analysis of fibrin networks using topological data analysis - a feasibility study.

Blood clot formation, a crucial process in hemostasis and thrombosis, has garnered substantial attention for its implications in various medical conditions. Microscopic examination of blood clots provides vital insights into their composition and structure, aiding in the understanding of clot pathophysiology and the development of targeted therapeutic strategies. This study explores the use of topological data analysis (TDA) to assess plasma clot characteristics microscopically, focusing on the identification of the elements components, holes and Wasserstein distances. This approach should enable researchers to objectively classify fibrin networks based on their topologic architecture. We tested this mathematical characterization approach on plasma clots formed in static conditions from porcine and human citrated plasma samples, where the effect of dilution and direct thrombin inhibition was explored. Confocal microscopy images showing fluorescence labeled fibrin networks were analyzed. Both treatments resulted in visual differences in plasma clot architecture, which could be quantified using TDA. Significant differences between baseline and diluted samples, as well as blood anticoagulated with argatroban, were detected mathematically. Therefore, TDA could be indicative of clots with compromised stability, providing a valuable tool for thrombosis risk assessment. In conclusion, microscopic examination of plasma clots, coupled with Topological Data Analysis, offers a promising avenue for comprehensive characterization of clot microstructure. This method could contribute to a deeper understanding of clot pathophysiology and thereby refine our ability to assess clot characteristics.

Anticoagulation Strategies during Extracorporeal Membrane Oxygenation: A Narrative Review.

The development of extracorporeal life support technology has added a new dimension to the care of critically ill patients who fail conventional treatment options. Extracorporeal membrane oxygenation (ECMO)-specialized temporary life support for patients with severe cardiac or pulmonary failure-plays a role in bridging the time for organ recovery, transplant, or permanent assistance. The overall patient outcome is dependent on the underlying disease, comorbidities, patient reaction to critical illness, and potential adverse events during ECMO. Moreover, the contact of the blood with the large artificial surface of an extracorporeal system circuit triggers complex inflammatory and coagulation responses. These processes may further lead to endothelial injury and disrupted microcirculation with consequent end-organ dysfunction and the development of adverse events like thromboembolism. Therefore, systemic anticoagulation is considered crucial to alleviate the risk of thrombosis and failure of ECMO circuit components. The gold standard and most used anticoagulant during extracorporeal life support is unfractionated heparin, with all its benefits and disadvantages. However, therapeutic anticoagulation of a critically ill patient carries the risk of clinically relevant bleeding with the potential for permanent injury or death. Similarly, thrombotic events may occur. Therefore, different anticoagulation strategies are employed, while the monitoring and the balance of procoagulant and anticoagulatory factors is of immense importance. This narrative review summarizes the most recent considerations on anticoagulation during ECMO support, with a special focus on anticoagulation monitoring and future directions.

The course of adrenomedullin and endothelin levels in patients with vasodilatory shock after cardiac surgery compared to patients after uncomplicated elective cardiac surgery.

PURPOSE: The aim of this study was to analyse the course of adrenomedullin (ADM) and endothelin-1 (ET-1) levels in patients with vasodilatory shock after cardiac surgery and to explore differences compared to patients after uncomplicated coronary artery bypass graft (CABG) surgery. ADM and ET-1 are involved in the vasomotor response during vasodilatory shock. MATERIALS AND METHODS: We included 32 patients with vasodilatory shock (study group) and 10 patients after uncomplicated CABG surgery (control group). Daily measurements of MR-proADM and CT-proET-1 (stable surrogate markers for ADM and ET-1) were collected during the first 7 postoperative days. RESULTS: MR-proADM and CT-proET-1 levels were significantly elevated in the study group when compared to the control group. In addition, the course of both biomarkers was significantly different in the study versus control group. Higher levels of both biomarkers were associated with organ dysfunction (higher maximum multiple organ dysfunction score, acute kidney injury). CONCLUSIONS: Significantly higher levels of MR-proADM and CT-proET-1 and a different course of both biomarkers were observed in patients with vasodilatory shock after cardiac surgery and seemed to be associated with organ dysfunction.

The Pulmonary Artery Catheter in the Perioperative Setting: Should It Still Be Used?

