key: cord-0042177-xrj80f1j
authors: nan
title: Speaker abstracts
date: 2007-04-04
journal: Transfus Altern Transfus Med
DOI: 10.1111/j.1778-428x.2007.00053.x
sha: e17fe6bd85e9ca56fc0f939904f8836dedfd4a37
doc_id: 42177
cord_uid: xrj80f1j

nan

experimental days (P = 0.62). Transfusion of erythrocytes stored for 3 weeks significantly improved the DSST (P < 0.001), and the improvement did not differ between ÔfreshÕ erythrocytes and those stored for 3 weeks (P = 0.96). 17 The DSST results after transfusion produced an in vivo hemoglobin concentration of 7 g/dL that did not differ from the DSST results at an equivalent hemoglobin concentration during the production of anemia. Results for the secondary outcome measure, heart rate, were similar. We conclude that although 3 weeks of storage of erythrocytes depletes 2,3-DPG and increases hemoglobin affinity for oxygen (P50 = 15 mmHg) they are as efficacious as are erythrocytes stored for 3 h in reversing acute anemia-induced neurocognitive deficits. Potential Conflict of Interest Statement: The author was an employee of Novo Nordisk A/S, the manufacturer of recombinant activated coagulation factor VII (NovoSeven Ò ) from February 2005 to March 2007, and currently is a consultant for Novo Nordisk A/S. The study described here was completed in 2004. February 2006. Published and unpublished randomized trials were included, in any language. Eligible trials had to be randomized trials comparing two or more colloids in adults undergoing surgery, reporting at least one relevant clinical or economic outcome. Hydroxyethyl starches (HES) were stratified according to the molar substitution ratio. Results: A total of 73 randomized trials met inclusion criteria. Volume of colloid administered did not differ significantly between groups, except for gelatin vs. HES and gelatin vs. albumin wherein patients in the gelatin arm were administered a greater volume of colloid (approximately 400-500 mL extra). Blood loss increased significantly with HES > 0.4 vs. albumin (WMD 81 mL, 95% CI, 14-148 mL, P = 0.02). When HES of low molar substitution (0.4) was compared with HES of higher molar substitution ( ‡ 0.5), there was significantly less blood loss for HES 0.4 (WMD -259 mL, 95% CI, -437 to -81 mL, P = 0.004). There was significantly less blood loss for HES 0.4 vs. gelatin (WMD -93 mL, 95% CI, -163 to -24 mL, P = 0.009). The number of patients transfused and the number of RBC or FFP units transfused did not differ significantly between colloids. However, HES ‡ 0.5 may be associated with a higher exposure to blood products (P = 0.07, P = 0.08). Colloids provide similar clinical and resourcerelated outcomes in adults in the perioperative period, specifically as it relates to hemodynamic parameters, allergic reactions, renal dysfunction, hospital length of stay and mortality (range from 0.5% with HES 0.4-2.4% in albumin studies). However, a number of comparisons between colloids were inadequately powered to rule out the possibility of true differences. Conclusions: HES 0.4 is associated with a reduction in blood loss of a magnitude of 15% (vs. a gelatin and HES ‡ 0.5). HES > 0.4 is associated with a larger perioperative blood loss than albumin (magnitude 10%). No other significant difference in clinical outcomes is observed between colloids. Considering limitations of this meta-analysis, clinicians have three options: waiting for a proper randomized controlled trial, seeking evidence in populations other than perioperative patients (SAFE study) or creating a point of view on current level of evidence, physiological facts and safety profiles. , and achieves a normal acid-base balance with bicarbonate (24) or metabolizable anions. A solution with a potential base excess (BEpot) of 0 mmol/L would be optimal, acetate as the metabolizable anion has a number of advantages, especially over lactate with several negative effects. 2 Benefits: Other than volume overload, a major benefit for the physician is that infusion of such a balanced solution is devoid of the risk of iatrogenic disruptions in the electrolyte and acid-base status including osmolality. The same balanced intravenous fluid for use as either a colloid isotonic, iso-oncotic solution for intravascular volume replacement, or a crystalloid isotonic solution for extracellular fluid replacement confers the following benefits: (i) there is no risk of hyperchloremia of the extracellular space and the attendant risk of renal vasoconstriction and reduced diuresis, possibly leading to significant prolonged overhydration and weight gain persisting for several days; (ii) after infusion and anion metabolism, a solution with a BEpot of 0 mmol/L has no effect on the patient's acid-base balance and, therefore, can cause neither acidosis nor alkalosis nor dilution acidosis, an iatrogenic disorder caused by bicarbonate dilution in the entire extracellular space; and (iii) a strictly isotonic solution rules out the risk of development of cerebral edema. 

Fluid management in fast-track surgery Henrik Kehlet, MD, PhD Section of Surgical Pathophysiology, the Juliane Marie Center, Rigshospitalet, Copenhagen, Denmark Postoperative outcome is determined by multiple factors. 1 Perioperative fluid management may influence several organ functions and thereby recovery. 2 For example, it is well established that administration of > 1 liter intraoperatively in minor procedures improves recovery, probably by compensating for preoperative dehydration and minor fluid shifts. 2 In major procedures avoidance of fluid excess 2 and goal-directed therapy 3 also improves recovery with a reduced morbidity and hospital stay. 3 Despite perioperative fluid management being important for postoperative recovery, the available studies do not allow final conclusions on timing, composition and exact amount of fluids, need for vasopressors and specific problems with central neuroaxial blockade on an individual procedure-specific basis. This may be important as postoperative fluid kinetics may be proceduredependent. 4 Furthermore, only two randomized studies 5, 6 are available where fluid therapy has been assessed within the concept of fast-track surgery (which otherwise has been documented to improve outcome) compared with traditional care, 1, 7 and also compared with all fluid studies performed without fast-track care. 2 In conclusion, future fluid outcome studies should be randomized, with a well-defined evidencebased component of care (fast-track surgery) and initially with a focus on functional outcomes such as pulmonary function and tissue oxygenation, orthostatic function, exercise tolerance, ileus, nausea and vomiting, vasoactive endocrine responses, coagulation/fibrinolytic function and inflammatory responses (CRP/IL-6), all in well-defined, procedure-specific studies. 2 Anemia and the Brain S6 Anemia and the brain Philippe Van der Linden, MD, PhD Department of Anesthesia, CHU Brugmann -HUDERF, Brussels, Belgium Maintenance of adequate tissue oxygenation during an acute reduction in red blood cell concentration depends on both an increase in cardiac output and in blood oxygen extraction. 1 These two mechanisms require the preservation of an ample circulating blood volume. In addition to physiological adaptations which optimize overall cardiac output, organ-specific regulation of blood flow also occurs during hemodilution. Organs with high metabolic oxygen requirements, including the heart and the brain, receive a disproportional increase in blood flow during anemia, favoring optimal tissue oxygen delivery to these vital organs. The preferential increase in cerebral blood flow is inversely proportional to the reduction in blood oxygen content, and may ensure that cerebral tissue oxygenation is maintained at very low hematocrits. The mechanisms by which the increase in cerebral blood flow occurs have been attributed to passive changes in blood viscosity and active cerebral vasodilation. Although the relative contribution of each of these components remains debated, active cerebral vasodilation is probably an important contributor to the maintenance of adequate cerebral tissue oxygenation during anemia. Among the different mechanisms that might be responsible for active cerebral vasodilation, nitric oxide (NO) seems to play a major role, as it has been demonstrated to impact changes in cerebral blood flow under a number of different physiological conditions. 2 Experimental studies support the hypothesis that the neuronal NO synthase-mediated NO production contributes not only to maintaining baseline cerebral blood flow, but also to regulated increases in cerebral blood flow in response to different physiological stimuli, including hypoxia, hypercapnia, acidosis and anemia. 2 Coronary blood flow increases even more than cerebral blood flow as myocardial oxygen demand increases during anemia. When the hematocrit is reduced to a value of 10-12%, myocardial oxygen consumption more than doubles and coronary vasodilation is nearly maximal. When hematocrit falls below these values, coronary blood flow can no longer match the increased myocardial oxygen demand and ischemia develops, resulting in cardiac failure. Several experimental studies have demonstrated a decrease in systemic oxygen uptake when hematocrit values are close to 10%, and anaerobic metabolism ensues. At this point of extreme hemodilution, cerebral cortical tissue hypoxia can be measured, despite an increase in internal carotid blood flow and cerebral oxygen extraction. 3 These experimental results and others are in contrast with increasing evidence of impaired cerebral function and physiology occurring in humans at hematocrit values near 20%. Indeed, studies involving patients undergoing cardiopulmonary bypass (CPB) and those suffering from chronic renal failure provide evidence of anemia-induced cerebral dysfunction and injury. With respect to patients undergoing CPB, clinical studies have associated low hematocrit on CPB with increased stroke rate and impaired psychomotor development. 4, 5 Such neurological injury occurs despite the finding that the brain is preferentially perfused during CPB. Mechanisms implicated include an increase in emboli directed to the brain due to the relative increase in cerebral blood flow and reduced cerebral oxygen delivery. Patients undergoing dialysis for chronic renal failure also suffered from impaired cognitive function associated with anemia, which appears to be independent of uremic encephalopathy. Partial or complete correction of their anemia with erythropoietin therapy resulted in improved cognitive function, suggesting that enhanced cerebral oxygen delivery may, at least partially, have contributed. 6 Finally, Weiskopf et al. demonstrated similar results in healthy volunteers who were exposed to acute hemodilution. Isovolemic anemia to hemoglobin concentrations between 5 g/dL and 6 g/dL resulted in significant reductions in reaction time and increase in error rates, which improved after re-infusion of autologous blood to achieve a hemoglobin concentration of 7 g/dL or with the administration of 100% oxygen in breathing air. 7, 8 It is well possible that techniques used to measure tissue hypoxia in experimental studies have not been sensitive enough to detect cerebral hypoxia occurring at higher hemoglobin concentration. In rats, Hare et al. reported an increase in cerebral cortical neuronal NO synthase messenger RNA at hemoglobin concentration near 5-6 g/ dL. 9 These observations support the hypothesis of an increased hypoxic gene expression at hemoglobin concentrations well above the point at which cerebral tissue hypoxia has previously been demonstrated. Further characterization of hypoxic cerebral gene expression in anemic animals has been recently provided. 10 A better understanding of the mechanisms responsible for anemia-related cerebral injury could provide physiological endpoints, which could help to better define the transfusion trigger in anemic patients. 11 The hemoglobin concentration at which the consequences of anemia-induced organ injury exceed the risks associated with allogeneic blood transfusion remains yet to be determined. 12 10. 

