Lelubre and Vincent Annals of Intensive Care 2011, 1:43

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REVIEW Open Access

Red blood cell transfusion in the critically ill

patient
Christophe Lelubre and Jean-Louis Vincent*

Abstract
Red blood cell (RBC) transfusion is a common intervention in intensive care unit (ICU) patients. Anemia is frequent
in this population and is associated with poor outcomes, especially in patients with ischemic heart disease.
Although blood transfusions are generally given to improve tissue oxygenation, they do not systematically increase
oxygen consumption and effects on oxygen delivery are not always very impressive. Blood transfusion may be
lifesaving in some circumstances, but many studies have reported increased morbidity and mortality in transfused
patients. This review focuses on some important aspects of RBC transfusion in the ICU, including physiologic
considerations, a brief description of serious infectious and noninfectious hazards of transfusion, and the effects of
RBC storage lesions. Emphasis is placed on the importance of personalizing blood transfusion according to
physiological endpoints rather than arbitrary thresholds.

Introduction cohort study in Scotland, 25% of patients admitted to

Red blood cell (RBC) transfusion is commonly required in the ICU had a hemoglobin level < 9 g/dl [2]. Similar
critically ill patients. Several recent, observational, multi- results were reported in the ABC study [3], in which
center studies reported that approximately one third of 29% of patients had a hemoglobin concentration < 10 g/
critically ill patients received a blood transfusion at one dl on admission. Even in nonbleeding ICU patients,
time or another during their stay in the intensive care unit hemoglobin levels tend to decrease early [3]. This
(ICU) (Table 1). Because of the frequent use of this inter- decrease is more pronounced in septic than in nonseptic
vention, it is important for the ICU physician to be aware patients [4], at least in part because of their inflamma-
of recent developments in this continuously evolving field tory response; more frequent blood sampling may also
of medicine. In this narrative review, we consider some contribute.
key aspects of transfusion medicine in the ICU, focusing Interestingly, anemia and the need to restore adequate
on aspects relevant to the critically ill patient, including oxygen delivery (DO2) are the most common indications
prevalence and reasons for blood transfusion, epidemiol- for transfusion, rather than acute bleeding [3,5-10]. Ane-
ogy and etiology of anemia in these patients, pathophysio- mia in the critically ill patient is a multifactorial phe-
logical considerations on tolerance to anemia, and efficacy nomenon that has been compared to the so-called
of RBC transfusion. Safety concerns, including questions “anemia of chronic illness” [11]. Apart from evident
of RBC storage and leukoreduction, are then discussed, causes of anemia, such as primary blood losses (e.g.,
followed by a proposal for an integrated approach to trauma, surgery, gastrointestinal bleeding), multiple
transfusion decisions and a discussion on economic other etiologies contribute to its pathophysiology and
aspects and alternatives to blood transfusion. often coexist in the same patient [11]. These include
blood losses related to minor procedures or phlebotomy,
Epidemiology of anemia and red blood cell and hemodilution secondary to fluid resuscitation. Some
transfusion in the ICU studies have suggested that blood sampling may average
Anemia is common in ICU patients and appears early in as much as 40 ml/day [3,4], but the amount of blood
the ICU course [1]. In an observational, multicenter, required may decrease with technological developments
in analytic methods. Other mechanisms for anemia
* Correspondence: [email protected] include an inflammatory response with blunted erythro-
Department of Intensive Care, Erasme Hospital, Université libre de Bruxelles,
Route de Lennik 808, 1070 Brussels, Belgium poietin (EPO) production, abnormalities in iron

© 2011 Lelubre and Vincent; licensee Springer. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
 http://www.annalsofintensivecare.com/content/1/1/43
Lelubre and Vincent Annals of Intensive Care 2011, 1:43
