Transfusion Medicine Reviews xxx (2017) xxx–xxx

Contents lists available at ScienceDirect

Transfusion Medicine Reviews

journal homepage: www.tmreviews.com

Patient Blood Management in the Intensive Care Unit

Aryeh Shander ⁎, Mazyar Javidroozi, Gregg Lobel
Department of Anesthesiology, Critical Care and Hyperbaric Medicine, Englewood Hospital and Medical Center and TeamHealth Research Institute, Englewood, NJ

a r t i c l e i n f o a b s t r a c t

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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

Anemia, Transfusion and Outcomes in Critically ill Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Transfusion Practices and Guidelines in the ICU . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Patient Blood Management in the Intensive Care Unit. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Patient Blood Management Programs in Practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Conflict of Interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Funding Sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

Definition and History of Patient Blood Management
Changing views on the role of allogeneic blood transfusions in the
management of patients—including the critically ill—can perhaps be
best portrayed by the emergence of Patient Blood Management (PBM).
⁎ Corresponding author at: Aryeh Shander, MD, Department of Anesthesiology, Critical
Care and Hyperbaric Medicine, Englewood Hospital and Medical Center, 350 Engle Street,
Englewood, NJ 07631.
E-mail address: aryeh.shander@ehmc.com (A. Shander).
At its core, PBM marks a fundamental transition from a “product-
based” approach to a “patient-based” approach when it comes to blood
transfusion [1]. The key questions here is not about transfusing or not
transfusing blood, but doing what is best for the patient, be it transfusion
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
evidence-based medical and surgical concepts designed to maintain
hemoglobin concentration, optimize hemostasis, and minimize blood
loss in an effort to improve patient outcome” [2,3]. Alternatively, it is

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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
2 A. Shander et al. / Transfusion Medicine Reviews xxx (2017) xxx–xxx
defined by the AABB as “an evidence-based, multidisciplinary approach
to optimizing the care of patients who might need transfusion.”1 These
definitions have undergone a number of revisions, and what sets the
current SABM definition apart from the earlier versions is the emphasis
on improved patient outcomes as the end point. There is no mention
of blood transfusion, underscoring the patient-centered approach and
fundamental focus on the medical condition, diagnosis and proper
treatment [1].
For decades, blood transfusion was recognized as the unchallenged
mainstay treatment for anemia across patient populations, and issues
such as transfusion-transmitted infections were viewed rather as
temporary nuisances that could be adequately controlled with various
testing and screening strategies [4]. First calls for an alternative came
from patients for whom blood was not an option for religious or personal
reasons and those who could not be transfused for medical reasons [5],
and who often suffered grave consequences including long-lasting se-
quelae and increased risk of death when faced with severe anemia [6].
Strategies were developed to preserve and improve the clinical outcomes
of these patients without the help of allogeneic blood transfusions. These
“alternative” approaches included proactive optimization of hemoglobin
levels in anticipation of a high blood loss scenario, maximizing hemato-
poiesis during the acute anemic episode to ameliorate the severity of
anemia and improve the odds of recovery, avoiding and minimizing
blood loss, maintaining adequate oxygen delivery to the tissues, and
minimizing tissue oxygen demand and consumption. These strategies
collectively became known as “Bloodless Medicine and Surgery” [7,8].
Two large studies have looked at the outcomes of severely anemic
(hemoglobin ≤8 g/dL) critically ill patients who were managed without
transfusion at centers without and with Bloodless Medicine and Surgery
programs. In the study by Carson et al on 300 patients [6], the adjusted
odds ratio (OR) of mortality in patients with postoperative hemoglobin
level ≤8 g/dL increased 2.5 times for every 1-g/dL drop in the hemoglobin
level, reaching highest in hemoglobin levels below 5 to 6 g/dL [6]. In
another study performed at a referral center with an established Blood-
less Medicine and Surgery program on 293 patients [9], the adjusted
odds of death increased by 1.82 (95% confidence interval [CI] 1.2-2.59)
for every 1 g/dL drop in nadir hemoglobin level. The proportion of pa-
tients with extremely low hemoglobin levels was much lower compared
with the study by Carson et al [6], an observation which is attributed to
improved care for these patients under the Bloodless Medicine and
Surgery program which might have helped patients recover from their
severe anemia more effectively [9]. In a follow-up study comparing the
outcome of these patients with a matched cohort of severely anemic
patients who were managed with transfusion, the overall mortality
rates were not statistically significantly different [10]. This observation
supports the positive impact of Bloodless Surgery and Medicine pro-
grams on outcomes in patients who cannot be transfused.
Individual strategies employed in Bloodless Medicine and Surgery
are relatively simple and routinely available and can be applied in
many other patients. This, alongside with the revelations that allogeneic
blood transfusions can be associated with harm that go much beyond
the transmission of dangerous infections gave rise to the idea of Blood
Conservation—placing the main focus on conserving patient's blood as
a valuable and limited resource [11].
Anemia, Transfusion and Outcomes in Critically ill Patients
Critically ill patients are among the leading recipients of allogeneic
blood transfusions. Risk factors of transfusion in perioperative setting
include low hemoglobin level, excessive blood loss, and inappropriate
transfusion practices [12]. All these factors are also common in the critical
care setting.
1
AABB, Patient Blood Management, available at: http://www.aabb.org/pbm/Pages/
default.aspx (Last accessed on May 17, 2017).
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
Anemia reduces oxygen carrying capacity of blood, which could
result in tissue ischemia. Blood transfusion is considered as a
quick and simple way to increase hemoglobin level, restore oxygen
carrying capacity and hemodynamic stability. Nonetheless, alloge-
neic blood is a complex allograft which interacts in many ways
with the recipient, going further beyond simple increasing of oxygen
delivery [13,14].
Anemia is common in patients admitted to intensive care units
(ICUs), and it is often multi-factorial, with anemia of inflammation
being the leading etiology [15]. Iron deficiency is the other commonly
present etiology [16,17]. As many as two-third of patients admitted to
ICU are anemic at admission, and the prevalence reaches up to 95% by
the third day of ICU stay [16,18-23]. Many patients leave the ICU while
still anemic and it persists in as many as half of the patients six months
later [24]. Anemia is an independent risk factor for morbidity and
mortality during hospital stay [16,25-27] and long-term mortality
following discharge from the ICU [28].
Given the high prevalence of anemia in the ICU, it is not surprising
that transfusion rates are also exceptionally high among the critically
ill patients. Analysis of data from critically ill patients admitted to 139
centers across the US hospitals has shown that anemia more than
doubles the odds of blood transfusion [29]. The reported transfusion
rates in the ICUs vary from the center but usually range from 33% to
75% (Table 1) [18,23,30-35].
There are many reasons for being concerned about the high and
variable transfusion rates in the ICUs, ranging from economic issues
and availability to the unresolved safety and efficacy concerns [36-39].
Red blood cell (RBC) transfusion is associated with risks despite limited
evidence of benefit [40]. While the new and emergent infections that
are not being screened for remain a potential threat [41], the risk of
transmission of widely recognized infections such as viral hepatitis
and human immunodeficiency virus has been greatly reduced to less
than 1 per 10 million units of blood in developed nations [42]. Non-
infectious risks of transfusion have become the leading concern and they
include transfusion-related acute lung injury (TRALI) [43], transfusion-
associated circulatory overload (TACO) [44], immunomodulation [45],
alloimmunization [46], febrile reactions [47], bacterial contamination
(mostly in platelet units) [41] and rarely graft-versus-host disease
(GVHD) [48].