Transfusion and the brain Santiago Ramo´n Leal-Noval, MD Critical Care and Emergency Department, Virgen del Rocıó University Hospital, Seville, Spain A growing body of literature suggests that anemia-induced cerebral injury may contribute to patient morbidity and mortality. Nevertheless, though extreme anemia is harmful for the brain, physiological data indicating the optimal hemoglobin concentration are lacking, and the optimal hematocrit level to trigger transfusion has still not been delimitated. Hematocrit contributes to blood viscosity, and clinical studies have demonstrated an inverse relationship between hematocrit and cerebral blood flow (CBF). Therefore, a high hematocrit level may potentially decrease the CBF and increase the risk of cerebral ischemia. 1 Evidence of impaired cerebral function occured in healthy volunteers at hemoglobin concentrations near 5-6 g/dL, and improved after the reinfusion of autologous blood to achieve a hemoglobin concentration around 7 g/dL. 2 Recent studies carried out in cardiac surgery patients on cardiopulmonary bypass suggest hemoglobin values near 8 g/dL as a possible optimal transfusion trigger. 3 The injured brain may represent an organ that is particularly vulnerable to adverse consequences of anemia. However, the subgroup analysis of the TRICC trial involving 76 patients with severe brain injury did not find any differences regarding morbidity and mortality between patients transfused using a restrictive vs. liberal strategy. 4 These results have been corroborated in a recent study showing that patients with severe traumatic brain injury should not have a different transfusion threshold than other critical-care patients. 5 Monitoring of neurotrauma patients includes transcranial cerebral oximetry and brain tissue oxygen pressure. Both of these may detect significant rises in cerebral tissue oxygenation in response to blood transfusion and might potentially be developed into a transfusion trigger in the neurocritical-care population. [6] [7] [8] The hemoglobin concentration at which the consequences of anemia-induced brain injury exceed the risk associated with allogeneic blood transfusion remains to be determined. With increased life expectancy, the incidence and prevalence of brain diseases has dramatically increased. Stroke and a wide spectrum of neuropsychiatric illnesses such as schizophrenia, multiple sclerosis, Alzheimer's disease or traumatic head injury, all lead to severe disability. However, targeted, effective and causal therapies for treatment of these very heterogeneous diseases are lacking, and there is not much hope that the situation will change within the next few decades. Therefore, any approach aiming at an improvement of disease condition or a slowing of disease progression is of tremendous importance for affected individuals, as well as for socio-economic considerations. In this regard, the neuroprotective approach using erythropoietin (EPO) for treatment of brain disease represents a totally new frontier. Rather than specifically targeting the cause of a particular disease entity, EPO influences components of the Ôfinal common pathwayÕ that determines disease severity and progression in a large number of entirely different brain diseases. EPO acts in an anti-apoptotic, anti-inflammatory, anti-oxidant, neurotrophic, angiogenetic, stem-cell modulatory fashion. Due to these properties, it has been found by numerous investigators to be protective in a large number of animal models of neuropsychiatric disease. The Go¨ttingen EPO Stroke Trial represents the first effective use in man of a neuroprotective therapy in an acute brain disease, while an experimental EPO therapy to combat cognitive decline in patients with schizophrenia will be introduced as a neuroprotective/neuroregenerative strategy for a chronic brain disease. Last but not least, results of an exploratory trial on the use of EPO in multiple sclerosis as an example of a chronic inflammatory disease of the nervous system will be presented. The hallmark characteristic of most transfusion-transmissible infections (TTIs) has generally been their persistence. Carriage or latency has been a prerequisite of agents such as HBV, HCV, HIV, HTLV or CMV. Now we are seeing a shift towards the transfusion risk from residual TTIs being posed by certain agents that cause acute (and not chronic) infections, with short-lived viremia. In these instances the risk only becomes significant when the incidence of infection is high, often in a population with low levels of previous exposure to the agent and therefore little Ôherd immunity.Õ Currently the best recognized example is West Nile virus (WNV) which has swept across North America and has caused numerous transfusion-transmitted infections. 1 Typically, the threat to transfusion posed by such agents is mainly localized to regions where an epidemic is waxing. Nevertheless, the increasing frequency of rapid airline traffic means that visitors to endemic areas may present a transfusion risk to blood recipients on return to their home countries. Respiratory infections (hitherto not considered a risk via transfusion) have recently attracted considerable attention. The outbreaks of severe acute respiratory syndrome (SARS, caused by a coronavirus) and the continuing threat of a global influenza A pandemic related to the H 5 N 1 Ôbird fluÕ strain 2 are again acute infections which would pose a potential TTI risk in non-immune populations if their incidence became high following global dissemination by air travel (by either humans or birds!). Nucleic acid amplification testing (NAT), probably on single samples, would be the only appropriate laboratory testing option. Agents such as GBV-C, TTV and SEN-V, which fortunately are non-pathogenic, are however transfusion-transmissible. Had they proved to be pathogenic, NAT would have been the necessary testing format. For example, the persistent agent GBV-C (although a flavivirus related to HCV) is only associated with seropositivity in its host after the clearance of viral nucleic acid. It is fortuitous that NAT methodology was developed prior to the emergence of the threat from acute infections. It has certainly proved its worth in the WNV epidemic in North America. Threats from acute infections continue to arise, such as outbreaks of chikungunya in certain French territories. The possibility of new transfusion risks due to chronic infections such as human herpesvirus-8 (HHV-8) 3 and simian foamy virus (SFV) 4 continues. New serological assays, NAT or the perfection of pathogen-reduction technologies will figure prominently in the armory of preventative interventions.

Immunological side effects of blood transfusion Volker Kretschmer, MD, PhD and Ralf Karger, MD, MSc Institute for Transfusion Medicine and Hemostaseology, University Hospital, Philipps University, Marburg, Germany Immunological side effects of transfusion still play a greater role than transfusion-transmitted infections. Immunization: The importance of immunization is usually underestimated. Between 20 and 50% of patients receiving non-leukodepleted blood develop leukocyte antibodies (mainly against HLA antigens), and about 9% who receive red cell concentrates (RCC) develop red cell antibodies. The consequences are: (i) delayed or even impossible supply with compatible RCCs; (ii) immune reactions in subsequent transfusions if the antibodies cannot be taken into account (emergencies, low antibody level); (iii) therapeutic inefficacy of random platelets and granulocytes; and (iv) hemolytic disease of the newborn or fetal/ neonatal immune thrombocytopenia. Immune reactions: Nature and frequency of immune reactions depend on type and amount of blood components administered, and vary extremely between various centers of different countries: (i) nonhemolytic pyrogenic reactions due to leukocyte antibodies when cellular blood products with ‡ 5 x 10 8 leukocytes are transfused (RCCs < 1-7%, leukodepleted (LD) RCCs < 0.1%, platelet concentrates (PC) 9-30%, LD-PCs < 1%). Similar reactions occur with LD blood because of cytokines and chemokines released during filtration and storage (< 1%); (ii) TRALI syndrome, mainly with plasma products containing leukocyte antibodies (1:1200-1:100 000 units); (iii) allergic reactions caused by antibodies against donor proteins (approx. 1%, severe in about 1:100 000); (iv) posttransfusion immune thrombocytopenia by platelet-specific antibodies, extremely rare with LD units; (v) acute hemolytic reactions which are predominantly caused by clerical or methodical errors (1:6000-1:33 000 RCCs); (vi) fatal delayed hemolytic reactions because of low antibody levels prohibiting detection by pre-transfusion routine testing (1:1000-1:11 000 RCCs); (vii) Graft-versus-host disease in recipients of cellular blood products being unable to eliminate viable donor lymphocytes either because the patients are severely immunocompromised or because the recipient's immune system does not recognize the transfused donor cells as nonself (e.g. cells from relatives).

Immunosuppression , transfusion-related acute lung injury (TRALI) has become the most important cause of morbidity and mortality related to blood transfusion in the USA. 1 However, the reported incidence of TRALI may represent only the tip of the iceberg. TRALI appears to be grossly under-reported, in particular in critically ill patients who have additional risk factors for acute lung injury (ALI). [2] [3] [4] In this presentation, we will summarize and discuss the preliminary results of a recently completed prospective clinical study of TRALI in critically ill patients. Using a recommended standardized clinical definition of TRALI, we have found that potentially modifiable transfusion factors play a role in the development of ALI in significant numbers of critically ill patients exposed to blood transfusions. To the extent that transfusion factors indeed cause or contribute to the development of ALI, they represent attractive targets for prevention of ALI. Specific transfusion interventions, including rational use of blood products and alternatives, as well as donor management strategies will be discussed.

