Daniel Bolliger

Principles and Practice of Thromboelastography in Clinical Coagulation Management and Transfusion Practice

In the recent years, thromboelastography has become a popular monitoring device for hemostasis and transfusion management in major surgery, trauma, and hemophilia. Thromboelastography is performed in whole blood and assesses the viscoelastic property of clot formation under low shear condition. Thromboelastography can be performed with a variety of activator and inhibitors at different concentrations representing the most important factors for different intervals and clot formation variables reported in multiple studies and algorithms. Furthermore, fibrinogen levels and platelet counts have a major influence on thromboelastographic variables. In addition, differences in patient populations, devices, and preanalytical conditions contribute to some conflicting findings in different studies.

Finding the optimal concentration range for fibrinogen replacement after severe haemodilution: an in vitro model

BACKGROUND Replacement of fibrinogen is presumably the key step in managing dilutional coagulopathy. We performed an in vitro study hypothesizing that there is a minimal fibrinogen concentration in diluted whole blood above which the rate of clot formation approaches normal. METHODS Blood samples from six healthy volunteers were diluted 1:5 v/v with saline keeping haematocrit at 24% using red cell concentrates. We measured coagulation factors and thrombin generation in plasma at baseline and after dilution. Thromboelastometry was used to evaluate (i) speed and quality of clot formation in diluted samples supplemented with fibrinogen 50-300 mg dl(-1) and (ii) clot resistance to fibrinolysis. Diluted and undiluted samples with no added fibrinogen served as controls. RESULTS Coagulation parameters and platelets were reduced by 74-85% after dilution. Peak thrombin generation was reduced by 56%. Adding fibrinogen led to a concentration-dependent improvement of all thromboelastometric parameters. The half maximal effective concentration (EC50) for fibrinogen replacement in haemodiluted blood was calculated to be 125 mg dl(-1). Adding tissue plasminogen activator, 0.15 microg ml(-1), led to a decrease of clot firmness and lysis time. CONCLUSIONS The target plasma concentration for fibrinogen replacement was predicted by these in vitro results to be greater than 200 mg dl(-1) as only these concentrations optimized the rate of clot formation. This concentration is twice the level suggested by the current transfusion guidelines. Although improved, clots were prone to fibrinolysis indicating that the efficacy of fibrinogen therapy may be influenced by co-existing fibrinolytic tendency occurring during dilutional coagulopathy.

Pathophysiology and Treatment of Coagulopathy in Massive Hemorrhage and Hemodilution

Fluid resuscitation after massive hemorrhage in major surgery and trauma may result in extensive hemodilution and coagulopathy, which is of a multifactorial nature. Although coagulopathy is often perceived as hemorrhagic, extensive hemodilution affects procoagulants as well as anticoagulant, profibrinolytic, and antifibrinolytic elements, leading to a complex coagulation disorder. Reduced thrombin activation is partially compensated by lower inhibitory activities of antithrombin and other protease inhibitors, whereas plasma fibrinogen is rapidly decreased proportional to the extent of hemodilution. Adequate fibrinogen levels are essential in managing dilutional coagulopathy. After extensive hemodilution, fibrin clots are more prone to fibrinolysis because major antifibrinolytic proteins are decreased. Fresh frozen plasma, platelet concentrate, and cryoprecipitate are considered the mainstay hemostatic therapies. Purified factor concentrates of plasma origin and from recombinant synthesis are increasingly used for a rapid restoration of targeted factors. Future clinical studies are necessary to establish the specific indication, dosing, and safety of novel hemostatic interventions.

Rivastigmine for the prevention of postoperative delirium in elderly patients undergoing elective cardiac surgery : A randomized controlled trial

