REVIEW

CURRENT
OPINION Is hemoglobin good for cerebral oxygenation
and clinical outcome in acute brain injury?
Shane W. English a,b,c and Lauralyn McIntyre a,b,c

Purpose of review
The purpose of this review is to highlight the role of hemoglobin in cerebral physiology and
pathophysiology. We review the existing as well as recent evidence detailing the effects of red blood cell
transfusion on cerebral oxygenation and clinical outcome.
Recent findings
Hemoglobin is a key component in oxygen delivery, and thus cerebral oxygenation. Higher hemoglobin
levels and red blood cell transfusion are associated with higher cerebral oxygen delivery and decreased
cerebral ischemic burden. Recent studies suggest that this may be associated with improved clinical
outcomes. However, these results are limited to only a few, small studies and the results have not been
consistent. Further studies are required.
Summary
Hemoglobin is important for cerebral oxygenation and strategies to minimize anemia should be
undertaken. Although higher hemoglobin levels are associated with less cerebral ischemia and better
clinical outcome, whether this remains true whenever red blood cell transfusion is used to achieve this result
remains unclear.
Keywords
anemia, brain oxygen, cerebral oxygen delivery, red blood cell transfusion

INTRODUCTION If cardiac output is fixed or maximized, as can be

The aim of this review is to provide an overview of
the relationship between haemoglobin (Hb) and
cerebral oxygenation, and the effects of anemia
and red blood cell (RBC) transfusion on cerebral
oxygenation. We highlight what is known and what
is new in this area and direct the reader to upcoming
trials that may further guide clinical management as
their results become available.
AN OVERVIEW OF NORMAL CEREBRAL
OXYGENATION
The brain has the third highest metabolic rate (cere-
bral metabolic rate – CMRO2) of all human organs
and tissues and has very limited capacity for energy
production outside of oxygen-coupled glucose
metabolism [1,2]. Thus, to maintain normal func-
tion, the steady flow of oxygenated arterial blood, or
oxygen delivery (DO2) is essential. The delivery of
oxygen to the brain, like other systems, is thus
dependent on cardiac output and the arterial con-
tent of oxygen in the following relationship [3]:
DO2 ¼ CO  CaO2
the case in critical illness, the only modifiable factor
in the delivery of oxygen is the content of oxygen in
arterial blood (CaO2), almost entirely driven by Hb
concentration and oxygen saturation (SaO2):
CaO2 ¼ (Hb)  SaO2 þ 0.0031  PaO2
Here we use cardiac output (CO) as a surrogate
for cerebral blood flow (CBF), which has its own set
of determinants including brain compliance, blood
viscosity, and vascular resistance and reactivity, any
or all of which may be affected by brain injury [4].
Oxygen uptake or utilization (VO2) is the rate at
which oxygen dissociates from Hb to the microcir-
culation of the perfused tissues [5]. The ratio of
a
Clinical Epidemiology Program, bCentre for Transfusion Research,
Ottawa Hospital Research Institute and cDepartment of Medicine (Criti-
cal Care), University of Ottawa, Ottawa, Canada
Correspondence to Shane W. English, Centre for Practice-Changing
Research, The Ottawa Hospital – General Campus, 501 Smyth Road,
PO Box 201B, Ottawa, ON K1H 8L6, Canada.
Tel: +1 613 737 8899; e-mail: senglish@ohri.ca
Curr Opin Crit Care 2018, 24:91–96
DOI:10.1097/MCC.0000000000000485

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Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Neuroscience
KEY POINTS
 Hemoglobin is the key readily modifiable determinant
of cerebral oxygenation.
 Anemia negatively affects cerebral oxygenation and is
associated with worse outcomes.
 Increasing evidence suggests that RBC transfusion may
help cerebral oxygenation but it remains unclear if
clinical outcomes are affected.
utilization to delivery (VO2/DO2) is the oxygen-
extraction ratio – with highest ratios observed in
periods of DO2 – uptake dependence. Under normal
conditions, the brain enjoys luxury perfusion in an
approximate 3 : 1 oxygen delivery to oxygen utiliza-
tion, or approximately 150 ml O2/min delivered for
approximately 50 ml O2/min consumed [1,6]. Via
numerous autoregulatory pathways (perhaps most
importantly cerebrovascular autoregulation), stable
DO2 is maintained by alterations in cerebral blood
&
flow [7 ].
IS ANEMIA BAD FOR CEREBRAL
OXYGENATION?
A decrease in cerebral oxygen supply (DO2, e.g.
anemia) in the face of sustained or increased
demand (i.e. VO2) will lead to a high oxygen-extrac-
tion ratio and may result in hypoxic and/or ischemic
insults in the absence of or with inadequate
compensatory mechanisms.
