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Available online xxxx Patient Blood Management underscores a fundamental shift from a product-centered approach to a patient-
centric approach through timely application of evidence-based medical and surgical concepts designed to main-
Keywords: tain hemoglobin concentration, optimize hemostasis, and minimize blood loss in an effort to improve patient
Patient blood management outcome. In this concept, allogeneic blood transfusion is not viewed as the treatment of default for anemic pa-
Critical care tients, but one among many treatment modalities that should be weighed based on its merits—potentials risks
Inflammation
and benefits—for the individual patient in the context of other alternatives. Patient blood management provides
Iron
Anemia
a multidisciplinary framework for patient-centered decision making with strategies focusing on the management
Hemoglobin of anemia, optimization of coagulation and hemostasis, and utilization of blood conservation modalities. Among
Transfusion the critically ill patients, Patient Blood Management can be particularly effective given the extremely high prev-
Mortality alence of anemia, variable and unjustified transfusion practices, high frequency of coagulation disorders, and
Hemostasis avoidable sources of blood loss such as unnecessary diagnostic blood draws. Proper management of
Outcomes anemia—prevention, screening/monitoring, diagnostic workup, and treatment including hematinic agents—is
the key to effective implementation of patient blood management. Blood transfusions should be used in accor-
dance of current guidelines, which are supportive of more restrictive transfusion strategies in most critically ill
patients. Emerging studies report on the success of Patient Blood Management programs in reducing transfusion
utilization, reducing the burden of anemia in patients, and improving patient outcomes including shortened
length of hospital stays, less frequency of complications and lower risk of mortality.
© 2017 Published by Elsevier Inc.
Contents
Definition and History of Patient Blood Management At its core, PBM marks a fundamental transition from a “product-
based” approach to a “patient-based” approach when it comes to blood
Changing views on the role of allogeneic blood transfusions in the transfusion [1]. The key questions here is not about transfusing or not
management of patients—including the critically ill—can perhaps be transfusing blood, but doing what is best for the patient, be it transfusion
best portrayed by the emergence of Patient Blood Management (PBM). or other appropriate treatment modalities.
Patient Blood Management is defined by the Society for the Advance-
ment of Blood Management (SABM) as “the timely application of
⁎ Corresponding author at: Aryeh Shander, MD, Department of Anesthesiology, Critical
Care and Hyperbaric Medicine, Englewood Hospital and Medical Center, 350 Engle Street,
evidence-based medical and surgical concepts designed to maintain
Englewood, NJ 07631. hemoglobin concentration, optimize hemostasis, and minimize blood
E-mail address: aryeh.shander@ehmc.com (A. Shander). loss in an effort to improve patient outcome” [2,3]. Alternatively, it is
http://dx.doi.org/10.1016/j.tmrv.2017.07.007
0887-7963/© 2017 Published by Elsevier Inc.
Please cite this article as: Shander A, et al, Patient Blood Management in the Intensive Care Unit, Transfus Med Rev (2017), http://dx.doi.org/
10.1016/j.tmrv.2017.07.007
2 A. Shander et al. / Transfusion Medicine Reviews xxx (2017) xxx–xxx
defined by the AABB as “an evidence-based, multidisciplinary approach Anemia reduces oxygen carrying capacity of blood, which could
to optimizing the care of patients who might need transfusion.”1 These result in tissue ischemia. Blood transfusion is considered as a
definitions have undergone a number of revisions, and what sets the quick and simple way to increase hemoglobin level, restore oxygen
current SABM definition apart from the earlier versions is the emphasis carrying capacity and hemodynamic stability. Nonetheless, alloge-
on improved patient outcomes as the end point. There is no mention neic blood is a complex allograft which interacts in many ways
of blood transfusion, underscoring the patient-centered approach and with the recipient, going further beyond simple increasing of oxygen
fundamental focus on the medical condition, diagnosis and proper delivery [13,14].
treatment [1]. Anemia is common in patients admitted to intensive care units
For decades, blood transfusion was recognized as the unchallenged (ICUs), and it is often multi-factorial, with anemia of inflammation
mainstay treatment for anemia across patient populations, and issues being the leading etiology [15]. Iron deficiency is the other commonly
such as transfusion-transmitted infections were viewed rather as present etiology [16,17]. As many as two-third of patients admitted to
temporary nuisances that could be adequately controlled with various ICU are anemic at admission, and the prevalence reaches up to 95% by
testing and screening strategies [4]. First calls for an alternative came the third day of ICU stay [16,18-23]. Many patients leave the ICU while
from patients for whom blood was not an option for religious or personal still anemic and it persists in as many as half of the patients six months
reasons and those who could not be transfused for medical reasons [5], later [24]. Anemia is an independent risk factor for morbidity and
and who often suffered grave consequences including long-lasting se- mortality during hospital stay [16,25-27] and long-term mortality
quelae and increased risk of death when faced with severe anemia [6]. following discharge from the ICU [28].
