Early Goal-Directed Hemostatic Therapy for Severe Acute Bleeding Management in the Intensive Care Unit: A Narrative Review.

This is a narrative review of the published evidence for bleeding management in critically ill patients in different clinical settings in the intensive care unit (ICU). We aimed to describe "The Ten Steps" approach to early goal-directed hemostatic therapy (EGDHT) using point-of-care testing (POCT), coagulation factor concentrates, and hemostatic drugs, according to the individual needs of each patient. We searched National Library of Medicine, MEDLINE for publications relevant to management of critical ill bleeding patients in different settings in the ICU. Bibliographies of included articles were also searched to identify additional relevant studies. English-language systematic reviews, meta-analyses, randomized trials, observational studies, and case reports were reviewed. Data related to study methodology, patient population, bleeding management strategy, and clinical outcomes were qualitatively evaluated. According to systematic reviews and meta-analyses, EGDHT guided by viscoelastic testing (VET) has been associated with a reduction in transfusion utilization, improved morbidity and outcome in patients with active bleeding. Furthermore, literature data showed an increased risk of severe adverse events and poor clinical outcomes with inappropriate prophylactic uses of blood components to correct altered conventional coagulation tests (CCTs). Finally, prospective, randomized, controlled trials point to the role of goal-directed fibrinogen substitution to reduce bleeding and the amount of red blood cell (RBC) transfusion with the potential to decrease mortality. In conclusion, severe acute bleeding management in the ICU is still a major challenge for intensive care physicians. The organized and sequential approach to the bleeding patient, guided by POCT allows for rapid and effective bleeding control, through the rational use of blood components and hemostatic drugs, since VET can identify specific coagulation disorders in real time, guiding hemostatic therapy with coagulation factor concentrates and hemostatic drugs with individual goals.

Management of severe peri-operative bleeding: Guidelines from the European Society of Anaesthesiology and Intensive Care: Second update 2022.

BACKGROUND: Management of peri-operative bleeding is complex and involves multiple assessment tools and strategies to ensure optimal patient care with the goal of reducing morbidity and mortality. These updated guidelines from the European Society of Anaesthesiology and Intensive Care (ESAIC) aim to provide an evidence-based set of recommendations for healthcare professionals to help ensure improved clinical management. DESIGN: A systematic literature search from 2015 to 2021 of several electronic databases was performed without language restrictions. Grading of Recommendations, Assessment, Development and Evaluation (GRADE) was used to assess the methodological quality of the included studies and to formulate recommendations. A Delphi methodology was used to prepare a clinical practice guideline. RESULTS: These searches identified 137 999 articles. All articles were assessed, and the existing 2017 guidelines were revised to incorporate new evidence. Sixteen recommendations derived from the systematic literature search, and four clinical guidances retained from previous ESAIC guidelines were formulated. Using the Delphi process on 253 sentences of guidance, strong consensus (>90% agreement) was achieved in 97% and consensus (75 to 90% agreement) in 3%. DISCUSSION: Peri-operative bleeding management encompasses the patient's journey from the pre-operative state through the postoperative period. Along this journey, many features of the patient's pre-operative coagulation status, underlying comorbidities, general health and the procedures that they are undergoing need to be taken into account. Due to the many important aspects in peri-operative nontrauma bleeding management, guidance as to how best approach and treat each individual patient are key. Understanding which therapeutic approaches are most valuable at each timepoint can only enhance patient care, ensuring the best outcomes by reducing blood loss and, therefore, overall morbidity and mortality. CONCLUSION: All healthcare professionals involved in the management of patients at risk for surgical bleeding should be aware of the current therapeutic options and approaches that are available to them. These guidelines aim to provide specific guidance for bleeding management in a variety of clinical situations.

Red Blood Cell Transfusion in the Intensive Care Unit.

