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Ann Thorac Surg 2006;82:2323-2334
© 2006 The Society of Thoracic Surgeons

Reviews

Indications for Blood Transfusion in Cardiac Surgery

Gavin J. Murphy, MD, FRCS*, Gianni D. Angelini, MD, FRCS

Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Bristol, United Kingdom

Accepted for publication June 12, 2006.

* Address correspondence to Dr Murphy, Bristol Heart Institute, Bristol Royal Infirmary, Bristol BS2 8HW, United Kingdom (Email: gavinmurphy{at}bristol.ac.uk).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Indications for Blood...
 References
 
In addition to its life-saving effect in hemorrhagic shock, transfusion of allogenic packed red blood cells can be beneficial in situations where a critically low hematocrit is contributing to a state of oxygen-supply dependency. These benefits are countered by the risks of transfusion-associated lung injury, transfusion-associated immunomodulation, and cellular hypoxia after RBC transfusion. The critical hematocrit is patient and organ specific, and varies intraoperatively according to the duration and temperature of bypass, as well as for a variable postoperative period. Future randomized studies must prospectively evaluate regional indicators of tissue oxygenation in transfusion algorithms.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Indications for Blood...
 References
 
Adult cardiac surgery utilizes a significant proportion of all red blood cell (RBC) transfusions in the United Kingdom and the United States. The evidence base upon which RBCs are transfused is poor, however, and the majority of transfusions are administered because the hemoglobin concentration or hematocrit has fallen below a predefined threshold. This threshold varies widely both within and between institutions, with 25% to 95% of patients undergoing cardiac surgery receiving blood transfusions in cross-sectional surveys [1, 2], suggesting that many RBC transfusions, and subsequent transfusion-associated morbidity is unnecessary. The well-publicized risks of infection and hemolytic reactions arising from transfusion errors are rare (Table 1), and less well recognized risks such as immunomodulation and tissue injury are now thought to contribute much more significantly to transfusion-associated morbidity. Low hemoglobin concentrations and reduced oxygen delivery also increase morbidity [3, 4], and in some of these cases blood transfusion will improve outcome [5]. The aim of this study was to review the evidence regarding the hazards of low hemoglobin concentrations/oxygen delivery and transfusion in contemporary practice, with a view to outlining future prospective studies of transfusion protocols in cardiac surgery.


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  		Table 1. Risks From Blood Transfusion in Western Europe and North America
 

   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Indications for Blood...
 References
 
The following search was conducted in PubMed: ([coronary artery bypass] or [aortic aneurysm] or [heart valve] or [myocardial ischemia] or [organ dysfunction] or [TRALI] or [TRIM] or [neutrophil activation] or [endothelial activation] or [systemic inflammatory response] or [SIRS] or [oxygen delivery] or [oxygen extraction] or [transfusion-associated immunomodulation] or [transfusion-associated lung injury] or [transfusion-associated lung morbidity] or [transfusion-associated morbidity]) and ([anemia] or [hemoglobin] or [transfusion] or [hematocrit]] or [oxygen extraction] or [oxygen delivery]). To reflect contemporary practice, the search was limited to English language publications between January 1, 1996, and February 7, 2006. Inclusion criteria included randomized controlled trials, case control or observational cohort studies that had assessed the role of anemia or transfusions on outcomes in cardiac surgery. Duplicate publications were omitted. Relevant studies in related specialties such as acute coronary syndromes or critical care were also considered for the insight they might provide into these issues in a cardiac surgery population.

Effect of Hemoglobin Concentration on Outcome After Cardiac Surgery
Low hemoglobin concentrations in cardiac surgery are associated with organ dysfunction that can be attributed to insufficient oxygen delivery. These include myocardial injury, increased inotrope requirements, neurologic dysfunction and stroke, renal dysfunction and postoperative dialysis, prolonged ventilation, and increased perioperative mortality (Table 2) [3, 4, 6–21]. The majority of the studies are retrospective and suffer from the possibility that operator bias as well as potential confounders not included in retrospective analyses may influence the results. Three potential confounders missing in many of these analyses are as follows: firstly, the failure to include transfusion as a variable, even though transfusion has been associated with adverse outcome in multiple studies, and is a covariate of low hemoglobin; secondly, low hemoglobins may only be detrimental in the presence of impaired pump flows or cardiac output, that is low oxygen delivery [4, 22]; and thirdly, impaired physiologic reserve, a key determinant of both postoperative anemia and outcome, is impossible to quantify retrospectively.