An even greater concern comes from a multitude of studies that have
linked allogeneic blood transfusions with a long list of unfavorable out-
comes such as sepsis and infection, multi-organ dysfunction, thrombo-
embolic events, cardiac complications, stroke, respiratory distress and
failure, renal injury, need for prolonged care, and mortality [25,49].
When these events occur in critically ill patients, they may not always
be linked directly to transfusion, but when cohorts of patients are
studied, it is often seen that the risk of occurrence of these events is
higher in those who had received transfusion [50].
A common shortcoming of many of these studies is the uncontrolled
retrospective design that can introduce bias. For the results to be
reliable, patients who are transfused and those who are not should be
otherwise comparable with similar baseline risk profile, an issue
which is often not the case [51]. While this concern has some validity,
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].
On the other hand, randomized controlled trials on “liberal” versus
“restrictive” transfusion strategies have their own limitations [51,52].
In either study arm, some patients may benefit for the allocation while
other may be harmed suggesting that a unified transfusion strategy
(rather than individualized approach) may be akin to collective punish-
ment. Our search should be directed toward identifying those who
will benefit from transfusions whilst others might achieve better out-
comes with other therapies. To this end, well-designed observational
studies can provide as much valuable evidence as randomized con-
trolled trials [51,52].
 A. Shander et al. / Transfusion Medicine Reviews xxx (2017) xxx–xxx
Table 1
Reported transfusion rates and hemoglobin levels across ICUs
Study Patient population
Corwin et al (2004) [18] 4892 patients admitted to 284 ICUs across the U.S.
(CRIT Study)
Palmieri et al (2006) [30] 666 patients with major burn admitted to 21 centers
Rao et al (2002) [31] 1247 consecutive patients admitted to ICUs in the U.K.
Shapiro et al (2003) [32] 576 trauma patients admitted to 111 ICUs (from
CRIT study)
Vincent et al (2002) [23] 3534 consecutive patients from 145 ICUs in
Western Europe (ABC Study)
Vincent et al (2008) [33] 3147 consecutive patients admitted to 198 ICUs in
Europe
Walsh et al (2004) [34] 1023 consecutive patients admitted to 10 ICUs
across Scotland
Zilberberg et al (2008) [35] 4344 patients receiving mechanical ventilation for
4 days or more
Transfusion Practices and Guidelines in the ICU
Critically ill patients have been among the leading target populations
for the studies looking into revising and improving transfusion practices.
In the Transfusion Requirements in Critical Care (TRICC) trial, 838 anemic
critically ill patients were randomly assigned to a restrictive transfusion
strategy (based on hemoglobin threshold of b7 g/dL) versus a liberal
transfusion strategy (based on hemoglobin threshold of b10 g/dL) [53].
Among those less acutely ill and younger than 55 years, the restrictive
transfusion strategy reduced mortality rate compared with the liberal
strategy, while in other sub groups, the mortality outcomes were compa-
rable except for patients with acute cardiac ischemia and infarction who
had a non-significant increased risk when managed with the restrictive
transfusion strategy [53].
Meta-analysis of pooled results from several randomized trials has
generally supported the conclusion that restrictive transfusion strate-
gies are effective in reducing transfusion rates and utilization, while
being associated with similar or improved clinical outcomes compared
with liberal transfusion strategies [54,55]. Among those undergoing
cardiovascular surgery, restrictive transfusion strategy was associated
with reduced blood transfusions and no significant adverse impact on
the risk of myocardial infarction, renal failure, stroke, and mortality
compared with liberal transfusion strategies [56].
In Transfusion Requirements in Septic Shock (TRISS) trial, 1005 ICU
patients with septic shock and hemoglobin ≤9 g/dL were randomized
to receive 1 unit of red blood cell transfusion at hemoglobin ≤7 g/dL
(restrictive group) or ≤9 g/dL (liberal arm) [57]. Rates of mortality,
ischemic events and need for life support were similar between the
study arms [57]. Post hoc analysis of subgroups of patients with severe
comorbidities did not reveal any significant differences in mortality
rates either [58]. Upon long-term follow up of the patients from TRISS
trial, mortality rates and the physical and mental Health-related Quality
of Life scores at 1 year were comparable between the study arms [59].
In a meta-analysis on 3469 critically ill patients randomized in 10
studies, no significant difference in the 90-day mortality rates between
the restrictive and liberal transfusion strategies was found [60]. In
another meta-analysis of data from 2156 patients admitted to ICU or
patients with cardiovascular disease participating in 6 trials, there was
no statistically significant difference in mortality rates between the
restrictive and liberal transfusion arms in all patients and in the sub-
group of patients with chronic cardiovascular disease [61]. Interestingly,
there was a near-significant trend toward less mortality rate in critically
ill patients randomized to restrictive transfusion, while a statistically
non-significant trend toward less mortality rate was observed in
patients with acute coronary syndrome randomized to liberal transfu-
sion strategies.
One of the subgroups of patients that were studied in the meta-
analysis by Hovaguimian and Myles were acute medical or surgical
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
3
Mean ICU admission Pre-transfusion ICU transfusion Mean units transfused
hemoglobin hemoglobin rate per patient
11.0 ± 2.4 g/dL Mean 8.6 ± 1.7 g/dL 44.1% 4.6 ± 4.9
- Mean 9.3 ± 0.1 g/dL 74.7% 13.7 ± 1.1
- b9 g/dL in 75% of episodes 53.4% 5.7 ± 5.2
11.1 ± 2.4 g/dL Mean 8.9 ± 1.8 g/dL 55.4% 5.8 ± 5.5
11.3 ± 2.3 g/dL Mean 8.4 ± 1.3 g/dL 37.0% 4.8 ± 5.2
- - 33.0% -
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)
11.1 ± 2.4 g/dL 8.2 ± 1.4 g/dL 67.0% 9.1 ± 12.0
care including those admitted at ICU (4129 participants in 10 trials)
[62]. While restrictive transfusion was likely to be associated with
increased risk of ischemic complications and early mortality among
patients undergoing cardiovascular surgery, no increased risk was
observed in critically ill patients [62].
In another meta-analysis of 12 587 patients participating in 31 clinical
trials—many of which were from ICU and critical care settings—restrictive
transfusion strategies were associated with 43% reduction in transfusion
rates compared with liberal transfusions strategies [63]. Overall, this
reduction in transfusion rate and utilization was not associated with any
significant changes in the risk of 30-day mortality, cardiac events, stroke,
pneumonia, infection, or thromboembolism [63]. The authors concluded
that while more data are needed for some specific patient populations,
in most other patients including the critically ill patients, allogeneic
blood can be safely withheld at hemoglobin levels above 7 to 8 g/dL [63].
Current transfusion guidelines for the critically ill patients generally
follow the findings of the trials and the hemoglobin thresholds used as
part of transfusion decisions have been adjusted accordingly. According
the guidelines developed for critically care and trauma settings [64,65]
and hospitalized adult patients [66], RBC transfusion is indicated in
patients with evidence of hemorrhagic shock and may be indicted in
those with evidence of acute hemorrhage and hemodynamic instability
or insufficient oxygen delivery (DO2) [64]. Restrictive transfusion strategy
(hemoglobin threshold b7 g/dL with target range of 7-9 g/dL) is recom-
mended in hemodynamically stable critically ill patients with absence of
comorbidities that might affect the decision otherwise [64-66]. Examples
of such comorbidities include acute myocardial infarction or myocardial
ischemia. However, use of hemoglobin thresholds for making transfusion
decisions is discouraged, and RBC transfusion should be decided based
on patient intravascular volume status, presence of shock, severity and
duration of anemia, and cardiopulmonary physiologic parameters. The
guidelines recommend single-unit RBC transfusions (except in acute
hemorrhage as needed). RBC transfusion should be considered when
hemoglobin b7 g/dL in critically ill patients requiring mechanical ventila-
tion, in resuscitated critically ill trauma patients, and patients with stable
cardiac disease and when hemoglobin ≤8 g/dL in patients with acute
coronary syndrome. On the other hand, transfusion needs should be
assessed for each septic patient individually. No benefit is supported for
liberal transfusion strategy in patients with moderate to severe traumatic
brain injury, and RBC transfusions are not indicated to facilitate weaning
from mechanical ventilation [64-66].
