Post on 14-Dec-2016
ORIGINAL ARTICLE
The impact of anemia in moderate to severe traumatic braininjury
O. Okoye • K. Inaba • M. Kennedy •
A. Salim • P. Talving • D. Plurad • L. Lam •
D. Demetriades
Received: 31 January 2013 / Accepted: 1 June 2013
� Springer-Verlag Berlin Heidelberg 2013
Abstract
Purpose The impact of anemia and restrictive transfusion
strategies in traumatic brain injury (TBI) is unclear. The
purpose of this study was to examine the outcome of
varying degrees of anemia in patients who have sustained a
TBI.
Methods We performed a retrospective study of all adult
patients with isolated blunt TBI admitted between January
2003 and June 2010. The impact of increasing severity of
anemia (Hb B8, B9, or B10 g/dl measured on three con-
secutive draws within the first 7 days of admission) and
transfusions on complications, length of stay, and mortality
was examined using univariate and multivariate analysis.
Results Of the 31,648 patients with blunt trauma admitted
to the trauma service during the study period, 812 had an
isolated TBI, among which 196 (24.1 %) met at least one
of the anemia thresholds within the first 7 days [78 %
male, mean age 47 ± 23 years, Injury Severity Score
16 ± 8, and head Abbreviated Injury Scale 3.3 ± 1.0].
Using a logistic regression model, anemia even as low as
8 g/dl was not associated with an increase in mortality
[AOR8 = 0.8 (0.2, 3.2), p = 0.771; AOR9 = 0.8 (0.4,
1.6), p = 0.531; AOR10 = 0.6 (0.3, 1.3), p = 0.233] or
complications. However, for all patients, the transfusion of
packed red blood cells was associated with a significant
increase in septic complications [AOR = 3.2 (1.5, 13.7),
p = 0.030].
Conclusion The presence of anemia in patients with TBI
as low as 8 g/dl was not associated with increased mor-
tality or complications, while the transfusion of red blood
cells was associated with a significant increase in septic
complications. Prospective evaluation of an optimal
transfusion trigger in head-injured patients is warranted.
Keywords Traumatic brain injury � Surgery �Outcome measures � Guidelines
Introduction
Transfusion practices in the intensive care unit (ICU) have
undergone considerable changes over the last decade.
There is an increasing body of evidence supporting more
restrictive transfusion strategies across a wide range of
critically ill patient populations, including those who have
sustained traumatic injury [1–3].
Less clear, however, is the benefit of a restrictive
transfusion threshold for patients with traumatic brain
injury (TBI). The management of TBI patients focuses
on avoiding secondary neurologic insult from reduced
oxygen delivery as a result of hypoperfusion, hypox-
emia, and anemia. In theory, the transfusion of red blood
cells to correct anemia in TBI patients would seem
appropriate in order to optimize oxygen-carrying
capacity, and this has been demonstrated in a few small
studies [4, 5]. Practically, however, large studies have
failed to show a clear benefit of a more liberal transfu-
sion strategy [6, 7]. The available literature on anemia
and TBI is limited by inconsistent definitions of anemia
and by mixed results, with some studies showing worse
outcomes with anemia [8, 9] and others showing no
detrimental effect [10, 11].
O. Okoye � K. Inaba (&) � M. Kennedy � A. Salim � P. Talving �D. Plurad � L. Lam � D. Demetriades
Division of Trauma Surgery and Surgical Critical Care (Acute
Care Surgery), University of Southern California, 2051 Marengo
Street, Room C5L100, Los Angeles, CA 90033-4525, USA
e-mail: kenji.inaba@med.usc.edu; kinaba@surgery.usc.edu
123
Eur J Trauma Emerg Surg
DOI 10.1007/s00068-013-0307-1
Given our increasing understanding that the transfusion
of blood products is not without consequences and that
these infectious and inflammatory risks are not negligible
[2, 12, 13], the current study examines the outcomes
associated with varying degrees of anemia, as well as the
impact of red blood cell transfusion, in patients who have
sustained a TBI. Having previously established that anemia
as low as 9 g/dl is safely tolerated in TBI [12], in this
analysis, a threshold of 8 g/dl was specifically examined.