Loukia D. Loukopoulos Aerospace Experimental Psychologist; Lieutenant, Medical Service Corps, United States Navy Risk management (RM) defines a process designed to reduce loss in an activity. It is a multi-disciplinary, proactive method of addressing identified risks that may range from confirmed to assumed, from quantifiable to immeasurable, from tangible to perceived. The RM process is iterative and involves a sequence of steps to identify and evaluate risks; design, prioritize, and implement countermeasures; monitor and assess progress, before making necessary adjustments and starting over again. RM is relatively straight-forward in its application to simple systems that behave in predictable, linear ways and whose risks are easily defined and measured. More complex, high-risk activities, however, such as that of transfusion medicine, require inventive ways to adapt the RM process in order to effectively address complex risks that span health, financial, and even social issues. Examples from another relatively complex activity, aviation, are used to illustrate proven concepts and techniques for managing risk in that field. The defining characteristics of complex systems, the features that make them prone to risk, as well as specific factors that induce risk in such systems, are discussed. Emphasis is on a whole-system approach that looks at the human, technical, and organizational components of an activity, and bases solutions on harmonizing their interactions.

Valuable tools, such as Threat and Error Management, and a Safety Management System, as they are currently being used in the aviation industry, are discussed with a view towards their potential applicability to transfusion medicine.

Hemostasis S13 Point-of-care monitoring for the diagnosis and optimal management of perioperative bleeding George J. Despotis, MD Department of Anesthesiology and Blood Bank, Washington University School of Medicine, St Louis, MO, USA Bleeding-related risks (i.e. as related to transfusion or end-organ injury/ischemia) highlight the relative importance of rapid diagnosis of the etiology of bleeding (i.e. identification of specific abnormalities within the hemostatic system) during surgery which can allow specific pharmacological and transfusion-based therapies to be initiated. This approach, when coupled to a standardized transfusion algorithm, can potentially improve outcomes after cardiac surgery. Although this information is applicable to multiple perioperative scenarios, this discussion will be limited to the cardiac surgical environment. Clinicians in the past have resorted to empiric and Ôshot-gunÕ approaches when managing excessive bleeding due to the lack of immediately available results from laboratory-based coagulation tests. On this basis, the use of point-of-care (POC) tests of hemostatic function to facilitate the optimal management of excessive bleeding and reduce transfusion have been investigated. Accordingly, point-ofcare tests that assess platelet function may also identify patients at risk of acquired, platelet-related bleeding. In addition, rapid acquisition of coagulation data can also allow physicians to better differentiate between microvascular bleeding and surgical bleeding. Seven of eight recently published studies have demonstrated that implementation of a standardized approach to manage bleeding (e.g. algorithm), when coupled with either point-of-care or laboratory tests of hemostatic function, can optimize the management of bleeding and consistently reduce total donor exposures by 50%. Although previous studies have not been able to conclusively show that DDAVP can reduce bleeding and transfusion when administered prophylactically, more recent evidence indicates that this agent may be useful in preventing excessive bleeding when a test (POC) reveals platelet dysfunction. Therefore, bleeding may be reduced by DDAVP in certain distinct patient subsets such as those with an acquired platelet defect (e.g. post-CPB, uremia), as well as patients with Type 1 von Willebrand's disease. Recombinant activated factor VII (rFVIIa) is licensed for use in bleeding episodes in hemophiliac patients with inhibitors. It has been used off-label in major surgery in nonhemophiliac patients. Although, only anecdotal reports and results from small clinical studies are presently available, publication of results from randomized trials are forthcoming.

Although several case reports have indicated that this agent can reverse life-threatening bleeding, other reports indicate that there is variability in the effectiveness of rFVIIa in the management of bleeding and in reducing transfusion requirements. Our previous recommendations suggest use of this agent as a Ôrescue therapyÕ when the following criteria are met: in the setting of life-threatening perioperative bleeding that has no identifiable surgical source and that is unresponsive to routine (at least a couple of rounds) of hemostatic therapy (e.g. platelets, FFP and cryoprecipitate). As any factor concentrate can potentially lead to life-threatening thrombotic complications in a subset of high-risk patients (i.e. patients with congenital or acquired thrombotic disorders, or systemic activation of the hemostatic system such as with DIC or after cardiac surgery), large clinical trials evaluating the efficacy and safety of rFVIIa are needed before its use as a first-line therapy can be recommended. In summary, use of POC tests of hemostatic function can facilitate the optimal management of excessive bleeding and reduce transfusion. Accordingly, POC tests that assess platelet function may also identify patients at risk for acquired, platelet-related bleeding. In addition, rapid acquisition of coagulation data can allow physicians to better differentiate between microvascular bleeding and surgical bleeding. An ideal algorithm would encompass test systems that evaluate heparin, fibrinolysis, coagulation factor levels, qualitative and quantitative platelet abnormalities. Although use of potent factor concentrates may be life-saving in the setting of intractable bleeding, at the current time off-label administration of these agents should be limited to scenarios involving bleeding that is unresponsive to routine therapy based on safety and cost. The ability to optimize the management of bleeding which can lead to a reduction in use of blood products, operative time or re-exploration rates, has important implications not only for disease prevention, but also for blood inventory and costs, as well as overall healthcare costs.

Recombinant activated factor VII is safe and effective in the management of critical bleeding. Con

Jean-Franc¸ois Hardy, MD, FRCPC Department of Anesthesiology, University of Montreal, Montreal, QC, Canada Recombinant activated factor VII (rFVIIa) has been approved for the treatment of bleeding in hemophilia patients. Case reports and case series suggest that rFVIIa is effective in the management of uncontrolled bleeding of diverse origins in patients with a (baseline) normal hemostatic system. While such results are interesting and suggest possible efficacy, the gold standard in establishing the benefits and harms of an intervention is the randomized controlled trial (RCT). In this presentation, we review all published RCTs that have evaluated the hemostatic efficacy and safety of rFVIIa in non-hemophilia patients. In total, at the time of writing, 13 RCTs had been published on the use of rFVIIa to control bleeding in patients either with (6 RCTs) 1-6 or without (7 RCTs) 7-13 a hemostatic defect at the time of administration of the drug. Results of studies in patients with a known hemostatic defect at the time of administration of the drug showed either no benefit 1,3,4,6 or a very marginal one. 2, 5 In patients with no known hemostatic defect prior to the bleeding episode for which the trial drug was administered, the only truly positive results are those of the acute intracerebral hemorrhage (ICH) study by Mayer et al. 11 Intracranial bleeding, mortality and severe incapacity were reduced significantly by rFVIIa. However, the incidence of arterial thrombotic adverse events was increased significantly in patients treated with the drug (an incidence of 5% vs. 0% in the placebo group). Results of the retropubic prostatectomy trial were not convincing due to the very high blood losses in the control group. 9 All other trials reported negative results by intent-to-treat analysis of the data. 7, 8, 10, 12, 13 Two studies reported a significant benefit in selected patients (post-hoc, subgroup analyses). 7, 8 While the latter results suggest a beneficial effect of the drug in some patients, they cannot be considered positive and await confirmation by subsequent RCTs in those specific patient populations. In summary, at present, published RCTs do not support the efficacy of rFVIIa to control bleeding and reduce transfusions in various patient populations. In addition, the safety of rFVIIa remains a concern. 14 Consequently, in light of the available evidence, the use of rFVIIa to prevent or to control bleeding cannot be recommended.

George J. Despotis, MD Department of Anesthesiology and Blood Bank, Washington University School of Medicine, St Louis, MO, USA Potentially lethal transfusion-related complications include the transmission of pathogens (e.g. HIV, Hepatitis B, C, bacteria and parasites), as well as vCJD, acute hemolytic reactions, allergic reactions, transfusion-associated acute lung injury (TRALI), and alloimmunization-related diseases (e.g. posttransfusion purpura, platelet refractoriness and transfusion-associated graft-versus-host disease). Currently, the three leading causes of death as reported to the US Food and Drug Administration (FDA) are TRALI, bacterial contamination of blood components, and ABO-incompatible transfusion reactions. In addition, the literature is revealing new potential, albeit controversial problems related to transfusion such as its effect on long-term survival, perioperative infection, multi-organ system failure, and platelet-related mortality. In fact, at least three recent randomized controlled trials have indicated that transfusion of non-leukoreduced red blood cells is associated with a substantially increased risk of mortality (10-20 000 deaths/million units transfused when compared with 20-100 deaths/million units transfused with TRALI) in susceptible high-risk populations (i.e. patients undergoing cardiac surgery). Blood shortages related to increasing consumption (i.e. expanding geriatric population) along with a shrinking supply (i.e. exclusion of donors related to more extensive donor exclusion criteria designed to prevent disease transmission, and elimination of alternative sources of blood such as from Great Britain due to concerns of vCJD transmission, thereby reducing the US national blood supply by 5%) may limit our ability to adequately manage our anemic and bleeding patients. This highlights the relative importance of implementation of blood management strategies to prevent transfusion-related disease as well as blood shortages. Bleeding after cardiac surgery can result in hypoperfusion and anemia-related end-organ dysfunction and mortality, as well as transfusion-related complications. Several large studies have demonstrated that if bleeding is excessive to the point that re-exploration is required, overall mortality increases three-to fourfold. There is also an increased incidence of several other important complications such as sepsis, multi-organ system failure, renal failure, etc. Patients at risk of excessive bleeding include those with an established hereditary disorder [e.g. von Willebrand's disease (VWD), hemophilia, connective tissue disorders, quantitative or qualitative platelet abnormalities], end-stage hepatic or renal disease, as well as patients with acquired defects of the hemostatic system. In a patient with a history of bleeding, use of the PFA-100 test preoperatively can potentially identify patients with either VWD or platelet abnormalities, who may benefit from either pharmacological (e.g. DDAVP) or transfusion-based therapy. Rarely, patients with platelet (i.e. platelet refractoriness) or coagulation factor inhibitors are also at increased risk. Although congenital abnormalities of the hemostatic system can predispose patients to excessive perioperative bleeding, acquired defects especially with cardiac surgery and trauma more commonly lead to bleeding. There are certain distinct patient subgroups who are at greater risk of developing excessive bleeding such as patients undergoing second-and third-time operative procedures, patients undergoing more complex procedures, cardiac patients who require