Exceptions to this general recommendation include patients with
severe sepsis during the early treatment phase and with clear evidence
of inadequate DO2, those with traumatic brain injury with evidence of
brain ischemia, and patients with ischemic stroke or severe thrombocy-
topenia [64-66].
It is important to remember that hemoglobin is a concentration that
does not reflect red cell mass consistently. A patient with hemoglobin
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
hemoglobin of 8 g/dL, although the former is more likely to be trans-
fused [67]. Transfusion decisions should be made with consideration
of the whole clinical picture as well as the alternative treatments, to
make sure we are treating the patient and not just a number [2].
Patient Blood Management in the Intensive Care Unit
Barring the rare catastrophic hemorrhagic cases that may catch the
clinicians off-guard, many patients undergo a series of events over
time that eventually make them potential candidates for allogeneic
blood transfusion. Hence the clinicians often have ample time and
several opportunities to intervene and not only prevent a transfusion
from becoming necessary but also contribute significantly to improving
the outcomes of their patients. This notion underscores a cornerstone of
PBM which is a proactive philosophy of care. It is very important to
remain vigilant at all time and actively screen for, diagnose and manage
risk factors before they can impact the outcomes. Equally important is
adopting a preventive approach throughout the course of care—“why
transfuse when anemia can be prevented by applying some simple
measures” [11].
PBM provides an evidence-based framework and a multidisciplinary
road map for integration of various strategies—which are themselves
part of standard care—in management of patients. An individualized
plan of care should be developed to specifically address the needs of
the individual patient with consideration of all available treatment
options (including allogeneic blood when indicated) [68]. The key
strategies employed in PBM include (Fig 1) [1,2]:
- Managing anemia
- Optimizing coagulation and hemostasis
- Utilization of multi- and interdisciplinary blood conservation
modalities
- Patient-centered decision making
Given the central role of reduce hemoglobin and anemia in increased
risk of transfusion and unfavorable outcomes [17,25], prevention and
timely detection and management of anemia are cornerstones of PBM.
Proactive prevention and management of anemia can be best achieved
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
in the weeks prior to an elective surgical procedure to allow enough
time for diagnostic work up and proper management of anemia [17].
While routine implementation of this strategy can eventually help
patients admitted to surgical ICUs, other patients admitted to ICU will
also benefit tremendously from ongoing anemia screening and early
identification, proper diagnosis and management during their ICU
stay. This is because of the high incidence of hospital-acquired anemia
(HAA) that is particularly high in ICU patients. It has been reported
that as many as 75% of non-anemic patients admitted to hospital develop
HAA during their stay, and HAA is shown to contribute to prolongation of
length of hospital stay and increased risk of mortality [69]. One common
and easily modifiable risk factor for development of HAA is unnecessary
diagnostic blood draws that are commonly performed in hospitalized
patients. Not surprisingly, the frequency and amount of diagnostic
blood draws usually increase with the severity of illness of patients,
and hence, those admitted to the ICU are particularly in high risk [70].
Diagnostic blood draws for a patient can lead to up to 70 mL of blood
loss on a daily basis. To better understand the magnitude of this loss,
one has to remember that the normal daily RBC production in an average
70-kg healthy adult is around 17.5 mL [71]. In a study of 155 critically ill
patients staying in the ICU for a month or longer, hemoglobin level
dropped from 11.1 ± 2.5 g/dL at admission to 9.0 ± 1.1 g/dL on day 21
of ICU stay. Transfused patients (62%) had significantly greater acuity
of illness, lower hemoglobin level, larger volumes of diagnostic blood
draws, and longer duration of ICU stay, while they suffered a greater
risk of mortality. An increase of just 3.5 ml/day in the diagnostic blood
draws was associated with doubling of the odds of being transfused
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
clinical management of patients, avoid standing orders, and draw just
the minimum amount of blood needed for the test [73]. Implementation
of closed-loop systems that return the otherwise wasted blood back to
the patient, point-of-care microanalytic tests and various noninvasive
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].
In a study of a closed-loop blood sampling device among 250 critically
ill patients, use of the device was associated with reduced RBC transfusion
by almost half and reduced decline of hemoglobin level during ICU stay
[75]. In another study, combined use of an ongoing educational program
 A. Shander et al. / Transfusion Medicine Reviews xxx (2017) xxx–xxx
and changes in orders (requiring the staff to order the needed tests on a
daily basis in lieu of placing orders for recurring daily tests), reducing
duplicate tests and adding laboratory reviews was able to reduce the
number of unnecessary laboratory tests significantly [76].
Critically ill patients are likely to receive various medications and
understanding their interactions and side effects that might be affecting
the hematopoietic or coagulation systems is particularly important.
Anemia is a relatively common side effect for many medications used
routinely in the ICU. Common ways medications can induce anemia
include hemolysis and suppression of production and release of en-
dogenous erythropoietin from the kidneys [77-79]. The possibility
of drug-induced anemia should be considered when deciding on
new medications and during the diagnostic work up of new-onset
or exacerbating anemia, and if patient is being started on a new medica-
tion that is known to cause anemia, increased vigilance and continuous
screening for anemia may be warranted (Table 2) [80]. For a critically ill
patient who is planned to undergo an invasive procedure, the dose of
anticoagulant and anti-platelet agents should be reviewed and adjusted
if and when necessary [11,81].
Anemia has become synonymous with low hemoglobin concentra-
tion with little regard to the pathology behind this condition, which
may lead to a single non-specific therapeutic intervention in ICU
patients when their hemoglobin level reaches a certain threshold.
When anemia is present, it should not be ignored and appropriate treat-
ment, guided by the etiology of anemia should be initiated [17,26,82].
Pharmacologic alternatives to transfusion are discussed at length in
other parts of this Special Edition but due to importance of anemia
and its treatment options, a brief overview is provided here. Hematinic
agents are the mainstay treatment for anemia. Erythropoiesis stimulating
agents (ESAs) have been investigated and used for treatment of anemia
in the critically ill patients. Efficacy of these agents in increasing the
hemoglobin level and reducing transfusions has been well established.
In their study of 1302 critically ill anemia patients, Corwin et al showed
that weekly administration of an ESA can significantly reduce RBC
transfusions and lead to higher hemoglobin levels, without any other
significant impact on clinical outcomes [83]. However, in their subse-
quent study of 1460 patients in ICU, they did not detect any significant
impacts on blood transfusions [84]. This unexpected result can be
explained by the adoption of more restrictive transfusion practices
(that would limit the power of studies looking at transfusion as an
endpoint), and lack of iron repletion to avoid iron-restricted hemato-
poiesis in the patients treated with ESA [79,85].
