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The expected cost explosion in transfusion medicine increases the socio-economic significance of specific institutional transfusion programs. In this context the estimated use of the patient's physiologic tolerance represents an integral part of any blood conservation concept. The present article summarizes the mechanisms, influencing factors and limits of this natural tolerance to anemia and deduces the indication for perioperative red blood cell transfusion. The current recommendations coincide to the effect that perioperative transfusion is unnecessary up to a Hb concentration of 10 g/dl (6.21 mmol/l) even in older patients with cardiopulmonary comorbidity and is only recommended in cases of Hb <6 g/dl (<3.72 mmol/l) in otherwise healthy subjects including pregnant women and children. Critically ill patients with multiple trauma and sepsis do not seem to benefit from transfusions up to Hb concentrations >9 g/dl (>5.59 mmol/l). In cases of massive hemorrhaging and diffuse bleeding disorders the maintenance of a Hb concentration of 10 g/dl (6.21 mmol/l) seems to contribute to stabilization of coagulation.

Inherent risks and increasing costs of allogeneic transfusions underline the socioeconomic relevance of safe and effective alternatives to banked blood. The safety limits of a restrictive transfusion policy are given by a patient's individual tolerance of acute normovolaemic anaemia. latrogenic attempts to increase tolerance of anaemia are helpful in avoiding premature blood transfusions while at the same time maintaining adequate tissue oxygenation. Autologous transfusion techniques include preoperative autologous blood donation (PAD), acute normovolaemic haemodilution (ANH), and intraoperative cell salvage (ICS). The efficacy of PAD and ANH can be augmented by supplemental iron and/or erythropoietin. PAD is only cost-effective when based on a meticulous donation/transfusion plan calculated for the individual patient, and still carries the risk of mistransfusion (clerical error). In contrast, ANH has almost no risks and is more cost-effective. A significant reduction in allogeneic blood transfusions can also be achieved by ICS. Currently, some controversy regarding contraindications of ICS needs to be resolved. Artificial oxygen carriers based on perfluorocarbon (PFC) or haemoglobin (haemoglobin-based oxygen carriers, HBOCs) are attractive alternatives to allogeneic red blood cells. Nevertheless, to date no artificial oxygen carrier is available for routine clinical use, and further studies are needed to show the safety and efficacy of these substances.

The expected cost-explosion in transfusion medicine (increasing imbalance between donors and recipients, treatment of transfusion-associated complications) increases the socio-economic significance of the development of safe and effective synthetic oxygen carriers as an alternative to the transfusion of allogeneic red blood cells. Currently two types of artificial oxygen carriers have been tested for safety and efficacy in cases of severe anemia otherwise requiring transfusion. Solutions based on human or bovine hemoglobin (HBOC) possess vasoconstrictor properties in addition to their oxygen transport capacity. The impact of vasoconstriction on tissue perfusion and organ function is however not yet fully understood. Nevertheless, in 2001 the bovine HBOC Hemopure was approved in South Africa for treatment of acutely anemic surgical patients. The purely synthetic perfluorocarbon (PFC) emulsions increase the physically dissolved portion of arterial oxygen content. Due to their particulate nature (emulsion droplets) PFCs may only be infused in low doses to avoid overload and malfunction of phagocytic cells of the reticulo-endothelial system. As part of a multimodal blood conservation program (including normovolemic hemodilution and hyperoxia) the low-dose administration of Oxygent effectively increases intraoperative anemia tolerance. Although reduction of perioperative allogeneic blood transfusion has already been demonstrated for HBOC and PFC, the global clinical establishment of artificial oxygen carriers is not to be expected in the near future.

Background: Fluid resuscitation from hemorrhagic shock is intended to abolish microcirculatory disorders and to restore adequate tissue oxygenation. Diaspirin cross-linked hemoglobin (DCLHb) is a hemoglobin-based oxygen carrier (HBOC) with vasoconstrictive properties. Therefore, fluid resuscitation from severe hemorrhagic shock using DCLHb was expected to improve perfusion pressure and tissue perfusion of kidneys and pancreas., Methods: In 20 anesthetized domestic pigs with an experimentally induced coronary stenosis, shock (mean arterial pressure 45 mmHg) was induced by controlled withdrawal of blood and maintained for 60 min. Fluid resuscitation (replacement of the plasma volume withdrawn during hemorrhage) was performed with either 10% DCLHb (DCLHb group, n = 10) or 8% human serum albumin (HSA) oncotically matched to DCLHb (HSA group, n = 10). Completion of resuscitation was followed by a 60-min observation period. Regional blood flow to the kidneys and the pancreas was measured by use of the radioactive microspheres method at baseline, after shock and 60 min after fluid resuscitation., Results: All animals (10/10) resuscitated with DCLHb survived the 60-min observation period, while 5/10 control animals died within 20 min due to persisting subendocardial ischemia. In contrast to HSA survivors, pancreas and kidneys of DCLHb-treated animals revealed lower total and regional organ perfusion and regional oxygen delivery. Renal and pancreatic blood flow heterogeneity was higher in the DCLHb group., Conclusion: DCLHb-induced vasoconstriction afforded superior myocardial perfusion, but impaired regional perfusion of the kidneys and the pancreas.