Methods
After institutional review board (IRB) approval, all patients
sustaining a blunt TBI admitted to the Los Angeles
County ? University of Southern California Medical
Center Surgical Intensive Care Unit (SICU) between Jan-
uary 1, 2003 and June 30, 2010 were identified through the
institutional trauma registry. Included patients had a history
of head trauma and an intracranial abnormality on initial
head computed tomography (CT). Patients who died within
48 h of hospital admission, had an Abbreviated Injury
Scale (AIS) C3 in other body regions, or sustained non-
survivable head injuries (head AIS = 6) were excluded.
Patient variables abstracted included age, gender,
admission vital signs, Glasgow Coma Scale (GCS), Injury
Severity Score (ISS), AIS, blood products transfused, daily
hemoglobin (Hb) levels during the first week of hospital
stay, ICU length of stay (LOS), hospital LOS, complica-
tions [acute respiratory distress syndrome (ARDS), sepsis
and acute renal failure (ARF), as well as mortality. ARDS
was defined as the presence of: (a) PaO2/FiO2 B200,
(b) chest radiograph demonstrating bilateral infiltrates, and
(c) no evidence of cardiac failure on pulmonary artery
catheterization (PaOP B18 mmHg) or by echocardiogra-
phy or clinical examination. Sepsis was defined as the
presence of an infection plus at least two of the following:
(a) heart rate[90 bpm, (b) respiratory rate[20 breaths/min,
(c) temperature \36 �C or [38 �C, (d) white blood cell
count \4,000 cells/mm3 or [12,000 cells/mm3, or [10 %
immature neutrophils.
ARF was defined as: (a) serum creatinine three-fold
higher than the normal limit, or (b) glomerular filtration
rate decrease[75 % from baseline, or (c) serum creatinine
C4 mg/dl with an acute rise [0.5 mg/dl, or (d) urinary
output \0.3 ml/kg/h 9 24 h, or anuria 9 12 h. Coagu-
lopathy was defined as a raised international normalized
ratio (INR) above the normal reference range (C1.5), a
prolonged activated partial thromboplastin time (aPTT)
[36 s, or a platelet count \100,000.
Per protocol, patients admitted to the ICU have a com-
plete blood count (CBC), chemistry panel, and coagulation
panel drawn at admission and every 6 h until they became
clinically stable. These blood draws were then performed
daily. Additional laboratory investigations are performed
as clinically indicated.
Persistent anemia was defined and analyzed at three
different thresholds (Hb B8, B9, and B10 g/dl). To meet
the definition of anemia, patients had to have met the
threshold on three consecutive days within the first week of
admission. Demographic characteristics, clinical factors,
and outcomes were compared between anemic and non-
anemic patients for each of the anemia thresholds. The
relationship between persistent anemia during the first
week of admission and patient outcomes was evaluated
using univariate and multivariate analyses. Continuous
variables were dichotomized for analysis using clinically
relevant cut-points: age (C55 vs.\55 years), systolic blood
pressure on admission (\90 vs. C90 mmHg), GCS (B8 vs.
[8), ISS (C15 vs. \15), and AIS (C3 vs. \3).
Univariate analysis compared the anemic and non-ane-
mic patients. The two-sample t- or Mann–Whitney U-tests
were used to compare means and the Chi-square or Fisher’s
exact test was used to compare proportions. Variables
differing significantly at p \ 0.05 were entered into a
binomial logistic regression model. Continuous variables
are reported as the mean ± standard deviation (SD).
Logistic regression was used to report on categorical
variables, while linear regression was used for conti-
nuous variables. All statistical analyses were performed
using SPSS for Windows, version 17.0 (SPSS, Chicago, IL,
USA).