Strategies were developed to preserve and improve the clinical outcomes Given the high prevalence of anemia in the ICU, it is not surprising
of these patients without the help of allogeneic blood transfusions. These that transfusion rates are also exceptionally high among the critically
“alternative” approaches included proactive optimization of hemoglobin ill patients. Analysis of data from critically ill patients admitted to 139
levels in anticipation of a high blood loss scenario, maximizing hemato- centers across the US hospitals has shown that anemia more than
poiesis during the acute anemic episode to ameliorate the severity of doubles the odds of blood transfusion [29]. The reported transfusion
anemia and improve the odds of recovery, avoiding and minimizing rates in the ICUs vary from the center but usually range from 33% to
blood loss, maintaining adequate oxygen delivery to the tissues, and 75% (Table 1) [18,23,30-35].
minimizing tissue oxygen demand and consumption. These strategies There are many reasons for being concerned about the high and
collectively became known as “Bloodless Medicine and Surgery” [7,8]. variable transfusion rates in the ICUs, ranging from economic issues
Two large studies have looked at the outcomes of severely anemic and availability to the unresolved safety and efficacy concerns [36-39].
(hemoglobin ≤8 g/dL) critically ill patients who were managed without Red blood cell (RBC) transfusion is associated with risks despite limited
transfusion at centers without and with Bloodless Medicine and Surgery evidence of benefit [40]. While the new and emergent infections that
programs. In the study by Carson et al on 300 patients [6], the adjusted are not being screened for remain a potential threat [41], the risk of
odds ratio (OR) of mortality in patients with postoperative hemoglobin transmission of widely recognized infections such as viral hepatitis
level ≤8 g/dL increased 2.5 times for every 1-g/dL drop in the hemoglobin and human immunodeficiency virus has been greatly reduced to less
level, reaching highest in hemoglobin levels below 5 to 6 g/dL [6]. In than 1 per 10 million units of blood in developed nations [42]. Non-
another study performed at a referral center with an established Blood- infectious risks of transfusion have become the leading concern and they
less Medicine and Surgery program on 293 patients [9], the adjusted include transfusion-related acute lung injury (TRALI) [43], transfusion-
odds of death increased by 1.82 (95% confidence interval [CI] 1.2-2.59) associated circulatory overload (TACO) [44], immunomodulation [45],
for every 1 g/dL drop in nadir hemoglobin level. The proportion of pa- alloimmunization [46], febrile reactions [47], bacterial contamination
tients with extremely low hemoglobin levels was much lower compared (mostly in platelet units) [41] and rarely graft-versus-host disease
with the study by Carson et al [6], an observation which is attributed to (GVHD) [48].
improved care for these patients under the Bloodless Medicine and An even greater concern comes from a multitude of studies that have
Surgery program which might have helped patients recover from their linked allogeneic blood transfusions with a long list of unfavorable out-
severe anemia more effectively [9]. In a follow-up study comparing the comes such as sepsis and infection, multi-organ dysfunction, thrombo-
outcome of these patients with a matched cohort of severely anemic embolic events, cardiac complications, stroke, respiratory distress and
patients who were managed with transfusion, the overall mortality failure, renal injury, need for prolonged care, and mortality [25,49].
rates were not statistically significantly different [10]. This observation When these events occur in critically ill patients, they may not always
supports the positive impact of Bloodless Surgery and Medicine pro- be linked directly to transfusion, but when cohorts of patients are
grams on outcomes in patients who cannot be transfused. studied, it is often seen that the risk of occurrence of these events is
Individual strategies employed in Bloodless Medicine and Surgery higher in those who had received transfusion [50].
are relatively simple and routinely available and can be applied in A common shortcoming of many of these studies is the uncontrolled
many other patients. This, alongside with the revelations that allogeneic retrospective design that can introduce bias. For the results to be
blood transfusions can be associated with harm that go much beyond reliable, patients who are transfused and those who are not should be
the transmission of dangerous infections gave rise to the idea of Blood otherwise comparable with similar baseline risk profile, an issue
Conservation—placing the main focus on conserving patient's blood as which is often not the case [51]. While this concern has some validity,
a valuable and limited resource [11]. it is noteworthy to point to the documented highly variability in trans-
fusion practices which greatly undermines this notion that transfused
patients are invariably sicker than their non-transfused peers [36,51].
Anemia, Transfusion and Outcomes in Critically ill Patients On the other hand, randomized controlled trials on “liberal” versus
“restrictive” transfusion strategies have their own limitations [51,52].
