Donat R. Spahn

Aspirin is recommended as a lifelong therapy that should never be interrupted for patients with cardiovascular dis- ease. Clopidogrel therapy is mandatory for six weeks after placement of bare-metal stents, three to six months after myocardial infarction, and at least 12 months after placement of drug-eluting stents. Because of the hypercoagulable state induced by surgery, early withdrawal of antiplatelet therapy for secondary prevention of cardiovascular disease increases the risk of postoperative myocardial infarction and death five- to 10-fold in stented patients who are on continuous dual antiplatelet therapy. The shorter the time between revascularization and surgery, the higher the risk of adverse cardiac events. Elective surgery should be postponed beyond these periods, whereas vital, semiurgent, or urgent operations should be performed under continued dual antiplatelet therapy. The risk of surgical hemorrhage is increased approximately 20 percent by aspirin or clopidogrel alone, and 50 percent by dual antiplatelet therapy. The present clinical data suggest that the risk of a cardiovascular event when stopping antiplatelet agents preoperatively is higher than the risk of surgical bleeding when continuing these drugs, except during surgery in a closed space (e.g., intracranial, posterior eye chamber) or surgeries associated with massive bleeding and difficult hemostasis.

In the past, red blood cells were given in case of acute anemia, the decision being often based on the hemoglobin concentration alone. The clinical situation and the comorbidities of the patient as well as the secondary were given only a little, if any, consideration. Presently, the evidence shows that red blood cells transfusion has to be individualized in every single patient, taking into consideration the risks of the transfusion, the coexisting medical problems and the patient's tolerance to acute anemia. Experimental and clinical research confirms that a much lower hemoglobin concentration can be tolerated than previously admitted if normovolemia is preserved, the most important transfusion trigger being a sign of insufficient oxygen consumption and signs of an inadequate circulation.

Antiplatelet drugs and intraoperative haemorrhage Current literature demonstrates that there is less risk involved in maintaining anti-aggregant therapy (which might imply to transfuse more the patients), than in stopping it, which then increases dangerously the risk of coronary thrombosis. Aspirin, as a secondary preventive drug, should not be interrupted. Clopidogrel is essential for protection against thrombosis in areas where the endothelium is not intact. Unless there is a high hemorrhagic risk in closed cavities (intracranial surgery), clopidogrel should not be interrupted. Furthermore, any surgical intervention increasing the coagulability of the platelets, it seems particularly dangerous to stop such medication perioperatively.

Donor blood is a limited resource and its transfusion is associated with significant adverse effects. Therefore, alternatives have been searched, the ultimate being artificial oxygen (O2) carriers. There are two main groups of artificial O2 carriers: hemoglobin based and perfluorocarbon emulsions. The hemoglobin molecule in hemoglobin based artificial O2 carriers needs to be stabilized to prevent dissociation of the α2β2-hemoglobin tetramer into ab-dimers in order to prolong intravascular retention and to eliminate nephrotoxicity. Other modifications serve to decrease O2 affinity in order to improve O2 off-loading to tissues. In addition, polyethylene glycol may be surface conjugated to increase molecular size. Finally, certain products are polymerized to increase the hemoglobin concentration at physiologic colloid oncotic pressure. Perfluorocarbons are carbon-fluorine compounds characterized by a high gas dissolving capacity for O2 and CO2 and chemical and biologic inertness. Perfluorocarbons are not miscible with water and therefore need to be brought into emulsion for intravenous application. Development, product specification, physiologic effects, efficacy to decrease the need for donor blood in surgery and side effects of the following products are described: Diaspirin cross-linked hemoglobin (HemAssist), human recombinant hemoglobin (rHb1.1 and rHb2.0), polymerized bovine hemoglobin-based O2 carrier (HBOC-201), human polymerized hemoglobin (PolyHeme®), hemoglobin raffimer (Hemolink™), maleimide-activated polyethylene glycol-modified hemoglobin (MP4) and perflubron emulsion (Oxygent™). In addition, enzyme cross-linked poly-hemoglobin, hemoglobin containing vesicles (nano-dimension artificial red blood cells) and an allosteric modifier (RSR13) are discussed. The most advanced products are in clinical phase III trials but no product has achieved market approval yet in the US, Europe or Canada.