Objective:Cardiac surgery is frequently followed by postoperative delirium, which is associated with increased 1-year mortality, late cognitive deficits, and higher costs. Currently, there are no recommendations for pharmacologic prevention of postoperative delirium. Impaired cholinergic transmission is believed to play an important role in the development of delirium. We tested the hypothesis that prophylactic short-term administration of oral rivastigmine, a cholinesterase inhibitor, reduces the incidence of delirium in elderly patients during the first 6 days after elective cardiac surgery. Design:Double-blind, randomized, placebo-controlled trial. Setting:One Swiss University Hospital. Patients:One hundred twenty patients aged 65 or older undergoing elective cardiac surgery with cardiopulmonary bypass. Intervention:Patients were randomly assigned to receive either placebo or 3 doses of 1.5 mg of oral rivastigmine per day starting the evening before surgery and continuing until the evening of the sixth postoperative day. Measurements and Main Results:The primary predefined outcome was delirium diagnosed with the Confusion Assessment Method within 6 days postoperatively. Secondary outcome measures were the results of daily Mini-Mental State Examinations and clock drawing tests, and the use of a rescue treatment consisting of haloperidol and/or lorazepam in patients with delirium. Delirium developed in 17 of 57 (30%) and 18 of 56 (32%) patients in the placebo and rivastigmine groups, respectively (p = 0.8). There was no treatment effect on the time course of Mini-Mental State Examinations and clock drawing tests (p = 0.4 and p = 0.8, respectively). There was no significant difference in the number of patients receiving haloperidol (18 of 57 and 17 of 56, p = 0.9) or lorazepam (38 of 57 and 35 of 56, p = 0.6) in the placebo and rivastigmine groups, respectively. Conclusion:This negative or, because of methodologic issues, possibly failed trial does not support short-term prophylactic administration of oral rivastigmine to prevent postoperative delirium in elderly patients undergoing elective cardiac surgery with cardiopulmonary bypass.

The prognostic value of pre-operative and post-operative B-type natriuretic peptides in patients undergoing noncardiac surgery: B-type natriuretic peptide and N-terminal fragment of pro-B-type natriuretic peptide: A systematic review and individual patient data meta-analysis

OBJECTIVES The objective of this study was to determine whether measuring post-operative B-type natriuretic peptides (NPs) (i.e., B-type natriuretic peptide [BNP] and N-terminal fragment of proBNP [NT-proBNP]) enhances risk stratification in adult patients undergoing noncardiac surgery, in whom a pre-operative NP has been measured. BACKGROUND Pre-operative NP concentrations are powerful independent predictors of perioperative cardiovascular complications, but recent studies have reported that elevated post-operative NP concentrations are independently associated with these complications. It is not clear whether there is value in measuring post-operative NP when a pre-operative measurement has been done. METHODS We conducted a systematic review and individual patient data meta-analysis to determine whether the addition of post-operative NP levels enhanced the prediction of the composite of death and nonfatal myocardial infarction at 30 and ≥180 days after surgery. RESULTS Eighteen eligible studies provided individual patient data (n = 2,179). Adding post-operative NP to a risk prediction model containing pre-operative NP improved model fit and risk classification at both 30 days (corrected quasi-likelihood under the independence model criterion: 1,280 to 1,204; net reclassification index: 20%; p < 0.001) and ≥180 days (corrected quasi-likelihood under the independence model criterion: 1,320 to 1,300; net reclassification index: 11%; p = 0.003). Elevated post-operative NP was the strongest independent predictor of the primary outcome at 30 days (odds ratio: 3.7; 95% confidence interval: 2.2 to 6.2; p < 0.001) and ≥180 days (odds ratio: 2.2; 95% confidence interval: 1.9 to 2.7; p < 0.001) after surgery. CONCLUSIONS Additional post-operative NP measurement enhanced risk stratification for the composite outcomes of death or nonfatal myocardial infarction at 30 days and ≥180 days after noncardiac surgery compared with a pre-operative NP measurement alone.

The Predictive Ability of Pre-Operative B-Type Natriuretic Peptide in Vascular Patients for Major Adverse Cardiac Events: An Individual Patient Data Meta-Analysis

OBJECTIVES The aims of this study were to perform an individual patient data meta-analysis of studies using B-type natriuretic peptides (BNPs) to predict the primary composite endpoint of cardiac death and nonfatal myocardial infarction (MI) within 30 days of vascular surgery and to determine: 1) the cut points for a natriuretic peptide (NP) diagnostic, optimal, and screening test; and 2) if pre-operative NPs improve the predictive accuracy of the revised cardiac risk index (RCRI). BACKGROUND NPs are independent predictors of cardiovascular events in noncardiac and vascular surgery. Their addition to clinical risk indexes may improve pre-operative risk stratification. METHODS Studies reporting the association of pre-operative NP concentrations and the primary study endpoint, post-operative major adverse cardiovascular events (defined as cardiovascular death and nonfatal MI) in vascular surgery, were identified by electronic database search. Secondary study endpoints included all-cause mortality, cardiac death, and nonfatal MI. RESULTS Six data sets were obtained, 5 for BNP (n = 632) and 1 for N-terminal pro-BNP (n = 218). An NP level higher than the optimal cut point was an independent predictor for the primary composite endpoint (odds ratio: 7.9; 95% confidence interval: 4.7 to 13.3). BNP cut points were 30 pg/ml for screening (95% sensitivity, 44% specificity), 116 pg/ml for optimal (highest accuracy point; 66% sensitivity, 82% specificity), and 372 pg/ml for diagnostic (32% sensitivity, 95% specificity). Subsequent to revised cardiac risk index stratification, reclassification using the optimal cut point significantly improved risk prediction in all groups (net reclassification improvement 58%, p < 0.000001), particularly in the intermediate-risk group (net reclassification improvement 84%, p < 0.001). CONCLUSIONS Pre-operative NP levels can be used to independently predict cardiovascular events in the first 30 days after vascular surgery and to significantly improve the predictive performance of the revised cardiac risk index.