Importance: Red blood cell (RBC) transfusion is common among patients admitted to the intensive care unit (ICU). Despite multiple randomized clinical trials of hemoglobin (Hb) thresholds for transfusion, little is known about how these thresholds are incorporated into current practice. Objective: To evaluate and describe ICU RBC transfusion practices worldwide. Design, Setting, and Participants: International, prospective, cohort study that involved 3643 adult patients from 233 ICUs in 30 countries on 6 continents from March 2019 to October 2022 with data collection in prespecified weeks. Exposure: ICU stay. Main Outcomes and Measures: The primary outcome was the occurrence of RBC transfusion during ICU stay. Additional outcomes included the indication(s) for RBC transfusion (consisting of clinical reasons and physiological triggers), the stated Hb threshold and actual measured Hb values before and after an RBC transfusion, and the number of units transfused. Results: Among 3908 potentially eligible patients, 3643 were included across 233 ICUs (median of 11 patients per ICU [IQR, 5-20]) in 30 countries on 6 continents. Among the participants, the mean (SD) age was 61 (16) years, 62% were male (2267/3643), and the median Sequential Organ Failure Assessment score was 3.2 (IQR, 1.5-6.0). A total of 894 patients (25%) received 1 or more RBC transfusions during their ICU stay, with a median total of 2 units per patient (IQR, 1-4). The proportion of patients who received a transfusion ranged from 0% to 100% across centers, from 0% to 80% across countries, and from 19% to 45% across continents. Among the patients who received a transfusion, a total of 1727 RBC transfusions were administered, wherein the most common clinical indications were low Hb value (n = 1412 [81.8%]; mean [SD] lowest Hb before transfusion, 7.4 [1.2] g/dL), active bleeding (n = 479; 27.7%), and hemodynamic instability (n = 406 [23.5%]). Among the events with a stated physiological trigger, the most frequently stated triggers were hypotension (n = 728 [42.2%]), tachycardia (n = 474 [27.4%]), and increased lactate levels (n = 308 [17.8%]). The median lowest Hb level on days with an RBC transfusion ranged from 5.2 g/dL to 13.1 g/dL across centers, from 5.3 g/dL to 9.1 g/dL across countries, and from 7.2 g/dL to 8.7 g/dL across continents. Approximately 84% of ICUs administered transfusions to patients at a median Hb level greater than 7 g/dL. Conclusions and Relevance: RBC transfusion was common in patients admitted to ICUs worldwide between 2019 and 2022, with high variability across centers in transfusion practices.

Management and outcomes of pregnant ICU patients with severe COVID-19 pneumonia in Qatar: A retrospective cohort study.

INTRODUCTION: Pregnant women are considered a high-risk group for COVID-19 due to their increased vulnerability to viral infections. The impact of COVID-19 on pregnant women is not well understood, and there is a need for data on managing severe COVID-19 in pregnant patients. This retrospective descriptive cohort study described the characteristics, hospital stay, interventions, and outcomes of pregnant patients admitted to the intensive care units (ICUs) with severe COVID-19 pneumonia in Qatar. METHODS: Data were collected from medical records and chart reviews of pregnant women admitted to Hamad Medical Corporation (HMC) with COVID-19 pneumonia from March 01, 2020, to July 31, 2021. The inclusion criteria encompassed pregnant women with a positive polymerase chain reaction (PCR) antigen test or radiological changes at admission, requiring respiratory support, and hospitalized for more than 24 hours. RESULTS: A total of 43 pregnant women were included in this study. Most patients were admitted during the first wave of the pandemic, with a median gestational age of 212 days [interquartile range 178-242 days] at presentation. The most common respiratory support methods were high-flow nasal cannula, non-invasive positive pressure ventilation, and invasive positive pressure ventilation. Convalescent plasma therapy was administered to 58% of patients, and tocilizumab was used in 28%. Renal replacement therapy was required by 4.6% of patients and 7% required extracorporeal membrane oxygenation. CONCLUSION: This study provides valuable insights into the impact of COVID-19 on pregnant patients admitted to the ICUs in Qatar. The results suggest that pregnant patients with COVID-19 pneumonia require close monitoring and appropriate interventions to minimize adverse outcomes for both mother and fetus. The data may contribute to future guidelines and management strategies for severe COVID-19 in pregnant patients.

Point-of-Care Platelet Function Monitoring: Implications for Patients With Platelet Inhibitors in Cardiac Surgery.

