Oliver M. Theusinger

Activity-based costs of blood transfusions in surgical patients at four hospitals

BACKGROUND: Blood utilization has long been suspected to consume more health care resources than previously reported. Incomplete accounting for blood costs has the potential to misdirect programmatic decision making by health care systems. Determining the cost of supplying patients with blood transfusions requires an in‐depth examination of the complex array of activities surrounding the decision to transfuse.

Hyperfibrinolysis diagnosed by rotational thromboelastometry (ROTEM) is associated with higher mortality in patients with severe trauma.

BACKGROUND: We investigated whether hyperfibrinolysis and its severity was associated with outcome of traumatized and nontraumatized patients. METHODS: From April 2008 to April 2010, all emergency patients with hyperfibrinolysis were enrolled in this study. Hyperfibrinolysis patients were divided into traumatized (trauma hyperfibrinolysis group) and nontraumatized (nontrauma hyperfibrinolysis group). The trauma hyperfibrinolysis group was matched with 24 polytrauma patients without hyperfibrinolysis (matched trauma group). Data from rotational thromboelastometry measurements, blood gas analysis (metabolic state), laboratory analysis, injury severity score, and 30-day mortality were collected. RESULTS: Thirty-five patients with hyperfibrinolysis were identified (13 traumatized, 22 nontraumatized). Overall mortality for hyperfibrinolysis was 54%. Mortality in the trauma hyperfibrinolysis group (77% ± 12%) was significantly higher than in the nontrauma hyperfibrinolysis group (41% ± 10%; P = 0.001, 95% CI 5%–67%) and the matched trauma group (33% ± 10%; P = 0.009, 95% CI 13%–74%). Hyperfibrinolysis is significantly (P = 0.017) associated with mortality in trauma patients. In the blood gas analysis representing the metabolic state, only pH (P = 0.02) and potassium (P = 0.01) were significantly lower in the trauma hyperfibrinolysis group compared to the nontrauma hyperfibrinolysis group. CONCLUSIONS: Mortality from hyperfibrinolysis is significantly higher in trauma compared with nontrauma patients, and hyperfibrinolysis is an independent factor predicting mortality in trauma patients. Rotational thromboelastometry provides real-time recognition of hyperfibrinolysis allowing early treatment.

Treatment of iron deficiency anemia in orthopedic surgery with intravenous iron: efficacy and limits: a prospective study.

Background:Preoperative anemia is frequent in patients undergoing orthopedic surgery. The purpose of this study was to assess the preoperative increase of hemoglobin in iron deficiency anemia patients treated with intravenous iron. Methods:After obtaining written informed consent, 20 patients with iron deficiency anemia received 900 mg intravenous iron sucrose over 10 days starting 4 weeks before surgery. Changes of hemoglobin and iron status were measured over 4 weeks and at discharge. In the last 11 patients, endogenous erythropoietin was also measured. Data were analyzed using the Friedman test followed by pairwise Wilcoxon signed rank tests with Bonferroni correction. Results:Hemoglobin increased significantly (P < 0.0001) after intravenous iron treatment. Overall, the mean maximum increase was 1.0 ± 0.6 g/dl (range, 0.2–2.2 g/dl). Ferritin increased from 78 ± 70 to 428 ± 191 &mgr;g/l (P = 0.0001), ferritin index decreased from 2.7 ± 2.4 to 1.5 ± 1.0 (P = 0.0001), and soluble transferrin receptor decreased from 4.1 ± 2.3 mg/l to 3.7 ± 2.3 mg/l (P = 0.049), whereas transferrin saturation (20.5 ± 9.0 to 22.9 ± 9.0%) and serum iron (13.3 ± 4.6 to 13.1 ± 4.5 &mgr;m) did not change significantly after intravenous iron treatment. Endogenous erythropoietin decreased from 261 ± 130 pg/ml to 190 ± 49 pg/ml 2 weeks after intravenous iron treatment (P = 0.050, not significant after Bonferroni correction). No adverse events related to intravenous iron were observed. The maximum increase of hemoglobin was observed 2 weeks after the start of intravenous iron treatment, indicating that administration of intravenous iron 2–3 weeks before surgery may be optimal. Conclusion:Treatment with intravenous iron allows correcting iron deficiency anemia before elective surgery.