In severe hemorrhagic shock, left ventricular (LV) diastolic dysfunction is an early sign of cardiac failure due to compromised myocardial oxygenation. Immediate fluid replacement or, in particular, administration of a hemoglobin-based oxygen carrier (diaspirin cross-linked hemoglobin; DCLHb) improves myocardial oxygenation; therefore, positive effects on LV diastolic function could be expected. The effects of fluid resuscitation from severe hemorrhagic shock with DCLHb were investigated in 20 anesthetized domestic pigs. After generation of a critical left anterior descending coronary artery stenosis (narrowing of the artery until disappearance of reactive hyperemia after a 10-second complete vessel occlusion), hemorrhagic shock (mean arterial blood pressure 45 mm Hg) was induced within 15 min by controlled blood withdrawal and maintained for 60 min. Fluid resuscitation consisted of replacement of the plasma volume withdrawn during hemorrhage by infusion of either 10% DCLHb (DCLHb group, n = 10) or 8% human serum albumin (HSA) oncotically matched to DCLHb (HSA group, n = 10). After completion of resuscitation, an observation period of 60 min elapsed. Measurements of central hemodynamics, myocardial oxygenation, and LV diastolic function were performed at baseline, after induction of critical coronary artery stenosis, after 60 min of hemorrhagic shock, immediately after resuscitation, and 60 min later. While 5 out of 10 animals treated with HSA died within the first 20 min after fluid resuscitation from acute LV pump failure, all DCLHb-treated animals survived until the end of the protocol (p < 0.05). Despite superior myocardial oxygenation due to augmentation of the arterial O(2) content as well as of coronary perfusion pressure, no beneficial effects on LV diastolic function were observed after infusion of DCLHb. Peak velocity of LV pressure decrease (dp/dt(min)) did not reveal significant differences between the two groups. Immediately after completion of fluid resuscitation with DCLHb, the time constant of LV diastolic relaxation (tau) was prolonged when compared with HSA-treated animals (p < 0.05), indicating retardation of early LV diastolic relaxation. Our data suggest that DCLHb fails to improve LV diastolic function after fluid resuscitation from severe hemorrhagic shock. However, positive effects on myocardial perfusion and oxygenation result in a significant reduction of the mortality of severe hemorrhagic shock., (Copyright 2001 S. Karger AG, Basel)

Objective: To evaluate the effects of resuscitation with a 10% diaspirin-crosslinked hemoglobin (DCLHb) solution on global hemodynamic variables, systemic and myocardial oxygen transport and tissue oxygenation, and contractile function of the left ventricle in an experimental model of severe hemorrhagic shock and critical stenosis of the left anterior descending coronary artery (LAD)., Design: Prospective, placebo-controlled, randomized study., Setting: Experimental animal laboratory., Subjects: A total of 20 anesthetized pigs., Interventions: After implementation of a permanent critical LAD stenosis (ie, maintenance of basal blood flow but absence of reactive hyperemia after a 10-sec complete vessel occlusion), hemorrhagic shock (target mean aortic pressure, 45 mm Hg) was induced within 15 mins by programmed withdrawal of blood and maintained for 60 mins. Subsequently, the volume of plasma lost during hemorrhage was replaced by either a balanced electrolyte solution containing 10 g/dL DCLHb (DCLHb group; n = 10) or an 8 g/dL human albumin solution (HSA) oncotically matched to DCLHb (HSA group; n = 10). Data were collected immediately after the infusion of the different solutions and again after 60 mins had elapsed., Measurements and Main Results: Although five of ten HSA-treated animals died of acute left ventricular failure within the first 20 mins after complete fluid resuscitation, all of the DCLHb-treated animals survived the 60-min observation period after resuscitation (p < .05). This significant difference in mortality is explained by higher coronary perfusion pressure in DCLHb-treated animals (75 +/- 17 vs. 27 +/- 17 torr DCLHb vs. HSA group; p < .05) and persistence of subendocardial ischemia and hypoxia (radioactive microspheres method) in HSA-treated animals on resuscitation particularly affecting the LAD-supported myocardium (subendocardial oxygen delivery: 20 +/- 11 vs. 3 +/- 1 mL oxygen x g(-1) x min(-1), DCLHb vs. HSA group; p < .05). Except for enhanced myocardial contractility immediately on infusion of DCLHb (maximal left ventricular pressure increase: 2373 +/- 782 vs. 1730 +/- 543 torr x sec(-1) DCLHb vs. HSA group; p < .05), no differences were detected between groups concerning the variables of systemic oxygen transport, tissue oxygenation, and regional contractile function of the myocardium (determined with microsonometry)., Conclusions: Fluid resuscitation with 10% DCLHb solution completely reverses hemorrhagic shock-induced subendocardial ischemia and hypoxia in the presence of compromised coronary circulation and thereby prevents early death after resuscitation.

