Review Article  |   July 2000
Eliminating Blood Transfusions: New Aspects and Perspectives
Author Affiliations & Notes
  • Donat R. Spahn, M.D.
  • Mattias Casutt, M.D.
  • *Professor of Anesthesiology. †Resident.
Article Information
Review Article
Review Article   |   July 2000
Eliminating Blood Transfusions: New Aspects and Perspectives
Anesthesiology 7 2000, Vol.93, 242-255. doi:
Anesthesiology 7 2000, Vol.93, 242-255. doi:
ALLOGENEIC blood transfusions are associated with risks. 1 As a result, a variety of blood conservation techniques have been developed, but these techniques are also not risk free. 2 The aim of the this article is to review efficacy and risks of allogeneic red blood cell (RBC) transfusions and blood conservation techniques to enable the anesthesiologist to choose the techniques with the lowest risk for his or her patient.
Allogeneic Blood Transfusions
The potential for adverse effects, 1 high costs, 3–5 and intermittent blood shortages 6,7 mandate a wise use of allogeneic RBC transfusions. Public concern reflected in “look back” programs for human immunodeficiency virus and hepatitis C infections 8–11 and an increasing number of patients demanding treatment without allogeneic RBC transfusions represent additional reasons to develop effective alternatives. Finally, the efficacy of allogeneic RBC transfusions to ameliorate tissue oxygenation, oxygen consumption, 12 or outcome has been challenged. 13–15 
Without any doubt, allogeneic RBC transfusions are crucial in the treatment of patients with trauma and major blood loss. 16 In less extreme conditions, however, the efficacy of allogeneic RBC transfusions has been challenged. 13,17 Two transfusion regimens (restrictive, aiming at a hemoglobin concentration of 7–9 g/dl, vs  liberal, aiming at a hemoglobin concentration of 10–12 g/dl) were compared in a prospective randomized study in 838 patients treated in an intensive care unit (ICU). 13 In the restrictive transfusion group, a mean hemoglobin concentration of 8.5 ± 0.7 g/dl was observed, less blood (2.6 ± 4.1 U) was transfused, and a higher percentage of patients avoided any RBC transfusion (33%), as opposed to the liberal transfusion group, which had a mean hemoglobin concentration of 10.7 ± 0.7 g/dl and 5.6 ± 5.3 U transfused (avoidance: 0%). Thirty-day mortality was similar in the restrictive and liberal groups (18.7%vs  23.3%), but hospital mortality, adjusted multiorgan dysfunction score, and the incidence of pulmonary edema and myocardial infarction were significantly lower in the restrictive transfusion group. There is no obvious explanation for these results. However, a limited capacity of allogeneic RBC older than 7 days to restore compromised oxygen consumption 12,18 might be one contributing factor. Transfusion of old RBC in septic ICU patients has also been associated with a decrease in gastric pH 19 and even with increased mortality. 20 
Adverse Effects
Adverse effects of allogeneic RBC transfusions include transmission of infectious diseases, immunosuppression, transfusion-related acute lung injury, transfusion reactions, graft-versus  -host reactions, and other rare or yet unknown side effects. 1 
Transmission of Infectious Diseases.