Table 1 Multicenter observational studies of transfusion in general ICU patients
Author Year study was Country/region No. of patients and Percentage Pretransfusion Mean no. of units Mean age of
conducted number of ICUs transfused in ICU hemoglobin level transfused in ICU blood (days)
Hebert et al. [9] 1993 Canada 5,298 patients in 6 ICUs 25.0 Mean: 8.6 ± 1.3 g/dl NS NS
Vincent et al. [3] 1999 Western Europe 3,534 patients in 146 ICUs 37.0 Mean: 8.4 ± 1.3 g/dl 4.8 ± 5.2 16.2 ± 6.7
Rao et al. [6] 1999 UK 1,247 patients in 9 ICUs 53.0 Median: 8.5 (IQR: 7.9-9) 6.75 (hemorrhage) and 4.25 NS
g/dl (anemia)
Corwin et al. [5] 2000 - 2001 USA 4,892 patients in 284 ICUs 44.0 Mean: 8.6 ± 1.7 g/dl 4.6 ± 4.9 21 ± 11.4
Walsh et al. [7] 2001 UK (Scotland) 1,023 patients in 10 ICUs 39.5 Median: 7.8 (7.3-8.5) g/dl Mean: 1.87 unit/ICU NS
admission
French et al. [10] 2001 Australia and New 1,808 patients in 18 ICUs 19.8 Median: 8.2 Mean: 4.18 NS
Zealand (range: 4.4-18.7) g/dl
Vincent et al. [34] 2002 Western and Eastern 3,147 patients in 198 ICUs 33.0 Median: 8.2 g/dl 5.0 ± 5.8 NS
Europe
Westbrook et al. [8] 2008 Australia and New 5,128 patients in 47 ICUs 14.7 Mean: 7.7 g/dl Median: 2 (IQR: 1-4) Median: 14
Zealand (IQR: 9.5-21.5)
ICU intensive care unit; NS not specified; IQR interquartile range

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metabolism, and altered proliferation and differentiation dependent on the hemoglobin level. Hence, blood
of medullar erythroid precursors [11]. As a consequence, transfusions can, theoretically at least, limit tissue
RBC deformability is decreased [12], whereas RBC hypoxia [13,25,26]. But does this really happen in clini-
adherence to the endothelium is increased, especially in cal practice? It is obvious that RBC transfusions can be
septic patients, potentially leading to microcirculatory lifesaving in situations of acute severe anemia or in
impairment and tissue hypoxia [13]. bleeding patients in whom RBC administration can
increase both oxygen arterial content and cardiac out-
Tolerance to anemia in healthy subjects and in put. However, in the absence of bleeding, the increase
the critically ill patient in hemoglobin concentration could very well be offset
Tolerance to anemia is highly dependent on the volume by a decrease in cardiac output because of the increase
status of the patient, physiological reserve, and the in blood viscosity associated with a decreased sympa-
dynamics of the anemia (for example, chronic, such as thetic response [27,28]. DO 2 has been shown to
the anemia of sepsis, versus acute, such as hemorrhagic increase following RBC transfusion in numerous stu-
conditions). Normovolemic anemia is better tolerated dies [26], but not in all [29].
than anemia in hypovolemic states (e.g., acute bleeding The effects of RBC transfusion on the relationship
in trauma patients or surgery) in which cardiac output between DO2 and oxygen uptake (VO2) are even more
acutely decreases. In healthy subjects submitted to nor- difficult to predict. Some studies reported that VO 2
movolemic hemodilution, cardiac output increases increased following RBC transfusion, whereas others did
because of decreased blood viscosity (especially relevant not [26], and variable effects have been reported on tis-
in severe anemia) and increased adrenergic response, sue perfusion as assessed by gastric mucosal pH or
allowing tachycardia and increased myocardial contracti- near-infrared spectroscopy (NIRS) [30]. The reasons for
lity. Other phenomena include blood flow redistribution these contradictory results lie primarily in the degree of
(to heart and brain) and an increased oxygen extraction severity of hypoxia preceding the RBC transfusion [31],
ratio (reflected by a decrease in mixed venous saturation which influences the dependency of VO2 on DO2. Meth-
[SvO 2 ]). These mechanisms allow healthy humans to odological problems (imprecision in determination of
tolerate severe degrees of normovolemic anemia [14,15], VO2, assessment of global VO2 instead of regional VO2,
although side effects, such as arrhythmias or ST poor correlation between systemic oxygenation para-
changes, can be observed in extreme cases [16,17]. The meters, and oxygenation in the microcirculation [13])
myocardium is the organ at risk in cases of acute ane- also may contribute to these discrepancies [31].