Normal physiologic responses of the brain
to anemia
In the setting of anemia, and resultant decrease in
CaO2, normal physiologic responses includes an
increase in cerebral blood flow (namely an increase
in cardiac output through increases in heart rate
and/or stroke volume) and a decrease in blood vis-
&
cosity (wherever isovolemia is maintained) [7 ,8].
Whenever CBF has peaked or in the setting of
decreased CBF, prior to reaching hypoxic and ische-
mic thresholds, brain oxygen extraction fraction is
&
increased in response to anemia [7 ,9], utilizing the
supply/demand reserve. Thus, a drop in Hb without
an increase in CBF results in a drop in DO2. This may
lead to an increase in oxygen extraction fraction,
which has been shown to precede cerebral tissue
hypoxia and brain injury [10]. Increased regional
oxygen extraction fractions are a marker for poten-
tially reversible ischemia and is associated with
stroke [11].
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Physiologic responses to anemia in the
injured brain
In the injured brain, normal adaptive responses to
anemia may be adversely affected by and/or contrib-
ute to further secondary brain injury. The negative
physiological effects of brain injury generally relate
to anemia, hypoxemia, elevated intracranial pres-
sure (ICP), vasospasm, loss of or compromised cerebral
autoregulation, and flow-metabolism uncoupling
[12]. Consequently, both a drop in CaO2 and
changes to CBF are important pathophysiologic
factors following brain injury that contribute to
further brain damage through alterations in cerebral
metabolism, ischemia, tissue hypoxia, or the down-
stream effects of these [13,14]. Normal physiological
cerebral vasodilation in response to anemia (and
consequential decreased CaO2) leads to increased
cerebral blood volume and may potentiate hyperemia,
edema, and increased ICP. This in turn leads to further
edema, increased pressure, altered cerebral blood
flow, and the ischemic injury propagates. The exact
consequences on cerebral oxygenation and by
further extension, clinical outcomes have varied
(see the following).
Anemia in clinical studies of acute
brain injury
At least in healthy controls, anemia is well tolerated
with respect to neurologic function. Changes in
reaction time and memory have been demonstrated
to be affected only with isovolemic hemodilution
below 70 g/l [15]. These changes were observed in
the absence of abnormal measures of systemic
effects of severe anemia (i.e. normal lactate and
preserved total body oxygen consumption). Signifi-
cant advances in technology have improved the
ability to measure and monitor cerebral oxygen-
ation. Historically, jugular venous oxygen satura-
tion monitoring was one of the few measures of
global cerebral oxygenation. More recently, local
or regional measures obtained by direct cerebral
tissue partial pressure oxygen monitoring has domi-
nated the invasive measure of cerebral oxygenation.
Near infrared spectroscopy (NIRS) has also become
prevalent in modern practice, as a noninvasive mea-
sure, predominantly of venous oxygen saturation,
providing a measure of oxygen utilization [5,16].
These techniques have provided new insights into
the cerebral effects of anemia and responses
to transfusion.
The CONFOCAL study (cerebral oxygenation
and neurological outcomes following critical illness
study [16]) was an observational study in the general
critically ill population (n ¼ 104) in which cerebral
Volume 24  Number 2  April 2018
 Hemoglobin’s role in cerebral oxygenation English and McIntyre
oxygenation as measured by NIRS was shown to
positively correlate with Hb concentration
(r ¼ 0.339, 95% CI 0.147–0.506) [17 ]. Further, they
&
demonstrated an association between poor cerebral
oxygenation and delirium (P ¼ 0.017), such that poor
cerebral oxygenation remained an independent risk
factor for delirium, whenever controlling for higher
narcotic doses and a history of alcohol abuse (per 10%
increase in mean cerebral oxygenation during first
24 h OR ¼ 0.16, 95% CI 0.05–0.56). Similarly, in the
vascular and cardiac surgery populations, poor cere-
bral oxygenation as measured by NIRS has been
associated with worse outcomes including higher
rates of delirium, cognitive dysfunction, organ dys-
&
function, ICU, and hospital lengths of stay [18 ].