Results
Over the 7-year study period, 31,648 blunt trauma patients
were admitted to the Los Angeles County ? University of
Southern California Medical Center. Of these, 2,307 (7 %)
sustained a TBI. After the exclusion of 1,495 patients
(65 %) who sustained either non-survivable injuries or
multisystem trauma, 812 patients (35 %) were included in
the study. The mean age of the study patients was
48 ± 23 years and 78 % were male. The mean Hb on
admission was 13.1 ± 2.1 mg/dl, with 73 patients (9 %)
presenting with an Hb B10 g/dl on the initial laboratory
assessment. Admission coagulopathy occurred in 20 % of
patients. The mean head AIS and ISS were 3.3 ± 1.0 and
15.9 ± 8.5, respectively. Within the first week of hospi-
talization, 23 % of the patients received C1 U of packed
red blood cells (pRBC). Table 1 summarizes the cohort’s
demographic and clinical characteristics.
Of the 812 patients with TBI, 325 (40 %) had at least
one Hb measurement B10 g/dl within the first week. 187
patients (23 %) met the B10 anemia threshold with three
consecutive values B10 g/dl, 128 (16 %) met the B9
O. Okoye et al.
123
Ta
ble
1C
har
acte
rist
ics
of
the
stu
dy
po
pu
lati
on
atv
ary
ing
cut-
po
ints
for
anem
ia
An
emia
B8
g/d
l9
3d
ays
(18
)
No
n-a
nem
ic
(79
4)
p-V
alu
eA
nem
ia
B9
g/d
l9
3d
ays
(12
8)
No
n-a
nem
ic
(68
4)
p-V
alu
eA
nem
ia
B1
0g
/dl
93
day
s(1
87
)
No
n-a
nem
ic
(62
5)
p-V
alu
e
Ag
e
Mea
n±
SD
51
.1±
20
.44
7.6
±2
2.7
0.5
23
50
.4±
22
.54
7.2
±2
2.6
0.1
37
48
.7±
22
.84
7.4
±2
2.6
0.4
85
n(%
)C
55
8/1
8(4
4.4
%)
30
7/7
94
(38
.7%
)
0.6
31
56
/12
8(4
3.8
%)
25
9/6
84
(37
.9%
)
0.2
36
78
/18
7(4
1.7
%)
23
7/6
25
(37
.9%
)
0.3
92
Mal
eg
end
er,
n(%
)1
1/1
8(6
1.1
%)
62
0/7
94
(78
.1%
)
0.0
93
88
/12
8(6
8.8
%)
54
3/6
84
(79
.4%
)
0.0
11
13
5/1
87
(72
.2%
)4
96
/62
5
(79
.4%
)
0.0
45
Sy
sto
lic
blo
od
pre
ssu
re
Mea
n±
SD
13
0±
22
14
3±
29
0.0
59
14
0±
30
14
4±
29
0.2
94
14
0±
30
14
4±
28
0.0
97
Hy
po
ten
sio
n(S
BP
B9
0m
mH
g)
1/1
7(5
.9%
)1
3/7
81
(1.7
%)
0.2
62
2/1
26
(1.6
%)
12
/67
2(1
.8%
)1
.00
05
/18
5(2
.7%
)9
/61
3(1
.7%
)0
.33
3
GC
S
n(%
)B
84
/18
(22
.2%
)1
93
/78
4
(24
.6%
)
1.0
00
43
/12
6(3
4.1
%)
15
4/6
76
(22
.8%
)
0.0
09
59
/18
5(3
1.9
%)
13
8/6
17
(22
.8%
)
0.1
71
Mea
nH
bo
nad
mis
sio
n9
.7±
1.5
13
.2±
2.0
\0
.00
11
1.1
±2
.01
3.6
±1
.8\
0.0