Although most physicians are comfortable managing the limited anticoagulant effect of aspirin, the recent administration of potent P2Y12 receptor inhibitors in patients undergoing cardiac surgery remains a dilemma. Guidelines recommend discontinuation of potent P2Y12 inhibitors 5- to- 7 days before surgery to reduce the risk of postoperative hemorrhage. Such a strategy might not be feasible before urgent surgery, due to ongoing myocardial ischemia or in patients at high risk for thromboembolic events. Recently, different point-of-care devices to assess functional platelet quality have become available for clinical use. The aim of this narrative review was to evaluate the implications and potential benefits of platelet function monitoring in guiding perioperative management and therapeutic options in patients treated with antiplatelets, including aspirin or P2Y12 receptor inhibitors, undergoing cardiac surgery. No objective superiority of one point-of-care device over another was found in a large meta-analysis. Their accuracy and reliability are generally limited in the perioperative period. In particular, preoperative platelet function testing has been used to assess platelet contribution to bleeding after cardiac surgery. However, predictive values for postoperative hemorrhage and transfusion requirements are low, and there is a significant variability between and within these tests. Further, platelet function monitoring has been used to optimize the preoperative waiting period after cessation of dual antiplatelet therapy before urgent cardiac surgery. Furthermore, studies assessing their value in therapeutic decisions in bleeding patients after cardiac surgery are scarce. A general and liberal use of perioperative platelet function testing is not yet recommended.

Pneumorrhachis and pneumothorax after epidural analgesia: A case report and review.

Epidural analgesia or anesthesia is a common procedure for pain relief, especially in obstetrics. Pneumorrhachis and pneumothorax are rare complications of epidural analgesia. They are considered asymptomatic entities but have recently caused increased morbidity and mortality. As the use of epidural analgesia and anesthesia increased significantly in the last decade, clinicians must be aware of this entity. This is a case report of pneumorrhachis causing pneumothorax and pneumomediastinum leading to respiratory distress. Case: A 26-year-old obese primigravida at 37 weeks' gestation and with failure of progression of labor underwent lower segment cesarean section under epidural anesthesia. The procedure including the delivery of fetus was uneventful. In the post-anesthesia care unit, the patient became tachypneic, and her oxygen saturation was low despite supplemented oxygen by face mask and adequate analgesia. She was afebrile and was admitted to the surgical intensive care unit (SICU) for further management. In the SICU, incentive spirometry was initiated, and analgesia with intravenous fentanyl was given. Her echocardiogram was normal. Computer tomographic examination ruled out pulmonary embolism but showed pneumorrhachis with extension into the mediastinum and right apical pneumothorax. She was hemodynamically stable. In the next two days, her tachypnea settled, and the oxygen saturation improved to normal. On the third day, she was transferred to the ward and discharged home from there. She was followed up in the outpatient clinic after one and four weeks and was doing well, and her repeat imaging studies were normal. Conclusion: Epidural analgesia can lead to pneumorrhachis and can cause pneumothorax leading to respiratory distress.

Shifts of Transfusion Demand in Cardiac Surgery After Implementation of Rotational Thromboelastometry-Guided Transfusion Protocols: Analysis of the HEROES-CS (HEmostasis Registry of patiEntS in Cardiac Surgery) Observational, Prospective Open Cohort Database.

OBJECTIVES: Rotational thromboelastometry (ROTEM)-guided transfusion algorithms in cardiac surgery have been proven to be successful in reducing blood loss in randomized controlled trials. Using an institutional hemostasis registry of patients in cardiac surgery (HEROES-CS), the authors hypothesized that the use of ROTEM-guided transfusion algorithms would save blood products and overall costs in cardiac surgery in every day practice. DESIGN: Observational, prospective open cohort database. SETTING: Single-center academic hospital. PARTICIPANTS: Cardiac surgery patients. INTERVENTIONS: Implementation of ROTEM-guided bleeding management. MEASUREMENTS AND MAIN RESULTS: A classical-guided algorithm and a ROTEM-guided algorithm were used for patient blood management in 2 cohorts. Primary outcome was the use and amount of blood products and hemostatic medication. Secondary outcomes were amount of rethoracotomies, length of stay, and 30-day mortality. Finally, costs and savings were calculated. The classical-guided cohort comprised 204 patients, and ROTEM-guided cohort comprised 151 patients. Baseline characteristics showed excellent similarities after propensity score matching of 202 patients. Blood loss was lower after ROTEM guidance (p < 0.001). Absolute risk reduction was 17% for red blood cells (p = 0.024), 12% for fresh frozen plasma (p = 0.019), and 4% for thrombocyte concentrates (p = 0.582). More tranexamic acid was given, but not more fibrinogen concentrate, while desmopressin was given less often. Hospital length of stay was reduced by an overall median of 2 and a mean of 4 days (p < 0.001). Mortality and rethoracotomy rates were not affected. Potential savings were about €4,800 ($5,630) per patient. CONCLUSIONS: Implementation of a ROTEM-guided transfusion algorithm in cardiac surgery patients reduced the use of blood products and hemostatic medication, hereby saving costs. Reductions in mortality and rethoracotomy rates could not be found.