long CPB periods (e.g. combined valve/coronary revascularization, aortic aneurysm repair involving deep hypothermic circulatory arrest), patients receiving one or more antithrombotic medications in the immediate preoperative period (e.g. clopidogrel, abciximab, low-molecular-weight heparin, etc.) and less commonly patients with an established hereditary (e.g. VWD and hemophilia) or acquired (e.g. platelet or coagulation factor inhibitor) disorder of the hemostatic system. Up to 50% of critically ill children received a red blood cell (RBC) transfusion during their stay in a pediatric intensive care unit (PICU). 1,2 A large variation in stated and in observed practice pattern has been reported. For example, in two different surveys using a questionnaire, 3,4 the hemoglobin concentration that would prompt pediatric intensivists to prescribe an RBC transfusion to patients with stabilized septic shock ranged from 7 to 12 g/dL. The same range was observed in a prospective bedside survey. 2 Hemoglobin concentration is clearly the most important determinant when a decision is made to prescribe an RBC transfusion. 2, 3 However, what the threshold hemoglobin concentration should be and how other determinants, such as hemodynamic instability, should modulate this threshold is unclear. Three prospective studies run in Kenya involving 4935 hospitalized patients suggested that the survival of children who had a hemoglobin concentration below 5 g/dL is better if they received an RBC transfusion. 5, 7 Therefore, it is probably appropriate to consider that all critically ill children with a hemoglobin concentration below 5 g/dL should receive an RBC transfusion. A large noninferiority randomized clinical trial, the TRIPICU study (ISRCTN37246456), compared two RBC strategies in 637 stable critically ill children: a restrictive strategy where the threshold hemoglobin concentration was 7 g/dL; and a liberal strategy with a threshold of 9.5 g/dL. The results supported the hypothesis that the restrictive strategy was not inferior to the liberal strategy; actually, the results were similar in both groups. 8 In medicine, primum non nocere is always true. Therefore, we recommend that an RBC transfusion should not be given to stable critically ill children unless their hemoglobin concentration drops below 7 g/dL. What the optimal hemoglobin concentration in unstable patients and in children with cardiac diseases is remains to be determined.

Is it safe to limit allogeneic red blood cell transfusions during infancy?

Ronald G. Strauss, MD University of Iowa College of Medicine, Iowa City, IA, USA Because of several potential risks, it is sound medical practice to give transfusions only when the benefits are certain. However, because many transfusion risks are quite small, it is important not to place patients at risk of undertransfusion by being overly restrictive-specifically for RBC transfusions-and permitting the hematocrit level to drop to harmfully low levels before transfusing. Two randomized clinical trials have assessed clinical outcomes in preterm infants allocated to be transfused at relatively high pretransfusion hematocrit/hemoglobin levels (standard or liberal transfusion group) vs. lower pretransfusion hematocrit/hemoglobin levels (conservative or restrictive transfusion group). 1,2 Both studies (Iowa and Canada) found that fewer RBC transfusions were given to infants in the restrictive group. In the Canadian study, clinical outcomes including death, severe retinopathy, bronchopulmonary dysplasia and brain injury were not significantly different between the two groups, suggesting no benefit to maintaining relatively high hematocrit/hemoglobin levels by RBC transfusion. 1 In contrast, infants in the restrictive transfusion group of the Iowa study were more likely to have apnea, intraparenchymal brain hemorrhage and periventricular leukomalacia, suggesting that restrictive RBC transfusion practices may be harmful to preterm infants, possibly due to harmfully low pretransfusion hematocrit levels. 2 Additional, welldesigned clinical trials will be needed to resolve this discrepancy and to determine best practices. Until more data clarify this issue, it seems prudent to transfuse preterm infants per standard guidelines/practices and to use restrictive practices only in study settings with informed consent and oversight by human experimentation committees. always maintains an equilibrium between activators and inhibitors throughout intrauterine life, not only up until birth, but throughout the entire lifetime. 1 An increase in factor levels is observed after the thirty-fourth week of intrauterine life for most of the coagulation activators and inhibitors, but only factors V and VIII reach adult values at birth. In general, deficits in coagulation factors and inhibitors of coagulation persist until at least the age of 6 months. In elderly people, elevated coagulation factors and markers of coagulation activation point to a hypercoagulable state with increased risk of thromboembolism despite concomitant elevation of coagulation inhibitors. Also, the fibrinogen of infants, especially of infants with congenital heart defects, exists in a dysfunctional state. 2 In addition, showing an absence of CPB-induced increase of P-selectin and a smaller decrease of glycoprotein Ib, neonatal platelets are intrinsically hyporeactive to various stimuli (e.g. cardiopulmonary bypass). 3, 4 Nevertheless, despite quantitative deficiencies in coagulation factors and reduced platelet function, global coagulation tests demonstrate functional maturity of the coagulation system in young children. This finding may help to explain why young children do not have a propensity to bleed excessively during surgery or other invasive procedures despite their deficient coagulation systems. 5 The coagulation system of infants and neonates may also be altered by different diseases, especially by cyanotic heart disease. For example AT III and protein C activity in cyanotic children is significantly decreased when compared with acyanotic children. In addition, a positive correlation between oxygen saturation and arterial oxygen saturation has been found. These conditions tend to normalize after cardiac repair relating perhaps to improved systemic oxygenation. Although the coagulation system of infants and children is functionally intact, it is more vulnerable due to surgery, especially cardiac surgery with its major procedures leading to extensive fluid shifts, hemodilution during extracorporeal circulation, hypothermia, etc. Therefore, precise management of blood coagulation is of critical importance in neonates and infants. It is essential to diagnose perioperative hemostatic disturbances quickly and precisely in order to administer the adequate amount of blood products if indicated, and to avoid their unnecessary usage with possible adverse consequences. Conventional laboratory coagulation tests are time-consuming and describe only parts of the whole coagulation process. In contrast, whole blood coagulation tests such as activated clotting time or RoTEM Ò tests may provide quick and timely useful information and may help to decide when and how to intervene in managing perioperative coagulopathies. Until now pediatric studies have not been conducted with the RoTEM Ò device (Pentapharm), and normal values are only available for the adult population. To avoid incorrect interpretations and application of extrapolated data to children, it is a precondition to know the devicespecific and activation-specific baseline parameters and age-related differences. Preliminary results showed that the hemostatic system in cyanotic congenital heart disease (CCHD) patients is functionally intact, but in some aspects borderline with and with greater variability than that in healthy children. This could be interpreted as a reduction in the procoagulatory potential in some of those partly very sick children, mainly in the 0-1 month age group and to a lesser extent in 1-3 months. In comparison with CCHD patients, healthy children showed relatively homogenous values with a tendency to Ôhypercoag-ulabilityÕ; the maximum level was found in the 1-3 month age group, slowing down to adult values in the course of the first year of life. 6 Pro and Con Discussion: Blood Salvage in Obstetric Hemorrhage S19 Blood salvage in obstetric hemorrhage. Con

Hans Gombotz, MD Department of Anesthesiology and Intensive Care, General Hospital Linz, Austria In contrast to the situation in developing countries, in the western hemisphere peripartum hemorrhage has steadily declined, but is still the leading cause of maternal and fetal morbidity and mortality. Peripartum hemorrhage occurred in approximately 6.7/1000 deliveries 1 and accounted for 17% of maternal deaths in the US between 1991 and 1999. 2 Among white women, the risk ratios for death from hemorrhage, but also infection, embolism, hypertensive disorders of pregnancy, cardiomyopathy, cerebrovascular accidents, or other medical conditions ranged from 1.8 to 2.7 for those aged 35-39 years, and from 2.5 to 7.9 for those 40 years and older. Among black women, the risk ratios for death from these conditions ranged from 2.0 to 4.1 for those aged 35-39 years, and from 4.3 to 7.6 for those 40 years and older. 3 In another investigation, a maternal age of ‡ 35 years was also an independent risk factor for excess blood loss irrespective of the mode of delivery, even after adjusting for age-related complications such as leiomyoma, placenta previa, and low-lying placenta. 4 The increased blood volume associated with normal pregnancy typically compensates for the obligatory blood loss that occurs during vaginal or cesarean delivery. However, in some patients blood loss may overwhelm compensatory mechanisms and may result in hypovolemia and shock with a significant threat for both the mother and the fetus. Peripartum hemorrhage includes a wide variety of pathophysiological events and despite advances in prevention, diagnosis and treatment, massive blood loss during pregnancy remains still a threat. 6 During or after cesarean delivery, of 9596 women a total of 336 received RBC transfusions. 7 The overall incidence of transfusion in this patient population declined from 6.2 to 3.2% during the study period (P < 0.001). Slightly more than half (54.4%) of all transfusions were given in the operating room or recovery room. The majority of patients (68.4%) received 2 RBC units, 11.6% received a one-unit transfusion, and 8.3% received 5 units or more. The most common obstetric diagnoses associated with RBC transfusion were disorders of placental implantation, preeclampsia, premature labor with tocolytic therapy, fetal distress, and augmentation of dysfunctional labor. In another evaluation, of 3962 patients who also underwent cesarean section, 132 (3.3%) required a blood transfusion during their hospital stay. Since then, even the necessity for admission type and screen testing for all women has been called into question because of the low transfusion frequency. 6, 8 In general, malignancy, bacterial infection, use of collagen or hemostatic material are contraindicated for the use of cell salvage except in emergency situations. [9] [10] [11] [12] Another concern may be that amniotic fluid, a potent activator of coagulation, and fetal debris may not be adequately removed, and transfusion may precipitate the anaphylactoid syndrome of pregnancy. In addition, the specific components of amniotic fluid that lead to the sudden dyspnea and cardiopulmonary collapse typically seen in fatal cases are still unknown. Some investigators believe that particulate contaminants are responsible for amniotic fluid embolization, 13,14 whereby cell washing has been shown not to remove fetal squamous cells. 15, 16 On the other hand, it has been shown that otherwise healthy parturients had abundant apparently fetal squames in their circulation. 17 Tissue factor is another cause of disseminated intravascular coagulopathy after embolism of amniotic fluid. Although this factor may be removed by routine cell salvage, there is no guarantee that amniotic fluid embolism may be prevented as other factors may still be transfused.