In contrast to healthy controls, in patients with
acute brain injury, even moderate anemia appears to
be directly associated with tissue hypoxia and clini-
cal outcome. In traumatic brain injury for example,
Oddo et al. [19] demonstrated with brain tissue
oxygen monitoring that Hb levels less than 90 g/l
are independently (controlling for age, admission
Glasgow coma scale (GCS), Marshall computed
tomography (CT) grade and APACHE II score) asso-
ciated with critical brain tissue oxygen tension
(<20 mmHg), and that these factors together are
associated with poor outcome. Specifically, a Hb
less than 90 g/l with low-brain tissue oxygen tension
(<20 mmHg) was found to be independently associ-
ated with poor outcome at 30 days [defined as a
Glasgow Outcome Scale score of 3; study of 80
patients, adjusted odds ratio (OR) 6.24, 95% confi-
dence interval (CI) 1.61–24.22] [19]. The same
author reported similar findings in a severe sub-
arachnoid hemorrhage population (Hunt and Hess
grade 4 or 5, N ¼ 20): Hb levels less than 90 g/l were
significantly, and independently associated with
lower brain tissue oxygen tension levels and higher
metabolic markers of cellular hypoxia (increased
lactate/pyruvate levels) and greater incidence of
brain hypoxia [20]. In the ischemic stroke popula-
tion, even mild anemia (haemoglobin <120 g/l in
women and <130 g/l in men) was independently
associated with poor outcome (death at discharge
and 12 months) [21].
DOES TRANSFUSION WITH RED
BLOOD CELLS OPTIMIZE CEREBRAL
OXYGENATION AND CLINICAL
OUTCOMES?
Only briefly reviewed above, the evidence to date
strongly suggests that anemia is bad, particularly in
acute brain injury, and is associated with worse
outcomes. We now review the physiological and
clinical evidence for RBC transfusion as a strategy
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to improve cerebral oxygenation, and ultimately
clinical outcomes.
Red blood cell transfusion and cerebral
oxygenation
With the use of brain tissue oxygen monitoring, we
can now quantify the benefit of improving DO2 to
tissue at risk from ischemia [13,20]. In a study of 29
spinal or aortic surgery patients undergoing 84
intraoperative transfusions, RBC transfusion was
associated with an increase in cerebral oxygenation
as measured by NIRS (mean increase of 4.2%, 95%
CI ¼ 3.2–5.2), and the rise in cerebral oxygenation
correlated with the rise in Hb concentration
(r ¼ 0.59, P < 0.001) [22]. In a small observational
study of consecutive patients with traumatic brain
injury or subarachnoid hemorrhage (N ¼ 35), RBC
transfusion resulted in a mean increase in brain
tissue oxygen by 49%, in responders, unrelated to
changes in cerebral perfusion pressure [23]. In sub-
arachnoid hemorrhage, wherever a significant num-
ber of patients must face not only the primary brain
injury postbleed but other threats from delayed
cerebral ischemia, most notably vasospasm, DO2
only significantly improved with RBC transfusion
in those patients with a Hb less than 90 g/l [24].
Neither hypertension nor fluid boluses led to signif-
icant improvements. Notably in this study, transfu-
sion and its effect on viscosity did not translate in a
drop in CBF. Two small subarachnoid hemorrhage
studies (N ¼ 8 and 17) in patients with anemia (Hb
<100 g/l) demonstrated stable CBF, an increase in
DO2 and a decrease in OEF following a RBC transfu-
sion [25,26]. However, in this study, RBC transfu-
sion at Hb greater than 100 g/l was associated with a
drop in CBF. Although Kurtz et al. demonstrated
similar increases in DO2 with RBC transfusion in an
SAH population (N ¼ 15) there was no appreciable
effect on cerebral metabolism (as measured by lac-
tate to pyruvate ratios – although these ratios were
&
already normal at baseline) [27 ]. In contrast, a
larger study of 52 patients with SAH using PET
scanning to measure CBF, DO2, and utilization while
undergoing RBC transfusion at baseline Hb between
&&
70 and 130 g/l [28 ] found that transfusion was
associated with a 10% (P ¼ 0.001) increase in global
cerebral DO2, and more than 15% increase
(P < 0.001) in vulnerable regions of brain wherever
baseline DO2 was already reduced. Although RBC
transfusion was associated with a drop in CBF glob-
ally, an increase in CBF was found in the vulnerable
regions of the injured brain. Improved DO2 was
observed across the spectrum of anemia including
61% of patients with a baseline Hb greater than or
equal to 90 g/l.
www.co-criticalcare.com 93
Neuroscience
The recent BOOST 2 (Brain Oxygen Optimiza-
tion in Severe Traumatic Brain Injury – Phase 2)
randomized trial examined two different manage-
ment protocols in 119 patients with severe trau-
matic injury – one directed towards optimizing
ICP management (incorporating traditional strate-
gies of optimal cerebral perfusion and intracranial
hypertension management) and the other (the
intervention protocol) towards optimizing cerebral
&&
oxygenation [29 ]. The intervention protocol
included RBC transfusion to target a Hb level greater
than 100 g/l for optimizing cerebral oxygenation.