Surgical intensive care - current and future challenges?

Bjorn Ibsen, an anesthetist who pioneered positive pressure ventilation as a treatment option during the Copenhagen polio epidemic of 1952, set up the first Intensive Care Unit (ICU) in Europe in 1953. He managed polio patients on positive pressure ventilation together with physicians and physiologists in a dedicated ward, where one nurse was assigned to each patient. In that sense Ibsen is more or less the father of intensive care medicine as a specialty and also an advocate of the one-to-one nursing ratio for critically ill patients. Nowadays, the Surgical Intensive Care Unit (SICU) offers critical care treatment to unstable, severely, or potentially severely ill patients in the perioperative setting, who have life-threatening conditions and require comprehensive care, constant monitoring, and possible emergency interventions. Hence there is one very specific challenge in the surgical setting: the intensivist has to manage the patient flow starting from admission to the hospital through to the operating theater, in the SICU, and postoperatively for the discharge to the ward. In other words, the planning of the resources (most frequently availability of beds) has to be optimized to prevent cancellations of elective surgical procedures but also to facilitate other emergency admissions. SICU intensivists take the role of arbitrators between surgical demand and patient's interests. This means they supervise the safety, efficacy, and workability of the process with respect to all stakeholders. This notion was reported in 2007 when Stawicki and co-workers performed a small prospective study concluding that it appears safe if the dedicated intensivist takes over the role of the last arbitrator supported by a multidisciplinary team.1 However, demographic changes in many countries during the last few decades have given rise to populations which are more elderly and sicker than before. This impacts on the healthcare system in general but on the intensivist and the ICU team too. In addition, in a society with an increased life expectancy, the balance between treatable disease, outcome, and utilization of resources must be maintained. This fact gains even more importance as patients and their families claim "high end" treatment. Such a demand is reflected looking at the developments that have taken place over the last 25 years. Mainly, the focus of intensive care medicine was on technical support or even replacement of failing organ systems such as the lungs, the heart, or the kidneys by veno-venous extracorporeal membrane oxygenation (VV-ECMO), veno-arterial ECMO (VA-ECMO), and continuous veno-venous hemofiltration (CVVH) respectively. This means "technical care" became a core capability and expectation of critical care medicine. In parallel, medical treatment became more standardized. For example, lung protective ventilation strategies, early enteral feeding, and daily sedation vacation are part of modern protocols. As a consequence, ventilator time has been reduced and patients therefore develop delirium less frequently. These measures, beside others, are implemented in care bundles to improve the quality of care of patients by the whole ICU team. The importance of specialty trained teams was already pointed out 35 years ago when Li et al.,2 demonstrated in a study performed in a community hospital that the mortality was decreased if an ICU was managed 24/7 by an on-site physician. The association of improved outcomes and presence of a critical care trained physician (intensivist) has been shown in several studies since that time.3,4,5,6 A modern multidisciplinary critical care team consists at least of an intensivist, ICU nurse, pharmacist, respiratory therapist, physiotherapist, and the primary team physician. Based on clinical needs, the team can be supplemented by oncologists, cardiologists, or other specialties. Again, this approach is supported by research: a recent retrospective cohort study from the California Hospital Assessment and Reporting Taskforce (CHART) on 60,330 patients confirmed the association between improved patient outcome and such a multidisciplinary team.7 If such an intensive care team makes a difference, why do not all patients at risk receive advanced ICU-care? It was already demonstrated by Esteban et al., in a prospective study that patients with severe sepsis had a mortality rate of 26% when not admitted to an ICU in comparison to 11% when they were admitted to an ICU.8 Meanwhile, we know that early referral is particularly important, because for ischemic diseases the timing appears to make a difference in terms of full recovery. So, the following questions arise: Should intensive care be rolled out to each ward and physical admission to an ICU or be restricted to special cases only? For this purpose, the so-called "Rapid Response Teams" (RRT) or "Medical Emergency Team" (MET), which essentially are a form of an ICU outreach team, were implemented. The name, composition, or exact role of such team varies from institution to institution and country to country. Alternatively, should all ward staff be educated to recognize sick patients earlier for a timely transfer to a dedicated area? This would mean that ICU-care would be introduced in the ward. A first attempt to answer this question, whether to deploy critical care resources to deteriorating patients outside the ICU 24/7, was given by Churpek et al.9 The success of the rapid response teams could be related to decreased rates of cardiac arrest outside the ICU setting and in-hospital mortality. Interestingly, an analysis of the registry database of the RRT calls in this study showed that the lowest frequency of calls occurred between 1:00 AM to 6:59 AM time period. In contrast, the mortality was highest around 7 AM and lowest during noon hour. This indicates that not simply the availability of such a team makes a difference but also the alertness of the ward-teams is of high importance to identify deteriorating patients in a timely manner. Essentially, this would necessitate ward staff being trained to provide a higher level of care enabling them to better recognize when patients become sicker to avoid a delayed call to the ICU. Alternatively, a system in which the intensivist plays a major role in daily ward rounds could be beneficial. So, the ward doctor should become an intensivist. However, the latter means the ICU is rolled out across the whole hospital which would consume a huge amount of resources. Another option would be 24/7 remote monitoring of patients at risk that notifies the intensivist or RRT in case of need. The infrastructure, technology, and manpower to put this in place also has associated costs. As the demand for ICU care will rise further in the future, intensivists will play an even more important role in the healthcare system that itself is under enormous economic pressure to ensure the best quality of care for critically ill patients. Besides excellent knowledge and hard skills, intensivists need to be team players, communicators, facilitators, and arbitrators to achieve the best results in collaboration with all involved in patient treatment.