With newer devices, alpha-fetoprotein, phospholipids, tissue factor, fetal squamous cells and other cellular debris can be at least partially reduced. 18 Because of the documented removal of free hemoglobin, bromocresol green dye, and heparin from salvaged blood, we can just hypothesize that if one factor is effectively removed, the other factors are also equally removed. The salvaged blood product can be further improved with the additional use of a leukocyte-depletion filter after washing. 11, 19 However, even after this procedure, washed blood is likely to contain fetal red blood cells in addition to other adverse components. As a consequence, isoimmunization of the mother is possible, and anti-D immune globulin should be administered when appropriate. Thus, the general use of cell salvage with leukocytedepletion filtration in obstetric hemorrhage cannot be recommended. Blood transfusion in obstetrics is rare and mostly related to previously identifiable risk factors. Therefore, other blood-conservation strategies such as predonation of autologous blood could be implemented. Adverse components in blood can indeed be significantly reduced by washing and filtering, but they cannot be totally eliminated. Processed blood is also likely to contain residual fetal cells. Filtering salvaged blood is time-consuming and its effectiveness is dependent on the initial cell content of the blood collected. The risk of retranfusion of potentially contaminated blood has to be considered in the light of the increasing safety of allogeneic blood transfusions. Up to now there have been growing numbers of successful case reports regarding the use of cell salvage in obstetrics showing a high tolerance to retransfusion of washed and filtered autologous blood. Nevertheless, the effectiveness and safety of this method has to be documented in larger studies. Therefore, autotransfusion by using cell salvage combined with leukocyte-depletion filtration should be limited to life-threatening obstetric hemorrhage and offered to Jehovah's Witness patients.

Blood salvage in obstetric hemorrhage. Pro Dafydd Thomas, MBChB, FRCA Intensive Therapy Unit, Morriston Hospital / Ysbyty Treforus, Swansea NHS Trust, Swansea / Abertawe, Wales, UK Hemorrhage is a well-recognized cause of maternal morbidity and mortality. Current pressures on a continued safe blood supply for the UK population, as a consequence of variant Creutzfeldt-Jakob disease 1,2 amongst other pressures, mean that consideration is being given to alternative techniques that may lessen demand on allogeneic blood supplies. The current debate is whether it is advisable to use such techniques during obstetric surgical intervention. Such procedures may result in significant hemorrhage, and the use of cellsalvage autotransfusion is considered by some to be worthwhile and indicated in these instances. 3 Previous UK Consensus Conferences 4,5 have advised that cell salvage is only efficient and cost-effective when blood loss is between 500 and 1 000 mL. The majority of uncomplicated cesarean deliveries lose < 500 mL and so one is hard pressed to advocate the use of cell salvage routinely in obstetrics. However, the latest figures from CEMACH 6 do show a significant mortality from obstetric hemorrhage. A report describing predictors of obstetric morbidity stated that there were 6.7/1000 incidences of specific morbidity for severe obstetric hemorrhage. It went on to summarize that most obstetric morbidity is related to hemorrhage and severe eclampsia, whilst cesarean section quadruples the risk of morbidity. Amniotic fluid embolism (AFE) is a catastrophic syndrome presenting with a complex clinical picture of cardiovascular collapse, acute left ventricular failure with pulmonary edema, disseminated intravascular coagulation and neurological impairment. 8 The resultant clinical situation requires aggressive supportive therapy. There has historically been a reluctance to use intraoperative cell salvage in obstetrics because of the fear that it may precipitate AFE. In researching the topic, it appears that the diagnosis of AFE is a presumed diagnosis made when a woman collapses during the peripartum, or following the demise of such individuals when at postmortem fetal squames and other fetal debris may be found in the pulmonary circulation. This, however, is an unreliable finding. Fetal squames are indistinguishable from skin squames, which may appear in the pulmonary circulation following aggressive resuscitation using central venous access. In the USA, current data from the National Amniotic Fluid Registry suggest the process is more similar to anaphylaxis than to embolism. 9 Other researchers have noted that fetal squames are present in the fetal circulation of laboring parturients who do not develop AFE. 10, 11 Prior to advocating the use of cell salvage in obstetrics, there is a need to discuss the following main issues: 1. If there are fetal markers in all parturient women during the birthing process, then the theory of an anaphylactic reaction becomes more convincing. 2. What markers can we measure in maternal blood which predict fetal contamination? 3. Are these markers removed by the washing process of automated cell salvage? 4. Is there anything else that can be done to reduce the likelihood of contamination with free amniotic fluid when intraoperative cell salvage is used? 5. Is there a technique available to further reduce fetal contamination? 6. In my discussion promoting the use of intraoperative cell salvage in obstetrics, I hope to convince the audience that its use is indicated, provided it is needed and that standard operating procedures are followed. This will of course require all users to have the necessary competencies to use the equipment correctly. Footnote: With more widespread use of intraoperative cell salvage, it is important that adverse reports thought to be due to the use of intraoperative cell salvage be reported. However, complete data from the institutions using the technique are required so that a true incidence of adverse events can be made with numerator and denominators being reported. State-of-the-Art Lecture: Acute Normovolemic Hemodilution S21 Acute normovolemic hemodilution Konrad Messmer, MD University of Munich, Germany Acute normovolemic hemodilution (ANH) was initially introduced as a means of avoiding transfusion of allogeneic blood in patients undergoing elective surgery with anticipated major blood losses. Prerequisite to accepting intentional anemia was the systematic investigation of the mechanisms allowing the adaptation of the organism to the acute dilution-associated reduction of the oxygen content of arterial blood. Numerous studies from various laboratories around the world have addressed the cardiovascular responses to acute anemia induced by exchange of whole blood for red blood cell (RBC)-free crystalloid and/or colloidal solutions. There is general agreement that the maintenance of normovolemia is the basis for eliciting and preserving an effective cardiovascular compensation for intentional dilutional anemia. While the macrocirculation responds with an increase in cardiac output and organ blood flow (provided that normovolemia is maintained), the microcirculation responds with an increase of red cell flow velocity, a more homogeneous distribution of microvascular flow and a wellmaintained functional capillary density (number of RBC-perfused capillaries). These changes allow the preservation of organ tissue oxygenation until the so-called critical hematocrit is reached. It appears that in the absence of disease, in particular coronary artery disease, hematocrit values around 20% can be tolerated; this value defines the so-called transfusion trigger. Above this hematocrit value, the dilutional reduction of whole blood viscosity is considered as a beneficial effect (moderate hemodilution); below 20% hematocrit (extreme hemodilution), low blood viscosity may be harmful because the local shearing forces may be too low to release nitric oxide from the microvascular endothelium and thus impair functional capillary density. For this reason, an elevation of plasma viscosity by means of a colloid with relatively increased viscosity seems preferable. If very low hematocrit values are encountered, hyperoxic ventilation presents as an additional safety mechanism. For clinical hemodilution, the target hematocrit can be calculated by different mathematical formulae. The occurrence of tachycardia in a diluted patient calls for instantaneous control of hematocrit, volume status and assessment of ST-segment changes in the ECG. The efficacy of ANH in avoiding allogeneic blood transfusions depends upon the patient's initial hematocrit, the target hematocrit desired and the amount of blood loss. While age per se is no contraindication to ANH, patients with coronary and pulmonary disease, as well as those presenting with coagulation disorders, should not undergo routine hemodilution. The efficacy of ANH is a matter of debate; nevertheless, hemodilution with the concept of tolerance of low hemoglobin and hematocrit concentrations is the basic element of all strategies to avoid blood transfusions. The treatment safety when started < 6 h after surgery (Arixtra Ò ) was not optimal, leading to a reconsideration of the benefits of an early start of this agent in orthopedic surgery. More bleeding was seen in patients who received the first fondaparinux injection soon after surgery (< 6 h). This tendency was more pronounced in a ÔfragileÕ population defined as patients > 75 years old, < 50 kg and/or creatinine clearance (CLcr) < 50 mL/min. Strict adherence to the recommended timing of the first fondaparinux injection reduced the risk of bleeding among the ÔfragileÕ patients to the same level as ÔnormalÕ patients. 2 Furthermore, the recent FLEXTRA study has shown that starting fondaparinux prophylaxis the day after surgery was equally safe and effective. In cases of major bleeding in fondaparinux-treated patients, it has been suggested that recombinant activated factor VIIa could be useful. However, this solution has only be tested on healthy volunteers. 3 As already mentioned, many other antithrombotic agents are being developed. Some of them are still in the pipeline but some compounds are well advanced and not far from regulatory approval. As soon as these agents become available, physicians will have to consider the bleeding risk. Furthermore, most of these drugs (exception for dabigatran) are eliminated by the kidneys and therefore may accumulate in the elderly.

