Caveh Madjdpour

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.

Physiologic transfusion triggers : Do we have to use (our) brain?

WE have all learned that 2,3-diphosphoglycerate (2,3-DPG) progressively decreases during storage of erythrocytes, resulting in an increase of the affinity of hemoglobin for oxygen. As a consequence, these erythrocytes seem to be less capable of releasing large amounts of oxygen to the tissue. Therefore, it has been proposed to transfuse fresh rather than stored erythrocytes. For example, in a model of sepsis, only fresh (and not stored) erythrocytes could restore oxygen consumption. Also, in septic patients with increased lactate levels, oxygen consumption did not increase after erythrocyte transfusions, and gastric mucosal pH even decreased after the transfusion of erythrocytes older than 15 days. Therefore, it is surprising that Weiskopf et al. in this issue of ANESTHESIOLOGY found that transfusion of autologous erythrocytes stored for approximately 3 weeks is as efficacious as the transfusion of fresh (3–4 h) erythrocytes in reversing anemia induced cognitive dysfunction. This finding is particularly surprising because the expected decrease in 2,3-DPG and the increase in the affinity of hemoglobin for oxygen was observed in the stored erythrocytes that reversed cognitive dysfunction. Does this indicate that the retransfused stored erythrocytes had regained—at least partially—their 2,3-DPG levels at the time of testing? This is possible because Beutler and Wood have shown that 1 h after transfusion, approximately 25–30% of prestorage 2,3-DPG was restored in donor erythrocytes. This does not necessarily mean that fresh and stored erythrocytes result in an equal increase of cerebral tissue oxygenation, which is the likely mechanism responsible for the reversal of the cognitive dysfunction after isovolemic hemodilution. Perhaps the stored erythrocytes improved cerebral oxygenation sufficiently to reverse the cognitive dysfunction, whereas the fresh erythrocytes may have increased cerebral oxygenation to a greater extent. However, this did not translate into measurably better cognitive function. A more gradual increase of the hemoglobin concentration from 5 to 7 g/dl with intermittent neuropsychological testing might have resulted in a detectable difference in favor of fresh versus stored erythrocytes. In addition, it is important to note that the study subjects were healthy young volunteers. Storage changes of erythrocytes may have had less impact on tissue oxygenation in these individuals than in patients with underlying diseases such as sepsis or coronary artery disease. Last but not least, a recent study has challenged the common understanding that 2,3-DPG levels in stored erythrocytes are the key factor for oxygen off-loading capacity of transfused erythrocytes. In this study, human erythrocytes stored for 2–3 weeks and containing almost no 2,3-DPG were equally efficacious in maintaining intestinal microvascular oxygen partial pressure as erythrocytes that were stored for 2–6 days. Only erythrocytes stored for 5–6 weeks were less efficacious. Although undoubtedly there are differences between the oxygenation of the intestine and the brain, both studies indicate that 2,3-DPG levels of transfused erythrocytes may not play a major role with respect to their capacity for tissue oxygenation. Apart from their contribution to the discussion of old versus fresh erythrocyte transfusions, Weiskopf et al. have opened the “window to the brain” with respect to monitoring the adequacy of cerebral oxygenation during acute anemia. Monitoring the effect of acute anemia on the cerebral function is essential because most experts would agree that erythrocyte transfusions are indicated to “treat or prevent imminent inadequate tissue oxygenation.” Current monitoring assesses the heart for development of myocardial ischemia by electrocardiogram and transesophageal echocardiography. Also, the entire circulation can be evaluated by measuring mixed venous hemoglobin saturation in the presence of a pulmonary artery catheter and by calculating oxygen consumption using indirect calorimetry. With circulatory monitoring only, however, we have no direct access to the state of oxygenation and function of other organs. Monitoring the function of the brain in relation to the hemoglobin concentration is an important step toward physiologic transfusion triggers. However, cognitive testing with horizontal addition, digit symbol substitution, and memory tests requires the cooperation of the patient and thus is unpractical during major operations or after trauma when patients normally are anesthetized. Anemia sensitive neurologic monitoring during general anesthesia is an area that requires further development, e.g., analysis of evoked potentials aimed at central processing may in the future enable on-line monitoring of the adequacy of cerebral oxygenation. This Editorial View accompanies the following article: Weiskopf RB, Feiner J, Hopf H, Lieberman J, Finlay HE, Quah C, Kramer JH, Bostrom A, Toy P: Fresh blood and age stored blood are equally efficacious in immediately reversing anemiainduced brain oxygenation deficits in humans. ANESTHESIOLOGY 2006; 104:911–20.