Critically ill patients are among the leading recipients of allogeneic In either study arm, some patients may benefit for the allocation while
blood transfusions. Risk factors of transfusion in perioperative setting other may be harmed suggesting that a unified transfusion strategy
include low hemoglobin level, excessive blood loss, and inappropriate (rather than individualized approach) may be akin to collective punish-
transfusion practices [12]. All these factors are also common in the critical ment. Our search should be directed toward identifying those who
care setting. will benefit from transfusions whilst others might achieve better out-
comes with other therapies. To this end, well-designed observational
1
AABB, Patient Blood Management, available at: http://www.aabb.org/pbm/Pages/ studies can provide as much valuable evidence as randomized con-
default.aspx (Last accessed on May 17, 2017). trolled trials [51,52].
Please cite this article as: Shander A, et al, Patient Blood Management in the Intensive Care Unit, Transfus Med Rev (2017), http://dx.doi.org/
10.1016/j.tmrv.2017.07.007
A. Shander et al. / Transfusion Medicine Reviews xxx (2017) xxx–xxx 3
Table 1
Reported transfusion rates and hemoglobin levels across ICUs
Study Patient population Mean ICU admission Pre-transfusion ICU transfusion Mean units transfused
hemoglobin hemoglobin rate per patient
Corwin et al (2004) [18] 4892 patients admitted to 284 ICUs across the U.S. 11.0 ± 2.4 g/dL Mean 8.6 ± 1.7 g/dL 44.1% 4.6 ± 4.9
(CRIT Study)
Palmieri et al (2006) [30] 666 patients with major burn admitted to 21 centers - Mean 9.3 ± 0.1 g/dL 74.7% 13.7 ± 1.1
Rao et al (2002) [31] 1247 consecutive patients admitted to ICUs in the U.K. - b9 g/dL in 75% of episodes 53.4% 5.7 ± 5.2
Shapiro et al (2003) [32] 576 trauma patients admitted to 111 ICUs (from 11.1 ± 2.4 g/dL Mean 8.9 ± 1.8 g/dL 55.4% 5.8 ± 5.5
CRIT study)
Vincent et al (2002) [23] 3534 consecutive patients from 145 ICUs in 11.3 ± 2.3 g/dL Mean 8.4 ± 1.3 g/dL 37.0% 4.8 ± 5.2
Western Europe (ABC Study)
Vincent et al (2008) [33] 3147 consecutive patients admitted to 198 ICUs in - - 33.0% -
Europe
Walsh et al (2004) [34] 1023 consecutive patients admitted to 10 ICUs 10.6 ± 1.3 g/dL Median 7.8 (IQR 7.4-7.9) g/dL 39.5% 1.87 (95% CI 1.79 to 1.96)
across Scotland
Zilberberg et al (2008) [35] 4344 patients receiving mechanical ventilation for 11.1 ± 2.4 g/dL 8.2 ± 1.4 g/dL 67.0% 9.1 ± 12.0
4 days or more
Transfusion Practices and Guidelines in the ICU care including those admitted at ICU (4129 participants in 10 trials)
[62]. While restrictive transfusion was likely to be associated with
Critically ill patients have been among the leading target populations increased risk of ischemic complications and early mortality among
for the studies looking into revising and improving transfusion practices. patients undergoing cardiovascular surgery, no increased risk was
In the Transfusion Requirements in Critical Care (TRICC) trial, 838 anemic observed in critically ill patients [62].
critically ill patients were randomly assigned to a restrictive transfusion In another meta-analysis of 12 587 patients participating in 31 clinical
strategy (based on hemoglobin threshold of b7 g/dL) versus a liberal trials—many of which were from ICU and critical care settings—restrictive
transfusion strategy (based on hemoglobin threshold of b10 g/dL) [53]. transfusion strategies were associated with 43% reduction in transfusion
Among those less acutely ill and younger than 55 years, the restrictive rates compared with liberal transfusions strategies [63]. Overall, this
transfusion strategy reduced mortality rate compared with the liberal reduction in transfusion rate and utilization was not associated with any
strategy, while in other sub groups, the mortality outcomes were compa- significant changes in the risk of 30-day mortality, cardiac events, stroke,
rable except for patients with acute cardiac ischemia and infarction who pneumonia, infection, or thromboembolism [63]. The authors concluded
had a non-significant increased risk when managed with the restrictive that while more data are needed for some specific patient populations,
transfusion strategy [53]. in most other patients including the critically ill patients, allogeneic
Meta-analysis of pooled results from several randomized trials has blood can be safely withheld at hemoglobin levels above 7 to 8 g/dL [63].