Transmission of human immunodeficiency virus and hepatitis C virus has decreased over the years, and the estimated frequency of transmission is currently at 1/200,000–1/2,000,000 for human immunodeficiency virus and 1/30,000–1/150,000 for hepatitis C virus. 1 However, new viruses have been discovered recently in healthy unpaid blood donors, such as hepatitis G virus, 21,22 TT virus, 23–27 and human herpes virus 8 associated with Kaposi’s sarcoma. 28,29 In addition, transmission of parasitic and bacterial diseases occurs sporadically in highly civilized countries but represents a substantial problem in less developed areas. 30–32 Transmission of yet unknown viruses 29 and the new-variant Creutzfeld-Jakob disease via  RBC transfusion also appears possible and is a public concern. 33 
Allogeneic RBC transfusions induce immunomodulation with the recipient. 34–36 As a result, the incidence of postoperative infections is elevated in transfused patients, 35 and cancer recurrence may be favored. 35,37 An increased incidence of postoperative infections has been demonstrated in patients undergoing orthopedic, 38–40 abdominal, 3,4,41–43 and cardiac surgery. 44–47 Such infections prolong treatment in an ICU, 45 prolong hospitalization, 3,4,38,39,43 and increase total hospital costs. 3–5,40,43 Furthermore, there is a highly significant dose–response relation with an increasing incidence of postoperative infections related to an increasing number of allogeneic RBC transfusions administered. 38,40 Conversely, improved graft survival after kidney transplantation was recently confirmed in a prospective randomized multicenter study in patients receiving 3 U of allogeneic RBC before kidney transplantation. 48 
Leukocyte depletion may reduce immunomodulation. A reduced incidence of postoperative infections was observed after abdominal surgery in patients receiving leukocyte-depleted RBC transfusions, 43,49 resulting in reduced total hospital charges. 43 In cardiac surgery, a reduced mortality was observed in patients receiving leukocyte-depleted RBC transfusions, but infections were only reduced in a subgroup of patients receiving more than 3 U of RBC transfusions. 50 In contrast, Houbiers et al.  41 observed no reduction in postoperative infections due to leukocyte depletion.
The medical community has been reluctant to accept immunomodulation as a consequence of allogeneic RBC transfusions. There is a seemingly endless debate as to whether these findings are real, whether there is a cause-and-effect relationship, or whether they only result from uneven distribution of confounding factors. 36,51,52 Interestingly, several respected experts similarly concluded in recent publications that the ultimate proof for a clinically relevant immunomodulation may be lacking, but that they personally believe that immunomodulation due to allogeneic RBC transfusion with adverse clinical outcome is real. 36,51,52 
Transfusion-related Acute Lung Injury.
Transfusion-related acute lung injury is a clinical constellation of signs and symptoms, including dyspnea, hypotension, fever, and bilateral noncardiogenic pulmonary edema. 53 This condition develops rapidly within 2–4 h and may resolve within 4 days but often requires mechanical ventilation and ICU treatment. The incidence is relatively high. The estimation is at approximately 0.02%, or one case in 5,000 U transfused. 1,53 However, this estimate may be fraught with difficulties because this syndrome is a purely clinical diagnosis without a specific test resulting in a positive or negative result. The origin is thought to be due to (donor) antibodies against leukocytes of a recipient with a predisposing condition such as infection, surgery, or massive transfusion. 54,55 Also in ICU patients, a higher incidence of pulmonary edema (10.7%vs  5.3%) and a trend (P  = 0.06) toward a higher incidence of adult respiratory syndrome (11.4%vs  7.7%) was found in liberally transfused patients (5.6 ± 5.3 U of allogeneic RBC transfused) than in patients with a restrictive transfusion regimen (2.6 ± 4.1 U of allogeneic RBC transfused). 13 Some of these might represent transfusion-related acute lung injury.
Costs of allogeneic RBC transfusions are the sum of direct RBC costs and indirect long-term costs of delayed and remote costs originating from additional treatments and prolonged hospitalization. Avoiding allogeneic transfusions reduced total treatment costs in abdominal 4 and orthopedic surgery 5 by approximately $5,000 per patient. In a recent cohort study of 9,598 consecutive elderly patients with hip fracture, RBC transfusion was associated with a 35% greater risk of a serious bacterial infection and a 52% greater risk of pneumonia with $14,000 greater total costs for patients with postoperative infections. 40 Even when adjusting for 20 potentially confounding variables, including the occurrence of postoperative infections, an independent association of allogeneic RBC transfusion and longer hospital stay and higher costs was recently demonstrated. 3 On average, transfusion-related additional costs were $1,003 per patient. 3 This represents a very conservative estimation and is likely to significantly underestimate true transfusion-related costs because such an analysis attributes to the confounding variable alone any adverse effect that is due to synergism between allogeneic transfusion and the confounding variable. 56 This means that the extra costs for the treatment of a postoperative infection were attributed to the postoperative infection and not to the RBC transfusion. Even then, significant RBC transfusion–related extra costs were detected. 3 Similar results were reported from a previous analysis in patients undergoing primary hip replacement 57 and major orthopedic surgery. 58 
Alternatives to Allogeneic Red Blood Cell Transfusions
Preoperative Autologous Blood Donation
The efficacy of preoperative autologous blood donation (table 1) in reducing allogeneic RBC exposure is established. 59,60 However, cost efficacy, risks, and transfusion criteria of autologous versus  allogeneic RBC are still being discussed.