European guidelines on perioperative venous thromboembolism prophylaxis: Cardiovascular and thoracic surgery.

: None of the predictive models for venous thromboembolism (VTE) prophylaxis have been designed for and validated in patients undergoing cardiothoracic and vascular surgery. The presence of one or more risk factors [age over 70 years old, transfusion of more than 4 U of red blood cells/fresh frozen plasma/cryoprecipitate, mechanical ventilation lasting more than 24 h, postoperative complication (e.g. acute kidney injury, infection/sepsis, neurological complication)] should place the cardiac population at high risk for VTE. In this context, we suggest the use of pharmacological prophylaxis as soon as satisfactory haemostasis has been achieved, in addition to intermittent pneumatic compression (IPC) (Grade 2C). In patients undergoing abdominal aortic aneurysm repair, particularly when an open surgical approach is used, the risk for VTE is high and the bleeding risk is high. In this context, we suggest the use of pharmacological prophylaxis as soon as satisfactory haemostasis is achieved (Grade 2C). Patients undergoing thoracic surgery in the absence of cancer could be considered at low risk for VTE. Patients undergoing thoracic surgery with a diagnosis of primary or metastatic cancer should be considered at high risk for VTE. In low-risk patients, we suggest the use of mechanical prophylaxis using IPC (Grade 2C). In high-risk patients, we suggest the use of pharmacological prophylaxis in addition to IPC (Grade 2B).

Plasminogen associates with phosphatidylserine-exposing platelets and contributes to thrombus lysis under flow.

The interaction of plasminogen with platelets and their localization during thrombus formation and fibrinolysis under flow are not defined. Using a novel model of whole blood thrombi, formed under flow, we examine dose-dependent fibrinolysis using fluorescence microscopy. Fibrinolysis was dependent upon flow and the balance between fibrin formation and plasminogen activation, with tissue plasminogen activator-mediated lysis being more efficient than urokinase plasminogen activator-mediated lysis. Fluorescently labeled plasminogen radiates from platelet aggregates at the base of thrombi, primarily in association with fibrin. Hirudin attenuates, but does not abolish plasminogen binding, denoting the importance of fibrin. Flow cytometry revealed that stimulation of platelets with thrombin/convulxin significantly increased the plasminogen signal associated with phosphatidylserine (PS)-exposing platelets. Binding was attenuated by tirofiban and Gly-Pro-Arg-Pro amide, confirming a role for fibrin in amplifying plasminogen binding to PS-exposing platelets. Confocal microscopy revealed direct binding of plasminogen and fibrinogen to different platelet subpopulations. Binding of plasminogen and fibrinogen co-localized with PAC-1 in the center of spread platelets. In contrast, PS-exposing platelets were PAC-1 negative, and bound plasminogen and fibrinogen in a protruding "cap." These data show that different subpopulations of platelets harbor plasminogen by diverse mechanisms and provide an essential scaffold for the accumulation of fibrinolytic proteins that mediate fibrinolysis under flow.

Platelet Control of Fibrin Distribution and Microelasticity in Thrombus Formation Under Flow.