Concerns regarding their potential side effects including thrombo-
embolic events and cancer progression and other still-debated compli-
cations have impeded their appropriate use [86]. Bennett et al analyzed
the mortality data from 13 611 participants in 51 trials and the venous
thromboembolism (VTE) data from 8172 patients in 38 trials and
Table 2
Some of the medication that are commonly linked with anemia (drug-induced anemia) [80]
Type of anemia Medications
Immune hemolytic Antineoplastics, cefotetan, ceftriaxone, cephalosporins,
diclofenac, fludarabine, ibuprofen, methyldopa,
non-steroidal anti-inflammatories (NSAIDs), penicillin
derivatives, pipracillin, quinine/quinidine
Non-immune hemolytic Nitrofurantoin, phenazopyridine, primaquine, sulfa drugs
Meganoblastic Alkylating agents, metformin, methotrexate and other
antimetabolites, chemotherapeutic agents, oral
contraceptives, phenobarbital, phenytoin, primidone,
pyremethamine, sulfasalazine, triamterene,
trimethoprim-sulfamethoxazole
Sideroblastic Busulfan, isoniazid, linezolid, penicillamine, phenacetin,
progesterone replacement, tetracycline, triethylene
tetramine dihydrochloride, chloramphenicol
Aplastic Azathioprine, carbamazepine, chloramphenicol,
erythropoietin, isoniazid, procainamide, sulfonamides,
valproic acid
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
5
reported increased risk of mortality (OR 1.10, 95% CI 1.01 to 1.2) and
VTE (OR 1.57, 95% CI 1.31 to 1.87) in patients treated with ESAs [87].
A major caveat of the studies included in this meta-analysis is that
they all had a target hemoglobin level of N13 g/dL, and in fact, 3 trials
had a target hemoglobin of N15 g/dL for their ESA treatment protocol.
In the other meta-analysis, Glaspy et al looked at the data from 60 trials
enrolling 15 323 anemic cancer patients undergoing chemo and/or
radiotherapy and they concluded that ESA use was not associated
with increased risk of mortality (OR 1.06, 95% CI 0.97-1.15) or cancer
progression (OR 1.48, 95% CI 1.28-1.72), but the risk of VTE was
increased (OR 1.48, 95% CI 1.28-1.72) [88].
While no medication is without risks, risks of ESAs must be viewed in
context of competing treatment—namely, allogeneic blood transfusions
with their own long list of risks discussed earlier here. Additionally, it
has been argued that some increased complications observed in patients
treated with ESAs might be attributable to other factors such as pre-
existing conditions, failure to provide adequate anticoagulation prophy-
laxis or iron supplementation to support increase demand, and the
possibility of exposing patients to escalating and large doses of ESAs to
achieve predefined hemoglobin targets as was the case with studies in
Bennett et al meta-analysis [87]. The increased risk of VTE appears to
be more related with prolonged use of ESAs at higher doses, and this
risk can be mitigated with thromboprophylaxis [89].
Optimal dosing and strategies to use ESAs in the treatment of ane-
mia in the critically ill patients are still debated, [85] but as directed
by the general PBM philosophy, an individualized plan of care should
be developed for each patient, and the role of ESAs with their potential
risks and expected benefits must be weighed versus other options for
each individual patient, and whenever needed, prophylactic treatments
to reduce the risk of thromboembolic events should be considered [17].
Iron deficiency and iron deficiency anemia are very common in ICU
patients [17]. Anemia in critically ill patients is often thought to have an
inflammatory cause, but iron deficiency is often a contributing factor
[15,17]. In critically ill patients, inflammation reduces the bioavailable
iron through the hepcidin pathway [90]. As previously indicated, treat-
ment with ESAs can also increase the demand for iron and result in
functional iron deficiency [17]. Hence, iron supplementation is often
needed in anemic critically ill patients. When iron is needed, intrave-
nous iron (specially the newer formulations) is often the preferred
form as it bypasses the enteric absorption and acts much faster than
oral forms while offering better tolerance [91]. The safety profile of
newer intravenous iron formulations has been greatly improved [92].
Increased risk of infection following treatment with intravenous iron
is a commonly-cited concern, but this risk is not supported by a number
of studies [17,93]. Studies have suggested a synergistic effect when
intravenous iron and ESAs are used together, possibly allowing better
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-
pared with placebo group (97 vs 136 U) but the difference was not
statistically significant. Additionally, patients treated with intravenous
iron achieved higher hemoglobin levels during hospital stay and at
discharge, while no significant difference in safety outcomes was seen
between the study arms [95].
Current coverage and reimbursement policies in the US hinder the
use of ESAs and intravenous iron for treatment of anemia in many
patient populations, and their combined use is also restricted despite
purported benefits. There are calls for revision of these policies as they
are no longer supported by available evidence [96,97]. Additional
supplementation with folic acid and vitamin B12 might be needed to
support the increased hematopoiesis following administration of hema-
tinic agents [98,99].
Avoidance and minimization of blood loss is another fundamental
aspect of PBM. Several modalities and devices are available to this end
for surgical patients [82,100], including various autologous transfusion
strategies to minimize surgical blood loss [101]. Clinicians in the ICUs
6 A. Shander et al. / Transfusion Medicine Reviews xxx (2017) xxx–xxx
must remain vigilant and monitor patients particularly those in the
surgical ICU for new sources of bleeding.
Gastrointestinal bleeding (including stress-related mucosal bleeding)
is a common and preventable cause of blood loss in the critically ill
patients [102]. Stress ulcer prophylaxis has been recommended in
high-risk patients in ICU using proton pump inhibitors (PPIs) or hista-
mine 2 receptor antagonists (H2RAs). However, some studies suggest
that stress ulcer prophylaxis is not necessarily associated with im-
proved outcomes and use of PPI might even increase the risk of infec-
tions such as pneumonia and clostridium difficile–associated diarrhea.
Hence, the potential risks and benefits should be carefully balanced
when deciding on the use of these agents and their routine use in
all critically ill patients might not be supported by the current evidence
[102].
Arnold et al evaluated 100 patients in a medical-surgical ICU, and
reported that 90% of the patients experienced some bleeding complica-
tions and 20% had major bleeding events (480 total separate bleeding
events). Interestingly, the bleeding events were at the surgical site in
only 15% of the cases, and the most common sites of bleeding included
sites of insertion of vascular catheters and endotracheal tubes [103].
Thrombocytopenia, coagulopathy and coagulation disorders are
relatively common in critically ill patients. Thrombocytopenia is com-
monly encountered in the context of hemodilution (eg, following fluid
therapy or massive transfusion of RBC), increased consumption (eg, in
trauma, bleeding, or disseminated intravascular coagulation [DIC]),
increased destruction (eg, immune response) or suppressed production.
Patient presenting to ICU following coronary artery bypass surgery are
particularly at risk of being thrombocytopenic [104,105]. Critically ill pa-
tients are commonly treated with heparin (eg, for thromboprophylaxis
or during renal replacement therapy as discussed below) which makes
them prone to development of heparin-induced thrombocytopenia.
Use of low-molecular-weight heparin can reduce the risk [106]. Coagu-
lopathy and coagulation abnormalities particularly DIC are more likely
to be encountered in patients with sepsis or trauma [74,107]. Thrombotic
microangiopathy (TMA) is another condition that can be seen in critically
ill patients and result in hemolytic anemia as well as thrombocytopenia
and early detection and diagnosis can be life-saving with or without allo-
geneic transfusions [108]. Finally, patients with comorbidities that are
known to increase the risk of coagulation abnormalities and bleeding
(eg, liver disease) require closer watch.