Haemodilution-induced profibrinolytic state is mitigated by fresh-frozen plasma: implications for early haemostatic intervention in massive haemorrhage

BACKGROUND Fibrinolysis contributes to coagulopathy after major trauma and surgery. We hypothesized that progressive haemodilution is responsible, at least in part, for increased fibrinolytic tendency of blood clot. METHODS The study was performed in two parts. First, whole blood (WB) samples collected from six healthy, consented volunteers were diluted in vitro with either saline or fresh-frozen plasma (FFP) to 40% and 15% of baseline. We quantified factor levels related to coagulation and fibrinolysis, and measured endogenous thrombin generation in undiluted control plasma samples and in samples diluted with saline or FFP. Additionally, thromboelastometry was used to assess susceptibility to fibrinolysis after adding tissue plasminogen activator in undiluted WB samples and in samples diluted with saline before and after substitution of fibrinogen or FFP. Secondly, as a model of in vivo haemodilution, we evaluated the same parameters before and after operation in nine consented patients undergoing off-pump coronary artery bypass surgery. RESULTS The dilution with saline caused dose-dependent decreases in plasma levels of coagulation and antifibrinolytic factors, and in thrombin generation. In FFP-supplemented samples, factor levels and thrombin generation were maintained within normal ranges. Fibrinolytic tendency was significantly higher after haemodilution with saline independent of fibrinogen substitution compared with FFP. Similarly, increased tendency for fibrinolysis was also observed in the in vivo haemodilution. CONCLUSIONS We demonstrated in vitro and in vivo that progressive haemodilution decreases endogenous antifibrinolytic proteins including alpha(2)-antiplasmin and thrombin-activatable fibrinolysis inhibitor, resulting in increased fibrinolytic tendency. Therefore, early fluid replacement therapy with FFP might be advantageous after massive haemorrhage.

Rotational Thromboelastometry (ROTEM)-Based Coagulation Management in Cardiac Surgery and Major Trauma

m e r l a a a w p r FOR MAJOR BLEEDING related to severe trauma, major surgery, or chronic anticoagulation, a rapid assessment of hemostatic function is crucial so that optimal fluid replacements and blood transfusion can be administered without delays.1-6 Although the safety of blood products with regard to viral transmission risks has improved in recent years,7,8 transfusions of allogeneic erythrocyte and plasma products have been implicated in serious adverse events, including nosocomial infections, acute lung injury, and organ dysfunction.9-12 Obtaining conventional laboratory tests, such as the prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen level, during acute bleeding is difficult because of a long turn-around time ( 30 min).13,14 Furthermore, laboatory PT/international normalized ratio and aPTT may not be articularly useful in predicting bleeding after trauma or invaive procedures.15,16 The prime example of bleeding management is preemptive transfusions of fresh-frozen plasma (FFP) and platelet concentrates according to the erythrocyte requirement in major trauma cases.17,18 This so-called “damage control resuscitation” (DCR; able 1) originally was advocated for battlefield resuscitation n which laboratory testing and transfusion resources were imited. However, plasma product transfusion according to CR became increasingly popular in US civilian trauma ceners and operating rooms.17,19 The prevention of trauma-induced coagulopathy and subsequent nonsurgical bleeding is a major advantage of DCR,20 but the DCR approach lacks a specific target for replacement and a consideration for interindividual variability in coagulation factor levels and vascular (endothelial) responses. Implementing transfusion algorithms based on point-of-care (POC) coagulation testing can be effective in decreasing transfusion requirements in elective or urgent cardiac surgical settings.2,5,21-23 In this review, the practical use of thromboelastometry is discussed relating to the diagnosis of coagulopathy and optimizing hemostatic interventions.