OBJECTIVE: Platelet- and fibrin-dependent thrombus formation is regulated by blood flow and exposure of collagen and tissue factor. However, interactions between these blood-borne and vascular components are not well understood. APPROACH AND RESULTS: Here, we developed a method to assess whole-blood thrombus formation on microspots with defined amounts of collagen and tissue factor, allowing determination of the mechanical properties and intrathrombus composition. Confining the collagen content resulted in diminished platelet deposition and fibrin formation at high shear flow conditions, but this effect was compensated by a larger thrombus size and increased accumulation of fibrin in the luminal regions of the thrombi at the expense of the base regions. These thrombi were more dependent on tissue factor-triggered thrombin generation. Microforce nanoindentation analysis revealed a significantly increased microelasticity of thrombi with luminal-oriented fibrin. At a low shear rate, fibrin fibers tended to luminally cover the thrombi, again resulting in a higher microelasticity. Studies with blood from patients with distinct hemostatic insufficiencies indicated an impairment in the formation of a platelet-fibrin thrombus in the cases of dilutional coagulopathy, thrombocytopenia, Scott syndrome, and hemophilia B. CONCLUSIONS: Taken together, our data indicate that (1) thrombin increases the platelet thrombus volume; (2) tissue factor drives the formation of fibrin outside of the platelet thrombus; (3) limitation of platelet adhesion redirects fibrin from bottom to top of the thrombus; (4) a lower shear rate promotes thrombus coverage with fibrin; (5) the fibrin distribution pattern determines thrombus microelasticity; and (6) the thrombus-forming process is reduced in patients with diverse hemostatic defects.

The use of regression analysis in determining reference intervals for low hematocrit and thrombocyte count in multiple electrode aggregometry and platelet function analyzer 100 testing of platelet function.

Low platelet counts and hematocrit levels hinder whole blood point-of-care testing of platelet function. Thus far, no reference ranges for MEA (multiple electrode aggregometry) and PFA-100 (platelet function analyzer 100) devices exist for low ranges. Through dilution methods of volunteer whole blood, platelet function at low ranges of platelet count and hematocrit levels was assessed on MEA for four agonists and for PFA-100 in two cartridges. Using (multiple) regression analysis, 95% reference intervals were computed for these low ranges. Low platelet counts affected MEA in a positive correlation (all agonists showed r2 ≥ 0.75) and PFA-100 in an inverse correlation (closure times were prolonged with lower platelet counts). Lowered hematocrit did not affect MEA testing, except for arachidonic acid activation (ASPI), which showed a weak positive correlation (r2 = 0.14). Closure time on PFA-100 testing was inversely correlated with hematocrit for both cartridges. Regression analysis revealed different 95% reference intervals in comparison with originally established intervals for both MEA and PFA-100 in low platelet or hematocrit conditions. Multiple regression analysis of ASPI and both tests on the PFA-100 for combined low platelet and hematocrit conditions revealed that only PFA-100 testing should be adjusted for both thrombocytopenia and anemia. 95% reference intervals were calculated using multiple regression analysis. However, coefficients of determination of PFA-100 were poor, and some variance remained unexplained. Thus, in this pilot study using (multiple) regression analysis, we could establish reference intervals of platelet function in anemia and thrombocytopenia conditions on PFA-100 and in thrombocytopenia conditions on MEA.

Management of severe perioperative bleeding: guidelines from the European Society of Anaesthesiology: First update 2016.

: The management of perioperative bleeding involves multiple assessments and strategies to ensure appropriate patient care. Initially, it is important to identify those patients with an increased risk of perioperative bleeding. Next, strategies should be employed to correct preoperative anaemia and to stabilise macrocirculation and microcirculation to optimise the patient's tolerance to bleeding. Finally, targeted interventions should be used to reduce intraoperative and postoperative bleeding, and so prevent subsequent morbidity and mortality. The objective of these updated guidelines is to provide healthcare professionals with an overview of the most recent evidence to help ensure improved clinical management of patients. For this update, electronic databases were searched without language restrictions from 2011 or 2012 (depending on the search) until 2015. These searches produced 18 334 articles. All articles were assessed and the existing 2013 guidelines were revised to take account of new evidence. This update includes revisions to existing recommendations with respect to the wording, or changes in the grade of recommendation, and also the addition of new recommendations. The final draft guideline was posted on the European Society of Anaesthesiology website for four weeks for review. All comments were collated and the guidelines were amended as appropriate. This publication reflects the output of this work.

Validation of a modified thromboelastometry approach to detect changes in fibrinolytic activity.