Rotation thromboelastometry (ROTEM®) stability and reproducibility over time

BACKGROUND Thromboelastometry is a whole blood assay performed to evaluate the viscoelastic properties during blood clot formation and lysis. Rotation thromboelastography (ROTEM), Pentapharm GmbH, Munich, Germany) has overcome some of the limitations of classic thromboelastography. So far, no clinical validation on reproducibility (inter- and intra-assay variability) and sample stability over time has been published. METHODS To evaluate the pre-analytic aspects, sample stability over time was assessed in 48 patients in eight age groups. Citrated blood was stored at room temperature. Tests measured every 30 min from T 0 min up to T 120 min on two ROTEM devices were INTEM (ellagic acid activated intrinsic pathway), EXTEM (tissue factor-triggered extrinsic pathway) and FIBTEM (with platelet inhibitor (cytochalasin D) evaluating the contribution of fibrinogen to clot formation). Precision by intra- and inter-assay variability was evaluated at two points of time in 10 volunteers. Finally, reference intervals and effect of age and sex were evaluated. RESULTS Blood was stable over 120 min and no significant differences in ROTEM results were found. Maximum clot firmness measurements had a coefficient of variation of <3% for EXTEM, <5% for INTEM and <6% for FIBTEM. For clot formation time, the coefficient of variation was <4% for EXTEM and <3% for INTEM. Coefficient of variation for angle alpha was <3% for EXTEM and <6% for INTEM. The coefficient of variation for clotting time was <15% for both EXTEM and INTEM. Small but significant differences between ROTEM devices were found for maximum clot firmness in FIBTEM and INTEM as well as clot formation time and alpha angle in INTEM. CONCLUSIONS ROTEM yields stable results over 120 min with a minimal variability on the same ROTEM device. However, small but significant differences between ROTEM devices were observed. Analysis should be performed on the same ROTEM device if small differences are of importance for treatment.

In vitro factor XIII supplementation increases clot firmness in Rotation Thromboelastometry (ROTEM

Factor XIII (F XIII) is an essential parameter for final clot stability. The purpose of this study was to determine the impact of the addition of factor (F)XIII on clot stability as assessed by Rotation Thromboelastometry (ROTEM). In 90 intensive care patients ROTEM measurements were performed after in vitro addition of F XIII 0.32 IU, 0.63 IU, 1.25 IU and compared to diluent controls (DC; aqua injectabile) resulting in approximate F XIII concentrations of 150, 300 and 600%. Baseline measurements without any additions were also performed. The following ROTEM parameters were measured in FIBTEM and EXTEM tests: clotting time (CT), clot formation time (CFT), maximum clot firmness (MCF), maximum lysis (ML), maximum clot elasticity (MCE) and alpha-angle (alphaA). Additionally, laboratory values for FXIII, fibrinogen (FBG), platelets and haematocrit were contemporaneously determined. In the perioperative patient population mean FBG concentration was elevated at 5.2 g/l and mean FXIII concentration was low at 62%. The addition of FXIII led to a FBG concentration-dependent increase in MCF both in FIBTEM and EXTEM. Mean increases in MCF (FXIII vs. DC) of approximately 7 mm and 6 mm were observed in FIBTEM and EXTEM, respectively. F XIII addition also led to decreased CFT, increased alphaA, and reduced ML in FIBTEM and EXTEM. In vitro supplementation of FXIII to supraphysiologic levels increases maximum clot firmness, accelerates clot formation and increases clot stability in EXTEM and FIBTEM as assayed by ROTEM in perioperative patients with high fibrinogen and low FXIII levels.

Transfusion in trauma: why and how should we change our current practice?

Purpose of review Major trauma is often associated with hemorrhage and transfusion of blood and blood products, which are all associated with adverse clinical outcome. The aim of this review is to emphasize why bleeding and coagulation has to be monitored closely in trauma patients and to discuss the rationale behind modern and future transfusion strategies. Recent findings Hemorrhage is a major cause of early death after trauma. Apart from the initial injuries, hemorrhage is significantly promoted by coagulopathy. Early identification of the underlying cause of hemorrhage with coagulation tests (routine and bedside) in conjunction with blood gas analysis allow early goal-directed treatment of coagulation disorders and anemia, thereby stopping bleeding and reducing transfusion requirements. These treatment options have to be adapted to the civilian and noncivilian sector. Transfusion of blood and its components is critical in the management of trauma hemorrhage, but is per se associated with adverse outcome. Decisions must weigh the potential benefits and harms. Summary Future transfusion strategies are based on early and continuous assessment of the bleeding and coagulation status of trauma patients. This allows specific and goal-directed treatment, thereby optimizing the patients coagulation status early, minimizing the patients exposure to blood products, reducing costs and improving the patients outcome.