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  		Table 2. Studies Evaluating Effects of Hemoglobin Concentration or Hematocrit on Outcomes After Cardiac Surgery
 
The significance of these limitations is highlighted by the discordance between the findings of retrospective studies versus a prospective study of intraoperative anemia on outcome. Licker and colleagues [8], in a randomized trial of autologous predonation and acute normovolemic hemodilution (ANH) in patients undergoing on-pump coronary artery bypass graft surgery, demonstrated superior outcomes in the ANH group, in whom the median nadir hematocrit on cardiopulmonary bypass (CPB) was 20 compared with controls, in whom the median hematocrit was 27. Patients selected for inclusion in randomized trials often represent a fitter cohort, however, and retrospective "real world" studies consistently show significantly worse outcomes once hematocrits on bypass drop below 18 to 22 (Table 2).

In contrast, neither retrospective nor prospective studies appear to demonstrate an adverse effect of low postoperative hematocrit on outcome. Three retrospective studies have demonstrated a protective effect of postoperative anemia (Table 2). Neither nadir postoperative hematocrit nor postoperative transfusion was included in the multivariate analyses however. Bracey and colleagues [19] in a randomized trial of a restrictive transfusion threshold of 8 g/dL versus a liberal threshold of 9 g/dL demonstrated no detrimental effect of a restrictive threshold, although a significantly smaller number of units of nonleukodepleted RBCs were transfused in this group (0.9 ±1.5 units restrictive versus 1.4 ± 1.8 units control, p = 0.005). When only those patients whose nadir hemoglobins fell below 9 g/dL were considered, the restrictive threshold was also associated with shorter ventilation times (8.6 ± 4.5 hours versus 10.8 ± 5.1 hours, p = 0.008).

The discrepancy between the potentially injurious role of low hematocrits on bypass and the protective role post bypass can be explained by several factors. Firstly, the hierarchical oxygen delivery and altered autoregulation characteristic of CPB at varying pressures and temperatures is different from that which occurs in the postoperative period [23]. Secondly, the nadir hematocrit levels tolerated on bypass (hematocrit 18 to 24) are rarely observed in the postoperative period where transfusion thresholds generally lie between 23 and 27. And thirdly, it has been suggested that postoperative cardiac surgical patients rarely reach a state of oxygen-supply dependency unless low hemoglobin is also associated with a low cardiac output [22].

Insight into the nature of the critical hematocrit in cardiac surgery patients can be extrapolated from studies in related disciplines such as critical care and cardiology. In the landmark Transfusion Requirements in Critical Care (TRICC) study [24], Hebert and colleagues randomly assigned 838 noncardiac surgery critical care patients to either a restrictive transfusion threshold (7 g/dL) or a liberal transfusion threshold (10 g/dL). Patients in the restrictive group had significantly lower hemoglobins and received significantly fewer transfusions (55% versus 100%). The restrictive group had a significantly lower frequency of cardiac complications, adult respiratory distress syndrome, and episodes of pulmonary edema. In younger and less sick patients, the restrictive strategy was also associated with reduced mortality [24]. This finding suggests that low hemoglobins are well tolerated by critically ill patients. Studies in patients with acute coronary ischemia show associations between hemoglobins less than 10 to 12 g/dL and poor outcome [25, 26]. These studies are retrospective, however, most consider only admission hemoglobins, which are simply a surrogate for comorbidity, and few consider transfusion as variable in their analyses. Critical care patients with cardiac disease and hemoglobin values less than 9.5 g/dL had higher mortality rates in a retrospective study (55% versus 42%, p = 0.09) [27], as did anemic patients with cardiovascular disease undergoing noncardiac surgery who have refused blood transfusion [28]. A post hoc analysis of the TRICC study, in which only patients with known ischemic heart disease were included, showed a higher 30-day mortality in the restrictive group (26% versus 21%), although this did not reach statistical significance (p = 0.38).