BACKGROUND: Thus far, validated whole blood assays used in in vitro fibrinolysis experiments using thromboelastometry (ROTEM) are lacking or have yet to be tested in humans. The objective was first, to establish a standardized modified ROTEM approach to detect both hypo- and hyperfibrinolysis. And second, to perform a technical and clinical validation of the assay. METHODS: Blood was used of healthy volunteers, patients with sepsis, patients after cardiothoracic surgery, pregnant women, and cirrhotic liver disease patients. A whole blood tissue factor (TF) activated ROTEM assay with and without the addition of recombinant tissue plasminogen activator (rTPA) was developed. Plasma fibrinolysis determinants were measured in all volunteers and patients. RESULTS: Thirty five pM TF and additions of 125 and 175 ng/ml rTPA resulted in full lysis within 60 min in healthy volunteers. Coefficients of variation were below 10 % without and below 20 % with rTPA addition. In sepsis the hypofibrinolytic ROTEM profiles with 175 ng/ml rTPA were in line with the plasma determinants (high PAI-1, high fibrinogen, low tPA activity, and high d-dimers). After cardiothoracic surgery, reduced fibrinogen and platelet levels accounted for the reduced maximum clot firmness. The hypofibrinolytic profile is attributed to tranexamic acid use and elevated PAI-1 levels. The lowest rTPA concentration in cirrhosis resulted in hyperfibrinolysis in only few of the patients. In pregnancy normal profiles were found. DISCUSSION: Our high rTPA concentration demonstrates hypofibrinolytic profiles adequately in sepsis and after cardiothoracic surgery. Our low rTPA concentration of 125 ng/ml seems too high for demonstrating hyperfibrinolysis in cirrhotic liver disease. CONCLUSIONS: We were able to present a validated whole blood ROTEM approach to fibrinolysis testing using added rTPA, which can be of added value next to classical plasma based fibrinolysis assays.

Early platelet recovery following cardiac surgery with cardiopulmonary bypass.

Coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB) is frequently associated with low platelet count (PC) and disturbed platelet function (PF). While PC is easy to measure, PF is more difficult to assess. Moreover, the time-related platelet dysfunction and recovery after CPB is not fully elucidated. Platelet dysfunction could lead to bleeding but also to coronary graft failure. Laboratory tests could provide more insights into PF after CABG. The aim of the current study was to investigate the time-related PF induced by CPB. Blood samples of 20 patients with a preoperative PC of more than 250 × 109/L were collected before incision, after weaning from CPB, and 24 h postoperative. Platelet contribution to coagulation was quantified by PLTEM (calculated by means of EXTEM and FIBTEM results). PF was assessed by multiple electrode impedance aggregometry (MEIA) in whole blood and by light transmission aggregometry (LTA) in platelet-rich plasma after stimulation with arachidonic acid (AA), adenosine diphosphate, collagen, and thrombin-receptor-activating peptide. LTA and MEIA analysis demonstrated significant platelet dysfunction after CPB, with partial recovery within 24 h after surgery. AA-induced platelet aggregation increased to higher levels within 24 h after surgery compared to baseline values as measured by LTA. PLTEM maximum clot firmness remained unchanged throughout the study. Correlation analyses revealed that MEIA and rotational thromboelastometry (ROTEM), but not LTA, were dependent on PC and hematocrit. No correlations were found between LTA, MEIA, ROTEM, PC, and clinical outcome parameters. Our results demonstrate a reversible platelet dysfunction recovering within 24 h after CPB. Interestingly, AA-induced platelet aggregation increases to higher levels during the first 24 h postoperatively, which might be important for early initiation of antiplatelet therapy after CABG. MEIA as POC test is able to detect platelet dysfunction during cardiac surgery with a PC of ≥150 × 109/L.

Platelet Function During Hypothermia in Experimental Mock Circulation.