The pulmonary artery catheter (PAC) was introduced into clinical practice in the 1970s and was initially used to monitor patients with acute myocardial infarctions. The indications for using the PAC quickly expanded to critically ill patients in the intensive care unit as well as in the perioperative setting in patients undergoing major cardiac and noncardiac surgery. The utilization of the PAC is surrounded by multiple controversies, with literature claiming its benefits in the perioperative setting, and other publications showing no benefit. The right interpretation of the hemodynamic parameters measured by the PAC and its clinical implications are of the utmost essence in order to guide a specific therapy. Even though clinical trials have not shown a reduction in mortality with the use of the PAC, it still remains a valuable tool in a wide variety of clinical settings. In general, the right selection of the patient population (high-risk patients with or without hemodynamic instability undergoing high-risk procedures) as well as the right clinical setting (centers with experience and expertise) are essential in order for the patient to benefit most from PAC use.

MRI of middle ear cholesteatoma: The importance of observer reliance from diffusion sequences.

BACKGROUND AND PURPOSE: Diffusion-weighted imaging(DWI) in MRI has been developed as an important tool for the detection of cholesteatoma. Various DWI sequences are available. This study aims to evaluate the importance of the observer's reliance level for the detection of cholesteatoma. METHODS: Forty patients meeting the following criteria were included in the study: (1) chronic otitis media, (2) preoperative MRI including various DWI sequences, and (3) middle-ear surgery. The MRI protocol contained the following sequences: (1) axial and (2) coronal echoplanar imaging (EPI) readout-segmented (RESOLVE) DWI with Trace acquisition and (3) coronal non-EPI half-Fourier acquired single-shot turbo spin-echo (HASTE) DWI. Cholesteatoma diagnosis was based on standard diagnostic criteria for cholesteatoma with DWI. Additionally, the radiologists were asked to grade personal reliance on their diagnosis using a Likert-type scale from 1 = very insecure to 5 = very secure. RESULTS: Axial and coronal RESOLVE DWI showed a sensitivity of 77.3% and a specificity of 72.2%, respectively. The mean reliance was 3.9 for axial and 3.8 for coronal images. HASTE DWI had a sensitivity/specificity of 81.8%/66.7% with the highest reliance of all evaluated sequences (4.4). Cases with a reliance level of 5 showed a sensitivity/specificity of 100% in all sequences. A reliance level of 5 was given in the axial and coronal RESOLVE DWI in 32.5% of cases and in the HASTE DWI in 57.5%. CONCLUSION: The evaluated DWI sequences showed comparable results. The reliance level significantly improved the predictor of cholesteatoma disease with MRI techniques.

Anesthesia-Induced Oxidative Stress: Are There Differences between Intravenous and Inhaled Anesthetics?

Agents used for the induction of anesthesia have been shown to either promote or mitigate oxidative stress. A fine balance between the presence of reactive oxygen species (ROS) and antioxidants is crucial for the proper normal functioning of the cell. A basal concentration of ROS is essential for the manifestation of cellular functions, whereas disproportionate levels of ROS cause damage to cellular macromolecules such as DNA, lipids, and proteins, eventually leading to necrosis and apoptosis. Increased ROS has been linked with numerous illnesses, such as cardiovascular, immune system, liver, and kidney, and has been shown to promote cancer and accelerate aging. Knowledge of the various pharmacologic agents that increase or reduce oxidative stress may promote a safer way of inducing anesthesia. Furthermore, surgery itself leads to increased ROS production and ischemia/reperfusion injury. Indeed, increased perioperative oxidative stress has been correlated with increased postoperative complications and prolonged recovery. Anesthesiologists care for patients during the whole spectrum of perioperative care and thus are in a unique position to deliver countermeasures to oxidative stress. Using preferentially an induction agent which reduces oxidative stress might lead to better clinical outcomes and fewer postoperative complications. Propofol has been shown in several studies to reduce oxidative stress, which reduces postoperative complications and leads to a faster recovery, and thus might represent the preferred induction agent in the right clinical setting.

Administration of fibrinogen concentrate combined with prothrombin complex maintains hemostasis in children undergoing congenital heart repair (a long-term propensity score-matched study).

