As is evident from the oxygen delivery equation (DO₂) one of the most efficient means of increasing oxygen delivery to is increase the hemoglobin concentration (see Table 38.1). Therefore, the obvious indication to transfuse blood would be too increase oxygen delivery which should then theoretically increase tissue oxygen tension and tissue oxygen utilization. Unfortunately there is little data to support this concept and it is likely that blood transfusion increases oxygen utilization only in patients with a hemoglobin of less than 4 g/dL…. Yes that is right, less than 4 g/dL [8, 9]. A number of studies in critically ill patients have measured oxygen consumption before and for up to 6 h following a blood transfusion. All of these studies have failed to demonstrate an increase in tissue oxygen tension and oxygen utilization following blood transfusion [10–12]. Indeed, paradoxically (dependent on the age of the transfused cells), red blood transfusions may compromise tissue oxygenation.

Transfusion related immunomodulation (TRIM) occurs to some degree in almost all recipients of blood and blood products and are the cause of most of the complications associated with blood transfusion [14]. Clinical evidence for the existence of TRIM was first reported in 1973. Opelz and colleagues provided evidence that allogenic blood recipients had improved renal allograft survival [18]. This observation was subsequently confirmed in prospective clinical trials [19]. TRIM may result in either immune activation or immune suppression, this being dependent on the interaction between host and donor factors. Clinical syndromes associated with immune activation in the recipient include a variety of transfusion reactions including febrile non-hemolytic transfusion reactions (FNHTR), transfusion associated graft-versus-host disease (TA-GvHD), transfusion related acute lung injury (TRALI), alloimmunization and possible development of various autoimmune diseases. Syndromes associated with tolerance induction and immunosuppression include increased predisposition to nosocomial and postoperative infections, cancer recurrence, microchimerism and enhanced survival of various allografts in recipients.

While TRIM appears to be a ubiquitous phenomenon the mechanisms leading to immunomodulation remains poorly understood. A number of mechanisms have been proposed relating to the transfusion of donor antigen presenting cells (APC), donor stem cells (leading to microchimerism), donor white blood cells, donor immunoglobulins, donor cytokines from activated WBC’s and iron and free hemoglobin from hemolyzed red blood cells. It is likely that these mechanism act in concert to alter the immune status of the host. Allogenic blood transfusions introduce a multitude of foreign antigens including HLA-class II bearing donor dendritic antigen presenting cells (APC) in recipients. Blood transfusions induce TRIM in two opposite ways causing either i) allo-immunization or ii) tolerance induction. Immunization is reflected by the induction of HLA alloantibodies and T cell activation, while the induction of tolerance is suggested by enhanced renal, hepatic, cardiac, pancreatic and skin allograft survival in transfused versus non-transfused recipients. Presence or absence of “autologous” HLA-DR Ag on the leucocytes of the transfusion donor plays a decisive role whether immunization or immune suppression will ensue following allogenic blood transfusion [20]. Transfusions sharing at least one HLA-DR antigen with the recipient will induce tolerance while fully HLA-DR mismatched transfusions lead to immunization. Accumulation of various soluble bioactive substances occurs during storage and includes histamine, lipids, cytokines, fragments of cellular membranes, soluble HLA class I antigens, many of which are WBC derived and play an important role in TRIM. TRIM associated immunosuppression has been associated with a decrease in the helper:suppressor T-lymphocyte ratio, a decrease in natural killer cell function, defective antigen presentation and suppression of lymphocyte blastogenesis. Since WBC’s are assumed to play a pivotal role in TRIM, it has been suggested that leukodepleted blood may have less immunomodulating properties and hence reduce the complications associated with the transfusion of non-leukodepleted blood. Hebert and colleagues reported a retrospective before-and-after cohort study conducted from August 1998 to August 2000 in 23 hospitals in Canada, enrolling 14,786 patients who received RBC transfusion following cardiac surgery or repair of hip fracture [21]. A total of 6,982 patients were enrolled during the control period and 7,804 patients were enrolled following prestorage leukoreduction. In this study the adjusted odds of death following leukoreduction were reduced (OR 0.87; CI 0.75–0.99) but serious nosocomial infections did not decrease (OR 0.97; CI 0.87–1.09). Furthermore, the frequency of febrile non-hemolytic transfusion reactions (FNHTR) decreased significantly (OR 0.86; CI 0.79–0.94) as did antibiotic use (OR 0.90; CI 0.82–0.99). While the risk of nosocomial infections were not reduced in the study by Hebert et al., a meta-analysis investigating the use of leukodepleted RBC transfusions in surgical patients demonstrated a significant reduction of postoperative infections (OR 0.522; CI 0.33–0.82, p = 0.005) [22].