Table 1. Blood Conservation Strategies
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Table 1. Blood Conservation Strategies
Cost efficacy may seem low. 61 This is due to a high proportion of discarded units 59–61 and because only the costs of avoiding the transmission of viral diseases were modeled. 57 However, cost efficacy would be higher if a reduced incidence of postoperative infections, 3,4,35,38,39,41–46 a shorter ICU stay, 45 and a shorter hospitalization 3,4,38,39,43,62 with lower costs 57 were also taken into account. Nevertheless, it is mandatory to better select patients for preoperative autologous blood donation to avoid a 20–73% rate of discarded autologous units. 2,63 
The safety of preoperative autologous blood donation has been questioned after reports that severe complications requiring hospitalization were 12 times more frequent after autologous than after allogeneic blood donations. 64 However, allogeneic and autologous donors differed in age and first-time donor status. First-time donors had higher rates of adverse reactions and were significantly more frequent in the autologous donor group. 65,66 In contrast, a rare occurrence of complications has been documented in a recent report on autologous blood donation in 1,073 patients older than 65 yr. 67 In patients with cardiovascular disease, it is particularly important to distinguish between adverse events caused by blood donation and complications caused by the underlying cardiovascular pathology. Two life-threatening cardiac arrests and one fatal myocardial infarction occurred in patients on a waiting list for cardiac surgery and autologous blood donation before the first donation occurred. 68 Therefore, with appropriate selection and monitoring, autologous blood donation remains a safe procedure for patients who are healthy enough to undergo elective surgery. 69 In addition, autologous donation represents a positive experience for patients: 96% of autologous donors would donate again for themselves, and 94% would recommend preoperative autologous donations to others. 70 However, the need to visit a donation center several times before the operation is not appreciated by all, 71 and elderly patients with compromised mobility may have significant difficulties donating autologous blood preoperatively.
The risks of autologous RBC transfusions are less than those of allogeneic RBC transfusions. 1,2 Therefore, should we use identical transfusion triggers for autologous and allogeneic RBC transfusions? This question cannot be generally answered. 72,73 Because autologous RBC transfusions are not risk-free, 74–77 identical transfusion triggers may be adequate. However, with extremely low hemoglobin values, slightly more liberal transfusion triggers may be justifiable for autologous RBC transfusions.
Preoperative Use of Erythropoietin
Preoperative erythropoietin (table 1) is an established, efficacious but relatively expensive therapy to reduce allogeneic RBC transfusions. 78 However, with limited doses, costs may be comparable to autologous blood donation. 71 To optimize the hemoglobin response, oral or intravenous iron supplementation is recommended. 78–80 A nomogram relating the desired increase in RBC volume to an individual dose of erythropoietin may further help to increase cost efficacy. 78 
Preoperative erythropoietin is generally well tolerated. 78 Side effects such as hypertension and thrombotic events as observed in long-term treatment of patients with end-stage renal disease 78,81,82 are uncommon in surgical patients receiving erythropoietin for a limited period of time. 83,84 
Even in high-risk patients undergoing cardiac surgery in whom preoperative autologous blood donation was contraindicated, erythropoietin reduced the need for allogeneic RBC transfusion from 53% to 11%. 84 
Elevating the preoperative hemoglobin concentration by the use of erythropoietin may be attractive, with and without preoperative autologous donation, because a low preoperative hemoglobin concentration is a major risk factor for allogeneic RBC transfusions. 2,3,43,78 In addition, acute normovolemic hemodilution (ANH) can be used more efficiently, 85 and a larger blood loss may be tolerated before allogeneic RBC transfusions become necessary. 2,85 
Acute Normovolemic Hemodilution