generally supported the conclusion that restrictive transfusion strate- Current transfusion guidelines for the critically ill patients generally
gies are effective in reducing transfusion rates and utilization, while follow the findings of the trials and the hemoglobin thresholds used as
being associated with similar or improved clinical outcomes compared part of transfusion decisions have been adjusted accordingly. According
with liberal transfusion strategies [54,55]. Among those undergoing the guidelines developed for critically care and trauma settings [64,65]
cardiovascular surgery, restrictive transfusion strategy was associated and hospitalized adult patients [66], RBC transfusion is indicated in
with reduced blood transfusions and no significant adverse impact on patients with evidence of hemorrhagic shock and may be indicted in
the risk of myocardial infarction, renal failure, stroke, and mortality those with evidence of acute hemorrhage and hemodynamic instability
compared with liberal transfusion strategies [56]. or insufficient oxygen delivery (DO2) [64]. Restrictive transfusion strategy
In Transfusion Requirements in Septic Shock (TRISS) trial, 1005 ICU (hemoglobin threshold b7 g/dL with target range of 7-9 g/dL) is recom-
patients with septic shock and hemoglobin ≤9 g/dL were randomized mended in hemodynamically stable critically ill patients with absence of
to receive 1 unit of red blood cell transfusion at hemoglobin ≤7 g/dL comorbidities that might affect the decision otherwise [64-66]. Examples
(restrictive group) or ≤9 g/dL (liberal arm) [57]. Rates of mortality, of such comorbidities include acute myocardial infarction or myocardial
ischemic events and need for life support were similar between the ischemia. However, use of hemoglobin thresholds for making transfusion
study arms [57]. Post hoc analysis of subgroups of patients with severe decisions is discouraged, and RBC transfusion should be decided based
comorbidities did not reveal any significant differences in mortality on patient intravascular volume status, presence of shock, severity and
rates either [58]. Upon long-term follow up of the patients from TRISS duration of anemia, and cardiopulmonary physiologic parameters. The
trial, mortality rates and the physical and mental Health-related Quality guidelines recommend single-unit RBC transfusions (except in acute
of Life scores at 1 year were comparable between the study arms [59]. hemorrhage as needed). RBC transfusion should be considered when
In a meta-analysis on 3469 critically ill patients randomized in 10 hemoglobin b7 g/dL in critically ill patients requiring mechanical ventila-
studies, no significant difference in the 90-day mortality rates between tion, in resuscitated critically ill trauma patients, and patients with stable
the restrictive and liberal transfusion strategies was found [60]. In cardiac disease and when hemoglobin ≤8 g/dL in patients with acute
another meta-analysis of data from 2156 patients admitted to ICU or coronary syndrome. On the other hand, transfusion needs should be
patients with cardiovascular disease participating in 6 trials, there was assessed for each septic patient individually. No benefit is supported for
no statistically significant difference in mortality rates between the liberal transfusion strategy in patients with moderate to severe traumatic
restrictive and liberal transfusion arms in all patients and in the sub- brain injury, and RBC transfusions are not indicated to facilitate weaning
group of patients with chronic cardiovascular disease [61]. Interestingly, from mechanical ventilation [64-66].
there was a near-significant trend toward less mortality rate in critically Exceptions to this general recommendation include patients with
ill patients randomized to restrictive transfusion, while a statistically severe sepsis during the early treatment phase and with clear evidence
non-significant trend toward less mortality rate was observed in of inadequate DO2, those with traumatic brain injury with evidence of
patients with acute coronary syndrome randomized to liberal transfu- brain ischemia, and patients with ischemic stroke or severe thrombocy-
sion strategies. topenia [64-66].
One of the subgroups of patients that were studied in the meta- It is important to remember that hemoglobin is a concentration that
analysis by Hovaguimian and Myles were acute medical or surgical does not reflect red cell mass consistently. A patient with hemoglobin
Please cite this article as: Shander A, et al, Patient Blood Management in the Intensive Care Unit, Transfus Med Rev (2017), http://dx.doi.org/
10.1016/j.tmrv.2017.07.007
4 A. Shander et al. / Transfusion Medicine Reviews xxx (2017) xxx–xxx
concentration of 6 g/dL could have the same RBC mass of a patient with in the weeks prior to an elective surgical procedure to allow enough
hemoglobin of 8 g/dL, although the former is more likely to be trans- time for diagnostic work up and proper management of anemia [17].