mia in which both tachycardia and increased ventricle
contractility may increase myocardial oxygen demand. Safety concerns of blood transfusions
Because myocardial oxygen extraction is already almost Impact on outcome
maximal at rest, every increase in myocardial oxygen Red blood cell transfusions have been associated with
demand must be accompanied by increased coronary worse outcomes in several populations of patients,
blood flow [18]. This can become problematic in including critically ill patients. In a recent systematic
patients with stenotic coronary arteries especially when review of 45 observational studies reporting the
tachycardia is present, which can decrease diastole- impact of transfusions on patient outcome (mortality,
dependent left ventricle perfusion. infections, acute respiratory distress syndrome
Therefore, in critically ill patients, especially those [ARDS]) in populations of trauma, general surgery,
with heart failure or coronary artery disease (CAD), the orthopedic surgery, acute coronary syndrome, and
myocardium may not tolerate such low hemoglobin ICU patients, Marik and Corwin [32] identified RBC
levels [19]. In acute myocardial infarction, anemia may transfusion as an independent predictor of death
worsen myocardial ischemia, generate arrhythmias, and (pooled odds ratio (OR) from 12 studies, 1.7; 95%
potentially increase infarct size [20]. In patients with confidence interval (CI), 1.4-1.9), infectious complica-
acute coronary syndrome or heart failure, anemia tions (pooled OR from 9 studies, 1.8; 95% CI, 1.5-2.2),
increases morbidity and mortality [21,22]. For these rea- and ARDS (pooled OR from 6 studies, 2.5; 95% CI,
sons, patients with cardiac problems should be managed 1.6-3.3). In ICU patients, the three studies included in
with a more liberal approach to transfusion than other the review (ABC study [3], CRIT study [5], and a
patients [23,24]. study by Gong et al. [33]) consistently showed a sta-
tistically significant association of RBC transfusion
Purpose and efficacy of blood transfusion with mortality.
The primary purpose of blood transfusion is to On the other hand, analysis of data from a multicen-
increase DO 2 , which is determined by cardiac output ter, prospective, observational study of 3,147 patients in
and arterial content of oxygen, the latter being 198 European ICUs (the SOAP study) indicated that
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blood transfusions were not associated with increased are taken into account. Ruttinger et al. [52] illustrated
mortality by multivariate analysis or propensity match- this point very well. In a series of more than 3,000 sur-
ing [34]. In contrast, an extended Cox proportional gical patients, these authors showed by using a limited
hazard analysis showed that patients who received a multivariable analysis that transfusions were associated
transfusion in fact had a better survival, all factors being with a worse outcome, but a more complete analysis
otherwise equal. An increased rate of transfused leukor- cancelled out this statistical observation.
educed RBCs reported in this study (in which 76% of
centers routinely used leukoreduced RBCs) could per- Noninfectious serious hazards of transfusions
haps account for the differences between the earlier The reasons for the apparent worse outcome of trans-
ABC study [3] (in which 46% of centers used leukode- fused compared with nontransfused critically ill patients
pleted blood most of the time) and the SOAP study may be found in several detrimental effects of transfused
[34]. It also is possible that transfusion thresholds have blood, globally referred to under the acronym “Non-
become so low that the benefits of blood transfusion Infectious Serious Hazards Of Transfusion” or NISHOT
outweigh the risks. (Table 2) [53]. These include, among others, deleterious
In patients with acute coronary syndrome, several stu- effects on the immune system (transfusion-related
dies have shown poorer outcomes, including increased immunomodulation or “TRIM”) or on the cardiopul-
mortality, in transfused groups compared with nontrans- monary system, e.g., transfusion-related acute lung
fused patients after adjustment for potential confounders injury ("TRALI”) [54] or transfusion-associated circula-
[21,35-37]; similar findings have been reported in tory overload ("TACO”); the latter is currently the lead-
patients who undergo percutaneous coronary interven- ing reported cause of transfusion-associated mortality
tions (PCI) [38]. However, although still controversial, [55]. These effects may be enhanced by pathologic con-
RBC transfusions may be useful in subgroups of elderly ditions (e.g., sepsis) in which the microcirculation is
patients with acute myocardial infarction [39] or impaired [56] and/or when the RBCs have been stored
patients with ST elevation myocardial infarction for some time.