In four prospective randomized clinical trials, ANH (table 1) resulted in a reduced allogeneic RBC transfusion requirement. 86–89 In addition, ANH in combination with preoperative autologous blood donation 90 or intraoperative cell salvage 91 resulted in a particularly relevant reduction in allogeneic RBC transfusions. The use of ANH was also found to be an independent factor reducing allogeneic RBC transfusion in addition to maintaining normothermia and use of cell salvage in a multivariate regression analysis in orthopedic surgery. 92 ANH thus seems to be a clinically useful blood-saving technique. However, concerns have been raised in a consensus conference as to its efficacy, 93 and a meta-analysis concluded that the efficacy of ANH is not yet proven. 94 This conclusion is mainly based on concerns regarding control of perioperative transfusion regimens, and large, well-controlled, randomized studies with clearly predefined transfusion triggers were recommended. 94 
Acute normovolemic hemodilution may also be viewed as an alternative to preoperative autologous blood donation. In a prospective randomized study with predefined transfusion triggers in patients undergoing radical prostatectomy, these techniques were equal in avoiding allogeneic RBC transfusions and postoperative hemoglobin levels. 95 In contrast, costs for preoperative autologous blood donation were more than three times higher than the costs for ANH. ANH thus has been advocated as a legitimate alternative and more patient-friendly blood conservation technique. 96 
Future use of ANH may include it in combination with preoperative erythropoietin 95,96 and with artificial oxygen carriers, 97 a concept called “augmented ANH.”98,99 The combination of ANH with preoperative erythropoietin is particularly attractive because the efficacy of ANH is higher with a high hemoglobin before ANH, 2,85 and, conversely, a low preoperative hemoglobin concentration is one of the most significant predictors for the need of allogeneic RBC transfusions. 2,3,43,78 
Augmented ANH combines preoperative ANH with the intraoperative use of an artificial oxygen carrier. 98,99 Patients undergo ANH to relatively low hemoglobin levels preoperatively. During the operation, when the hemoglobin concentration further decreases because of surgical blood loss and fluid replacement, an artificial oxygen carrier is administered to enhance oxygen delivery and improve tissue oxygenation. As a consequence, lower levels of hemoglobin can be safely tolerated. At the end of the operation, the autologous blood collected during ANH is retransfused. This results in a relatively high hemoglobin concentration in the postoperative period, and oxygen delivery will again be provided by endogenous hemoglobin. 98 
Physiology and limits of ANH have been investigated in a variety of experimental and clinical studies. 100 With normovolemia, potential risks of ANH are primarily related to the decrease in hemoglobin concentration and the use of specific replacement fluids. Even patients with coronary artery disease, 89,101 compromised contractility, 101 mitral regurgitation, 102 and elderly patients 103 tolerate moderate ANH well. When colloids are being used as replacement fluids, there is a minimal risk of anaphylaxis, 104,105 and blood coagulation may become compromised, particularly after large-volume application of hydroxyethyl starch. 106 
Intraoperative Cell Salvage and Retransfusion
Intraoperative cell salvage (table 1) is an accepted and efficacious technique to decrease the need for allogeneic RBC transfusions. 59,107–109 However, cell salvage and washing with normal saline solution may have metabolic consequences. 110,111 A metabolic acidosis may develop due to a progressive loss of bicarbonate associated with a parallel increase in the chloride concentration (hyperchloremic acidosis). Calcium and magnesium concentrations also decrease with progressive cell salvage. 110,111 These disturbances in electrolyte and pH status may be limited when a balanced electrolyte solution is used to wash RBC instead of saline. 111 Periodic monitoring and eventual correction of acid base status and electrolyte concentration thus is advisable during prolonged periods of cell salvage.
Air embolism due to cell salvage 108 is a potentially fatal complication. 112 Analysis of several fatal incidences revealed that, in all cases, the processed RBC suspension was retransfused under pressure. Avoiding pressurized retransfusion and de-airing of the bag containing the processed RBC suspension are therefore important to make cell salvage safer.