One particular group of concern is the critically ill patients on renal
replacement therapy who are at increased risk of bleeding due to the
requirement for anticoagulation. The anticoagulant is often citrate or
heparin which can be delivered systematically or regionally. Overall,
regional citrate appears to offer similar or better clinical outcomes
compared with heparin, while prolonging the renal replacement circuit
and filter life and hence it is generally preferred [109]. The choice of
mode of dialysis in these patients can also affect the outcomes. In a
study of 252 critically ill patients with dialysis-dependent acute renal
failure, use of venous continuous veno-venous hemofiltration was asso-
ciated with increased rate of blood loss events and amount of blood loss
compared with intermittent hemodialysis, while transfusion rates
remain unchanged [110].
The management strategies for bleeding in critically ill patients
depend on the underlying conditions, and pharmacologic agents are
discussed at other parts of this Special Edition. PBM calls for active and
aggressive screening for and management of sources of bleeding in all
including the critically ill patients [111].
Patient Blood Management Programs in Practice
PBM has been proposed as a standard of care [3], and integration of
PBM strategies as hospital-wide multidisciplinary programs becomes a
necessity to maximize the impact of these strategies. Another important
aspect is to establish data collection systems for monitoring the effec-
tiveness of the PBM strategies and evaluating their impact on the
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
outcomes of the patients, which is the main goal, alongside with other
aspects such as resource utilization [5].
Reports from PBM programs are emerging and many appear to be
promising with encouraging results [112]. In a before-and-after study, im-
plementation of a PBM program in cardiac surgery service was associated
with approximately 25% reduction in blood loss, and 50% reduction in RBC
transfusion rates (and similar reduction in rate of transfusion of other
blood components) [113]. On the other hand, the length of hospital stay
decreased by 15% and the direct cost of care decreased by about 8.5%,
while clinical outcomes such as mortality remained unaffected [113].
In another prospective multicenter before-and-after study on around
130 000 surgical inpatients, transfusion rates in the pre- and post-
PBM periods were 6.53% and 6.34%, while the mean number of units
of blood transfused per patient reduced significantly from 1.21 before
implementing PBM to 1.0 after implementing the PBM program.
Following implementation of the PBM program, incidence of acute
renal failure also decreased from 2.39% to 1.67% [114].
Impressive improvements in reducing the frequency of anemia,
reducing transfusion rates and improving clinical outcomes (shorter
hospital stays and fewer complications) have been seen in patients
undergoing orthopedic procedures [115] and cardiac surgery [113]. In
another report, while introduction of a set of transfusion guidelines
was not found to be effective in surgical patients, implementing a
PBM program was effective in reducing transfusion utilization and
costs [116].
In a study of over 600 000 patients admitted between 2008 and 2014
to four major hospitals participating in the health-system-wide PBM
program implemented by the Western Australia Department of Health
[117], it was shown that following implementation of the PBM program,
allogeneic blood component utilization per patient was reduced by 41%
(P b .001), amounting to saving of up to 100 million dollars, while mean
pre-transfusion hemoglobin level was reduced from 7.9 g/dL to 7.3 g/dL.
The number of patients admitted for elective surgery who were anemic
on admission decreased from 20.8% to 14.4% (P = .001). More impor-
tantly, significant improvements in clinical outcomes including reduced
risk-adjusted mortality rate (OR 0.72, 95% CI 0.67-0.77, P b .001), short-
ened length of stay (incidence rate ratio 0.85, 95% CI 0.84-0.87, P b .001),
reduced hospital-acquired infections (OR 0.79, 95% CI 0.73-0.86,
P b .001) and reduced occurrence of acute myocardial infarction or
stroke (OR 0.69, 95% CI 0.58-0.82, P b .001) were observed [117].
While more studies are needed to better characterize the real-world
impact of PBM programs on clinical outcomes, the available evidence
supports the value of PBM strategies as part of standard care, and this
view is increasingly supported and endorsed by professional societies
and organizations as well as national and international health care
policy makers including the World Health Organization [118-120].
The patients who are at risk for anemia and transfusion are at the
forefront of those who stand to benefit greatly from PBM programs.
Those include all critically ill patients. Although we keep “producing”
transfusion guidelines that may help clinicians in some situations
[121], transfusion remain a default position for the critically ill while
anemia, an independent risk factor remains ignored. Adopting the
simple medical model of prevention, detection, diagnosis and proper
treatment including early intervention, could result in better outcomes
for the ICU population as shown for other patients populations. As such,
PBM, a bundled care, should be integrated as part of routine ICU patient
management strategies [114].
Conflict of Interest
AS has been a consultant or speaker with honorarium for or received
research support from, Masimo, Gauss, and Vifor; he is a founding
member of the Society for the Advancement of Blood Management
(SABM). MJ has been a consultant and contractor for SABM and Gauss
Surgical. GL declares no relevant conflict of interests.
 A. Shander et al. / Transfusion Medicine Reviews xxx (2017) xxx–xxx
Funding Sources
This work did not receive any specific grant from funding agencies in
the public, commercial, or not-for-profit sectors.
References
[1] Shander A, Hofmann A, Isbister J, Van AH. Patient blood management–the new
frontier. Best Pract Res Clin Anaesthesiol 2013;27:5–10.
[2] Shander A, Isbister J, Gombotz H. Patient blood management: the global view.
Transfusion 2016;56(Suppl. 1):S94–S102.
[3] Shander A, Bracey Jr AW, Goodnough LT, Gross I, Hassan NE, Ozawa S, et al. Patient
blood management as standard of care. Anesth Analg 2016;123:1051–3.
[4] Dwyre DM, Fernando LP, Holland PV. Hepatitis B, hepatitis C and HIV transfusion-
transmitted infections in the 21st century. Vox Sang 2011;100:92–8.
[5] Goodnough LT, Shander A, Spence R. Bloodless medicine: clinical care without
allogeneic blood transfusion. Transfusion 2003;43:668–76.
[6] Carson JL, Noveck H, Berlin JA, Gould SA. Mortality and morbidity in patients with
very low postoperative Hb levels who decline blood transfusion. Transfusion 2002;
42:812–8.
[7] Shander A, Goodnough LT. Objectives and limitations of bloodless medical care.
Curr Opin Hematol 2006;13:462–70.
[8] Martyn V, Farmer SL, Wren MN, Towler SC, Betta J, Shander A, et al. The theory and
practice of bloodless surgery. Transfus Apher Sci 2002;27:29–43.
[9] Shander A, Javidroozi M, Naqvi S, Aregbeyen O, Caylan M, Demir S, et al. An update
on mortality and morbidity in patients with very low postoperative hemoglobin
levels who decline blood transfusion (CME). Transfusion 2014;54:2688–95.
[10] Shander A, Javidroozi M, Gianatiempo C, Gandhi N, Lui J, Califano F, et al. Outcomes
of protocol-driven care of critically ill severely anemic patients for whom blood
transfusion is not an option. Crit Care Med 2016;44:1109–15.
[11] Shander A, Moskowitz DM, Javidroozi M. Blood conservation in practice: an over-
view. Br J Hosp Med (Lond) 2009;70:16–21.
[12] Gombotz H, Rehak PH, Shander A, Hofmann A. Blood use in elective surgery: the
Austrian benchmark study. Transfusion 2007;47:1468–80.
[13] Perros AJ, Christensen AM, Flower RL, Dean MM. Soluble mediators in platelet con-
centrates modulate dendritic cell inflammatory responses in an experimental
model of transfusion. J Interf Cytokine Res 2015;35:821–30.