Relative concentrations of haemostatic factors and cytokines in solvent/detergent-treated and fresh-frozen plasma

BACKGROUND Indications, efficacy, and safety of plasma products are highly debated. We compared the concentrations of haemostatic proteins and cytokines in solvent/detergent-treated plasma (SDP) and fresh-frozen plasma (FFP). METHODS Concentrations of the following parameters were measured in 25 SDP and FFP samples: fibrinogen (FBG), factor (F) II, F V, F VII, F VIII, F IX, F X, F XIII, von Willebrand factor (vWF), D-Dimers, ADAMTS-13 protease, tumour necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, IL-8, and IL-10. RESULTS Mean FBG concentrations in SDP and FFP were similar, but in FFP, the range was larger than in SDP (P<0.01). Mean F II, F VII, F VIII, F IX, and F XIII levels did not differ significantly. Higher concentrations of F V (P<0.01), F X (P<0.05), vWF (P<0.01), and ADAMTS-13 (P<0.01) were found in FFP. With the exception of F VIII and F IX, the range of concentrations for all of these factors was smaller (P<0.05) in SDP than in FFP. Concentrations of TNF-α, IL-8, and IL-10 (all P<0.01) were higher in FFP than in SDP, again with a higher variability and thus larger ranges (P<0.01). CONCLUSIONS Coagulation factor content is similar for SDP and FFP, with notable exceptions of less F V, vWF, and ADAMTS-13 in SDP. Cytokine concentrations (TNFα, IL-8, and IL-10) were significantly higher in FFP. The clinical relevance of these findings needs to be established in outcome studies.

Resuscitation and transfusion management in trauma patients: emerging concepts.

Purpose of reviewSevere trauma is associated with hemorrhage, coagulopathy and transfusion of blood and blood products, all associated with considerable mortality and morbidity. The aim of this review is to focus on resuscitation, transfusion strategies and the management of bleeding in trauma as well as to emphasize on why coagulation has to be monitored closely and to discuss the rationale of modern and future transfusion strategies. Recent findingsCoagulopathy and uncontrolled bleeding remain leading causes of death in trauma, lead to blood transfusions and increased mortality as it has been recently shown that blood transfusion per se results in an adverse outcome. In the last years, damage control resuscitation, a combination of permissive hypotension, hemostatic resuscitation and damage control surgery, has been introduced to treat severely traumatized patients in hemorrhagic shock. Goals of treatment in trauma patients remain avoiding metabolic acidosis, hypothermia, treating coagulopathy and stabilizing the patient as soon as possible. The place of colloids and crystalloids in trauma resuscitation as well as the role of massive transfusion protocols with a certain FFP : RBC ratio and even platelets have to be reevaluated. SummaryClose monitoring of bleeding and coagulation in trauma patients allows goal-directed transfusions and thereby optimizes the patients coagulation, reduces the exposure to blood products, reduces costs and may improve clinical outcome.

Prevention and treatment of coagulopathy in patients receiving massive transfusions