Traditionally, cell salvage was considered contraindicated in operations in nonsterile fields and during cancer surgery. 113 The concerns are that nonsterile material, infectious agents, and cancer cells were systemically disseminated. Indeed, high numbers of cancer cells were found in blood shed from the surgical field. 114 These cancer cells are not eliminated during the washing process. 115 Filtering and irradiation have been proposed to reduce or eliminate cancer cells in the RBC suspension. 115–117 Elimination of cancer cells originating from cultured cell lines might be possible by leukocyte depletion filters. 116–118 However, cultured cancer cell lines are selected for adhesion on artificial surfaces and thus may be retained better in leukocyte depletion filters than cancer cells from solid tumors. 119 It is therefore relatively unlikely that cells from solid clinical tumors are completely eliminated by leukocyte depletion filters. 115,118,120 It has been shown that solid tumor cells are only reduced by a factor of 1,000 by leukocyte depletion filters and not eliminated. 119 Because one single cell may form a metastasis, 121 irradiation of washed RBC with 50 Gy was proposed to completely abolish DNA metabolism and therefore functionally eliminate cancer cells. 115 
If cell salvage with irradiation of the RBC suspension allows the safe elimination of all cancer cells, cell salvage may also be offered in the future to patients undergoing tumor surgery. This would represent a significant achievement because a great portion of all allogeneic RBC transfusions are used for cancer surgery. 122 In addition, immunomodulation may be particularly undesirable for patients with malignancies.
Pharmacologic Treatment
The prophylactic use of aprotinin, ε-aminocapronic acid, and tranexamic acid (table 1) reduces allogeneic blood transfusions in cardiac surgery. 123–127 Initial concerns that aprotinin might cause an increase in graft occlusion rate or myocardial infarction have recently been found to be unjustified. 125,126,128,129 
Aprotinin may also be used in noncardiac operations such as liver resections 130 or major orthopedic surgery 131 to reduce blood loss and thus decrease allogeneic RBC exposure. 130 Furthermore, tranexamic acid has been successfully used in total knee arthroplasty to decrease allogeneic RBC transfusions. 132 However, there are also reports that allogeneic RBC transfusions were not decreased with prophylactic antifibrinolytic therapy despite antifibrinolytic efficacy. 133,134 The uncritical prophylactic use of antifibrinolytics in major noncardiac surgery may therefore not be advisable because of uncertain efficacy and extra costs. 123 
Anesthesia Technique
In addition to using a specific blood conservation strategy, anesthesiologists can contribute significantly to reduce allogeneic RBC transfusions by the use of specific anesthesia techniques (table 1). Maintaining normothermia, optimizing fluid replacement to maintain blood coagulation, and using hyperoxic ventilation and hypotensive anesthesia all contribute to minimizing allogeneic RBC transfusions.
Maintaining Normothermia.
Prospective randomized studies indicate that avoiding hypothermia in patients undergoing abdominal surgery reduces blood loss and allogeneic RBC transfusions, decreases postoperative infections, and shortens the duration of hospitalization. 135,136 In patients undergoing total hip replacement, blood loss and allogeneic RBC transfusions occurred less in normothermic than in mildly hypothermic (35.0 ± 0.5°C) patients. 137 In addition, maintaining normothermia was found to be an independent factor reducing allogeneic RBC transfusions in a multimodal blood conservation approach that included ANH, cell salvage, and active warming. 92 Despite one retrospective study in which hypothermia was not associated with increased allogeneic RBC transfusions, 138 maintaining normothermia is beneficial because hypothermia compromises blood coagulation, in particular platelet function. 139–141 
Optimal Fluid Replacement.
Maintaining normovolemia in the perioperative period is of paramount significance. 142 Therefore, significant amounts of replacement fluids are necessary during operations with relevant blood loss, in particular when preoperative ANH is being performed. The choice of replacement fluid therefore becomes critical to compromise blood coagulation as little as possible.
During ANH, RBCs as well as coagulation factors and platelets become diluted. 143 It is therefore understandable to intuitively assume that blood coagulation becomes progressively compromised as well. However, this may not be correct. It has been demonstrated that a 25% and 30%in vitro  hemodilution with crystalloids may, in fact, accelerate blood coagulation, as assessed by thromboelastography. 106,144 This was also observed in vivo  145–147 and may be related to an overproportional reduction in antithrombin III. 147 Moderate crystalloid ANH may therefore accelerate rather than inhibit blood coagulation. Eventually, with advanced crystalloid ANH, blood coagulation may become compromised. At present, the exact range of ANH is unknown when blood coagulation is accelerated and when compromised.