Clinicopathologic Effects of Low Hemoglobin
The point at which the hemoglobin concentration becomes critical varies considerably both between patients and for individual patients over the course of the perioperative period. Cardiopulmonary bypass, by disturbing local autoregulatory mechanisms, produces a mismatch between local oxygen supply and demand and potentially raises the critical hematocrit. In dogs on normothermic CPB, critical hematocrit was in the range of 18 to 20, higher than that reported [10] under non-CPB conditions [29]. The critical hematocrit is also affected by multiple factors that affect the balance of oxygen supply and demand including bypass temperature [30], rewarming [31], pump flow [4, 32], perfusion pressures [15, 32], and conditions where autoregulation is impaired such as diabetes mellitus or increased age [22]. Oxygen utilization is increased postoperatively, in part to reverse the residual oxygen debt that is evident post CPB, and this is affected by arterial oxygen saturations and cardiac output [22, 32]. If oxygen delivery is low in this period (<500 mL · min–1 · m–2 [22]) oxygen-supply dependency can occur, and the critical hematocrit may be higher. Dilutional anemia in cardiac surgical patients also affects hemostasis. Acute normovolemic hemodilution dilutes plasma proteins, and reduces platelet margination, platelet erythrocyte interaction, and the aggregability of erythrocytes. Studies in humans and animals have shown abnormal hemostasis before the development of oxygen-supply dependency after ANH [33].

The critical hematocrit at which different organs become supply dependent may be higher than that for body as a whole. In experimental models, ANH results in hierarchical autoregulation with perfusion directed preferentially to those organs with a lesser capacity to increase oxygen extraction, such as the heart and brain, at the expense of other tissues. In pigs undergoing ANH, the critical hematocrit at which mesenteric mucosal oxygen consumption becomes supply dependent [10, 11] was similar to that for global and cerebral oxygen consumption, whereas the critical hematocrit for the intestinal serosa was higher [17, 34]. Organ-specific critical hematocrits for oxygen-supply dependency are not reflected by global measures. Global oxygen-supply dependency is not detected in healthy adults undergoing ANH to hemoglobins as low as 5 g/dL despite asymptomatic ST-segment electrocardiogram changes plus delayed reaction times and degraded short-term memory suggestive of myocardial and cerebral hypoxia [35, 36].

Acute normovolemic hemodilution increases cerebral blood flow, preserving cerebral oxygenation over a wide range of oxygen delivery. Higher cerebral blood flows increasing the number of cerebral emboli have been suggested as an explanation for the increase in postoperative stokes in patients with profound hemodilution during CPB [11]. Focal neurologic injury may also be exacerbated by lower hematocrits, and hemodilution on CPB to a mean of 6 g/dL was associated with increased focal necrosis after a transient middle cerebral artery ligation in rats [37]. Cardiopulmonary bypass increases cerebral oxygen extraction owing to disordered autoregulation, with even higher rates of extraction in patients at risk of neurologic complications, such as diabetic patients or patients with previous stokes. Hypothermia may confer a measure of neuroprotection. In dogs, the critical hematocrit for cerebral oxygen delivery decreases with progressive hypothermia, with cerebral oxygen demand maintained to a hematocrit of 14, 11, and 10 at 38°C, 28°C, and 18°C, respectively [30]. In contrast, higher hematocrits on rewarming from hypothermic CPB (target hematocrit 30) improved overall outcome and reduced cognitive deficits compared with lower hematocrits (target hematocrit 20) in a randomized trial in children [31].

Reduced viscosity appears to improve myocardial tissue oxygenation in cardiac disease. Acute normovolemic hemodilution improved left ventricular contractility, independent of its effect on reduced afterload and increased preload in anesthetized dogs [38] as well as reducing myocardial injury in rats undergoing experimental myocardial infarction from transient arterial occlusion [39]. Moderate hemodilution to values between 28 and 30 improved diastolic left ventricular filling abnormalities in 15 of 22 patients with critical coronary artery lesions in one study [40]. Anemia reduces cardiovascular reserve to adverse perioperative events, however, and oxygen-supply dependency occurs at lower thresholds of blood loss, hypoxia, and oxygen demand in experimental models [41].