[14] Mincheff MS, Meryman HT. Blood transfusion, blood storage and immunomodulation.
Immunol Investig 1995;24:303–9.
[15] Napolitano LM. Anemia and red blood cell transfusion: advances in critical care.
Crit Care Clin 2017;33:345–64.
[16] Shander A. Anemia in the critically ill. Crit Care Clin 2004;20:159–78.
[17] Shander A, Goodnough LT, Javidroozi M, Auerbach M, Carson J, Ershler WB, et al.
Iron deficiency anemia—bridging the knowledge and practice gap. Transfus Med
Rev 2014;28:156–66.
[18] Corwin HL, Gettinger A, Pearl RG, Fink MP, Levy MM, Abraham E, et al. The CRIT
study: anemia and blood transfusion in the critically ill—current clinical practice
in the United States. Crit Care Med 2004;32:39–52.
[19] Corwin HL. Anemia and red blood cell transfusion in the critically ill. Semin Dial
2006;19:513–6.
[20] Napolitano LM. Scope of the problem: epidemiology of anemia and use of blood
transfusions in critical care. Crit Care 2004;8(Suppl. 2):S1–8.
[21] Nguyen BV, Bota DP, Melot C, Vincent JL. Time course of hemoglobin concentra-
tions in nonbleeding intensive care unit patients. Crit Care Med 2003;31:406–10.
[22] Thomas J, Jensen L, Nahirniak S, Gibney RT. Anemia and blood transfusion practices
in the critically ill: a prospective cohort review. Heart Lung 2010;39:217–25.
[23] Vincent JL, Baron JF, Reinhart K, Gattinoni L, Thijs L, Webb A, et al. Anemia and
blood transfusion in critically ill patients. JAMA 2002;288:1499–507.
[24] Bateman AP, McArdle F, Walsh TS. Time course of anemia during six months follow
up following intensive care discharge and factors associated with impaired recovery
of erythropoiesis. Crit Care Med 2009;37:1906–12.
[25] Shander A, Javidroozi M, Ozawa S, Hare GM. What is really dangerous: anaemia or
transfusion? Br J Anaesth 2011;107(Suppl. 1):i41–59.
[26] Shander A, Javidroozi M. The patient with anemia. Curr Opin Anaesthesiol 2016;29:
438–45.
[27] Vincent JL. Which carries the biggest risk: anaemia or blood transfusion? Transfus
Clin Biol 2015;22:148–50.
[28] Mukhopadhyay A, Tai BC, See KC, Ng WY, Lim TK, Onsiong S, et al. Risk factors for
hospital and long-term mortality of critically ill elderly patients admitted to an
intensive care unit. Biomed Res Int 2014;2014:960575.
[29] Dasta J, Mody SH, McLaughlin T, Leblanc J, Shen Y, Genetti M, et al. Current
management of anemia in critically ill patients: analysis of a database of 139
hospitals. Am J Ther 2008;15:423–30.
[30] Palmieri TL, Caruso DM, Foster KN, Cairns BA, Peck MD, Gamelli RL, et al. Effect of
blood transfusion on outcome after major burn injury: a multicenter study. Crit
Care Med 2006;34:1602–7.
[31] Rao MP, Boralessa H, Morgan C, Soni N, Goldhill DR, Brett SJ, et al. Blood component
use in critically ill patients. Anaesthesia 2002;57:530–4.
[32] Shapiro MJ, Gettinger A, Corwin HL, Napolitano L, Levy M, Abraham E, et al. Anemia
and blood transfusion in trauma patients admitted to the intensive care unit.
J Trauma 2003;55:269–73.
[33] Vincent JL, Sakr Y, Sprung C, Harboe S, Damas P. Are blood transfusions associated
with greater mortality rates? Results of the sepsis occurrence in acutely ill patients
study. Anesthesiology 2008;108:31–9.
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
7
[34] Walsh TS, Garrioch M, Maciver C, Lee RJ, Mackirdy F, McClelland DB, et al. Red cell
requirements for intensive care units adhering to evidence-based transfusion
guidelines. Transfusion 2004;44:1405–11.
[35] Zilberberg MD, Stern LS, Wiederkehr DP, Doyle JJ, Shorr AF. Anemia, transfusions
and hospital outcomes among critically ill patients on prolonged acute mechanical
ventilation: a retrospective cohort study. Crit Care 2008;12:R60.
[36] Shander A, Puzio T, Javidroozi M. Variability in transfusion practice and effective-
ness of strategies to improve it. J Cardiothorac Vasc Anesth 2012;26:541–4.
[37] Shander A, Goodnough LT. Why an alternative to blood transfusion? Crit Care Clin
2009;25:261–77 [Table].
[38] Isbister JP, Shander A, Spahn DR, Erhard J, Farmer SL, Hofmann A. Adverse blood
transfusion outcomes: establishing causation. Transfus Med Rev 2011;25:89–101.
[39] Shander A, Hofmann A, Ozawa S, Theusinger OM, Gombotz H, Spahn DR. Activity-
based costs of blood transfusions in surgical patients at four hospitals. Transfusion
2010;50:753–65.
[40] Marik PE, Corwin HL. Efficacy of red blood cell transfusion in the critically ill: a
systematic review of the literature. Crit Care Med 2008;36:2667–74.
[41] Shander A, Lobel GP, Javidroozi M. Transfusion practices and infectious risks. Expert
Rev Hematol 2016;9:597–605.
[42] Funk MB, Heiden M, Volkers P, Lohmann A, Keller-Stanislawski B. Evaluation of risk
minimisation measures for blood components—based on reporting rates of
transfusion-transmitted reactions (1997-2013). Transfus Med Hemother 2015;
42:240–6.
[43] Kenz HE, Van der LP. Transfusion-related acute lung injury. Eur J Anaesthesiol
2014;31:345–50.
[44] Li G, Rachmale S, Kojicic M, Shahjehan K, Malinchoc M, Kor DJ, et al. Incidence and
transfusion risk factors for transfusion-associated circulatory overload among
medical intensive care unit patients. Transfusion 2011;51:338–43.
[45] Refaai MA, Blumberg N. Transfusion immunomodulation from a clinical perspec-
tive: an update. Expert Rev Hematol 2013;6:653–63.
[46] Brown CJ, Navarrete CV. Clinical relevance of the HLA system in blood transfusion.
Vox Sang 2011;101:93–105.
[47] Hirayama F. Current understanding of allergic transfusion reactions: incidence,
pathogenesis, laboratory tests, prevention and treatment. Br J Haematol 2013;
160:434–44.
[48] Fast LD. Developments in the prevention of transfusion-associated graft-versus-
host disease. Br J Haematol 2012;158:563–8.
[49] Chatterjee S, Wetterslev J, Sharma A, Lichstein E, Mukherjee D. Association of blood
transfusion with increased mortality in myocardial infarction: a meta-analysis and
diversity-adjusted study sequential analysis. JAMA Intern Med 2013;173:132–9.
[50] Shander A, Fink A, Javidroozi M, Erhard J, Farmer SL, Corwin H, et al. Appropriateness
of allogeneic red blood cell transfusion: the international consensus conference on
transfusion outcomes. Transfus Med Rev 2011;25:232–46.
[51] Trentino K, Farmer S, Gross I, Shander A, Isbister J. Observational studies—should
we simply ignore them in assessing transfusion outcomes? BMC Anesthesiol
2016;16:96.
[52] Scott IA, Attia J. Cautionary tales in the interpretation of observational studies of
effects of clinical interventions. Intern Med J 2017;47:144–57.