In contrast, if colloids are being used during ANH, some degree of compromised blood coagulation is observed in most studies. 106,148,149 In general, gelatin has a moderate effect, similar to using human serum albumin, 106,148 or may even accelerate blood coagulation. 144,150 As a result, perioperative changes in hemostasis were found to be similar in hemodiluted and nonhemodiluted patients undergoing major orthopedic surgery when volume replacement was performed with a combination of gelatin and Ringer’s lactate. 150,151 In contrast, even medium-molecular-weight (200 kd) hydroxyethyl starch compromises coagulation significantly, 106,148,149 and high-molecular-weight (450–480 kd) hydroxyethyl starch compromises blood coagulation even more. 149 A combination of generous amounts of crystalloids with some colloids may be optimal to maintain blood coagulation and to avoid incremental blood loss due to coagulopathy, offsetting the efficacy of other blood conservation strategies.
Hyperoxic Ventilation.
Ventilation with pure oxygen may be beneficial during advanced ANH. In hemodiluted dogs with a hemoglobin concentration of 7.0 g/dl ventilated with pure oxygen, 15% of oxygen delivery and 47% of oxygen consumption was due to physically dissolved oxygen. 152 At a hemoglobin concentration of 3.0 g/dl, even 29% of oxygen delivery and 74% of oxygen consumption was due to physically dissolved oxygen, and mixed venous and coronary venous oxygen partial pressures were higher than at baseline with a hemoglobin concentration of 12.7 g/dl. Although there are no formal studies in patients, pure oxygen ventilation may also be beneficial during advanced stages of clinical ANH, as described in an elderly patient with a hemoglobin concentration of 1.1 g/dl in whom 47% of oxygen delivery and probably > 75% of oxygen consumption was due to physically dissolved oxygen. 153 
Hypotensive Anesthesia.
Controlled hypotension has been proposed to decrease surgical blood loss. Efficacy of this technique was confirmed 154 as well as refuted 155 in recent studies. Although the technique may seem safe when used at relatively high hemoglobin levels, 155 little is known on clinical safety of this technique when combined with ANH. The limited efficacy may be related to the fact that relatively low blood pressures (mean arterial pressure of 60–70 mmHg) are commonly tolerated in today’s anesthesia. Thus, a further decrease of mean arterial pressures to approximately 50 mmHg may only offer limited benefit regarding a reduction in surgical blood loss and allogeneic RBC transfusion requirements.
Surgical Technique
A surgical technique optimized at minimizing blood loss is extremely important to eliminate allogeneic RBC transfusions (table 1). It is interesting that major operations such as liver transplantations can be performed without allogeneic RBC transfusions 156 and without fresh-frozen plasma even in patients with a documented deficiency of clotting factors. 157 
Accepting Minimal Hemoglobin Levels
The minimal hemoglobin level tolerated without organ dysfunction (table 1) is often referred to as “critical hemoglobin.” Such a value cannot be defined in a generally applicable way, but it is intriguing to learn that even extreme ANH to a hemoglobin concentration of 5 g/dl was well tolerated in humans. 158 No signs of compromised oxygen delivery, such as a decrease in oxygen consumption or an increase in lactate, were observed, 158 not even after further compromising oxygen delivery by acute β blockade, 159 suggesting that a hemoglobin concentration of 5 g/dl was not yet critical. The critical hemoglobin level can therefore only be defined for certain organs, specific situations and disease states, and particular age groups. This has been reviewed previously. 100,160,161 
Several studies investigated the effect of ANH on splanchnic organs. One study showed that gastric blood flow was stable during ANH in dogs. 162 Despite the lack of an increase in gastric perfusion, intramucosal pH was maintained, and no evidence was found that oxygen delivery to the stomach would have been compromised. Jejunal oxygen delivery and consumption were equally maintained in pigs during extreme ANH to a hematocrit of approximately 10%. 163 In animals with normal splanchnic circulation, oxygen delivery is well maintained even during advanced ANH.