Effect of RBC Transfusion on Outcome After Cardiac Surgery
A summary of contemporary studies evaluating the effects of blood transfusion on outcomes in cardiac surgical patients is presented in Table 3 [9–11, 42–61]. These analyses often omitted crucial confounders such as nadir hemoglobin, the use of other blood components, whether the RBCs are leukodepleted, or the duration of storage before transfusion. All of the studies broadly agree in their conclusions, namely, that blood transfusion is associated with increased perioperative and long-term mortality including stroke, delirium, renal dysfunction and failure, bacteremia, surgical site infection, prolonged ventilation and the increased use of healthcare resources, with prolonged intensive care unit and hospital stays. Several studies also highlight longer-term morbidity that has additional economic implications [44, 52]. Transfusion is more than simply a covariate of low hemoglobin [9, 15]. Habib and colleagues [9] stratified patients according to the lowest hematocrit on CPB. Low hematocrit was associated with worse outcome; however, transfusion, analyzed as a variable within each stratum, was associated with an additional increase in morbidity.


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  		Table 3. Studies Evaluating the Effects of Blood Transfusion on Outcomes After Cardiac Surgery
 
Retrospective studies cannot demonstrate causality, and one cannot exclude the possibility that the tendency for sicker patients to receive more blood transfusions could explain almost all of these observations. The best evidence for causality comes from the TRICC study [24], in which patients randomly assigned to the restrictive transfusion threshold had significantly fewer blood transfusions and reduced morbidity (see above). Two prospective multicenter observational cohort studies demonstrated a clear association between transfusion and mortality in critical care (mortality odds ratio [OR], 1.37; 95% confidence interval [CI]: 1.02 to 1.84; p = 0.04 [62]; adjusted mortality OR, 1.65; 95% CI: 1.35 to 2.03; p < 0.001 [63]). Similar associations are reported in patients with acute myocardial ischemia (mortality OR, 1.67; 95% CI: 1.48 to 1.88 [64]). In contrast to those in cardiac surgery and critical care, several studies in anemic patients with full thickness myocardial infarction seem to suggest that transfusion may be beneficial (mortality OR, 0.42; 95% CI: 0.20 to 0.89 [25]), particularly for those more than 65 years old (mortality OR, 0.69; 95% CI: 0.53 to 0.89; hematocrit range, 30 to 33 [26]). This finding has potential implications for cardiac surgical patients in that elderly anemic patients with perioperative myocardial infarctions or low cardiac output may have different transfusion indications.

Clinicopathologic Effects of RBC Transfusion
Tissue hypoxia
Blood is transfused on the premise that restoring the hemoglobin concentration to above a specified threshold will improve tissue oxygenation. Both clinical and experimental studies have demonstrated, however, that the transfusion of stored RBCs fails to improve tissue oxygenation. In anemic ventilated cardiac surgery patients, transfusion of allogenic RBCs increases the oxygen delivery index but fails to increase oxygen consumption or skeletal muscle oxygen tension [65]. One explanation of this is that transfusion is associated with derangement of oxygen uptake at a microcirculatory level. Alternatively, it is possible that anemic cardiac surgical patients (hemoglobin 7.5 to 8.5 g/dL) rarely reach a state of oxygen-supply dependency, and therefore increased oxygen delivery may not necessarily result in increased oxygen uptake as anemic patients usually do not exhibit signs of tissue hypoxia unless they also have circulatory failure. In agreement with the former hypothesis, a 25% exchange transfusion with RBCs stored more than 28 days in anemic hamsters was shown to reduce microvascular oxygen extraction by 54%. This regional hypoxia was not detectable at the systemic level [66]. Similarly, studies in critically ill septic patients have shown that RBC transfusion reduces intragastric pH, an index of mesenteric ischemia [67], and fails to improve global oxygen consumption even where the nadir hemoglobin is less than 8 g/dL [68].