Effect of high-and low-molecular-weight low-substituted hydroxyethyl starch on blood coagulation during acute normovolemic hemodilution in pigs

Background:Hydroxyethyl starches (HES) with lower impact on blood coagulation but longer intravascular persistence are of clinical interest. The current study aimed to investigate in vivo the isolated effect of molecular weight on blood coagulation during progressive acute normovolemic hemodilution. Methods:Twenty-four pigs were normovolemically hemodiluted up to a total exchange of 50 ml · kg−1 · body weight−1 of HES 650/0.42 or HES 130/0.42. Serial blood sampling was performed to measure HES plasma concentration and to assess blood coagulation. Concentration–effect relations were analyzed by linear regression, followed by the Student t test on regression parameters. Results:Blood coagulation was increasingly compromised toward hypocoagulability by acute normovolemic hemodilution with both treatments (P < 0.01). Significantly greater impact on activated partial thromboplastin time (P = 0.04) and significantly stronger decrease of maximal amplitude (P = 0.04), angle &agr; (P = 0.02), and coagulation index (P = 0.02) was seen after acute normovolemic hemodilution with HES 650/0.42 as compared with HES 130/0.42. Except for factor VIII (P = 0.04), no significant differences between both treatments were observed when relating antihemostatic effects to HES plasma concentrations (P > 0.05). A significantly lesser decrease of hemoglobin concentration has been found with HES 650/0.42 as compared with HES 130/0.42 (P < 0.01) in relation to HES plasma concentrations. Conclusion:High-molecular-weight HES (650/0.42) shows a moderately greater antihemostatic effect than low-molecular-weight HES (130/0.42) during acute normovolemic hemodilution. However, similar effects on hemostasis were observed with both treatments when observed antihemostatic effects were related to measured HES plasma concentrations. In addition, HES 650/0.42 may have a lower efficacy in immediately restoring plasma volume.

Novel starches : Single-dose pharmacokinetics and effects on blood coagulation

Background:Carboxymethyl starch (CMS) and carboxymethylated hydroxyethyl starch (CM-HES) might offer advantages over hydroxyethyl starch (HES) with regard to their volume expansion effect and their pharmacokinetic characteristics. The goal of the current study was to determine the pharmacokinetics of CMS and CM-HES and to investigate their influence on blood coagulation in comparison with the standard low-molecular, low-substituted HES (130/0.42) used in Europe. Methods:The study was conducted as a randomized, blinded, parallel three-group study in 30 pigs. Twenty ml/kg of 6% HES (control), 6% CMS, or 6% CM-HES was infused as a single dose, and serial blood sampling was performed over 20 h to measure plasma concentration and molecular weight and to assess blood coagulation. Concentration–effect relations were assessed by pharmacokinetic–pharmacodynamic analysis. Results:CMS and CM-HES showed significantly higher plasma concentrations and molecular weights over 20 h (P for both < 0.001) with smaller volumes of distribution and longer elimination rates during the terminal phase (P for both < 0.01) when compared with HES. CMS and CM-HES impaired whole blood coagulation more than HES as assessed by Thrombelastograph® analysis (Haemoscope Corporation, Niles, IL). However, similar effects of all three starch preparations on blood coagulation were found when related to the plasma concentrations in mass units. Conclusions:Carboxymethylation of starch results in an increased intravascular persistence and a slower fragmentation compared with HES. The greater impairment of blood coagulation by CMS and CM-HES seems to be caused by the higher plasma concentrations.

Expression of visinin-like protein-3 in mouse kidney.

In renal proximal brush borders the Na/Pi cotransporter NaPi-IIa is part of a heteromultimeric complex including the PDZ proteins PDZK1 and NHERF1, which interact with the C terminus of NaPi-IIa. In this study, a yeast two-hybrid screen against the N terminus of the Na/Pi cotransporter NaPi-IIa was performed. Thereby we identified visinin-like protein-3 (VILIP-3), a member of neuronal calcium sensors. In this study, expression and protein localization of VILIP-3 in the mouse kidney was performed by immunofluorescence and RT-PCR using laser-assisted microdissected nephron segments. VILIP-3 was found to be abundant in distal and collecting ducts where it partly colocalized with calbindin D28K. In addition VILIP-3 was observed in the brush borders of proximal tubular S1 and S3 segments of both superficial and deep nephrons.

Novel polyanionic starches: pharmacokinetics and effect on blood coagulation: A-287

Department of Anaesthesiology, University Hospital Lausanne (CHUV), Lausanne, Switzerland Background and Goal of Study: Linkage of carboxy-methyl (CM) residues to the glucose units of starch results in CM starch (CMS) and – when combined with hydroxyethylation – in CM-hydroxyethyl (HE) starch (CM-HES). These polyanionic starches are more hydrophilic than conventional HES and might be promising alternatives as plasma substitutes. The goal of this study was to investigate the pharmacokinetics of these novel starches and to study their impact on blood coagulation. Materials and Methods: This trial was conducted as a randomized controlled in vivo study in 30 pigs (40 5 kg). After infusion of 20 ml/kg of HES (130/0.4) (control), CMS or CM-HES (6% each) over 30 minutes, serial blood samples were obtained over 20 hours. Plasma concentration was determined and blood coagulation was assessed by Thromboelastograph® (TEG®) analysis and plasma coagulation assays. Pharmacokinetic (PK)-pharmacodynamic (PD) analysis was performed based on a twocompartment model, using a linear model relating predicted concentration values to the observed effects. PK-PD parameters were compared by oneway ANOVA followed by Scheffé’s multiple comparisons test. Results: Data are given as mean (SD).