Cerebral blood flow increases during ANH in rats, 164,165 cats, 166 pigs, 167 dogs, 168,169 and humans, 170 thereby maintaining oxygen delivery to the brain. 170 Furthermore, cerebral oxygen consumption was not compromised in adult patients undergoing cardiopulmonary bypass at hemoglobin values of 6.2 g/dl, nor in a subset of patients with a mean hemoglobin value of 5.2 g/dl. 171 Even at hematocrit levels of approximately 14%172 and 10%, 166 brain function and brain oxidative metabolism were intact as assessed by electrocorticogram, somatosensory-evoked potentials, and high-energy phosphate determination. The increase in cerebral blood flow thus largely compensates the decrease in the arterial oxygen content provided that there are no major vascular stenoses in the cerebral circulation. However, even with a high-grade carotid stenosis, blood flow to the brain increases during moderate ANH. 173 
The increase in cerebral blood flow during ANH is certainly beneficial because it compensates the decrease in arterial oxygen content. However, the pressure of an intracranial pathology prone to increased intracranial pressure may lead to a further increase in intracranial pressure. 174 However, in patients without intracranial pathology, the increase in cerebral blood flow will not cause problems per se  .
Hemodilution tolerance has also been investigated in patients with coronary and cardiac diseases. Anesthetized patients with severe coronary artery disease tolerated ANH from a hemoglobin concentration of 12.6 ± 0.2 g/dl to 9.9 ± 0.2 g/dl without evidence of myocardial ischemia. 101 Increases in cardiac output and oxygen extraction compensated the decrease in arterial oxygen content due to ANH completely. Even patients with a 75% left main coronary artery stenosis tolerated limited intraoperative ANH. 89 
Patients with significant mitral valve regurgitation also tolerated ANH from a hemoglobin concentration of 13.0 ± 0.4 g/dl to 10.3 ± 0.4 g/dl well and compensated the decrease in arterial oxygen content with an increase in cardiac output and oxygen extraction. 102 Interestingly, patients with sinus rhythm and those with atrial fibrillation increased cardiac output and oxygen extraction similarly. Therefore, presence of a sinus rhythm may not be an absolute prerequisite for an adequate compensatory response during ANH.
Elderly patients (66–88 yr of age) tolerate moderate ANH to a hemoglobin concentration of 8.8 ± 0.3 g/dl well and were capable of fully compensating the decrease in arterial oxygen content by increases in cardiac output and oxygen extraction. 103 The autologous blood was retransfused at a median hemoglobin concentration of 7.7 g/dl, with 9 of 20 patients undergoing transfusion at a hemoglobin concentration less than 7 g/dl. None of these patients was hemodynamically unstable or showed evidence of myocardial ischemia before retransfusion. Therefore, age does not seem to limit tolerance to moderate ANH. This is in agreement with the results of a recent study on the individual effects of blood transfusion on oxygen dynamics in ICU patients after cardiovascular surgery. 175 Age did not influence the individual effect of allogeneic blood transfusions with respect to oxygen transport or consumption.
Compared with the intraoperative period, less is known on the critical hemoglobin level in the postoperative period. 100,160,161 According to our knowledge, there are only two prospective randomized studies in which the impact of a relatively low hemoglobin target range of 7–9 g/dl was compared with a relatively high target range of 10–12 g/dl. 13,176 In the initial pilot study, 70% of subjects were surgical patients, 176 and in the main study, 36% were postoperative. 13 No difference in outcome was found in the pilot study, 176 but hospital mortality, multiorgan failure, and the incidence of pulmonary edema and myocardial infarction were significantly lower in the restrictive (low hemoglobin target range) transfusion group in the main study. 13 In contrast to these prospective randomized studies, a retrospective study 177 and a study on patients enrolled in trials assessing the effect of preoperative erythropoietin concluded that a hematocrit < 28% would be associated with myocardial ischemia. 178 Both studies have been criticized. 161,179 In the study by Nelson et al.  , 177 patients experiencing myocardial ischemia at a hematocrit < 28% also had a higher incidence (77%) of preoperative myocardial ischemia than patients not experiencing postoperative myocardial ischemia (14%), and thus were more prone to myocardial ischemia irrespective of the postoperative hematocrit. 180,181 Patients with ischemic episodes in the study be Hogue et al.  178 also had more tachycardic episodes, defined as a heart rate of > 100 beats/min, a condition known to be associated with adverse cardiac events in the postoperative period. 182-185 In addition, the association between a low hematocrit and ischemic episode was indeed weak, with one-sided P  values of 0.03 and 0.04, reflecting standard P  values of 0.06 and 0.08 in usually used two-sided statistics. 178,179 In addition, exercise capacity was similar in patients after coronary artery bypass surgery transfused to a hematocrit of 28% and 31%, respectively. 186 Therefore, no generally applicable critical postoperative hemoglobin level exists, and allogeneic RBC transfusion should be guided by physiologic signs of inadequate oxygenation rather than arbitrary hemoglobin transfusion triggers. 187 
Even considering all of the above, we still cannot define the lowest hemoglobin concentration tolerated safely by a majority of patients. However, this knowledge may help to define this value for an individual patient undergoing a specific operation. The critical value also depends on the experience of the anesthesiologist and the intensive care physician, as well as the surgical technique and the likelihood of an imminent massive blood loss.