fused [67]. Transfusion decisions should be made with consideration While routine implementation of this strategy can eventually help
of the whole clinical picture as well as the alternative treatments, to patients admitted to surgical ICUs, other patients admitted to ICU will
make sure we are treating the patient and not just a number [2]. also benefit tremendously from ongoing anemia screening and early
identification, proper diagnosis and management during their ICU
Patient Blood Management in the Intensive Care Unit stay. This is because of the high incidence of hospital-acquired anemia
(HAA) that is particularly high in ICU patients. It has been reported
Barring the rare catastrophic hemorrhagic cases that may catch the that as many as 75% of non-anemic patients admitted to hospital develop
clinicians off-guard, many patients undergo a series of events over HAA during their stay, and HAA is shown to contribute to prolongation of
time that eventually make them potential candidates for allogeneic length of hospital stay and increased risk of mortality [69]. One common
blood transfusion. Hence the clinicians often have ample time and and easily modifiable risk factor for development of HAA is unnecessary
several opportunities to intervene and not only prevent a transfusion diagnostic blood draws that are commonly performed in hospitalized
from becoming necessary but also contribute significantly to improving patients. Not surprisingly, the frequency and amount of diagnostic
the outcomes of their patients. This notion underscores a cornerstone of blood draws usually increase with the severity of illness of patients,
PBM which is a proactive philosophy of care. It is very important to and hence, those admitted to the ICU are particularly in high risk [70].
remain vigilant at all time and actively screen for, diagnose and manage Diagnostic blood draws for a patient can lead to up to 70 mL of blood
risk factors before they can impact the outcomes. Equally important is loss on a daily basis. To better understand the magnitude of this loss,
adopting a preventive approach throughout the course of care—“why one has to remember that the normal daily RBC production in an average
transfuse when anemia can be prevented by applying some simple 70-kg healthy adult is around 17.5 mL [71]. In a study of 155 critically ill
measures” [11]. patients staying in the ICU for a month or longer, hemoglobin level
PBM provides an evidence-based framework and a multidisciplinary dropped from 11.1 ± 2.5 g/dL at admission to 9.0 ± 1.1 g/dL on day 21
road map for integration of various strategies—which are themselves of ICU stay. Transfused patients (62%) had significantly greater acuity
part of standard care—in management of patients. An individualized of illness, lower hemoglobin level, larger volumes of diagnostic blood
plan of care should be developed to specifically address the needs of draws, and longer duration of ICU stay, while they suffered a greater
the individual patient with consideration of all available treatment risk of mortality. An increase of just 3.5 ml/day in the diagnostic blood
options (including allogeneic blood when indicated) [68]. The key draws was associated with doubling of the odds of being transfused
strategies employed in PBM include (Fig 1) [1,2]: during later days of ICU stay beyond day 21 [72]. The easy solution to
this real problem is to limit blood tests only to those likely to affect the
- Managing anemia clinical management of patients, avoid standing orders, and draw just
- Optimizing coagulation and hemostasis the minimum amount of blood needed for the test [73]. Implementation
- Utilization of multi- and interdisciplinary blood conservation of closed-loop systems that return the otherwise wasted blood back to
modalities the patient, point-of-care microanalytic tests and various noninvasive
- Patient-centered decision making monitoring devices are other ways to consider to avoid larger volume
blood draws, or any blood draws at all in patients in the ICU [74].
Given the central role of reduce hemoglobin and anemia in increased In a study of a closed-loop blood sampling device among 250 critically
risk of transfusion and unfavorable outcomes [17,25], prevention and ill patients, use of the device was associated with reduced RBC transfusion
timely detection and management of anemia are cornerstones of PBM. by almost half and reduced decline of hemoglobin level during ICU stay
Proactive prevention and management of anemia can be best achieved [75]. In another study, combined use of an ongoing educational program
Fig 1. The Patient Blood Management matrix. These key strategies are used to achieve the goal of improved patient outcomes (modified from Society for the Advancement of
Blood Management).
Please cite this article as: Shander A, et al, Patient Blood Management in the Intensive Care Unit, Transfus Med Rev (2017), http://dx.doi.org/
10.1016/j.tmrv.2017.07.007
A. Shander et al. / Transfusion Medicine Reviews xxx (2017) xxx–xxx 5
and changes in orders (requiring the staff to order the needed tests on a reported increased risk of mortality (OR 1.10, 95% CI 1.01 to 1.2) and
daily basis in lieu of placing orders for recurring daily tests), reducing VTE (OR 1.57, 95% CI 1.31 to 1.87) in patients treated with ESAs [87].
duplicate tests and adding laboratory reviews was able to reduce the A major caveat of the studies included in this meta-analysis is that
number of unnecessary laboratory tests significantly [76]. they all had a target hemoglobin level of N13 g/dL, and in fact, 3 trials
Critically ill patients are likely to receive various medications and had a target hemoglobin of N15 g/dL for their ESA treatment protocol.
understanding their interactions and side effects that might be affecting In the other meta-analysis, Glaspy et al looked at the data from 60 trials
the hematopoietic or coagulation systems is particularly important. enrolling 15 323 anemic cancer patients undergoing chemo and/or
Anemia is a relatively common side effect for many medications used radiotherapy and they concluded that ESA use was not associated
routinely in the ICU. Common ways medications can induce anemia with increased risk of mortality (OR 1.06, 95% CI 0.97-1.15) or cancer
include hemolysis and suppression of production and release of en- progression (OR 1.48, 95% CI 1.28-1.72), but the risk of VTE was
dogenous erythropoietin from the kidneys [77-79]. The possibility increased (OR 1.48, 95% CI 1.28-1.72) [88].