(STEMI) [21].
Patients who undergo cardiac surgery seem to have Question of RBC storage
worse outcomes when transfused, including higher mor- During storage, RBCs undergo a series of biological and
tality [40,41], increased occurrence of postoperative biochemical changes collectively referred to as “the sto-
infections [41,42], increased time on mechanical ventila- rage lesion” [57]. This includes intracellular changes
tion [40,43], and higher incidence of postoperative acute (progressive depletion of 2,3-diphosphoglycerate [2,3-
kidney injury [41,44]. DPG] with increased affinity of hemoglobin for oxygen,
Other studies have reported that trauma patients depletion of ATP), membrane changes (membrane vesi-
[45,46], including those with burns [47], may have culation, morphological changes eventually leading to
increased mortality rates associated with receiving blood irreversibly deformed spheroechinocytes, lipid peroxida-
transfusions. In contrast, RBC transfusion has been tion and increased expression of phosphatidylserine,
reported to be associated with improved outcomes in decreased deformability), and changes in the storage
patients with traumatic brain injury or subarachnoid medium (decreased pH, increased potassium, release of
hemorrhage [48,49]. In the early resuscitation of patients proinflammatory cytokines). These stored RBCs also
with severe sepsis, implementation of a therapeutic pro- have an increased tendency to adhere to endothelium
tocol that included RBC transfusion to obtain a hemato- and could promote vasoconstriction; the stored RBCs
crit > 30% was associated with a significant reduction in act as a “sink” for nitric oxide [58]. Some animal studies
hospital mortality [50]. [13] have shown deleterious effects of old RBCs on the
These results should be interpreted with caution, microcirculation (potentially leading to tissue hypoxia
because most of these data come from observational, and organ dysfunction). A human study found an
retrospective studies, which are subject to numerous inverse correlation between the age of transfused RBCs
biases and sometimes control poorly for confounders, and maximal change in gastric mucosal pH, but these
despite the use of various statistical tools, such as logis- findings were challenged in subsequent studies [59-61].
tic regression [51]. It is clear that analyses should not The clinical consequences of storage lesions are still
include only admission data. For example, in a well- not clear. A recent review of the literature [57] identi-
defined patient population, such as after cardiac surgery, fied 24 studies that address the effects of RBC length of
patients who develop gastrointestinal bleeding and storage on clinical (mortality, infections, length of stay,
require a blood transfusion have a worse prognosis, length of mechanical ventilation) or physiological
which is not necessarily the result of the blood transfu- (microcirculation, gastric mucosal pH) endpoints. Some
sion. It is of paramount importance that all risks factors studies found associations between the age of transfused
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Table 2 Selected infectious and non-infectious hazards of RBC transfusion in the ICU environment
Estimated frequency (event/no. of Comment
transfusions)*
Infectious transmission [89,90]
HIV 1/2.3 106
HBV 1/350000
HCV 1/1.8 106
HTLV 1/2 1/2 106
Bacterial contamination 1/14,000 to 1/28,000 GNB such as Y. Enterocolitica mostly encountered
Noninfectious complications
Immune-mediated [53,89]
Acute hemolytic transfusion 1/10,000 to 1/50,000 Most frequently due to IgM, sometimes IgG
reactions
Febrile nonhemolytic 1/500 Reduced incidence with prestorage leukoreduction
transfusion reactions
Anaphylactic reactions 1/20,000 to 1/50,000 May be associated with IgA deficiency
Transfusion-related acute Highly variable (e.g., 1/29,000 [91], 1/46,700 [92], Must be differentiated from TACO
lung injury (TRALI) 1/173,000 [93] units transfused)
Posttransfusion purpura 1/143,000 Rare; occurs 5-10 days after transfusion
Transfusion-associated graft Rare (prevention by irradiation Mostly in immunocompromised hosts, poor prognosis
versus host disease of blood products)
Nonimmune-mediated [89,94]
Incorrect blood component 9.7/100,000 components Remains frequent despite prevention strategies; must be
transfused (IBCT) differentiated from near-miss transfusion
Transfusion-associated Up to 1% of transfusions Major cause of transfusion-related death
circulatory overload (TACO)
Hyperkalemia Mainly after transfusion in newborns
Hypocalcemia - hypothermia
Mainly after massive transfusion
Dilutional coagulopathy/
thrombocytopenia Mainly after massive transfusion
HIV human immunodeficiency virus; HBV hepatitis B virus; HCV hepatitis C virus; HTLV human T lymphotropic virus; GNB Gram-negative bacteria
*Frequencies may vary among studies and are only indicative

RBCs and poorer outcomes, whereas others did not. for ≤ 10 days or ≥ 21 days. The primary endpoint of
Overall, no clear detrimental effect of RBC age could be this study is the change in the Multiple Organ Dysfunc-
identified; however, definitive conclusions are difficult to tion Score (MODS) from baseline to day 7, with second-
obtain because of numerous statistical limitations and ary outcomes including all-cause 28-day mortality. The
biases inherent to the study designs [51,62]. Several, target number of patients is 1,832, and the anticipated
large, randomized, controlled trials in adult ICU and completion date is September 2013.