Management of patients with recent coronary artery stenting (Figure 1 ). 12 All but two (bleeding only) adverse events were of cardiac nature. The risk of suffering an event was 2.11-fold greater in patients with recent stents (< 35 days before surgery) as compared with PCI more than 90 days before surgery. In the nonsurgical setting, cardiologic trials documented greater bleeding risk when clopidogrel and aspirin were combined, compared to aspirin alone. 13 Most of the surgical data come from clinical studies in patients undergoing CABG surgery). 14,15 Clopidogrel, a thienopyridin, inhibits platelet aggregation by irreversible blockade of adenosine diphosphate-mediated platelet function. Normalization depends on the new platelet population. Most CABG studies demonstrated that clopidogrel given within 4-5 days before CABG surgery increased transfusion requirements and prolonged ICU stay. 14, 15 Recommended dual antiplatelet drug regime after stent implantation: The ACC/AHA Guidelines from 2002 concluded that there is uncertainty regarding how much time should pass between PCI and NCS procedures. If a coronary stent is used, a delay of at least 2 weeks and ideally 4-6 weeks should occur before NCS in order to allow four full weeks of dual antiplatelet therapy and reendothelialization of the stent to be completed or nearly so. 16 The new guidelines of the European Society of Cardiology for percutaneous coronary artery intervention recommend that after implantation of a bare metal stent, clopidogrel must be continued for 3-4 weeks and ASA lifelong; after drug-eluting stents, clopidogrel and ASA should be administered for 6-12 months to avoid late vessel thrombosis. 17 The new ACC/AHA 2005 Guideline update for percutaneous coronary intervention recommends that in patients who have undergone PCI, clopidogrel 75 mg daily should be given for at least 1 month after bare-metal stent implantation (unless the patient is at increased risk for bleeding, in which case it should be given for a minimum of 2 weeks), 3 months after sirolimus stent implantation, and 6 months after paclitaxel stent implantation, and ideally up to 12 months in patients who are not at high risk of bleeding (level of evidence B). 18 Perioperative management: Currently, many case reports and retrospective studies are available but no large prospective randomized trials. Therefore, we have to rely on recommendations of task forces and expert opinions. [16] [17] [18] [19] Basically, when assessing the perioperative risk of patients with recent coronary artery stenting before noncardiac surgery, we have to plot the risk of thrombosis vs. the risk of bleeding ( Figure 2 ). Dual antiplatelet regime can be stopped, changed or continued according to this assessment. Figure 3 shows the algorithm for the preoperative management according to the urgency of noncardiac surgical procedures. Depending on the calculation of the thrombosis/bleeding risk, three options are possible: 1. Continue clopidogrel + aspirin. E.g. peripheral vascular surgery can be performed under dual antiplatelet drug regime because vascular surgeons are familiar with such situations. 2. Continue aspirin, stop clopidogrel.

This concept balances in many cases the risk benefit ratio.

This option should be strictly restricted to high-bleeding procedures, such as urologic, intracranial and some types of tumor surgery. Essentially, patients with recent coronary artery stents and dual antiplatelet therapy scheduled for noncardiac surgery benefit from a close cooperation between the surgeon, the anesthesiologist and the cardiologist.

Semi-elective and urgent Elective 

Heparin-induced thrombocytopenia Ismaı¨l Elalamy, MD, PhD Hemostasis Unit, Tenon Hospital, Paris, France Heparin-induced thrombocytopenia (HIT) is a rare but potentially severe drug-induced adverse immune reaction. HIT can be postulated on occurrence of a rapid isolated decrease (> 40%) in the initial platelet count, whether or not this is associated with a thrombotic event. 1 For this paradoxical syndrome, the major problem is to recognize and treat it as early as possible in order to avoid the development of life-threatening complications. 2,3 HIT seems to be more common in connection with inflammatory diseases or sepsis, and in patients having undergone surgery, requiring a greater awareness on the part of physicians in these contexts. In 1992, Amiral et al. discovered the major target of HIT antibodies, namely a macromolecular complex associating heparin and a tetrameric protein, platelet factor 4 (PF4). 4 In some cases, modified PF4 can be replaced by other chemokines such as interleukin-8 or neutrophil-activating peptide-2. 5 These antibodies induce a systemic and multicellular activation of the vascular compartment leading to an acquired hypercoagulable state. Due to this increase in thrombin, arterial and mainly venous thromboses are frequently associated with the drop in the platelet count. [1] [2] [3] Unusual thrombotic episodes are reported such as bilateral adrenal hemorrhagic infarct, venous limb gangrene, or skin necrosis. 3, 4 HIT diagnosis must be based on both clinical features and laboratory analysis. There is no gold-standard criterion and a pretest scoring system has been proposed to evaluate HIT likelihood (the 4 Ts score). 3 Functional tests, such as platelet aggregation test or serotonin release assay, and immunoenzymatic tests, such as ELISA (heparin plateletinduced antibodies, Diagnostica Stago) or PaGIA (DiaMed), are generally performed by expert laboratories to confirm the presence of HIT antibodies. 6 Both tests are complementary in HIT diagnosis determination. HIT treatment also requires a multidisciplinary approach. In France, danaparoid (Orgaran Ò ) and lepirudin (Refludan Ò ) are the two alternative antithrombotic treatments approved in HIT. [7] [8] [9] A certificate should be given to each HIT patient, thus avoiding any further deleterious heparin exposure.

Prospects of a decentralized transfusion system: Norway

Hans Erik Heier, MD, PhD, MHA Department of immunology and transfusion medicine, Ullevaal University Hospital, Oslo, Norway Norway has 4.5 million inhabitants in an area about 80% the size of France. The distance from south to north is 2500 km. High mountains divide the country into natural regions and create difficulties for communication, which is further hampered by extreme weather conditions along the Atlantic coast. These natural conditions have brought about a general socio-political attitude of local selfsufficiency and independence. Each of the 54 somatic hospitals developed its own in-hospital blood bank and donor corps between 1949 and 1960. No domestic plasma fractionation industry was established. A process of gradually increasing coordination and harmonization of blood-bank activities has been taking place over the past 25 years. There is a national contract for plasma fractionation with the international fractionation industry, and all Council of Europe and EU standards are met by national guidelines and directives. Currently, hospital-based blood banks are being integrated into 27 health enterprise-based units, and there are plans of further integration within the five health trusts. Also, national competence centers for blood group serology and thrombocyte immunology have been established. Thus, Norway has developed a hospital-based, decentralized transfusion system with increasing integration of previous blood banks into larger units, and with increasing national coordination and standardization. This solution appears to be in accordance with the general sociopolitical trends of the country and helps to integrate all aspects of transfusion into the general somatic healthcare system. Furthermore, the system promotes close day-today contact between clinicians and transfusionists. The system provides national self-sufficiency of all standard blood and plasma products, and the frequency of errors recorded by the hemovigilance system is fairly similar to that seen in e.g. the UK. 1,2 There is active research in transfusion medicine in three university hospitals, and blood supply is in balance throughout the country. The Norwegian experience thus shows that all aspects of modern transfusion medicine can be managed adequately in a decentralized, centrally coordinated system. The possibility is open that extra-hospital regional or national systems for donor management and production may achieve higher cost-efficiency, but such studies may be hampered by differences of natural conditions and socio-political structures in the countries compared. A more challenging hypothesis is that the absence of a domestic plasma fractionation industry has led to lower consumption of blood products in general than in countries with high demand for plasma to a domestic industry. This may find support in the general history of the development of transfusion 3 and by comparing consumption of blood products in the Nordic countries. 4 Consumption is higher in Denmark, Finland and in Sweden than in Norway, the former three all having developed domestic fractionation industry, in contrast to Norway.