of drug-induced anemia should be considered when deciding on While no medication is without risks, risks of ESAs must be viewed in
new medications and during the diagnostic work up of new-onset context of competing treatment—namely, allogeneic blood transfusions
or exacerbating anemia, and if patient is being started on a new medica- with their own long list of risks discussed earlier here. Additionally, it
tion that is known to cause anemia, increased vigilance and continuous has been argued that some increased complications observed in patients
screening for anemia may be warranted (Table 2) [80]. For a critically ill treated with ESAs might be attributable to other factors such as pre-
patient who is planned to undergo an invasive procedure, the dose of existing conditions, failure to provide adequate anticoagulation prophy-
anticoagulant and anti-platelet agents should be reviewed and adjusted laxis or iron supplementation to support increase demand, and the
if and when necessary [11,81]. possibility of exposing patients to escalating and large doses of ESAs to
Anemia has become synonymous with low hemoglobin concentra- achieve predefined hemoglobin targets as was the case with studies in
tion with little regard to the pathology behind this condition, which Bennett et al meta-analysis [87]. The increased risk of VTE appears to
may lead to a single non-specific therapeutic intervention in ICU be more related with prolonged use of ESAs at higher doses, and this
patients when their hemoglobin level reaches a certain threshold. risk can be mitigated with thromboprophylaxis [89].
When anemia is present, it should not be ignored and appropriate treat- Optimal dosing and strategies to use ESAs in the treatment of ane-
ment, guided by the etiology of anemia should be initiated [17,26,82]. mia in the critically ill patients are still debated, [85] but as directed
Pharmacologic alternatives to transfusion are discussed at length in by the general PBM philosophy, an individualized plan of care should
other parts of this Special Edition but due to importance of anemia be developed for each patient, and the role of ESAs with their potential
and its treatment options, a brief overview is provided here. Hematinic risks and expected benefits must be weighed versus other options for
agents are the mainstay treatment for anemia. Erythropoiesis stimulating each individual patient, and whenever needed, prophylactic treatments
agents (ESAs) have been investigated and used for treatment of anemia to reduce the risk of thromboembolic events should be considered [17].
in the critically ill patients. Efficacy of these agents in increasing the Iron deficiency and iron deficiency anemia are very common in ICU
hemoglobin level and reducing transfusions has been well established. patients [17]. Anemia in critically ill patients is often thought to have an
In their study of 1302 critically ill anemia patients, Corwin et al showed inflammatory cause, but iron deficiency is often a contributing factor
that weekly administration of an ESA can significantly reduce RBC [15,17]. In critically ill patients, inflammation reduces the bioavailable
transfusions and lead to higher hemoglobin levels, without any other iron through the hepcidin pathway [90]. As previously indicated, treat-
significant impact on clinical outcomes [83]. However, in their subse- ment with ESAs can also increase the demand for iron and result in
quent study of 1460 patients in ICU, they did not detect any significant functional iron deficiency [17]. Hence, iron supplementation is often
impacts on blood transfusions [84]. This unexpected result can be needed in anemic critically ill patients. When iron is needed, intrave-
explained by the adoption of more restrictive transfusion practices nous iron (specially the newer formulations) is often the preferred
(that would limit the power of studies looking at transfusion as an form as it bypasses the enteric absorption and acts much faster than
endpoint), and lack of iron repletion to avoid iron-restricted hemato- oral forms while offering better tolerance [91]. The safety profile of
poiesis in the patients treated with ESA [79,85]. newer intravenous iron formulations has been greatly improved [92].
Concerns regarding their potential side effects including thrombo- Increased risk of infection following treatment with intravenous iron
embolic events and cancer progression and other still-debated compli- is a commonly-cited concern, but this risk is not supported by a number
cations have impeded their appropriate use [86]. Bennett et al analyzed of studies [17,93]. Studies have suggested a synergistic effect when
the mortality data from 13 611 participants in 51 trials and the venous intravenous iron and ESAs are used together, possibly allowing better
thromboembolism (VTE) data from 8172 patients in 38 trials and results with lower dosage and smaller risk of complications [94]. In
a randomized trial involving 140 critically ill patients, patients ran-
domized to intravenous iron received lower number of RBC units com-
Table 2 pared with placebo group (97 vs 136 U) but the difference was not
Some of the medication that are commonly linked with anemia (drug-induced anemia) [80]
statistically significant. Additionally, patients treated with intravenous
Type of anemia Medications iron achieved higher hemoglobin levels during hospital stay and at
Immune hemolytic Antineoplastics, cefotetan, ceftriaxone, cephalosporins, discharge, while no significant difference in safety outcomes was seen
diclofenac, fludarabine, ibuprofen, methyldopa, between the study arms [95].