The authors report a 77% reduction in cerebral
hypoxia burden (P < 0.0001) with the use of the
cerebral oxygenation optimization protocol.
These findings of improved markers of cerebral
oxygenation in acute brain injury have not been
unanimous. In a small observational study, 19
patients with severe traumatic brain injury received
20 RBC transfusions and found no significant
increase in cerebral oxygenation as measured by
NIRS despite significant increases in Hb levels
&
[30 ]. Zygun et al. [31] reported an increase in cere-
bral tissue oxygenation with RBC transfusion in a
study of 30 patients randomized to a transfusion of
two units of blood at thresholds of 80, 90 and 100 g/
l. However, this was only observed in approximately
60% of patients, whereas the other 40% either had
no increase or a decrease in cerebral tissue oxygen
measures posttransfusion. Improved tissue oxygen
did not seem to be associated with baseline Hb but
rather was associated with baseline metabolic
derangements. Furthermore, overall no significant
change in cerebral metabolism as measure by lactate
to pyruvate ratios was appreciated. Similar findings
were reported in an earlier prospective observational
study of severe traumatic brain injury and subarach-
noid hemorrhage patients (N ¼ 35), in which brain
tissue oxygenation increased in 74% of the recipi-
ents by a mean of 49%, but actually decreased in
the remaining participants, unrelated to severity of
anemia [23].
Red blood cell transfusion and clinical
outcomes in acute brain injury
As we have reviewed above, RBC transfusion may in
fact improve DO2 but this does not necessarily result
in improved oxygen utilization or clinical outcomes.
&&
Transfusion is not without risk [32 ], and now
numerous trials, both in general mixed critical care
populations as well as medical and surgical popula-
tions have demonstrated no significant benefit from
more liberal transfusion strategies [33,34]. However,
there is a growing interest in the role of cerebral
hypoxia in general ICU populations and how it is
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&
associated with brain dysfunction, like delirium [17 ].
Interestingly, changes in reaction time and memory
observed with severe isovolemic hemodilution (to Hb
levels below 70 g/l) in healthy controls were reversed
with autologous RBC transfusion [15]. Furthermore,
whether a restrictive transfusion strategy applies to a
population at greatest risk for compromised cerebral
oxygenation, such as the acutely brain-injured pop-
ulation, remains unclear.
A systematic review of comparative studies pub-
lished prior to early 2011 of RBC transfusion in the
neurocritically ill [35] included four studies in TBI
patients, one in subarachnoid haemorrhage (SAH)
and the final in a mixed population. Although all of
the studies were at high risk of bias, no significant
benefit in mortality or lengths of hospital stay was
demonstrated in the higher transfusion trigger
groups, which is consistent with randomized con-
trolled trial evidence from other critically ill pop-
ulations [34].
Several observational studies that were not
included in the above review have reported conflict-
ing results and have significant limitations including
selection bias, confounding by indication and resid-
ual confounding [14]. More recently, small random-
ized controlled trials of transfusion in the
neurocritical care population have been published.
In subarachnoid hemorrhage, a small pilot random-
ized trial (N ¼ 44) comparing two RBC transfusion
thresholds (100 vs. 115 g/l) demonstrated compara-
ble safety between the two arms but was not powered
for clinical outcomes, and showed no significant
difference in 28-day functional status [36]. The
thresholds tested in this trial were higher than stated
&&
thresholds utilized in current practice [37,38 ]. The
results of another pilot randomized trial in SAH
comparing two such thresholds (80 vs 100 g/l) are
&
forthcoming [39 ]. In traumatic brain injury, a 200-
patient randomized trial using a factorial design
compared two transfusion thresholds (70 vs. 100 g/
l) and erythropoietin vs. placebo, and found no sta-
tistically significant difference in 6-month neuro-
logic functional outcome [40]. This study did not
utilize the classically accepted definition of severe
traumatic brain injury for inclusion, but rather an
‘inability to follow commands’ and was not powered
to detect a clinically relevant effect. Interestingly, in a
secondary analysis, higher brain tissue oxygen levels
were observed over time in the higher threshold
group, though mean values in both groups remained
above ischemic threshold over the study period [41].
In the previously mentioned BOOST 2 trial in severe
traumatic brain injury, although not powered for
clinical outcomes, the authors reported a trend
towards improved 6-month neurologic functional
outcome (GOS-E) in the group managed with the
Volume 24  Number 2  April 2018
 Hemoglobin’s role in cerebral oxygenation English and McIntyre
&&
cerebral oxygenation optimization protocol [29 ].