Trauma is a serious global health problem, accounting for approximately one in 10 deaths worldwide. Uncontrollable bleeding accounts for 39% of trauma-related deaths and is the leading cause of potentially preventable death in patients with major trauma. While bleeding from vascular injury can usually be repaired surgically, coagulopathy-related bleeding is often more difficult to manage and may also mask the site of vascular injury. The causes of coagulopathy in patients with severe trauma are multifactorial, including consumption and dilution of platelets and coagulation factors, as well as dysfunction of platelets and the coagulation system. The interplay between hypothermia, acidosis and progressive coagulopathy, referred to as the ‘lethal triad’, often results in exsanguination. Current management of coagulopathy-related bleeding is based on blood component replacement therapy. However, there is a limit on the level of haemostasis that can be restored by replacement therapy. In addition, there is evidence that transfusion of red blood cells immediately after injury increases the incidence of post-injury infection and multiple organ failure. Strategies to prevent significant coagulopathy and to control critical bleeding effectively in the presence of coagulopathy may decrease the requirement for blood transfusion, thereby improving clinical outcome of patients with major trauma.

Recombinant activated factor VII (rFVIIa) (NovoSeven®, Novo Nordisk, Bagsvaerd, Denmark) was originally developed to treat bleeding in haemophiliacs with antibodies to factor VIII and IX.12 At present, rFVIIa is approved in the European Union for this indication and also for the treatment of bleeding in FVII deficiency and Glanzmann thrombasthenia refractory to platelet transfusions.

The development of hydroxyethyl starches (HES) with low impact on blood coagulation but higher volume effect compared with the currently used HES solutions is of clinical interest. We hypothesized that high molecular weight, low-substituted HES might possess these properties. Thirty pigs were infused with three different HES solutions (20 ml kg(-1)) with the same degree of molar substitution (0.42) but different molecular weights (130, 500 and 900 kDa). Serial blood samples were taken over 24 h and blood coagulation was assessed by Thromboelastograph analysis and analysis of plasma coagulation. In addition, plasma concentration and in vivo molecular weight were determined and pharmacokinetic data were computed based on a two-compartment model. Thromboelastograph analysis and plasma coagulation tests did not reveal a more pronounced alteration of blood coagulation with HES 500 and HES 900 compared with HES 130. In contrast, HES 500 and HES 900 had a greater area under the plasma concentration-time curve [1542 (142) g min litre(-1), P<0.001, 1701 (321) g min litre(-1), P<0.001] than HES 130 [1156 (223) g min litre(-1)] and alpha half life (t(alpha)(1/2)) was longer for HES 500 [53.8 (8.6) min, P<0.01] and HES 900 [57.1 (12.3) min, P<0.01] than for HES 130 [39.9 (10.7) min]. Beta half life (t(beta)(1/2)), however, was similar for all three types of HES [from 332 (100) to 381 (63) min]. In low-substituted HES, molecular weight is not a key factor in compromising blood coagulation. The longer initial intravascular persistence of high molecular weight low-substituted HES might result in a longer lasting volume effect.

Chirurgisch und traumatisch bedingte Blutverluste sind die häufigsten Ursachen von allogenen Bluttransfusionen, welche nach wie vor mit beträchtlichen Risiken verbunden sind. Nach Korrektur der Hypovolämie ist der Anästhesist häufig mit einer normovolämischen Anämie konfrontiert. Die klinische Relevanz dieses isolierten Hämoglobinabfalls besteht darin, dass die globale und/oder regionale Sauerstoffversorgung über eine kritische Schwelle hinaus beeinträchtigt sein kann, wonach sich eine Gewebshypoxie einstellt. Diese kritische Schwelle ist von Patient zu Patient verschieden und abhängig von dessen Kapazität, den Abfall des Sauerstoffgehaltes zu kompensieren. Aus diesem Grunde sollten primär physiologische Transfusionskriterien angewandt werden und nicht rigide nummerische Transfusionskriterien wie die Hämoglobinkonzentration, welche die individuelle Reserve eines Patienten weitgehend außer Acht lassen. Surgical blood loss and trauma are the major causes of allogeneic blood transfusions, which still bear considerable risks. After the correction of hypovolemia, the anesthesiologist often has to deal with normovolemic anemia. The clinical relevance of this isolated decrease in hemoglobin concentration consists in an eventually compromised global or regional oxygen supply with the development of tissue hypoxia below a critical threshold. This is an individual threshold for each patient and depends on his or her capacity to compensate the decrease in blood oxygen content. Therefore, physiologic transfusion triggers should primarily be applied and not rigid numeric transfusion triggers, such as hemoglobin concentration, which do not take into account each patient’s individual reserve.