non-steroidal anti-inflammatories (NSAIDs), penicillin Current coverage and reimbursement policies in the US hinder the
derivatives, pipracillin, quinine/quinidine use of ESAs and intravenous iron for treatment of anemia in many
Non-immune hemolytic Nitrofurantoin, phenazopyridine, primaquine, sulfa drugs
Meganoblastic Alkylating agents, metformin, methotrexate and other
patient populations, and their combined use is also restricted despite
antimetabolites, chemotherapeutic agents, oral purported benefits. There are calls for revision of these policies as they
contraceptives, phenobarbital, phenytoin, primidone, are no longer supported by available evidence [96,97]. Additional
pyremethamine, sulfasalazine, triamterene, supplementation with folic acid and vitamin B12 might be needed to
trimethoprim-sulfamethoxazole
support the increased hematopoiesis following administration of hema-
Sideroblastic Busulfan, isoniazid, linezolid, penicillamine, phenacetin,
progesterone replacement, tetracycline, triethylene tinic agents [98,99].
tetramine dihydrochloride, chloramphenicol Avoidance and minimization of blood loss is another fundamental
Aplastic Azathioprine, carbamazepine, chloramphenicol, aspect of PBM. Several modalities and devices are available to this end
erythropoietin, isoniazid, procainamide, sulfonamides, for surgical patients [82,100], including various autologous transfusion
valproic acid
strategies to minimize surgical blood loss [101]. Clinicians in the ICUs
Please cite this article as: Shander A, et al, Patient Blood Management in the Intensive Care Unit, Transfus Med Rev (2017), http://dx.doi.org/
10.1016/j.tmrv.2017.07.007
6 A. Shander et al. / Transfusion Medicine Reviews xxx (2017) xxx–xxx
must remain vigilant and monitor patients particularly those in the outcomes of the patients, which is the main goal, alongside with other
surgical ICU for new sources of bleeding. aspects such as resource utilization [5].
Gastrointestinal bleeding (including stress-related mucosal bleeding) Reports from PBM programs are emerging and many appear to be
is a common and preventable cause of blood loss in the critically ill promising with encouraging results [112]. In a before-and-after study, im-
patients [102]. Stress ulcer prophylaxis has been recommended in plementation of a PBM program in cardiac surgery service was associated
high-risk patients in ICU using proton pump inhibitors (PPIs) or hista- with approximately 25% reduction in blood loss, and 50% reduction in RBC
mine 2 receptor antagonists (H2RAs). However, some studies suggest transfusion rates (and similar reduction in rate of transfusion of other
that stress ulcer prophylaxis is not necessarily associated with im- blood components) [113]. On the other hand, the length of hospital stay
proved outcomes and use of PPI might even increase the risk of infec- decreased by 15% and the direct cost of care decreased by about 8.5%,
tions such as pneumonia and clostridium difficile–associated diarrhea. while clinical outcomes such as mortality remained unaffected [113].
Hence, the potential risks and benefits should be carefully balanced In another prospective multicenter before-and-after study on around
when deciding on the use of these agents and their routine use in 130 000 surgical inpatients, transfusion rates in the pre- and post-
all critically ill patients might not be supported by the current evidence PBM periods were 6.53% and 6.34%, while the mean number of units
[102]. of blood transfused per patient reduced significantly from 1.21 before
Arnold et al evaluated 100 patients in a medical-surgical ICU, and implementing PBM to 1.0 after implementing the PBM program.
reported that 90% of the patients experienced some bleeding complica- Following implementation of the PBM program, incidence of acute
tions and 20% had major bleeding events (480 total separate bleeding renal failure also decreased from 2.39% to 1.67% [114].
events). Interestingly, the bleeding events were at the surgical site in Impressive improvements in reducing the frequency of anemia,
only 15% of the cases, and the most common sites of bleeding included reducing transfusion rates and improving clinical outcomes (shorter
sites of insertion of vascular catheters and endotracheal tubes [103]. hospital stays and fewer complications) have been seen in patients
Thrombocytopenia, coagulopathy and coagulation disorders are undergoing orthopedic procedures [115] and cardiac surgery [113]. In
relatively common in critically ill patients. Thrombocytopenia is com- another report, while introduction of a set of transfusion guidelines
monly encountered in the context of hemodilution (eg, following fluid was not found to be effective in surgical patients, implementing a
therapy or massive transfusion of RBC), increased consumption (eg, in PBM program was effective in reducing transfusion utilization and
trauma, bleeding, or disseminated intravascular coagulation [DIC]), costs [116].