Randomized Comparison of Sevoflurane Versus Propofol to Reduce Perioperative Myocardial Ischemia in Patients Undergoing Noncardiac Surgery

Background— Volatile anesthetics provide myocardial preconditioning in coronary surgery patients. We hypothesized that sevoflurane compared with propofol reduces the incidence of myocardial ischemia in patients undergoing major noncardiac surgery. Methods and Results— We enrolled 385 patients at cardiovascular risk in 3 centers. Patients were randomized to maintenance of anesthesia with sevoflurane or propofol. We recorded continuous ECG for 48 hours perioperatively, measured troponin T and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) on postoperative days 1 and 2, and evaluated postoperative delirium by the Confusion Assessment Method. At 6 and 12 months, we contacted patients by telephone to assess major adverse cardiac events. The primary end point was a composite of myocardial ischemia detected by continuous ECG and/or troponin elevation. Additional end points were postoperative NT-proBNP concentrations, major adverse cardiac events, and delirium. Patients and outcome assessors were blinded. We tested dichotomous end points by &khgr;2 test and NT-proBNP by Mann–Whitney test on an intention-to-treat basis. Myocardial ischemia occurred in 75 patients (40.8%) in the sevoflurane and 81 (40.3%) in the propofol group (relative risk, 1.01; 95% confidence interval, 0.78–1.30). NT-proBNP release did not differ across allocation on postoperative day 1 or 2. Within 12 months, 14 patients (7.6%) suffered a major adverse cardiac event after sevoflurane and 17 (8.5%) after propofol (relative risk, 0.90; 95% confidence interval, 0.44–1.83). The incidence of delirium did not differ (11.4% versus 14.4%; P=0.379). Conclusions— Compared with propofol, sevoflurane did not reduce the incidence of myocardial ischemia in high-risk patients undergoing major noncardiac surgery. The sevoflurane and propofol groups did not differ in postoperative NT-proBNP release, major adverse cardiac events at 1 year, or delirium. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00286585.

The impact of hematocrit on fibrin clot formation assessed by rotational thromboelastometry.

BACKGROUND: Rotational thromboelastometry (ROTEM®)–based FIBTEM is used perioperatively to assess the extent of fibrin polymerization in whole blood. In FIBTEM, cytochalasin D eliminates the contribution of platelets to whole blood clotting, but changing levels in fibrin(ogen) and erythrocytes may differently affect clot formation. Because dynamic changes of hematocrit are not reflected in plasma fibrinogen measurements, we hypothesized that the lack of erythrocytes in isolated plasma measurements would affect the relationship between the Clauss method and whole blood–based FIBTEM during cardiac surgery. Therefore, in the current study we investigated the influence of perioperative hematocrit changes on FIBTEM and fibrinogen measurements. METHODS: Blood samples were collected from 6 consenting healthy volunteers. FIBTEM tests were run before and after serial in vitro dilutions of whole blood with saline or autologous plasma (5:1, 2:1, and 1:1 v/v). We then evaluated the relationship between FIBTEM–maximal clot firmness (MCF) and the Clauss fibrinogen method in relation to hematocrit values before and after cardiac surgery. Pearson correlation coefficients were determined between laboratory test results and ROTEM variables. RESULTS: Upon in vitro hematocrit reduction, FIBTEM-MCF was progressively decreased depending on the extent of saline dilution, but it was increased by 31% after 1:1 volume replacement with autologous plasma (P < 0.05). In samples from cardiac patients (150 measurements in 50 patients), the overall correlation coefficient between FIBTEM-MCF and plasma fibrinogen was 0.80 (P < 0.001). In hemodiluted blood samples (during surgery or at intensive care unit), FIBTEM-MCF 10 mm corresponded to plasma fibrinogen levels of 200 mg/dL. In the subgroup analysis (n = 50 each), according to hematocrit levels (<25%, ≥25% to 30%, ≥30%), plasma fibrinogen levels of 200 mg/dL corresponded to 11 mm, 10 mm, and 8 mm of FIBTEM-MCF, respectively. The correlation between FIBTEM-MCF and plasma fibrinogen was higher at lower hematocrit (<25%) than at higher hematocrit (>30%) (r = 0.88 and 0.67, respectively). CONCLUSIONS: Perioperative changes in hematocrit affect the correlation between plasma fibrinogen levels and FIBTEM-MCF values. The higher correlation between FIBTEM-MCF and plasma fibrinogen with lower hematocrit (<25%) indicates that FIBTEM is a practical method to determine the need for fibrinogen replacement in bleeding patients who typically develop perioperative anemia.