Patients undergoing massive transfusions frequently develop a coagulopathy, which is already present in a considerable percentage of patients upon admission to the emergency room. This derangement of coagulation may aggravate the bleeding tendency and is associated with significant morbidity and mortality. Existing guidelines for optimal transfusion therapy in massively bleeding patients advocate early administration of crystalloid or colloid fluids in conjunction with transfusion of red cells. And, according to the guidelines, fresh frozen plasma (FFP) and platelets should only be administered when a whole blood volume or more has been replaced and then only in patients with excessive or microvascular bleeding and, at best, according to conventional laboratory coagulation analysis. However, this approach may cause dilution coagulopathy and a further impairment of hemostasis due to direct effects of plasma replacement treatment on platelet-vessel wall interaction and thus compromise haemostatic ability further in severely bleeding patients. In recent years, there has been increasing evidence, although mainly coming from non-randomized studies, that early and more intense replacement of coagulation factors and platelets may improve the outcome in patients undergoing massive transfusion. The recommendations in the existing guidelines are based on the results of conventional coagulation assays such as the activated partial thromboplastin time. However, these assays poorly correlate with clinically relevant coagulopathies [1, 2]. Cell-based whole blood viscoelastical assays such as thromboelastography (TEG) provide quantitative information of the haemostatic process and thus give a profile of the haemostatic changes that occur during clotting. Such tests may provide a better guide for blood component therapy for patients with massive bleeding, although also for these tests the clinical relevance has never been adequately validated [3–5]. It seemed of interest to obtain information on these issues by sending the following questions to experts in the field. Question 1: What is your definition of ‘massive blood transfusion’? Question 2: When treating a patient with massive bleeding, do you still follow the official guidelines i.e. restoration of blood volume initially with cristalloids or colloids followed by packed red cells and subsequently the use of FFP, platelets, cryoprecipitate, and other coagulation concentrates depending on the results of coagulation tests and platelet counts? If no: please explain. Question 3: Or do you follow a more aggressive regimen administering FFP and platelets as part of the standard transfusion program? If so, which FFP:RBC ratio do you apply? Please describe your transfusion policy in detail. Question 4: If you use coagulation parameters in your setting, which tests do you apply? Do you think that the conventional tests are satisfactory for this purpose? If not, please explain why. What would be an acceptable turn-around time for any test? Question 5: Have you evidence that a more aggressive regimen with regard to FFP and platelet transfusions improves outcome? Or do you think FFP and platelet transfusion may be harmful? We received 12 contributions to this Forum. Many of the answers are extensive and contain much detailed information. It is impossible to include all this information in an editorial. The reader is therefore strongly advised to read the answers. Although some participants still use the standard definition of massive transfusion, i.e. 10 units of RBC within 24 h, most now use a different definition. Most

The Influence of Laboratory Coagulation Tests and Clotting Factor Levels on Rotation Thromboelastometry (rotem®) During Major Surgery with Hemorrhage

BACKGROUND: The aim of this study was to determine the association between standard laboratory tests, coagulation factor concentrations, and Rotation Thromboelastometry (ROTEM® delta, TEM® International GmbH, Munich, Germany) in patients undergoing major surgery with hemorrhage. METHODS: In 45 patient’s fibrinogen, factor VIII, factor XIII, International Normalized Ratio (INR), activated partial thromboplastin time (aPTT), thrombin time, hemoglobin, leukocytes, and platelet count were simultaneously measured intraoperatively with ROTEM (EXTEM, INTEM, FIBTEM, APTEM) measurements. ROTEM parameters were: clotting time (CT), clot formation time (CFT), maximum clot firmness (MCF), and &agr;-angle. Demographic and laboratory data were expressed as mean ± SD and median [range]; nonparametric Spearman rank correlations and multiple linear regressions were performed; P-values ⩽0.003 were considered significant. RESULTS: Significant correlations (P ⩽ 0.003) were found for CFT, &agr;-angle, and MCF, in EXTEM, INTEM, and APTEM with platelets, INR, and fibrinogen. Factor VIII (18 measurements) showed a strong correlation (r ≥ 0.7 or r ⩽ −0.7; all P ⩽ 0.003) with MCF, CFT, and &agr;-angle of EXTEM, INTEM, MCF of FIBTEM excluding CT of EXTEM, INTEM, FIBTEM and strong significant correlation for &agr;-angle of APTEM and moderate for CFT and MCF of APTEM. A significant moderate to strong correlation of factor XIII with MCF of EXTEM, INTEM, FIBTEM, and APTEM was found. Hemoglobin was moderately correlated (r = 0.3–0.7 or r = −0.3 to −0.7) with MCF in APTEM (P = 0.003). A moderate to strong correlation of the standard coagulation tests with all ROTEM parameters was found, in particular the CT. The aPTT correlated significantly moderate to strong with CT, CFT, &agr;-angle, and MCF of INTEM. However, multiple linear regressions were not able to show an influence of INR on ROTEM parameters except for APTEM-MCF. A significant impact of the aPTT on INTEM-CT was found. EXTEM, INTEM, and APTEM are significantly influenced by fibrinogen and platelets. CONCLUSIONS: The results confirm the clinical assumption that EXTEM, INTEM, and APTEM are associated with fibrinogen and platelets levels; INTEM-CT significantly to aPTT; and FIBTEM significantly to fibrinogen. Factor VIII showed a significant correlation with all ROTEM parameters except CT of EXTEM, INTEM, FIBTEM, and CFT and MCF of APTEM.