increased destruction (eg, immune response) or suppressed production. In a study of over 600 000 patients admitted between 2008 and 2014
Patient presenting to ICU following coronary artery bypass surgery are to four major hospitals participating in the health-system-wide PBM
particularly at risk of being thrombocytopenic [104,105]. Critically ill pa- program implemented by the Western Australia Department of Health
tients are commonly treated with heparin (eg, for thromboprophylaxis [117], it was shown that following implementation of the PBM program,
or during renal replacement therapy as discussed below) which makes allogeneic blood component utilization per patient was reduced by 41%
them prone to development of heparin-induced thrombocytopenia. (P b .001), amounting to saving of up to 100 million dollars, while mean
Use of low-molecular-weight heparin can reduce the risk [106]. Coagu- pre-transfusion hemoglobin level was reduced from 7.9 g/dL to 7.3 g/dL.
lopathy and coagulation abnormalities particularly DIC are more likely The number of patients admitted for elective surgery who were anemic
to be encountered in patients with sepsis or trauma [74,107]. Thrombotic on admission decreased from 20.8% to 14.4% (P = .001). More impor-
microangiopathy (TMA) is another condition that can be seen in critically tantly, significant improvements in clinical outcomes including reduced
ill patients and result in hemolytic anemia as well as thrombocytopenia risk-adjusted mortality rate (OR 0.72, 95% CI 0.67-0.77, P b .001), short-
and early detection and diagnosis can be life-saving with or without allo- ened length of stay (incidence rate ratio 0.85, 95% CI 0.84-0.87, P b .001),
geneic transfusions [108]. Finally, patients with comorbidities that are reduced hospital-acquired infections (OR 0.79, 95% CI 0.73-0.86,
known to increase the risk of coagulation abnormalities and bleeding P b .001) and reduced occurrence of acute myocardial infarction or
(eg, liver disease) require closer watch. stroke (OR 0.69, 95% CI 0.58-0.82, P b .001) were observed [117].
One particular group of concern is the critically ill patients on renal While more studies are needed to better characterize the real-world
replacement therapy who are at increased risk of bleeding due to the impact of PBM programs on clinical outcomes, the available evidence
requirement for anticoagulation. The anticoagulant is often citrate or supports the value of PBM strategies as part of standard care, and this
heparin which can be delivered systematically or regionally. Overall, view is increasingly supported and endorsed by professional societies
regional citrate appears to offer similar or better clinical outcomes and organizations as well as national and international health care
compared with heparin, while prolonging the renal replacement circuit policy makers including the World Health Organization [118-120].
and filter life and hence it is generally preferred [109]. The choice of The patients who are at risk for anemia and transfusion are at the
mode of dialysis in these patients can also affect the outcomes. In a forefront of those who stand to benefit greatly from PBM programs.
study of 252 critically ill patients with dialysis-dependent acute renal Those include all critically ill patients. Although we keep “producing”
failure, use of venous continuous veno-venous hemofiltration was asso- transfusion guidelines that may help clinicians in some situations
ciated with increased rate of blood loss events and amount of blood loss [121], transfusion remain a default position for the critically ill while
compared with intermittent hemodialysis, while transfusion rates anemia, an independent risk factor remains ignored. Adopting the
remain unchanged [110]. simple medical model of prevention, detection, diagnosis and proper
The management strategies for bleeding in critically ill patients treatment including early intervention, could result in better outcomes
depend on the underlying conditions, and pharmacologic agents are for the ICU population as shown for other patients populations. As such,
discussed at other parts of this Special Edition. PBM calls for active and PBM, a bundled care, should be integrated as part of routine ICU patient
aggressive screening for and management of sources of bleeding in all management strategies [114].
including the critically ill patients [111].
PBM has been proposed as a standard of care [3], and integration of AS has been a consultant or speaker with honorarium for or received
PBM strategies as hospital-wide multidisciplinary programs becomes a research support from, Masimo, Gauss, and Vifor; he is a founding
necessity to maximize the impact of these strategies. Another important member of the Society for the Advancement of Blood Management
aspect is to establish data collection systems for monitoring the effec- (SABM). MJ has been a consultant and contractor for SABM and Gauss
tiveness of the PBM strategies and evaluating their impact on the Surgical. GL declares no relevant conflict of interests.
Please cite this article as: Shander A, et al, Patient Blood Management in the Intensive Care Unit, Transfus Med Rev (2017), http://dx.doi.org/
10.1016/j.tmrv.2017.07.007
A. Shander et al. / Transfusion Medicine Reviews xxx (2017) xxx–xxx 7
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Please cite this article as: Shander A, et al, Patient Blood Management in the Intensive Care Unit, Transfus Med Rev (2017), http://dx.doi.org/
10.1016/j.tmrv.2017.07.007