[53] Hebert PC, Wells G, Blajchman MA, Marshall J, Martin C, Pagliarello G, et al. A
multicenter, randomized, controlled clinical trial of transfusion requirements in
critical care. Transfusion requirements in critical care investigators, Canadian
critical care trials group. N Engl J Med 1999;340:409–17.
[54] Carless PA, Henry DA, Carson JL, Hebert PP, McClelland B, Ker K. Transfusion
thresholds and other strategies for guiding allogeneic red blood cell transfusion.
Cochrane Database Syst Rev 2010;10:CD002042.
[55] Carson JL, Carless PA, Hebert PC. Transfusion thresholds and other strategies for
guiding allogeneic red blood cell transfusion. Cochrane Database Syst Rev 2012;
4:CD002042.
[56] Holst LB, Petersen MW, Haase N, Perner A, Wetterslev J. Restrictive versus
liberal transfusion strategy for red blood cell transfusion: systematic review
of randomised trials with meta-analysis and trial sequential analysis. BMJ
2015;350:h1354.
[57] Holst LB, Haase N, Wetterslev J, Wernerman J, Guttormsen AB, Karlsson S, et al.
Lower versus higher hemoglobin threshold for transfusion in septic shock. N Engl
J Med 2014;371:1381–91.
[58] Rygard SL, Holst LB, Wetterslev J, Johansson PI, Perner A. Higher vs. lower
haemoglobin threshold for transfusion in septic shock: subgroup analyses of the
TRISS trial. Acta Anaesthesiol Scand 2016;61:166–75.
[59] Rygard SL, Holst LB, Wetterslev J, Winkel P, Johansson PI, Wernerman J, et al. Long-
term outcomes in patients with septic shock transfused at a lower versus a higher
haemoglobin threshold: the TRISS randomised, multicentre clinical trial. Intensive
Care Med 2016;42:1685–94.
[60] Fominskiy E, Putzu A, Monaco F, Scandroglio AM, Karaskov A, Galas FR, et al. Liberal
transfusion strategy improves survival in perioperative but not in critically ill
patients. A meta-analysis of randomised trials. Br J Anaesth 2015;115:511–9.
[61] Ripolles MJ, Casans FR, Espinosa A, Martinez HE, Navarro PR, Abad GA, et al.
Restrictive versus liberal transfusion strategy for red blood cell transfusion in
critically ill patients and in patients with acute coronary syndrome: a systematic
review, meta-analysis and trial sequential analysis. Minerva Anestesiol 2015;82:
582–98.
[62] Hovaguimian F, Myles PS. Restrictive versus liberal transfusion strategy in the peri-
operative and acute care settings: a context-specific systematic review and meta-
analysis of randomized controlled trials. Anesthesiology 2016;125:46–61.
[63] Carson JL, Stanworth SJ, Roubinian N, Fergusson DA, Triulzi D, Doree C, et al. Trans-
fusion thresholds and other strategies for guiding allogeneic red blood cell transfu-
sion. Cochrane Database Syst Rev 2016;10:CD002042.
8 A. Shander et al. / Transfusion Medicine Reviews xxx (2017) xxx–xxx
[64] Napolitano LM, Kurek S, Luchette FA, Corwin HL, Barie PS, Tisherman SA, et al.
Clinical practice guideline: red blood cell transfusion in adult trauma and critical
care. Crit Care Med 2009;37:3124–57.
[65] Retter A, Wyncoll D, Pearse R, Carson D, McKechnie S, Stanworth S, et al. Guidelines
on the management of anaemia and red cell transfusion in adult critically ill
patients. Br J Haematol 2013;160:445–64.
[66] Carson JL, Guyatt G, Heddle NM, Grossman BJ, Cohn CS, Fung MK, et al. Clinical prac-
tice guidelines from the AABB: red blood cell transfusion thresholds and storage.
JAMA 2016;316:2025–35.
[67] Jacob M, Annaheim S, Boutellier U, Hinske C, Rehm M, Breymann C, et al.
Haematocrit is invalid for estimating red cell volume: a prospective study in
male volunteers. Blood Transfus 2012;10:471–9.
[68] Shander A, Gross I, Hill S, Javidroozi M, Sledge S. A new perspective on best trans-
fusion practices. Blood Transfus 2013;11:193–202.
[69] Koch CG, Li L, Sun Z, Hixson ED, Tang A, Phillips SC, et al. Hospital-acquired anemia:
prevalence, outcomes, and healthcare implications. J Hosp Med 2013;8:506–12.
[70] Lyon AW, Chin AC, Slotsve GA, Lyon ME. Simulation of repetitive diagnostic blood
loss and onset of iatrogenic anemia in critical care patients with a mathematical
model. Comput Biol Med 2013;43:84–90.
[71] Corwin HL, Parsonnet KC, Gettinger A. RBC transfusion in the ICU. Is there a reason?
Chest 1995;108:767–71.
[72] Chant C, Wilson G, Friedrich JO. Anemia, transfusion, and phlebotomy practices in
critically ill patients with prolonged ICU length of stay: a cohort study. Crit Care
2006;10:R140.
[73] Shander A, Javidroozi M. Blood conservation strategies and the management of
perioperative anaemia. Curr Opin Anaesthesiol 2015;28:356–63.
[74] McEvoy MT, Shander A. Anemia, bleeding, and blood transfusion in the intensive
care unit: causes, risks, costs, and new strategies. Am J Crit Care 2013;22:eS1-S13.
[75] Mukhopadhyay A, Yip HS, Prabhuswamy D, Chan YH, Phua J, Lim TK, et al. The use
of a blood conservation device to reduce red blood cell transfusion requirements: a
before and after study. Crit Care 2010;14:R7.
[76] Raad S, Elliott R, Dickerson E, Khan B, Diab K. Reduction of laboratory utilization in
the intensive care unit. J Intensive Care Med 2016.
[77] Shander A, Nemeth J, Cruz JE, Javidroozi M. Patient blood management: a role for
pharmacists. Am J Health Syst Pharm 2017;74:e83–9.
[78] Michel M. Classification and therapeutic approaches in autoimmune hemolytic
anemia: an update. Expert Rev Hematol 2011;4:607–18.
[79] Hayden SJ, Albert TJ, Watkins TR, Swenson ER. Anemia in critical illness: insights
into etiology, consequences, and management. Am J Respir Crit Care Med 2012;
185:1049–57.
[80] Shander A, Javidroozi M, Ashton ME. Drug-induced anemia and other red cell
disorders: a guide in the age of polypharmacy. Curr Clin Pharmacol 2011;6:295–303.
[81] Shander A, Javidroozi M. Strategies to reduce the use of blood products: a US
perspective. Curr Opin Anaesthesiol 2012;25:50–8.
[82] Shander A. Preoperative anemia and its management. Transfus Apher Sci 2014;50:
13–5.
[83] Corwin HL, Gettinger A, Pearl RG, Fink MP, Levy MM, Shapiro MJ, et al. Efficacy of
recombinant human erythropoietin in critically ill patients: a randomized
controlled trial. JAMA 2002;288:2827–35.
[84] Corwin HL, Gettinger A, Fabian TC, May A, Pearl RG, Heard S, et al. Efficacy and
safety of epoetin alfa in critically ill patients. N Engl J Med 2007;357:965–76.
[85] Napolitano LM. Epoetin alfa in the critically ill: what dose? Which route? Crit Care
Med 2009;37:1501–3.
[86] Goodnough LT, Shander A. Current status of pharmacologic therapies in patient
blood management. Anesth Analg 2013;116:15–34.