Legal issues in autologous blood use nity standards and specifications relating to a quality system for blood establishments. However, though increasingly safer, allogeneic blood transfusion (ABT) can never be risk-free. 1 Therefore, prior to give an ABT, it is mandatory to obtain patient's written consent, after provision of adequate information regarding ABT benefits, risks and possible alternatives. 2 On the other hand, the development of complex surgical procedures for the treatment of a number of diseases has increased the demand for ABT. All these have prompted the review of transfusion practice, and the search for blood conservation measures, such as use of autologous transfusion (peroperative autologous blood donation, PABD; acute normovolemic hemodilution, ANH; perioperative cell salvage and PCS). Regulations regarding PABD collection are now covered by the mentioned European Directives which are legally binding. However, the clinical use of PABD blood is not so regulated, being subject more to professional judgment as to clinical need. This needs to be covered by Guidelines, particularly where practice has changed and parts of which are now legally regulated. 3, 4 In contrast, there are no specific regulations regarding ANH or PCS. However, if ANH is considered as a modality of PABD, then the above-mentioned Directives might be applicable. In addition, some recommendations regarding the implementation of ANH have been issued. 1 In the operating theater, a threshold of 6-8 g/dL is fine; in critical care, 8 g/dL; and in both, the threshold rises if there is any suggestion of ischemic heart disease. 1 To date the implementation of these rules in both the operating room and the critical-care environment may have been patchy, but the trend in both areas is certainly towards lower thresholds, and this is reflected in less blood usage. [2] [3] [4] [5] [6] The remarkable Canadian study that allowed this radical departure from conventional wisdom was the TRICC study. The TRICC study was very convincing in several ways. There were large numbers, and although the numbers fell well short of a convincing power, the clear lack of difference in outcome between the restrictive and liberal groups was reassuring. This was compounded by the finding in the lower APACHE II group (< 20) that the liberal approach may be hazardous with an increased mortality. The real savings in terms of blood transfusion were very appealing, especially the fact that some patients could avoid blood transfusion altogether. 7 The subgroup of patients that still posed a potential problem was those with identified ischemic heart disease and, by default, those with unidentified heart disease, who are a significant part of both the operative and the critical care population. 8, 9 The rationale for anxiety was that, with critically reduced blood flow, oxygen carriage might be threatened. Several authors have drawn attention to this, but to date there is much conjecture but little data to support the existence of the problem, although there are many advocates of the more conservative threshold. 8, 10 In practice, higher thresholds tend to be used if ischemic heart disease is even suspected. 11, 12 The consequences have been all good. Reduced blood usage, reduced exposure of patients to blood and its less common but daunting infectious complications, and no obvious morbidity that has been reported. Presumably there is a reduced intensive-care unit mortality in those units implementing this strategy, but this has not yet been reported. There are of course a few questions still being asked. In specific specialty areas such as neonatal practice, does a restrictive transfusion policy have any adverse neurological effects, as at least one study seems to suggest? 13 The occasional orthopedic surgeon asks whether mobilization is impaired. In interventional cardiology, pre-existing anemia with hematocrit < 0.39 for men is associated with adverse events, suggesting correction would do better. However, there is no mention of transfusion and so this could be just another indicator of comorbidity. 14 The evidence to quieten these questions is yet to be forthcoming. The drive to reduce blood usage may be focusing thoughts away from areas that might be cause for disquiet for a discerning mind. Some of these thoughts are as follows. Teleologically, why is hemoglobin at the level that it is in normal humans? Why do athletes believe they function better with enhanced hemoglobin values? Why does everyone who has had an acutely low hemoglobin level say how awful they felt? Why do those with chronically low hemoglobin values around 7 g/dL function adequately but not exceptionally in terms of exercise tolerance? When one examines the available data since thresholds were established and the apparent evidence for increased mortality from transfusion, there is almost overwhelming support for the use of these low thresholds, but it does beg the question of why. We need to address these issues and be able to answer these questions. Athletes may be misguided, but do we have the answers about rehabilitation and exercise tolerance in the critically ill? What benefit is there of a oneday-earlier discharge if recuperation is impaired by a week? The answers are not yet available. It is quite clear from a physiological viewpoint that for oxygen delivery, relatively low values of hemoglobin are more than adequate, providing that the circulation is robust. The combination of cardiac output and blood oxygen content determines oxygen delivery and each can compensate for the other. Add in the additional compensatory physiological mechanisms for unloading oxygen in the periphery, and the redundancy in the system is obvious. 15 Current thresholds do not challenge oxygen delivery unless oxygen requirements are exceptional or the delivery system is compromised significantly, which can occur in the critically ill. This cannot be the explanation of why anemia Ôsaps strength.Õ Studies are needed to evaluate recuperation at low hemoglobin values. Given our current practice, we should be evaluating our patients leaving the intensive care unit with hemoglobin values < 9 g/dL. [16] [17] [18] [19] The other major issue that needs addressing is the higher mortality rate in the liberal group than in the restrictive group. The cause of that increased mortality is obscure. An editorial at the time suggested that multiple organ failure can hide such a mortality. 7 This interesting but unexplained finding that implicates a commonly used ÔdrugÕ would not be accepted as a conclusion from a drug trial and so we need to determine what these negative effects are specifically. There are clues. The incidence of cardiac events, including myocardial infarction, was higher. Pulmonary edema was more common, although how this overlaps with cardiac events is unclear. Similarly, ARDS was more common and whether the populations overlapped is not discernable. This seems to be where the problem lay in part. If blood predisposes to cardiac problems, the concept that it is linked to rheology re-invokes the original idea of optimizing hemoglobin vs. flow. 20 In the Ôat-riskÕ elderly population, this seems a likely candidate, but it should be noted that neurological sequelae were not affected in similar fashion. If rheology were the culprit, might not neurological sequelae have been more common? Infection seems to have been in the clear on the data presented. This poses problems on two fronts. Blood has a bad reputation not only for immunological suppressive activities, but also there is an association between blood, multi-organ failure and infection. That was not the case in the data presented. So why is blood bad for critically ill patients? These issues need to be addressed to consolidate the position of the lower thresholds that are being increasingly adopted, so that this practice can be more consistently rolled out with confidence.

Prophylactic use of fresh frozen plasma and platelet transfusions in critically ill patients Ognjen Gajic, MD, MSc, FCCP Division of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA Fresh frozen plasma (FFP) and platelet transfusions are commonly used in critically ill patients for both treatment and prevention of bleeding associated with coagulopathy or thrombocytopenia. 1 The indications for prophylactic use of FFP and platelets, particularly prior to minimally invasive interventions in the intensive care unit, have not been rigorously studied. Neither the current methods for measuring the degree of coagulopathy are predictive of postprocedural bleeding, 2 nor is routine prophylactic administration of FFP and platelets associated with decreased risk of bleeding complications. 3, 4 Common procedures such as central line placement, thoracocentesis, abdominal paracentesis, or liver biopsy can be safely performed by trained practitioners without the correction of abnormal coagulation. 1 Retrospective studies suggest that prophylactic administration of FFP and platelet transfusion may not be associated with decreased risk of bleeding, and that transfusion-related complications may increase patient morbidity. 5, 6 While awaiting the results of prospective studies, critical-care providers should carefully assess the potential risks and benefits of prophylactic FFP and platelet transfusions.

most important contributors. Although RBC transfusion remains a common practice in critically ill patients, it is associated with significant risks, such as disturbances in microcirculation and immunosuppresion. Because of these risks, transfusion practice is currently under systematic scrutiny and transfusion benefits are critically re-evaluated. At present, measures to prevent rather than to treat anemia in critically ill patients achieve high priority. Exogenous administration of recombinant human erythropoietin (rHuEPO) in patients with critical illness is a preventive strategy that has attracted much attention in recent years. The rationale for rHuEPO therapy in critically ill patients is that increased erythropoiesis will result in higher Hb levels and subsequently will reduce the need for RBC transfusion. Preventing anemia by administration of rHuEPO minimizes the risks of anemia without exposing the critically ill to the deleterious effect of RBC transfusion. It has been shown that administration of rHuEPO in selected ICU patients may significantly decrease RBC transfusion requirements, although the impact of this therapy on patientsÕ outcome as well as the cost/benefit ratio need further study. Absolute or relative volume deficits often occur during surgery. They may result from preoperative dehydration, bleeding, and/or vasodilation mediated by the use of vasoactive drugs or rewarming. 1 Fluid deficit can also develop in the absence of fluid loss secondary to increased capillary permeability, resulting in the development of a ÔthirdÕ space. Inadequate fluid administration can led to a reduced effective circulating volume, redistribution of blood flow towards vital organ (brain and heart), resulting in under-perfusion of other organs such as the gut, the kidneys, the muscles and the skin. Activation of the sympathetic nervous and the renine-aldosterone-angiotensin systems are compensatory mechanisms to maintain peripheral perfusion. Various circulating vasoactive substances and inflammatory mediators are also increased. Studies support the hypothesis that improving tissue perfusion may also result in reduced inflammatory activation and, hence, organ dysfunction. 2 Others have demonstrated that inadequate tissue perfusion measured with gastric tonometry is associated with adverse perioperative outcome. 3 However, excessive administration of fluid may also result in adverse outcome. Excess fluid in the intravascular compartment leads to increased venous pressure and results in interstitial fluid accumulation. This leads to peripheral and pulmonary edema, and consequent compromise of tissue oxygenation. Pulmonary edema is a major adverse outcome that results in an increased alveolar-arterial oxygen gradient and systemic hypoxia. There is evidence that intestinal edema can be associated with impaired gastrointestinal function tolerance for enteral nutrition, 4 an increased potential for the development of bacterial translocation and the development of multiple organ failure. 5 The balance between inadequate fluid administration with decreased tissue perfusion and excess fluid with edema formation will vary for specific types of surgery.

Perioperative fluid requirements will depend on the patient's preoperative volume status, and the length and the complexity of the surgery. Goals of perioperative fluid administration are to avoid dehydration, maintain an effective circulating blood volume and to prevent inadequate tissue perfusion. 1, 6 In this setting, two important factors need to be considered: the type of fluid to be administered and the criteria for guiding volume therapy. The choice between the different available solutions should be based on the physiological compartment that needs to be restored (i.e. intravascular, interstitial and intracellular). It will take into account not only the pharmacokinetic and the pharmacodynamic properties of the different solutions, but also their possible side effects and their costs. Patients Ôpatho-physiologyÕ is also important to consider. Available clinical outcome data (mortality and major morbidity) provide no evidence for the relative benefit between crystalloid and colloid fluid therapy, or between the different types of colloids. However, crystalloids appear less appropriate for resuscitation of the intravascular compartment as they are mainly distributed to the interstitial space. Colloids are more appropriate for treating intravascular volume deficits. The lower cost of synthetic colloid solutions is a powerful argument for using them rather than human albumin. Different approaches have been proposed to guide perioperative volume therapy. The traditional Ôcook bookÕ approach relies on the use of formulas based on a continuous predetermined rate of infusion of fluid with additional replacement of observed losses. Although it seems logical that some fluid is better than none, as the magnitude of surgical insult becomes greater, choosing what fixed dose to give becomes harder. 6 When significant amounts of fluid are required, an alternative approach based on potential physiological end-points is more effective. There is no evidence that tissue under perfusion could be avoided through the use of static measurements of intravascular pressures. Indeed, arterial blood pressure measurements do not reflect blood flow and hypovolemia may be present despite adequate filling pressures. Cardiac filling pressures [central venous pressure (CVP) and pulmonary occlusion pressure (PAOP)] are often misleading for assessing optimal left ventricular loading, as they may be influenced by several factors other than blood volume, including those affecting cardiac performance, vascular compliance, and intrathoracic pressure. 1 Several studies suggest that variations in systolic pressure and pulse pressure (systolic-diastolic) with positive pressure ventilation are a useful method of predicting circulatory responses to a Ôfluid challenge.Õ Although demonstrated in septic patients, this approach remains to be evaluated in surgical patients. Information may be gained by assessing the response of CVP or PAOP to a Ôfluid challengeÕ (i.e. a fixed volume of fluid is infused in 10-15 min). This approach has been shown to improve outcome when compared with ÔroutineÕ practice in orthopedic surgery. 7 Monitoring blood flow instead of intravascular pressure when performing a Ôfluid challengeÕ may be an even more efficient approach. Fluid challenge with monitoring of blood flow allows maximization of stroke volume without inappropriate excessive fluid infusion. Several studies have used esophageal Doppler monitoring to gain information on blood flow in the peroperative period. 2,7-11 They developed algorithms with the aim of maximizing stroke volume through infusion of repeated bolus of colloids and compared this with ÔstandardÕ fluid management. While performed in different types of surgery, all reported an improvement of patient outcome. Finally, as the ultimate goal of fluid therapy is the maintenance of tissue perfusion and cellular oxygenation, the use of tissue-perfusion indices appeared very appealing. 6 A number of technologies have been developed, to monitor local or general tissue perfusion perioperatively. Although no interventional study using one of these monitors to guide fluid therapy has demonstrated an improvement in outcome, 12 this approach requires further clinical investigation. Adequate fluid therapy improves patient outcome after surgery. Accurate dosing is certainly more important than the type of fluid used. This requires monitoring of arterial pressure and blood flow in major surgery. Further studies must focus on specific patient population who may benefit from a particular kind of fluid, and on the improvement of monitoring measures to recognize volume deficits and to guide fluid therapy.