BACKGROUND: Bleeding is a common problem in children with congenital heart disease undergoing major cardiac surgery requiring cardiopulmonary bypass (CPB). Little is known about optimal management with blood products. OBJECTIVE: To investigate clinical outcome and hemostatic effects of fibrinogen concentrate (FC) in combination with prothrombin complex concentrate (PCC) versus standard treatment with fresh frozen plasma (FFP) in children undergoing cardiac surgery. METHODS: For this single-institution cohort study, data on 525 children were analyzed. Propensity score matching in 210 children was applied to reduce the impact of various baseline characteristics. RESULTS: Three children treated with FC/PCC developed surgical site bleeding requiring surgical revision. One child developed central venous line-related thrombosis. Blood loss through chest tube drainage was independent of FC/PCC. Coagulation abnormalities were not present in any of these children. Time to extubation and ICU stay did not differ. In the FC/PCC group, children received (median, Q1, Q3) 52 mg/kg (32, 83) FC and 28IU/kg (13, 44) PCC. Fibrinogen concentration was comparable at baseline. On admission to the ICU, fibrinogen was higher in children receiving FC/PCC, namely, 232 mg/dL (196, 280), than in children receiving FFP (186 mg/dL, 149, 224; P < .001). On discharge from the ICU, values did not differ ((FC/PCC 416 mg/dL (288, 501)), non-FC/PCC 418 mg/dL (272, 585; P = 1.000)). CONCLUSION: FC/PCC was well tolerated and permitted hemostasis to be maintained, even in the very young. We were not able to detect a signal for inferiority of this treatment. We conclude that FC/PCC can safely replace FFP.

Cardiac output and cerebral blood flow during carotid surgery in regional versus general anesthesia: A prospective randomized controlled study.

OBJECTIVE: Carotid endarterectomy (CEA) is a preventive procedure aimed at decreasing the subsequent risk of fatal or disabling stroke in patients with significant carotid stenosis. It is well-known that carotid surgery under ultrasound-guided regional anesthesia (US-RA) causes a significant increase in blood pressure, heart rate and stress hormone levels owing to increased sympathetic activity. However, little is known about the effects on cardiac output (CO), cardiac index (CI), and cerebral blood flow (CBF) under US-RA as compared with general anesthesia (GA). METHODS: Patients scheduled for CEA were randomized prospectively to receive US-RA (n = 37) or GA (n = 41). The primary end point was the change in CI after induction of anesthesia and the change from baseline over time at four different times during the entire procedure in the respective randomized US-RA and GA groups. In addition to systolic blood pressure and heart rate, we also recorded peak systolic velocity, end-diastolic velocity, and minimum diastolic velocity as seen from transcranial Doppler ultrasound examination, as well as regional cerebral oxygenation (rSO2) as seen from near-infrared refracted spectroscopy to evaluate cerebral blood flow. RESULTS: In the US-RA group, the CI increased after induction of anesthesia (3.7 ± 0.8 L/min/m2) and remained constant until the end of the procedure. In the GA group CI was significantly lower (2.4 ± 0.6 L/min/m2; P < .001). After induction of anesthesia, the rSO2 remained constant in the GA group on both the ipsilateral (63 ± 9 rSO2) and the contralateral (65 ± 7 rSO2) sides; in contrast, it significantly increased in the US-RA group (ipsilateral 72 ± 8 rSO2; P < .001; contralateral 72 ± 6 rSO2; P < .001). The transcranial Doppler ultrasound parameters (peak systolic velocity, end-diastolic velocity, and minimum diastolic velocity) did not differ between the US-RA and the GA group. The clinical outcome was similarly favorable for both groups. CONCLUSIONS: CI was maintained near baseline values throughout the procedure during US-RA, whereas a significant decrease in CI values was observed during CEA under GA. Near-infrared refracted spectroscopy values, reflecting blood flow in small vessels, were higher in US-RA patients than in those with GA. These differences did not influence clinical outcome.

Guided vs. non-guided insertion of Ambu AuraGain™ in edentulous patients.

BACKGROUND: Supraglottic airway devices perform more poorly and have lower oropharyngeal leak pressure in edentulous patients than in patients with teeth. The Ambu Aura Gain is a newer second generation supraglottic airway device. OBJECTIVE: This randomized clinical trial assessed the oropharyngeal leak pressure in edentulous patients using the Ambu Aura Gain with a gastric tube for insertion guidance and without insertion guidance. MATERIAL AND METHODS: Patients with ASA (American Society of Anesthesiology) physical status I-III were recruited. Primary outcome was oropharyngeal leak pressure after insertion. Secondary outcome parameters were oropharyngeal leak pressure 15 min and 30 min after insertion, insertion time, insertion attempts and glottis view through flexible fiberscope. RESULTS: In this study 72 patients aged between 51 and 90 years (mean 73 years) were randomly allocated to the "with guidance" (n = 36) or the "without guidance" group (n = 36). Mean (SD) oropharyngeal leak pressure in "with guidance" and "without guidance" group was 24 cm H2O and 24 cm H2O (ns), respectively. A difference was found in mean insertion time with guidance versus without guidance group 52 s (45 s) vs. 26 s (15 s) (p < 0.001). No difference was found in any of the other secondary outcome parameters. CONCLUSION: A guided insertion technique does not improve oropharyngeal leak pressure of the Ambu AuraGain™ in edentulous patients. As the only difference is an increase in insertion time this technique is of no benefit for this population.