[87] Bennett CL, Silver SM, Djulbegovic B, Samaras AT, Blau CA, Gleason KJ, et al. Venous
thromboembolism and mortality associated with recombinant erythropoietin and
darbepoetin administration for the treatment of cancer-associated anemia. JAMA
2008;299:914–24.
[88] Glaspy J, Crawford J, Vansteenkiste J, Henry D, Rao S, Bowers P, et al.
Erythropoiesis-stimulating agents in oncology: a study-level meta-analysis of
survival and other safety outcomes. Br J Cancer 2010;102:301–15.
[89] Leyland-Jones B. Erythropoiesis stimulating agents: a personal journey. J Natl
Cancer Inst 2013;105:999–1001.
[90] Ganz T. Hepcidin and iron regulation, 10 years later. Blood 2011;117:4425–33.
[91] Auerbach M, Goodnough LT, Picard D, Maniatis A. The role of intravenous iron in
anemia management and transfusion avoidance. Transfusion 2008;48:988–1000.
[92] Lin DM, Lin ES, Tran MH. Efficacy and safety of erythropoietin and intravenous iron
in perioperative blood management: a systematic review. Transfus Med Rev 2013;
27:221–34.
[93] Torres S, Kuo YH, Morris K, Neibart R, Holtz JB, Davis JM. Intravenous iron following
cardiac surgery does not increase the infection rate. Surg Infect 2006;7:361–6.
[94] Auerbach M, Ballard H, Trout JR, McIlwain M, Ackerman A, Bahrain H, et al. Intrave-
nous iron optimizes the response to recombinant human erythropoietin in cancer
patients with chemotherapy-related anemia: a multicenter, open-label, randomized
trial. J Clin Oncol 2004;22:1301–7.
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
[95] Litton E, Baker S, Erber WN, Farmer S, Ferrier J, French C, et al. Intravenous iron or
placebo for anaemia in intensive care: the IRONMAN multicentre randomized
blinded trial: a randomized trial of IV iron in critical illness. Intensive Care Med
2016;42:1715–22.
[96] Shander A, Spence RK, Auerbach M. Can intravenous iron therapy meet the unmet
needs created by the new restrictions on erythropoietic stimulating agents? Transfu-
sion 2010;50:719–32.
[97] Munoz M, Gomez-Ramirez S, Kozek-Langeneker S, Shander A, Richards T, Pavia J,
et al. ‘Fit to fly’: overcoming barriers to preoperative haemoglobin optimization
in surgical patients. Br J Anaesth 2015;115:15–24.
[98] Goodnough LT. Erythropoietin and iron-restricted erythropoiesis. Exp Hematol
2007;35:167–72.
[99] Goodnough LT. Iron deficiency syndromes and iron-restricted erythropoiesis
(CME). Transfusion 2012;52:1584–92.
[100] Shander A, Javidroozi M. The approach to patients with bleeding disorders who do
not accept blood-derived products. Semin Thromb Hemost 2013;39:182–90.
[101] So-Osman C, Nelissen RG, Koopman-van Gemert AW, Kluyver E, Poll RG, Onstenk
R, et al. Patient blood management in elective total hip- and knee-replacement
surgery (part 2): a randomized controlled trial on blood salvage as transfusion
alternative using a restrictive transfusion policy in patients with a preoperative
hemoglobin above 13 g/dl. Anesthesiology 2014;120:852–60.
[102] Buendgens L, Koch A, Tacke F. Prevention of stress-related ulcer bleeding at the
intensive care unit: risks and benefits of stress ulcer prophylaxis. World J Crit
Care Med 2016;5:57–64.
[103] Arnold DM, Donahoe L, Clarke FJ, Tkaczyk AJ, Heels-Ansdell D, Zytaruk N, et al.
Bleeding during critical illness: a prospective cohort study using a new measure-
ment tool. Clin Invest Med 2007;30:E93–102.
[104] Drews RE. Critical issues in hematology: anemia, thrombocytopenia, coagulopathy,
and blood product transfusions in critically ill patients. Clin Chest Med 2003;24:
607–22.
[105] Greinacher A, Selleng K. Thrombocytopenia in the intensive care unit patient.
Hematology Am Soc Hematol Educ Program 2010;2010:135–43.
[106] Warkentin TE. Heparin-induced thrombocytopenia in critically ill patients. Semin
Thromb Hemost 2015;41:49–60.
[107] Moore HB, Winfield RD, Aibiki M, Neal MD. Is coagulopathy an appropriate therapeutic
target during critical illness such as trauma or sepsis? Shock 2017. http://dx.doi.org/
10.1097/SHK.0000000000000854 [Epub ahead of print].
[108] Kappler S, Ronan-Bentle S, Graham A. Thrombotic microangiopathies (TTP, HUS,
HELLP). Emerg Med Clin North Am 2014;32:649–71.
[109] Bai M, Zhou M, He L, Ma F, Li Y, Yu Y, et al. Citrate versus heparin anticoagulation
for continuous renal replacement therapy: an updated meta-analysis of RCTs.
Intensive Care Med 2015;41:2098–110.
[110] Pschowski R, Briegel S, von Haehling S, Doehner W, Bender TO, Pape UF, et al.
Effects of dialysis modality on blood loss, bleeding complications and transfusion
requirements in critically ill patients with dialysis-dependent acute renal failure.
Anaesth Intensive Care 2015;43:764–70.
[111] Goodnough LT, Shander A. Patient blood management. Anesthesiology 2012;116:
1367–76.
[112] Gross I, Shander A, Sweeney J. Patient blood management and outcome, too early
or not? Best Pract Res Clin Anaesthesiol 2013;27:161–72.
[113] Gross I, Seifert B, Hofmann A, Spahn DR. Patient blood management in cardiac
surgery results in fewer transfusions and better outcome. Transfusion 2015;55:
1075–81.
[114] Meybohm P, Richards T, Isbister J, Hofmann A, Shander A, Goodnough LT, et al.
Patient blood management bundles to facilitate implementation. Transfus Med
Rev 2017;31:62–71.
[115] Rineau E, Chaudet A, Chassier C, Bizot P, Lasocki S. Implementing a blood manage-
ment protocol during the entire perioperative period allows a reduction in transfu-
sion rate in major orthopedic surgery: a before-after study. Transfusion 2016;56:
673–81.
[116] Mehra T, Seifert B, Bravo-Reiter S, Wanner G, Dutkowski P, Holubec T, et al. Imple-
mentation of a patient blood management monitoring and feedback program sig-
nificantly reduces transfusions and costs. Transfusion 2015;55:2807–15.
[117] Leahy MF, Hofmann A, Towler S, Trentino KM, Burrows SA, Swain SG, et al. Im-
proved outcomes and reduced costs associated with a health-system-wide patient
blood management program: a retrospective observational study in four major
adult tertiary-care hospitals. Transfusion 2017. http://dx.doi.org/10.1111/trf.
14006 [Epub ahead of print].
[118] Spahn DR, Shander A, Hofmann A. The chiasm: transfusion practice versus patient
blood management. Best Pract Res Clin Anaesthesiol 2013;27:37–42.
[119] WHA63.12 - availability, safety and quality of blood products. WHA resolution;
sixty-third world health assembly. World Health Organization; 2010.
[120] Global forum for blood safety: Patient blood management—concept paper. World
Health Organization; 2011.
[121] Goodnough LT, Levy JH, Murphy MF. Concepts of blood transfusion in adults. Lancet
2013;381:1845–54.