Transfusion Algorithms Based on Coagulation Monitoring
Transfusion algorithms guided by coagulation monitoring may substantially reduce transfusion of allogeneic RBC, fresh-frozen plasma, and platelets in cardiac surgery. 188–191 Thereby, blood coagulation is monitored using laboratory-based or bedside techniques, and hemostatic and RBC transfusion therapy is guided by an algorithm. Such techniques allow detection of serious blood coagulation deficits, which may be treated by desmopressin, resulting in substantial reduction in RBC, fresh-frozen plasma, and platelet transfusions. 191 
Artificial Oxygen Carriers
Artificial oxygen carriers (table 1) are grouped into hemoglobin-based oxygen carriers and perfluorocarbon emulsions. These drugs are undergoing extensive clinical testing. Using human polymerized hemoglobin as a blood substitute in acute trauma and emergency surgery, allogeneic RBC transfusions could be reduced. 192 The efficacy of perflubron emulsion in reversing physiologic transfusion triggers has also been demonstrated in patients undergoing orthopedic surgery. 193 Should these artificial oxygen carriers prove to be efficacious and well tolerated, they have the potential to significantly reduce allogeneic RBC transfusion, particularly when used in combination with ANH. 97 
Combining Different Blood Conservation Strategies
There are few reports on the combined use of several blood conservation strategies. However, many of these techniques may be combined to improve overall efficacy. Preoperative erythropoietin with ANH 95 or cell salvage, preoperative autologous donation and cell salvage, advanced ANH in combination with artificial oxygen carriers, 17,97 and the concept of augmented ANH 98,99 may be particularly efficacious combinations. In addition, anesthesia techniques aimed at maintaining blood coagulation and normothermia by active warming and optimizing fluid replacement are of great clinical relevance in the context of blood conservation. Using a multimodality blood conservation program, starting with preoperative erythropoietin therapy in patients with a hematocrit < 36%, intraoperative ANH, cell salvage, aprotinin, and relatively low transfusion triggers allowed coronary artery bypass surgery to be performed in 100 consecutive patients without allogeneic blood transfusion. 194 Interestingly, duration of hospitalization and total treatment costs were also reduced.
Preoperative autologous blood donation and the use of erythropoietin are efficacious preoperative strategies. Intraoperatively, ANH, cell salvage, pharmacologic treatment with antifibrinolytics, specific anesthesiology and surgical techniques, coagulation monitoring–based transfusion algorithms, acceptance of minimal hemoglobin values, and soon artificial oxygen carriers may be used to avoid allogeneic RBC transfusions. Cell salvage, antifibrinolytics, and accepted minimal hemoglobin values may also be used in the postoperative period.
All of these techniques have been used efficaciously in certain situations and form the basis of an integral concept to avoid allogeneic RBC transfusions. Two major goals remain: (1) these strategies have to be implemented in general clinical practice; and (2) the most efficacious techniques and combinations thereof need to be defined for individual patients.
The authors thank Richard B. Weiskopf, M.D. (Professor of Anesthesiology, Department of Anesthesia, University of California, San Francisco, California), for reviewing the manuscript.
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Table 1. Blood Conservation Strategies
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Table 1. Blood Conservation Strategies