Alterations in platelet function are a common finding in surgical procedures involving cardiopulmonary bypass and hypothermia. Although the combined impact of hypothermia and artificial circulation on platelets has been studied before, the ultimate strategy to safely minimize the risk for bleeding and thrombosis is yet unknown. The aim of this study was to evaluate the use of a mock circulation loop to study the impact of hypothermia for platelet-related hemostatic changes. Venous blood was collected from healthy adult humans (n = 3). Closed mock circulation loops were assembled, each consisting of a centrifugal pump, an oxygenator with integrated heat exchanger, and a hardshell venous reservoir. The experiment started with the mock circulation temperature set at 37°C (T0 [0 h]). Cooling was then initiated at T1 (+2 h), where temperature was adjusted from 37°C to 32°C. Hypothermia was maintained from T2 (+4 h) to T3 (+28 h). From that point in time, rewarming from 32°C to 37°C was initiated with similar speed as cooling. From time point T4 (+30 h), normothermia (37°C) was maintained until the experiment ended at T5 (+32 h). Blood samples were analyzed in standard hematological tests: light transmission aggregometry (LTA) (arachidonic acid [AA], adenosine diphosphate [ADP], collagen [COL], thrombin-receptor-activating-peptide-14 [TRAP]), multiple electrode aggregometry (MEA) (AA, ADP, COL, TRAP), and rotational thromboelastometry (ROTEM) (EXTEM, FIBTEM, PLTEM). Hemoglobin, hematocrit, and platelet count decrease more substantially during temperature drop (37-32°C) than during hypothermia maintenance. Hb and Hct continue to follow this trend during active rewarming (32-37°C). PC increase from the moment active rewarming was initiated. None of the values return to the initial values. LTA values demonstrate a similar decrease in aggregation after stimulation with the platelet agonists between the start of the mock circulation and the start of cooling. Except for platelet stimulation using COL, this trend continues during temperature drop from 37°C to 32°C. LTA values using AA and TRAP demonstrate a considerable decline in platelet function throughout the experiment that was most pronounced after 24 h of circulation at 32°C. LTA values using ADP and COL further decline after rewarming. MEA ADP, ASPI, and COL identify platelet dysfunction patterns analogous with LTA, between the start of the mock circulation and the start of cooling. Except for MEA TRAP, this trend continues during temperature drop from 37°C to 32°C. MEA ASPI and ADP demonstrate a considerable decline in platelet function throughout the experiment, which was most pronounced after 24 h of circulation at 32°C. For MEA COL and TRAP, further decline in platelet function is observed after rewarming. This study quantitatively assessed the effect of temperature changes on platelet function during experimental mock circulation demonstrating a considerable decline in platelet function during hypothermia without uniform recovery of platelet function observed after rewarming.

A general review of major global coagulation assays: thrombelastography, thrombin generation test and clot waveform analysis.

Thrombosis and hemorrhage are major contributors to morbidity and mortality. The traditional laboratory tests do not supply enough information to diagnose and treat patients timely and according to their phenotype. Global hemostasis tests might improve this circumstance. The viscoelastic tests (ROTEM/TEG) demonstrated to ameliorate treatment of acute hemorrhage in terms of decreased amount of transfusion and lowered costs. Thrombin generation measurement is indicative for thrombosis and might also become an important tool in managing hemorrhage. While the clot waveform analysis is less well known it could be of worth in staging sepsis patients, early detection of DIC and also in diagnosis and treatment monitoring of hemophiliac patients. Although in different degree all three methods still need more background, standardization and acceptance before a wide clinical application.

Guideline-based development of quality indicators for prevention and management of postpartum hemorrhage.

INTRODUCTION: To systematically develop a set of guideline-based quality indicators for postpartum hemorrhage (PPH) as a tool to measure guideline adherence in actual PPH care. MATERIAL AND METHODS: A Rand-modified Delphi procedure was used to systematically achieve consensus among a panel of 22 experts on PPH care on recommendations extracted from evidence-based guidelines, Managing-Obstetrics-Emergencies-Trauma (MOET) instructions and international literature. The selected recommendations were individually rated on health gain (prevention of maternal mortality and morbidity) and overall efficiency by the expert panel. Subsequently, consensus about the most important recommendations to measure quality of PPH care among the panel members was reached, followed by a final approval. Last, definition of the final set by critical appraisal of the recommendations regarding measurability took place. The main outcome measure was a set of valid quality indicators for prevention and management of PPH. RESULTS: From the 69 extracted recommendations, 50 were selected and translated into 22 quality indicators on professional performance (n = 17) and organization of PPH care (n = 5). The professional performance indicators covered all fields of PPH care, such as prevention (n = 2) and management of PPH, including communication and documentation (n = 4), monitoring and prevention of shock (n = 3), use of blood products (n = 3) and treatment of PPH (n = 5). Organizational indicators (n = 5) were clustered into protocols and agreements, audit, accessibility and documentation. CONCLUSIONS: This study describes a stepwise systematic development of 22 performance and organizational indicators to use for measuring the whole care process of prevention and management of PPH.