As an alternative to transfusion of red blood cells, intravenously (iv) administered artificial oxygen (O(2)) carriers are intended to increase the reduced O(2) carrying capacity of blood in the case of acute severe anemia, i.e. hemorrhagic shock or extreme normovolemic hemodilution (ANH). Actually, two groups of artificial O(2) carriers are investigated: ultrapurified, stroma-free hemoglobin solutions (SFH) of human or bovine origin and synthetically produced perfluorocarbons (PFC). SFH may be administered in large amounts and are suitable for 1:1 replacement of blood losses in case of hemorrhage as well as for isovolemic exchange of blood during ANH. In both situations SFH solutions effectively restore (hemorrhagic shock) and maintain (extreme ANH) tissue oxygenation despite extremely low hematocrit values. The vasopressor property of the isolated Hb molecule leads to a species-dependent (rodent>pig>human) increase in systemic and pulmonary vascular resistance, but leaves overall distribution of cardiac output uninfluenced. Due to the particulate nature of PFC emulsions, iv administration has to be restricted to small doses (3-4.5 ml/kg body weight for the actually investigated 60% w/v perflubron emulsion) in order to avoid overload of the reticuloendothelial system. Thus PFC emulsions are unsuitable for isovolemic blood replacement in hemorrhagic shock or ANH. Low-dose iv PFC administration in already hemodiluted subjects, however, creates an additional margin of safety to guarantee adequate tissue oxygenation which allows for further, extreme ANH, without risking tissue hypoxia.

The expected explosion of costs in transfusion medicine due to the shortfall of healthy donors and the more frequent treatment of transfusion-associated complications (chronic hepatitis, cirrhosis, wound infection, tumor recurrence) increases the socio-economic importance of the development of safe and effective synthetic oxygen carriers as an alternative to the transfusion of homologous red blood cells. Currently two types of artificial oxygen carriers are experimentally and clinically investigated for their capacity to ensure adequate tissue oxygenation in the case of severe anemia. In addition to their oxygen transport capacity solutions based on free human or bovine hemoglobin provide vasoconstrictor properties. Their hyperoncotic properties make them particularly attractive for the treatment of severe hemorrhagic shock. Perfluorocarbon (PFC) emulsions allow an increase of the physically dissolved portion of arterial oxygen content. Due to their particulate nature (emulsion droplets) PFC may only be infused in low doses. Otherwise there is risk of overload and malfunction of phagocytic cells of the reticulo-endothelial system. In the case of an intraoperative blood-loss in preoperatively hemodiluted patients, bolus infusion of PFC represents an effective means to avoid immediate retransfusion of autologous blood and allows for further, extreme hemodilution without risking tissue hypoxia.

Intact cardiac compensatory mechanisms are necessary to maintain adequate tissue oxygenation during acute normovolemic hemodilution (ANH). Left ventricular (LV) perfusion, oxygenation and function were analyzed in an experimental whole-body model of profound ANH (Hct 9%) and effectiveness of a perfluorocarbon-based oxygen carrier in maintaining myocardial oxygenation and function was evaluated. A total of 22 anesthetized dogs were hemodiluted to Hct 20% followed by a simulated, controlled blood-loss phase in which dogs were randomized to either: (1) 1:1 exchange of lost blood with autologous red blood cells (RBC-group), (2) 1:1 exchange with a colloid (control-group) and (3) 1:1 exchange with a colloid after a single dose of 1.8 g/kg BW perflubron i.v. (PFC-group). Myocardial oxygen delivery and consumption as well as endocardial perfusion were determined using radioactive microspheres. LV myocardial contractility (LV MC) was assessed from: (1) the relationship between maximum rate of LV pressure increase (LVdp/dtmax) and LV enddiastolic volume (LVEDV) and (2) analysis of the LV endsystolic pressure volume relationship (ESPVR). LV diastolic properties were reflected by (1) minimum rate of LV pressure increase (LVdp/dtmin), (2) slope and intercept of the enddiastolic pressure-volume relationship (EDPVR) and (3) the time-constant of isovolumic LV pressure decline "tau 1/2". Full sets of LV MC data were obtained from 18 dogs (n = 6 per group). LV MC (LVdp/dtmax-LVEDV relation) increased after perflubron administration. At the lowest Hct level, all parameters reflecting LV MC as well as LVdp/dtmin were significantly higher in the PFC-group than in the control-group. After profound normovolemic hemodilution (Hct 9%) superiority of LV MC and LV diastolic properties was found, when myocardial oxygenation was supported by i.v. perflubron emulsion, a temporary O2 carrier.