01
11
.3±
2.0
13
.7±
1.7
\0
.00
1
Co
agu
lop
ath
yo
n
adm
issi
on
8/1
8(4
4.4
%)
15
8/7
94
(19
.8%
)
0.0
17
51
/12
8(3
9.8
%)
11
5/6
84
(16
.8%
)
\0
.00
17
0/1
87
(37
.4%
)9
6/6
25
(15
.4%
)
\0
.00
1
Hea
dA
IS
n(%
)[
31
0/1
8(5
5.6
%)
35
1/7
94
(44
.2%
)
0.3
49
69
/12
8(5
4%
)2
92
/68
4
(42
.7%
)
0.0
20
99
/18
7(5
3%
)2
62
/62
5
(43
.7%
)
0.0
09
Su
b-a
rach
no
id
hem
ato
ma
7/1
8(3
8.9
%)
27
5/7
94
(34
.6%
)
0.8
03
47
/12
8(3
6.7
%)
23
5/6
84
(34
.4%
)
0.6
14
70
/18
7(3
7.4
%)
21
2/6
25
(33
.9%
)
0.3
82
Su
b-d
ura
lh
emat
om
a1
2/1
8(6
6.7
%)
56
5/7
94
(71
.2%
)
0.7
93
92
/12
8(7
1.9
%)
48
5/6
84
(70
.9%
)
0.8
33
13
1/1
87
(70
.1%
)4
46
/62
5
(71
.4%
)
0.7
83
Ep
idu
ral
hem
ato
ma
2/1
8(1
1.1
%)
41
/79
4(5
.2%
)0
.24
61
2/1
28
(9.4
%)
31
/68
4(4
.5%
)0
.03
21
2/1
87
(6.4
%)
31
/62
5(5
.0%
)0
.45
7
Oth
erin
trac
ran
ial
ble
ed
11
/18
(61
.1%
)5
02
/79
4
(63
.2%
)
1.0
00
80
/12
8(6
2.5
%)
43
3/6
84
(63
.3%
)
0.9
21
11
4/1
87
(61
.0%
)3
99
/62
5
(63
.8%
)
0.4
90
ISS M
ean
±S
D1
7.6
±6
.51
5.8
±8
.50
.37
81
9.2
±8
.91
5.3
±8
.3\
0.0
01
19
.5±
9.9
14
.8±
7.7
\0
.00
1
n(%
)C
15
11
/18
(61
%)
43
3/7
94
(54
.5%
)
0.6
39
87
/12
8(6
8.0
%)
35
7/6
84
(52
.2%
)
0.0
01
13
2/1
87
(70
.6%
)3
12
/62
5
(49
.9%
)
\0
.00
1
pR
BC
tran
sfu
sio
n1
0/1
8(5
5.6
%)
17
9/7
94
(22
.5%
)
0.0
03
77
/12
8(6
0.2
%)
11
2/6
84
(16
.4%
)
\0
.00
11
01
/18
7(5
4.0
%)
88
/62
5
(14
.1%
)
\0
.00
1
pR
BC
un
its
(mea
n±
SD
)
8.7
±1
2.3
2.4
±7
.2\
0.0
01
7.2
±1
2.8
1.7
±5
.4\
0.0
01
6.8
±1
2.2
1.3
±4
.4\
0.0
01
FF
Pu
nit
s
(mea
n±
SD
)
4.9
±9
.31
.3±
4.2
\0
.00
13
.5±
7.5
1.0
±3
.4\
0.0
01
3.2
±6
.70
.8±
3.2
\0
.00
1
Pla
tele
tu
nit
s
(mea
n±
SD
)
1.9
±4
.70
.3±
1.4
\0
.00
10
.8±
2.2
0.2
±1
.40
.00
10
.6±
1.9
0.2
±1
.50
.00
6
The impact of anemia in moderate to severe traumatic brain injury
123
anemia threshold, and 18 (2 %) of the patients met the B8
anemia threshold with three consecutive values B8 g/dl
within the first week of hospitalization. No patients had an
Hb B7 g/dl. No significant differences in age were found
between the anemic and non-anemic patients at each of the
thresholds of anemia. Anemic patients were significantly
more likely to be coagulopathic on admission (44 vs. 20 %
at Hb B8 g/dl, p = 0.017; 40 vs. 17 % at Hb B9 g/dl,
p \ 0.001; and 37 vs. 15 % at Hb B10 g/dl, p \ 0.001).
