Patients with coexisting heart disease tolerate moderate normovolemic hemodilution or acute anemia well, provided that normovolemia is maintained [29–32]. However, an aggressive hemodilution, including normovolemic hemodilution, can cause myocardial ischemia that is reversible with a blood transfusion [33]. Among patients refusing any blood transfusions for religious reasons who have coexisting cardiovascular disease, postoperative hemoglobin levels below 6.0 g/dL were associated with an increased mortality and morbidity, and an increasingly greater difference in mortality and morbidity was observed between patients with and without coexisting cardiovascular diseases [34]. The question of when to transfuse an individual patient with a coexisting cardiac disease thus remains unanswered except at extremely low hemoglobin levels (e.g., <6.0 g/dL). Blood transfusions may be indicated in some anemic patients with coexisting cardiac disease [34–37].

Pooled data from randomized controlled trials in heterogeneous patient populations show that restricting blood transfusions to patients whose hemoglobin drops below 7 g/dL results in a significant reduction in total mortality, acute coronary syndrome, pulmonary edema, rebleeding, and bacterial infection, compared to a more liberal transfusion strategy [38]. The number needed to treat to save one life was 33. This strategy resulted in a 40 % reduction in the number of patients receiving a blood transfusion, with an average of 2 units less per person; however, over one-half of patients were still transfused.

Observational studies have consistently shown that transfusions are associated with an increased risk for adverse events after controlling for potential confounding variables, even when using a restrictive transfusion strategy [39–41]. It has been the traditional teaching that patients with cardiac ischemia should have a more liberal transfusion strategy to maintain oxygenation, but pooled observational studies show that transfusions are associated with especially high risk when given during an acute coronary syndrome [42, 43]. For patients with non-acute cardiac disease, subgroup analysis of data from a trial in critically ill patients showed that the restrictive strategy was not associated with worse outcomes for critically ill patients with cardiovascular disease [44].

It remains impossible to determine the optimum hemoglobin/hematocrit number at which a transfusion would be indicated generally and hence guidelines published in 2006 by the American Society of Anesthesiologists which state that “the decision of red blood cell transfusions should be based on the patient’s risk of developing complications of inadequate oxygenation” is valid even for patients with coexisting cardiovascular disease [36]. It is therefore important to recognize signs of inadequate oxygenation in patients with coexisting heart diseases. Inadequate oxygenation may become manifest locally in the form of myocardial ischemia or globally in the form of a general hemodynamic instability with a tendency to hypotension and tachycardia despite normovolemia [33]. Myocardial ischemia may be detected by continuous electrocardiogram (ECG) monitoring and by transesophageal echocardiography. New ST-segment depressions of greater than 0.1 mV or new ST-segment elevations of greater than 0.2 mV for more than 1 min are generally regarded as a marker of myocardial ischemia (Table 4.1) [33]. During progressive hemodilution, one observes mostly ST-segment depression, suggesting subendocardial ischemia. In controlled studies such anemia-related ischemia is reversible by decreasing the heart rate, if elevated, and by minimal transfusion to increase the hemoglobin by 1–2 g/dL [45]. Also, new wall motion abnormalities clinically detected by transesophageal echocardiography are suggestive of myocardial ischemia and can be treated by an increase in the hemoglobin of only 1–2 g/dL.

Early signs of an inadequate circulation are a general hemodynamic instability characterized by a relative tachycardia and hypotension, an oxygen extraction rate of greater than 50 %, a low mixed-venous oxygen partial pressure (PvO₂), and a decrease in oxygen consumption [33]. In a position paper of the College of American Pathologists, an oxygen extraction rate of greater than 50 %, a PvO₂ less than 25 mmHg, and a reduction in oxygen consumption to less than 50 % of baseline are described as threshold values above which a blood transfusion would be indicated [35]. An oxygen extraction of greater than 50 % has been found to indicate exhaustion of compensatory mechanism in several studies and thus represents a clear transfusion indication [46, 47]. In contrast, a threshold of 25 mmHg for PvO₂ appears very low, since the PvO₂ decreases below the threshold of 25 mmHg only after circulatory collapse. A PvO₂ threshold of 32 mmHg appears more reasonable, because oxygen consumption started to decrease at a PvO₂ of 32 mmHg during progressive normovolemic hemodilution in pigs [33]. A decrease in oxygen consumption by greater than 50 % at normovolemia is certainly a transfusion indication; however, such a large reduction usually is observed only after hemodynamic collapse. Indeed, oxygen consumption decreases very late. Therefore, any decrease of greater than 10 % in oxygen consumption at low hemoglobin levels should be viewed as a potential sign of a compromised oxygenation of the organism, and a blood transfusion should be considered, provided that normovolemia has been achieved [48].

The main goal of blood transfusions is to increase oxygen-carrying capacity and mitigate myocardial ischemia, but experimental studies indicate no increase in tissue oxygenation and improvement in clinical outcomes with transfusion in any setting or with any nadir hemoglobin level [39, 49, 50]. This inability to improve oxygen uptake in vital organs is due to the hemodynamic response to increased blood viscosity as well as to chemical changes in red cells during preservation and storage, such as depletion of 2,3 diphosphoglycerate and nitric oxide, that diminish the ability of transfusion to deliver oxygen [51–55]. With millions of blood transfusions given yearly over the past century, it would be hard to calculate how many deaths may have been contributed to by transfusions. The adverse effects seen with blood transfusions, including bacterial infections, acute respiratory distress syndrome, multiorgan failure, rebleeding, and total mortality, may be due to an inflammatory response to the transfused blood product. Very little mechanistic explanation is known for no benefit or increased risk with transfusion using liberal strategy among patients with anemia and ACS. One such recent work by Silvain et al. found that blood transfusion was associated with modest but significant increase in measures of platelet reactivity and was more robust in patients previously on P2Y12 inhibitors [56]. At present, there is no randomized trial evidence that blood transfusions improve oxygen delivery or clinical outcomes in any setting, which underscores the urgent need for a randomized control trial of transfusion strategies especially in patients with ACS and CHF. There are two randomized trials, the CRIT study [57] and the MINT trial [58] examining liberal vs restrictive transfusion strategy in patients with ACS and had contrasting results. However, they had small sample sizes and were grossly underpowered to make any relevant conclusions regarding clinically important intervention effects and essentially showed divergent results on clinical outcomes such as mortality.

There remains an urgent and unmet need, as noted in recent guidelines [59], for more studies to help guide clinicians in finding optimal treatment threshold and options in the setting of anemia and bleeding in patients with ACS and CHF.