cardiac surgery patients are currently ongoing to address The results of these trials, especially if older blood
the clinical relevance of RBC storage. In the multicenter, appears to be harmful, could have important logistic
double-blind prospective ABLE (Age of Blood Evalua- implications for blood banks [65,66].
tion) study [63], adult patients admitted to the ICU are
randomly assigned to receive leukoreduced RBCs stored Question of leukoreduction
for less than 7 days or issued according to standard pro- Many of the adverse effects associated with the transfu-
cedure (expected average storage time of 19 days). The sion of allogeneic RBCs have been shown to be related
primary endpoint of this study is 90-day all-cause mor- to the infusion of white blood cells (WBCs) present in
tality. The target number of patients is 2,510 (for an the blood product. Leukoreduction is a process in which
expected improvement in primary endpoint greater than WBCs are reduced in number through centrifugation or
5%) with an anticipated completion date by April 2013. filtration [67]. This process allows removal of approxi-
The Red Cell Storage Duration Study (RECESS) is a mately 99.995% of WBCs, but several thousand leuko-
multicenter, randomized study in patients (age 12 years cytes (0.005% of a 500 ml blood unit) may still be
and older) who undergo complex cardiac surgery and present in the processed blood [67]; hence, the word
are likely to require RBC transfusion [64]. Patients who “leukoreduction” is better than “deleukocytation.” The
need transfusion are randomized to receive RBCs stored beneficial effects of this process include decreased
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febrile nonhemolytic transfusion reactions, decreased < 30%, respectively), reported no difference in the pri-
transmission of certain pathogens, such as Epstein-Barr mary endpoint (composite of 30-day mortality and mor-
virus (EBV) or cytomegalovirus (CMV), parasites and bidity [cardiogenic shock, ARDS, acute kidney injury])
prions [67], and possibly decreased lung injury, such as between the groups [78].
TRALI. Moreover, prestorage leukoreduction, in which However, it is quite clear there is no “magic” hemo-
WBC removal occurs before RBC storage, avoids the globin or hematocrit trigger, and for the same level of
need for a leukodepletion filter during transfusion [67] hemoglobin, some patients will do well, whereas others
(but a 170-200-μm filter still needs to be incorporated will not. Thus, the decision to transfuse a patient should
into the intravenous blood line). be individualized, taking into account several factors,
In several studies, prestorage leukoreduction decreased including signs and symptoms of tissue hypoxia (angina
RBC storage lesions, with fewer immunomodulating pectoris, cognitive dysfunction diagnosed by neuropsy-
properties [68] and less adhesion of stored RBCs to the chological tests, or increased P300 latencies [79-81]),
endothelium [69]. A clinical benefit of leukoreduction is increased blood lactate levels [82], or electrocardio-
still somewhat controversial, particularly in the critically graphic changes suggestive of myocardial ischemia.