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.

Predicting Transfusion Requirements During Extracorporeal Membrane Oxygenation.

OBJECTIVE: Patients requiring extracorporeal membrane oxygenation (ECMO) have a well-known bleeding risk and the potential for experiencing possibly fatal thromboembolic complications. Risk factors and predictors of transfusion requirements during ECMO support remain uncertain. The authors hypothesized that compromised organ function immediately before ECMO support will influence transfusion requirements. DESIGN: A prospective observational study. SETTING: A tertiary, single-institutional university hospital. PARTICIPANTS: The study included 40 adult patients requiring ECMO for intractable cardiac and respiratory failure between July 2010 and December 2012. Blood samples were taken before initiation of ECMO (baseline), after 24 and 48 hours on ECMO, and 24 hours after termination of ECMO. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Independent of veno-arterial or veno-venous support, 26% of patients required≥2 packed red blood cells per day (PRBC/d) and 74% of patients required<2 PRBC/d during ECMO. Requirements of≥2 PRBC/d during ECMO support were associated with higher creatinine levels and lower prothrombin times (PT, %) at baseline and with impaired platelet function after 24 hours on ECMO. Platelet function, activated by thrombin receptor-activating peptide stimulation, decreased by 30% to 40% over time on ECMO. Receiver operating characteristic curve analysis showed cut-off values for creatinine of 1.49 mg/dL (sensitivity 70%, specificity 70%; area under the curve [AUC] 0.76, 95% confidence interval [CI] 0.58-0.94), for PT of 48% (sensitivity 80%, specificity 59%; AUC 0.69, 95% CI 0.50-0.87), and for thrombin receptor-activating peptide (TRAP) 32 U (sensitivity 90%, specificity 68%; AUC 0.76, 95% CI 0.59-0.93). CONCLUSIONS: The results of this study demonstrated that increased creatinine levels and lower PT before ECMO and secondary impaired platelet function significantly increased transfusion requirement.

Extracorporeal membrane oxygenation induces short-term loss of high-molecular-weight von Willebrand factor multimers.

BACKGROUND: High-molecular-weight (HMW) von Willebrand factor (vWF) multimers are crucial for primary hemostasis. Increased shear stress from ventricular assist devices can provoke premature degradation of HMW vWF multimers. Whether similar loss of vWF multimers occurs during extracorporeal membrane oxygenation (ECMO) is not clear. METHODS: We conducted a prospective observational study in a clinical cohort of patients who required ECMO for intractable cardiac and/or respiratory failure. The primary end point was the quantity and quality of HMW vWF multimer bands before, during, and after ECMO support. To investigate further changes in primary hemostasis, we also measured vWF antigen activity (vWF:Ag), vWF ristocetin cofactor activity (vWF:RCo), and factor VIII in 38 patients who required ECMO support before initiation of ECMO (baseline), after 24 and 48 hours on ECMO, and 24 hours after termination of ECMO therapy. RESULTS: Compared with baseline, vWF:Ag and vWF:RCo decreased after 24 hours of ECMO (mean ± SD, vWF:Ag, 307% ± 152% to 261% ± 138%, P = 0.002; vWF:RCo 282% ± 145% to 157% ± 103%, P < 0.0001) and remained lower during ongoing support (vWF:Ag 265% ± 128%, P = 0.025; vWF:RCo 163% ± 94%, P < 0.0001). After termination of ECMO, vWF:Ag was greater than baseline (359% ± 131%, P = 0.004) and vWF:RCo was similar to baseline levels (338% ± 142%, P = 0.046). Compared with baseline, the calculated vWF:RCo/vWF:Ag ratio decreased after 24 hours on support (0.96 ± 0.23 to 0.61 ± 0.17, P ≤ 0.0001) and remained lower during 48 hours on ECMO (0.63 ± 0.18, P ≤ 0.0001). After termination of ECMO support (0.94 ± 0.19, P = 0.437), values rapidly returned to baseline. The number of HMW vWF multimers (n) decreased from baseline after 24 hours on ECMO (21 ± 1.4 to 14 ± 1.8, P ≤ 0.0001) and after 48 hours on ECMO (15 ± 2.1, P ≤ 0.0001). Twenty-four hours after termination of ECMO support, HMW vWF multimeric pattern had returned to baseline values (21 ± 1.8, P = 0.551). CONCLUSIONS: Loss of HMW vWF multimer bands occurred in patients undergoing ECMO support and resolved after the termination of ECMO. Although not detectable with coagulation screening tests, a vWF:RCo/vWF:Ag ratio <0.7 during ECMO was highly indicative for loss of HMW vWF multimers. Our findings may at least in part explain increased bleeding tendency during ECMO therapy. Administration of vWF concentrates may support restoration of primary hemostasis in patients with relevant bleeding during ECMO support.