Tissue hypoxia has been attributed to the "storage lesion." Stored RBCs become depleted of 2-3-diphosphoglycerate, adenosine triphosphate, and nitrite reductase activity, disrupting normal oxygen transfer, reducing erythrocyte deformability, and altering normal autoregulatory mechanisms [69, 70]. Coupled with the release of harmful substances into the supernatant such as free hemoglobin, which chelates nitric oxide, the loss of negatively charged surface residues, and enhanced adhesiveness of stored RBCs, transfusion produces oxygen supply-demand mismatch, capillary sludging, and tissue hypoxia.

Systemic inflammation
The systemic inflammatory response occurs after any trauma or major operation. In cardiac surgery, this response is enhanced by cardiopulmonary bypass. Fransen and colleagues [71] prospectively evaluated the contribution of nonleukodepleted red cell transfusion to this response in 114 consecutive patients undergoing cardiac surgery. Patients who received packed red cells intraoperatively had higher levels of neutrophil activation, as measured by plasma levels of bactericidal permeability increasing protein, plus significantly elevated plasma levels of the proinflammatory monocyte-derived cytokine interleukin-6. The bactericidal permeability increasing protein levels were elevated in donor units, with higher levels in units that had been stored longer, indicating that donor leukocyte degranulation may have occurred during storage. Donor bactericidal permeability increasing protein levels contributed to only 15% of that in recipients, and interleukin-6 levels were undetectable in donor blood, indicating the observed levels in transfused patients were induced by transfusion. Transfused patients also had higher rates of postoperative infection, ventilation times, and lengths of stay when compared with nontransfused patients. A multivariate analysis identified RBC transfusion as the strongest predictor of adverse postoperative outcome [71].

Transfusion-associated lung injury and immunomodulation
Transfusion-associated lung injury, originally thought to represent an uncommon but severe complication of blood transfusion, is now more increasingly thought of as a broad spectrum of pulmonary dysfunction. Lung injury is thought to occur because of the degranulation of neutrophils sequestered in the pulmonary vasculature after an initial insult, in a two-hit mechanism. Cardiopulmonary bypass promotes endothelial activation and neutrophil sequestration, and patients undergoing cardiac surgery have been identified in epidemiologic studies as being at increased risk of developing transfusion-associated lung injury. The nature of the second insult is debated but may involve the transfer of donor specific antibodies or the transfer of lipid breakdown products (lysophosphatidylcholines) in the supernatant of cellular blood components. Lysophosphatidylcholines are stoichiometrically similar to platelet-activating factor, and transfusion-associated lung injury can be inhibited in experimental models by the administration of platelet-activating factor receptor antagonists [72]. Cell membrane microparticles are also a putative mechanism of transfusion-mediated injury. These subcellular particles circulate in healthy persons and are thought to mediate various responses to injurious stimuli and accumulate in stored blood products [73]. Nonimmunologic mechanisms of transfusion injury attributed to lysophosphatidylcholine or microparticles may explain the occurrence of transfusion-associated lung injury after the transfusion of autologous predonated RBCs [74], as well as the failure of stored predonated autologous red cells to reduce morbidity compared with allogenic transfusion in randomized clinical trials [75].

The specific mechanisms of transfusion-associated immunomodulation are also unclear; however, nonleukodepleted stored RBCs have been shown to contain high levels of immunoregulatory molecules, including cytokines, activated complement, soluble human leukocyte antigen class I, and Fas ligand [76]. Allogenic RBC transfusion results in a reduction in the helper/suppressor T-lymphocyte ratio, reduced natural killer cell and antigen presenting cell function, suppression of lymphocyte blastogenesis, and a reduction in delayed-type hypersensitivity and allograft tolerance [76].