ill patient where no randomized, controlled trial has Indirect measures of oxygenation, such as a decreased
been performed [70]. In a before-after study of 14,786 SvO2 or central venous oxygen saturation (ScvO2), also
patients who underwent cardiac surgery, repair of hip may be considered [82]. For example, in a study of early
fracture, or who required intensive care after surgery, goal-directed therapy in patients with severe sepsis or
there was a 1% decrease in mortality rate associated septic shock admitted to an emergency department, a
with the implementation of universal leukoreduction decrease in ScvO2 < 70% initiated a therapeutic inter-
[71]. In a recent meta-analysis of nine RCTs involving vention, including fluid resuscitation, inotropes, vaso-
3,093 surgical patients, the use of leukoreduction signifi- pressors, and RBC transfusion to increase hematocrit to
cantly reduced the odds of postoperative infection (sum- > 30% [50]. Use of a decreased ratio of cardiac index to
mary OR, 0.522; 95% CI, 0.332-0.821; p = 0.005) [72]. oxygen extraction (CI/EO2 ratio) may be better, because
This observation had been suggested in a previous this parameter also reflects the cardiac response to ane-
meta-analysis [73] but has been challenged by another mia [83].
recent meta-analysis [74]. Nevertheless, leukoreduction
makes sense, and many countries have adopted it as Economic aspects of blood transfusion
routine, even though costs are elevated. In Europe, at The costs of blood transfusion are particularly complex to
the time of the SOAP study in 2002, 76% of centers assess because of the many factors that have to be taken
reported using leukodepleted blood routinely [34], into consideration (blood collection and screening for
whereas an earlier study performed in the same coun- pathogens; blood component processing, including leukor-
tries reported lower rates [3]. eduction, storage, transport to the transfusion facility;
administration of blood to the patient; management of
The decision to transfuse potential short- and long-term transfusion-related side
Classically, the decision to transfuse is driven by arbi- effects) [84]. The subtype of the blood unit also may play a
trary “triggers” (hemoglobin level) rather than clinical or role because some products, such as CMV-negative or
physiologic findings. Data from the CRIT study [5], in autologous units, are costlier than classical allogeneic
which there was little evidence that age or comorbidities RBCs. Consequently, studies in this field have given extre-
significantly influenced transfusion practice, tend to sup- mely varied results, which are not easily comparable.
port this view. Evidence has shown increased costs of RBC transfusion
Current recommendations for RBC transfusion [75,76] over time [85], related to various factors, including (but
are mainly based on the famous “TRICC” (Transfusion not limited to) use of leukoreduction and more sophisti-
Requirements In Critical Care) trial in which patients cated methods for pathogen detection, such as nucleic
assigned to a restrictive transfusion strategy (transfusion acid testing (NAT) [84]. For example, a study in Canada
if hemoglobin level < 7 g/dl) had similar 30-day mortal- evaluated the mean societal cost of one allogeneic RBC
ity rates (and even lower mortality in subgroups with unit at 264.81 US$, twice the cost estimated 7 years ear-
APACHE II < 20 and patients younger than age 55 lier [86]. Generally, these reported values are probably
years) than patients transfused according to a more lib- underestimated, and some have calculated that the cost
eral strategy (transfusion if hemoglobin level < 10 g/dl) of blood to society could in fact be twofold higher [84].
[77]. In cardiac surgery patients, the recent randomized,
monocenter “TRACS” (Transfusion Requirements after Alternatives to blood transfusion
Cardiac Surgery) trial, which compared a restrictive to a Because of limited availability, costs and safety concerns
liberal strategy (transfusion when hematocrit < 24% or related to blood transfusion, several strategies to reduce
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blood transfusions can be considered in addition to 6. Rao MP, Boralessa H, Morgan C, Soni N, Goldhill DR, Brett SJ, Contreras M:
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Transfusion practice and guidelines in Australian and New Zealand
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CL drafted the manuscript. The manuscript was revised for intellectual 19. Levy PS, Kim SJ, Eckel PK, Chavez R, Ismail EF, Gould SA, Ramez Salem M,
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Competing interests H340-349.
The authors declare that they have no competing interests. 20. Kurek T, Lenarczyk R, Kowalczyk J, Swiatkowski A, Kowalski O, Stabryla-
Deska J, Honisz G, Lekston A, Kalarus Z, Kukulski T: Effect of anemia in
Received: 29 July 2011 Accepted: 4 October 2011 high-risk groups of patients with acute myocardial infarction treated
Published: 4 October 2011 with percutaneous coronary intervention. Am J Cardiol 2010, 105:611-618.
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