Results of rotational thromboelastometry, coagulation activation markers and thrombin generation assays in orthopedic patients during thromboprophylaxis with rivaroxaban and enoxaparin: a prospective cohort study.

BACKGROUND: A prospective observational study was conducted in two clinical cohorts of patients to compare the effect of enoxaparin and rivaroxaban on rotational thromboelastometry (ROTEM), coagulation activation markers and thrombin generation. METHODS: A total of 188 consecutive patients scheduled for major orthopedic surgery receiving 40-mg enoxaparin subcutaneously or 10-mg rivaroxaban orally were evaluated. Blood samples were taken before induction of anesthesia and on day 4 after surgery [postoperative day 4 (pod 4)]. The extrinsically (EXTEM) and the intrinsically (INTEM) activated ROTEM assay, antithrombin, prothrombin fragments (F1 + 2), thrombin-antithrombin complex (TAT) and D-dimers were measured, and the thrombodynamic ratio (TDR) was calculated. Thrombin generation was determined using calibrated automated thrombography. To compare the groups, changes (Δ) in baseline versus pod 4 were calculated. RESULTS: EXTEM clotting time (CT) increased more with rivaroxaban than with enoxaparin; values above the reference range were observed (median ΔEXTEM-CT 15 vs. 5 s, P ≤ 0.0001). The increase in INTEM-CT (values remained within the normal ranges) was slight with enoxaparin and significant with rivaroxaban; ΔINTEM-CT was comparable. EXTEM-TDR, unchanged with rivaroxaban, increased significantly with enoxaparin, whereas ΔINTEM-TDR was comparable. ΔAT, ΔF1 + 2 and ΔTAT were significantly lower in the rivaroxaban group. Endogenous thrombin potential (ETP), unchanged with rivaroxaban, decreased significantly with enoxaparin; the maximal rising slope (mean velocity rate index) decreased more with rivaroxaban. CONCLUSION: Data show that prolonged CT in the extrinsic ROTEM and thrombin generation assays reflecting initiation and propagation of thrombin may be useful for detecting treatment with rivaroxaban. The significance of observed differences in markers of coagulation needs to be investigated further.

The exclusive use of coagulation factor concentrates enables reversal of coagulopathy and decreases transfusion rates in patients with major blunt trauma.

BACKGROUND: FFP and coagulation factor concentrates are used to correct trauma-induced coagulopathy (TIC). However, data on coagulation profiles investigating effects of therapy are scarce. METHODS: This is an analysis of 144 patients with major blunt trauma ((ISS)≥15), who were enrolled in a prospective cohort study investigating characteristics and treatment of TIC. Patients who received fibrinogen concentrate and/or prothrombin complex concentrate alone (CF Group) were compared with those additionally receiving FFP transfusions (FFP Group). RESULTS: Sixty-six patients exclusively received CF, while 78 patients additionally received FFP. Overall, patients were comparable regarding age, gender and ISS (CF Group, ISS 37 (29, 50); FFP Group ISS 38 (33, 55), p=0.28). Patients treated with CF alone showed sufficient haemostasis and received significantly fewer units of red blood cells (RBC) and platelets than did those also receiving FFP [(RBC 2(0, 4) U vs. 9 (5, 12) U; platelets 0 (0, 0) U vs. 1 (0, 2) U, p<0.001)]. In addition, fewer patients in the CF Group developed multiorgan failure (MOF) (18.2% vs. 37.2%, p=0.01) or sepsis (16.9% vs. 35.9%, p=0.014) than in the FFP Group. Propensity score-matching (n=28 pairs) used to reduce the impact of treatment selection confirmed that additional FFP administration showed no benefit in restoring haemostasis, but was associated with significantly higher transfusion rates for RBC and platelets. CONCLUSION: The use of CF alone effectively corrected coagulopathy in patients with severe blunt trauma and concomitantly decreased exposure to allogeneic transfusion, which may translate into improved outcome.