Leukodepletion
Prestorage leukocyte depletion of blood components reduces the levels of inflammatory mediators in the stored supernatant caused by neutrophil lysis and degranulation and has been shown to reduce transfusion-associated morbidity. Two meta-analyses of randomized trials of leukodepleted versus nonleukodepleted RBC transfusion demonstrated that prestorage leukodepletion in cardiac surgical patients was associated with a significant improvement in outcome. Fergusson and colleagues [77] demonstrated a reduction in postoperative infection (risk ratio, 0.77; 95% CI: 0.61 to 0.97) and postoperative mortality (risk ratio, 0.42; 95% CI: 0.24 to 0.73) with leukodepletion, while Vamvakas [78] demonstrated an increase in short-term mortality with nonleukodepleted RBC transfusion (OR, 2.26; 95% CI: 1.31 to 3.90; p < 0.05). In both meta-analyses, the benefits of leukodepletion were most evident in cardiac surgery patients, and it was hypothesized that this may reflect the transfusion of bioactivators into an already activated inflammatory system associated with the use of CPB [77]. Some randomized trials in cardiac surgical patients have shown only marginal clinical benefits with leukodepletion, however, and clinical and experimental studies suggest that nonleukocyte dependent mechanisms also have a role in the pathogenesis of transfusion-associated morbidity. Retrospective studies have demonstrated significant associations between transfusion of prestorage leukodepleted RBCs and surgical site infection, stroke, renal failure, and pulmonary injury after cardiac surgery (Table 3). The significance of the "storage lesion" itself has recently been questioned. A prospective multicenter cohort study in critical care showed no association between length of storage and adverse outcome [63], and a prospective randomized clinicoexperimental study of stored versus nonstored RBC transfusion in the critically ill demonstrated no difference in global or tissue oxygenation, or clinical outcome between the groups [79].


   Indications for Blood Transfusion in Cardiac Surgery
Top
 Abstract
 Introduction
 Material and Methods
 Indications for Blood...
References
 
Red blood cell transfusion can be lifesaving for the treatment of hemorrhagic shock. The transfusion of stored red cells can also improve oxygen delivery when perioperative oxygen extraction is critical or oxygen delivery is low [5]. These benefits must be countered by the risks of lung injury, immunomodulation, and cellular hypoxia associated with transfusion. The determination of when the benefits of transfusion outweigh the risks is unclear from the available evidence. Oxygen-supply dependency and hence critical hematocrit is patient and organ specific, and varies for the individual perioperatively. Measuring global oxygen extraction as an aid to identifying the critical hematocrit perioperatively has several significant limitations: firstly, it requires invasive monitoring; secondly, in the presence of oxygen-supply dependency, the Fick equation grossly underestimates true oxygen consumption [80]; thirdly, the reproducibility of the Fick calculation becomes progressively less at lower hematocrits [80]; and finally, global measures of tissue supply and demand often fail to detect regional oxygen supply demand mismatch.

Detection of regional oxygen-supply dependency is possible and may increasingly be used in transfusion algorithms, although the benefits of such goal directed-therapy remain to be evaluated. Noninvasive measurement of cerebral mixed venous oxygen saturation and laser Doppler flowmetry of the intestinal mucosa provide indicators of regional oxygenation for the brain and gut, respectively, although these techniques may be cumbersome in routine practice. Hematocrit, which is monitored frequently in the perioperative period in cardiac surgery, is a poor indicator of oxygen delivery over a range of values, although in rats undergoing ANH, oxygen-supply dependency correlated well with hematocrits below a critical threshold [81]. Simple hemoglobin transfusion triggers, such as those suggested by Bracey and colleagues [19], may therefore be useful if matched with some other markers of inadequate tissue perfusion. Paone and colleagues [82] utilized a mixed venous oxygen saturation less than 55% as a transfusion trigger on bypass in combination with a postoperative trigger of hematocrit less than 20% in an unmatched cohort of patients undergoing cardiac surgery. They demonstrated a reduction in the frequency of blood transfusion, rapid postoperative restoration of hematocrits greater than 25%, and low postoperative morbidity. Sehgal and coworkers [83] used a physiologic on-pump transfusion trigger of mixed venous oxygen saturation less than 55% with similar results.

Future prospective trials must evaluate physiologic triggers in combination with existing clinical and laboratory indices of oxygen-supply dependency. Given the case volume of modern cardiac surgical practice, randomized trials evaluating indications for transfusion should be relatively inexpensive and simple to perform.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Indications for Blood...
 References
 

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