Mortality in this group was 25% compared with
34% in the ICP-only group. Finally, in a recent mixed
neurocritical care population trial, patients with a Hb
between 70 and 100 g/l were randomized to a RBC
transfusion management strategy triggered by a Hb
threshold (target maintenance of Hb between 85 and
100 g/l) vs. a management strategy aimed at main-
taining cerebral oxygen saturations greater than 60%
&&
(as measured by NIRS) [42 ]. Targeting a cerebral
oxygen saturation led to fewer units of RBCs trans-
fused per study patient and a lower mean Hb level
while on protocol compared with the transfusion
threshold group. They found no significant differ-
ence in neurologic outcome at discharge, hospital
length of stay or mortality at 1 year.
To date, the available trial evidence supporting
RBC transfusion for optimizing cerebral oxygen-
ation are limited to small studies that have been
underpowered to detect meaningful clinical out-
come affects. Further adequately powered and rig-
orously designed trials examining the effect of RBC
transfusion on cerebral oxygenation and more
importantly, clinical outcomes in acute brain injury
are still urgently needed.
STUDIES ON THE HORIZON
There are several ongoing trials in Neurocritical Care
that have the potential to make significant contri-
butions relating to the role of Hb, specifically RBC
transfusion, in optimizing clinical outcomes in
brain injury and are worthy of keeping watch for.
These include:
(1) SAHaRA (NCT03309579): this is a Canadian-led
prospective randomized open-label blinded
endpoint trial in 740 adults with incident aneu-
rysmal subarachnoid hemorrhage and moderate
anemia (Hb  100 g/l) examining the effect of a
liberal versus restrictive RBC transfusion trigger
strategy (100 vs. 80 g/l) during the first 21
days. The primary outcome is functional neuro-
logic outcome at 12 months using the modified
Rankin Scale.
(2) HEMOTION (NCT03260478): another Canadian-
led randomized trial examining two different RBC
transfusion trigger strategies (restrictive: 70 g/l
vs. liberal: 100 g/l) during initial ICU stay in 712
adults with moderate and severe traumatic brain
injury. The primary outcome is functional neuro-
logic outcome at 6 months using the Glasgow
Outcome Scale – extended version.
(3) BOOST 3 (https://nett.umich.edu/clinical-trials/
boost-3): the investigators propose to enrol 1094
patients within 6 h of severe traumatic brain injury
to test the effect of a protocol based on brain-tissue
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oxygen monitoring compared with a protocol
based on ICP management without brain tissue
oxygen monitoring has an effect on 6 month
neurologic functional outcome as assessed by
the Glasgow Outcome Scale –extended version.
CONCLUSION
Hb is a key determinant in DO2 and hence in cere-
bral oxygenation. Low Hb, anemia, may not only
negatively affect cerebral oxygenation but also in
the injured brain, initiate a myriad of compensatory
effects that may in fact propagate cerebral ischemia.
Higher Hb portends to better cerebral oxygenation.
Despite the physiologic rationale, whether this
remains true whenever higher Hb levels is achieved
with RBC transfusion is less evident – although the
majority of the existing literature would support this
notion. Furthermore, it is less evident if improved
DO2 results in improved utilization and metabo-
lism. Even less clear is at what trigger or threshold is
optimizing Hb with transfusion beneficial on clini-
cal outcome. Further study is still required.
Acknowledgements
None.
Financial support and sponsorship
S.E. is currently receiving grants from the Canadian
Institutes of Health Research and Canadian Blood Ser-
vices.
Conflicts of interest
There are no conflicts of interest.
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&& transfusion thresholds in patients with acute brain injury: an international
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This publication is the most recent in a series of published surveys examining
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39. English SW, Fergusson D, Chassé M, et al., Canadian Critical Care Trials
& Group. Aneurysmal SubArachnoid Hemorrhage—Red Blood Cell Transfu-
sion And Outcome (SAHaRA): a pilot randomised controlled trial protocol.
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This protocol study describes the methodological considerations of an ongoing
RBC transfusion trigger pilot trial in aneurysmal subarachnoid hemorrhage
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transfusion threshold on neurological recovery after traumatic brain injury.
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threshold on cerebral hemodynamics and oxygenation. J Neurotrauma 2015;
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&& transfusion guided by near infrared spectroscopy in neurocritically ill patients
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2017; 34:2553–2559.
This trial conducted in mixed neurocritical care population compared a transfusion
trigger strategy to a transfusion strategy directed by cerebral oxygenation mea-
surements using NIRS. It is the first trial of its kind in this population.
Volume 24  Number 2  April 2018