Transfused RBC’s are stored refrigerated in a preservative solution. Saline-adenine-glucose-mannitol (SAG-M) is the most commonly used preservative solution and enables refrigerated storage of RBCs for up to 42 days following collection. This “shelf-life” is based on criteria set by the Food and Drug Administration (FDA), which requires that 75 % of transfused RBCs must be recoverable in the peripheral blood circulation 24 h after transfusion [23]. The reported mean storage duration of blood in the US is 18 days [2]. However this varies widely, with larger tertiary/quaternary hospitals generally transfusing older blood than smaller community hospitals. The mean age of blood transfused in ICU patients varies from about 16 to 24 days with “younger” blood being transfused in European as compared to US ICUs [6, 7]. Differences in blood banking protocols may explain this finding.

During refrigerated storage of RBC units, the RBCs undergo numerous physicochemical changes, collectively referred to as the RBC storage lesion, which affects the quality, function and in vivo survival of the transfused RBCs [24, 25]. Many of these changes are the consequence of oxidative stress, leading to the generation of reactive oxygen species, altered proteins and lipids, loss of cell membrane and cell constituents forming microparticles and changes to the RBC cytoskeleton resulting in alterations in the shape and deformability of the RBC. With storage the RBC loses its biconcave shape, become more spherical and spiculated. The physical changes that occur to stored RBCs appear to be similar to those that occur to diseased RBCs (such as in malaria, sickle cell disease, thalassemia). Loss of RBC membrane results in the formation of microparticles which float in the supernatant. As a result of ongoing glycolytic metabolism, lactic acid and protons accumulate in the storage solution. Furthermore, stored white cells become activated resulting in the release of cytokine and other inflammatory mediators.

In health, the amount of oxygen delivered to the whole body exceeds resting oxygen requirements almost fourfold. An isolated decrease in hemoglobin concentration to 10 g/dL with all other parameters remaining constant will result in an oxygen delivery that remains approximately twice that of the resting oxygen consumption. Humans have a remarkable ability to adapt to anemia by increasing cardiac output (in the absence of volume depletion), increasing microcirculatory density, as well as by increasing red cell synthesis of 2,3-DPG with a resultant rightward shift of the oxyhemoglobin dissociation curve (aids oxygen unloading) and by increasing oxygen extraction. Healthy volunteers can tolerate isovolemic hemodilution down to hemoglobin concentration of 4.5 g/dL without apparent harmful effects [54]. However, due to the high extraction ratio of oxygen in the coronary circulation, coronary blood flow appears to be the major factor which limits the tolerance of low hemoglobin concentrations. In experimental animal models of coronary stenosis, depressed cardiac function occurs at hemoglobin concentrations between 7 and 10 g/L [55, 56].

Extensive experience in patients who decline blood for religious reason, as well as in patients with chronic renal disease, myelodysplastic syndromes and severe autoimmune hemolytic anemias have confirmed that humans tolerate extreme anemia quite well [57, 58]. The best data comes from the Jehovah Witness literature [57]. Carson and colleagues performed a retrospective cohort study in 1,958 patients who underwent surgery and declined blood transfusions for religious reasons [59, 60]. In those patients without cardiovascular disease and with a blood loss of less than 2.0 g/dL there was no significant increase in perioperative mortality (for a baseline hemoglobin of 6–6.9 g/dL and a decline in hemoglobin of less than 2 g/dL the odds ratio (OR) for death was 1.4; 95 % CI, 0.5–4.2). However, in patients with cardiovascular disease, pre-operative anemia was associated with a significant increase in peri-operative mortality. This data confirms that humans can adapt to very low hemoglobin levels with cardiovascular disease being the major limiting factor.