Crystalloid restriction in surgical patients Physiological principles dictate that patients undergoing surgery retain sodium and water in the perioperative period. Although this observation initially led to the administration of minimal perioperative fluid volumes, the work of Shires resulted in aggressive crystalloid resuscitation in an attempt to compensate for Ôthird spaceÕ losses. 1 This approach was extended by a number of studies suggesting that plasma volume expansion with colloids against a marker of cardiac performance (usually stroke volume) appeared to decrease perioperative morbidity. 2 However, recently the Ôthird spaceÕ concept has been questioned 3 and attention has focused on the potential adverse effects of excess administration of crystalloid solutions. The problem of crystalloid excess leading to diminished pulmonary function has been well recognized in thoracic surgery, but it has also been shown that weight gain in the postoperative period, which equates to fluid overload, is associated with increased morbidity and mortality. Studies in trauma resuscitation suggest that targeting supranormal hemodynamic values by aggressive crystalloid resuscitation increases the risk of abdominal compartment syndrome and may increase mortality. 4 In elective surgical procedures, particularly those involving the bowel, it has also been shown that generous crystalloid loading may lead to increased tissue-healing complications as well as adverse cardiopul-monary events. 5, 6 The problems are compounded by the fact that neither of the two widely used solutions, 0.9% saline or lactated Ringer's solution, have an ideal electrolyte composition. Balancing these competing concepts is difficult, particularly as there is no good clinical measure of appropriate volume expansion. Current evidence appears to support an approach restricting the administration of crystalloid to replacing actual crystalloid loss, while maintaining, or even expanding, plasma volume with suitable colloid solutions. 7 Measurement of volume replacement remains difficult, but the response of stroke volume or other measures such as pulse pressure variation may provide better guides than static pressure measures against which to administer fluid.

Hans-Ju¨rgen Dieterich, MD Department of Anesthesiology and Intensive Care Medicine, Tu¨bingen University Hospital, Tu¨bingen, Germany Inflammation may occur as a local phenomenon (e.g. at the site of surgical procedure) or a systemic process (e.g. in trauma, shock or sepsis). Fluid therapy plays an important role in the management of these situations. We have learned that Ôgoal-orientedÕ fluid therapy brings better results in different settings. The former recommendation Ôin doubt, give volumeÕ is only acceptable in the first-line treatment of shock. In the management of moderate-to high-risk surgery, one main component of the fluid regimes should be a modern starch-based colloid solution (HES). In several clinical studies it could be shown that this may reduce length of stay in the hospital and improve patientsÕ comfort. 1 After abdominal aortic surgery, HES is superior to gelatin regarding perioperative pulmonary function. 2 In trauma patients, HES is superior to gelatin regarding early parameters of capillary damage (albumin excretion rate) as well as late parameters (e.g. PaO 2 /FiO 2 oxygenation index). 3 In intensive care, many experimental results also support the combined use of crystalloids and modern HES solutions. It has been shown that HES 130 decreases the albumin escape rate in a sepsis model 4 more than HES 200, as one basic mechanism of colloids that has been identified in vitro is the attenuation of leukocyte-endothelial interaction by inhibition of integrin-function. 5 In vivo the use of HES 130 dampens the hypoxiainduced increase in vascular leakage and acute inflammation. 6 Modern HES is a safe colloid in combination with crystalloids and, in addition to the unspecific volume-expanding effect, it has an anti-inflammatory effect in clinical and experimental settings. have serious limitations (low number, randomization bias and inconsistency), while the six observational ones 5-10 are limited by the selection of the control groups. Consequently, the quality of evidence is rated as moderate, low and very low. For pregnant women with anemia, two RCTs with a high quality of evidence show a clear advantage for IV iron, 11, 12 whereas one is negative. 13 One observational study with a positive result has low quality of evidence. 14 One randomized trial comparing recombinant human erythropoietin + IV iron to IV iron alone showed improvement of iron status in both groups, but hemoglobin increases were higher in the combination group. 15 For women with postpartum anemia, the main limitation of RCTs is the small number of participants; the quality of evidence is high for one 16 and low for one. 17 A parallel-group nonrandomized study found improved ferritin levels with IV iron compared to oral iron, 18 and a retrospective case series reported increased hemoglobin levels and decreased transfusion requirements following the introduction of IV iron. 19 One RCT compared IV iron alone or with the addition of recombinant human erythropoietin and concluded that the combination was more effective than iron alone in raising hemoglobin concentrations and restoring iron stores. 20 Conclusions: For patients undergoing orthopedic surgery and expected to develop severe postoperative anemia, we currently suggest IV iron administration during the perioperative period. For all other types of surgery, no recommendation can be made. Treatment of iron deficiency in pregnancy should be started with oral iron in the first or second trimester, while in the third trimester administration of IV iron should be considered. When, despite oral iron treatment, hemoglobin increase is < 0.5 g/dL in 2 weeks, IV iron should be considered if the gestational age is > 14 weeks. In postpartum women without ongoing bleeding and hemoglobin < 6 g/dL, transfusion may be considered. In women with hemoglobin between 6 and 9.5 g/dL, IV iron should be given associated with erythropoietin in non-responders. We strongly recommend further large prospective RCTs in these clinical settings. 

Managing severe anemia in Africa: opportunities and challenges Imelda Bates, MD, FRCP, FRCPath Tropical Hematology, Liverpool School of Tropical Medicine, Liverpool, UK Worldwide, there are 300-500 million cases of malaria and 1 million deaths each year. 90% of these deaths are in young children in Africa and > 50% are due to severe anemia. The pattern of blood usage in African countries with high malaria transmission is very different from that in wealthy countries. In high malaria transmission areas in Africa, 80-90% of blood is for emergencies; > 70% of pregnant women are anemic and > 20% of children under 1 year have Hb < 8 g/dL. These two groups are the biggest users of blood. 89% of children with severe, complicated anemia die unless they can get a transfusion. Furthermore, transfusions are unavailable or ineffective in > 40% of children who need them. Severe anemia is responsible for 25% of maternal deaths in Africa. Emergency supply of safe blood is therefore essential to save lives. Hemoglobin measurement is often the least accurate test performed in peripheral laboratories without automated hematology analyzers, yet it is critical for guiding transfusion practice. Only a minority of African countries have a centralized national blood service. Given that such systems are expensive, they can only be established and maintained in the poorest countries with external support. Most countries operate a hospital-based transfusion service. Consequently, overall in Africa, 84% of donors are family Ôreplace-mentÕ donors who are screened by individual hospitals. Countries that cannot afford a nationalized transfusion service have found innovative ways to improve the quantity and quality of blood for transfusion. More attention needs to be focused on scaling up measures that are effective in reducing the need for transfusions, such as public-health interventions to reduce anemia and strict implementation of transfusion guidelines.

The effect of the addition of adenine and nucleosides at the beginning of storage on the concentrations of phosphates of human erythrocytes during storage in acid-citrate-dextrose and citrate-phosphate-dextrose

Depletion and regeneration of 2,3-diphosphoglyceric acid in stored red blood cells

The in vivo regeneration of red cell 2,3 diphosphoglyceric acid DPG after transfusion of stored blood

Effect of organic and inorganic phosphates on the oxygen equilibrium of human erythrocytes

The effect of organic phosphates from the human erythrocyte on the allosteric properties of hemoglobin

Defective gas transport function of stored red blood cells

In vivo regeneration of red cell 2,3-diphosphoglycerate following transfusion of DPG-depleted AS-1, AS-3 and CPDA-1 red cells

Restoration in vivo of erythrocyte adenosine triphosphate, 2,3-diphosphoglycerate, potassium ion, and sodium ion concentrations following the transfusion of acid-citrate-dextrose-stored human red blood cells

Relationship of posttransfusion viability to deformability of stored red cells

Alteration of deformability of the erythrocyte membrane in stored blood

Erythrocytes stored in CPD SAG-mannitol: evaluation of their deformability

The effect of storage time of human red cells on intestinal microcirculatory oxygenation in a rat isovolemic exchange model

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Acute severe isovolemic anemia impairs cognitive function and memory in humans

Oxygen reverses deficits of cognitive function and memory and increased heart rate induced by acute severe isovolemic anemia

Acute isovolemic anemia impairs central processing as determined by P300 latency

Fresh blood and aged stored blood are equally efficacious in immediately reversing anemia-induced brain oxygenation deficits in humans

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Apoptosis, transforming growth factor-beta, and the immunosuppressive effect of transfusion

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Nitroindazole impedes erythrocyte flow response to isovolemic hemodilution in the cerebral capillary circulation

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The influence of hemodilution on outcome after hypothermic cardiopulmonary bypass: results of a randomized trial in infants

Normalizing hematocrit in dialysis patients improves brain function

Acute severe isovolemic anemia impairs cognitive function and memory in humans

Oxygen reverses deficits of cognitive function and memory and increased heart rate induced by acute severe isovolemic anemia

Hemodilution anemia is associated with increased cerebral neuronal nitric oxide synthase gene expression

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Acknowledgement: Supported by NIH grant P01 HL46925.