The benefit/harm of blood transfusion are related to a number of factors including:

No randomized clinical trial comparing transfusion with no transfusion has been performed. However, a number of randomized clinical trials have been conducted that compared a more or less restrictive transfusion strategy using different transfusion triggers. Three randomized controlled trials which enrolled 2,364 patients evaluated a restrictive hemoglobin transfusion trigger of <7 g/dL as compared with a more liberal trigger. These studies include:

The pooled results from these three studies showed that a restrictive hemoglobin transfusion trigger of <7 g/dL resulted in reduced in-hospital mortality (RR 0.74; CI 0.60–0.92), total mortality (RR, 0.80; CI, 0.65–0.98), rebleeding (RR, 0.64; CI, 0.45–0.90), acute coronary syndrome (RR, 0.44; CI, 0.22–0.89), pulmonary edema (RR, 0.48; CI, 0.33–0.72), and bacterial infections (RR, 0.86; CI, 0.73–1.00), compared with a more liberal strategy [17].

Carson et al. randomized 2,016 patients >50 years of age who had undergone hip surgery and had risk factors for cardiovascular disease to a liberal transfusion strategy (trigger of 10 g/dL) or a restrictive transfusion strategy (trigger of 8 g/dL) [64]. There is no difference in morbidly or mortality between the two groups. In a pilot study, Walsh et al. randomized “older” (>55 years of age) patients requiring mechanical ventilation to a restrictive (transfusion trigger < 7 g/dL) or liberal transfusion strategy (transfusion trigger < 9 g/dL) [65]. Mortality at 180 days postrandomization trended toward higher rates in the liberal group (55 %) than in the restrictive group (37 %); relative risk was 0.68 (95 % CI, 0.44–1.05; p = 0.073).

Anemia is a well-recognized to be a poor prognostic factor in patients with congestive cardiac failure as well as acute coronary syndromes (ACS) [66, 67]. However, this does not mean that blood transfusion improves outcome. Kansagara et al. performed a meta-analysis which included 6 RCT’s and 26 observational studies investing the role of blood transfusion in patients with heart disease [68]. These authors concluded that “evidence from suggests that liberal transfusion protocols do not improve short-term mortality rates compared with less aggressive protocols (RR 0.94; CI 0.61–1.42).” Chatterjee et al. performed a meta-analysis investigating the association between blood transfusion and outcomes in patients with acute myocardial infarction [69]. In this meta-analysis blood transfusion increased all-cause mortality (OR 2.91; CI, 2.46–3.44, p < 0.001). Multivariate meta-regression revealed that blood transfusion was associated with a higher risk for mortality independent of baseline hemoglobin level, nadir hemoglobin level, and change in hemoglobin level during the hospital stay. Blood transfusion was also significantly associated with a higher risk for subsequent myocardial infarction (OR 2.04; CI 1.06–3.93, p = 0.03). Rao and colleagues examined the potential impact of red blood cell transfusion in 24,111 patients with ACS [70]. Blood transfusion was an independent predictor of myocardial infarction and 30-day all-cause mortality (adjusted hazard ratio 3.94). Furthermore, the 30-day mortality was significantly increased when transfusions were given to patients with hematocrits of 25 % or above (compared to those with a hematocrit below 25 %). Similarly Aronson and colleagues demonstrated an increase in mortality and the composite end-point of death/recurrent MI/heart failure in patients with acute myocardial infarction who had a hemoglobin > 8 g/dL and received a blood transfusion [71].

The 2012 guidelines from the American Association of Blood Banks (AABB) recommend adhering to a restrictive transfusion strategy (7–8 g/dL) in hospitalized, stable patients (Grade: strong recommendation; high-quality evidence) [72]. Furthermore these guidelines state that “transfusion decisions should be influenced by symptoms as well as hemoglobin concentration” (Grade: weak recommendation; low-quality evidence). The 2013 guidelines from the American College of Physicians recommend recommends using a restrictive blood cell transfusion strategy (trigger hemoglobin threshold of 7–8 g/dL compared with higher hemoglobin levels) in hospitalized patients with coronary heart disease (Grade: weak recommendation; low-quality evidence) [73].

Based on current evidence in patients who are not actively bleeding, RBC transfusions should be restricted to those patients with a Hb < 7 g/dL. However, it is likely that many patients can tolerate a hemoglobin concentration lower 7 g/dL, suggesting that the patients’ physiologic reserve, presence of coronary artery disease and other comorbidities should be taken into account when making blood transfusion decisions. Furthermore, in most instances patients should be given one unit of RBC at a time. One unit of packed RBCs should increase levels of hemoglobin by 1 g/dL and the hematocrit by 3 %.