Similarly, anemic patients had higher head AIS and ISS
scores. Anemic patients were significantly more likely to
be given a pRBC transfusion in the first week of hospital
admission (56 vs. 23 % at Hb B8 g/dl, p = 0.003; 60 vs.
16 % at Hb B9 g/dl, p \ 0.001; and 54 vs. 14 % at Hb
B10 g/dl, p \ 0.001) (Table 1).
Overall, 5 patients (0.6 %) developed ARF, 10 (1.2 %)
ARDS, and 16 (2 %) developed sepsis during their hospital
stay. Anemia at all three thresholds studied was not asso-
ciated with increased rates of these complications. Trans-
fusion did significantly increase the risk of septic
complications [AOR = 3.2 (1.5, 13.7) p = 0.030)
(Table 2).
The overall mortality for the cohort was 8.9 %. After
adjusting for differences in these populations, no significant
difference could be found at any of the thresholds [Hb8;
AOR = 0.8 (0.2, 3.2) p = 0.771, Hb9; AOR = 0.8 (0. 4,
1.6) p = 0.531, Hb10; AOR = 0.6 (0.3, 1.3) p = 0.233].
Anemia at all three thresholds was associated with longer
ICU and hospital LOS. The effect was more pronounced at
the B9 and B10 thresholds, though this finding did not
persist after multivariate correction (Table 3).
Discussion
The determination of appropriate transfusion triggers has
been an ongoing area of controversy in both the trauma
and the general medical literature. The dogmatic assertion
that all patients must be maintained at a minimum
hematocrit of 30 % [14] has been challenged in well-
designed trials illustrating the tolerability of anemia in a
wide range of patient populations, including critically ill
patients [1], those with a history of cardiac disease [15] or
post-cardiac surgery [16], and those who have sustained
traumatic injuries [3].
The amount of oxygen reaching end organs is depen-
dent on local blood flow and the arterial oxygen content,
which, in turn, is dependent on the concentration of Hb. In
the presence of anemia, numerous cerebrovascular com-
pensatory mechanisms act to improve flow. Worsening
anemia ultimately leads to a collapse of these mechanisms;
however, the threshold when this occurs is yet to be
identified [6]. Studies evaluating the impact of anemia onTa
ble
1co
nti
nu
ed
An
emia
B8
g/d
l9
3d
ays
(18
)
No
n-a
nem
ic
(79
4)
p-V
alu
eA
nem
ia
B9
g/d
l9
3d
ays
(12
8)
No
n-a
nem
ic
(68
4)
p-V
alu
eA
nem
ia
B1
0g
/dl
93
day
s(1
87
)
No
n-a
nem
ic
(62
5)
p-V
alu
e
Cry
op
reci
pit
ate
un
its
(mea
n±
SD
)
1.8
±5
.70
.2±
2.1
0.0
02
0.6
±2
.90
.2±
2.1
0.0
40
0.5
±2
.60
.2±
2.2
0.0
38
Ery
thro
po
ieti
nu
se1
/18
(5.6
%)
38
/79
4(4
.8%
)0
.59
21
7/1
28
(13
.3%
)2
2/6
84
(3.2
%)
\0
.00
12
4/1
87
(12
.8%
)1
5/6
25
(2.4
%)
\0
.00
1
p-V
alu
esw
ere
esti
mat
edu
sin
gF
ish
er’s
exac
tte
sto
rP
ears
on
’sC
hi-
squ
are
for
cate
go
rica
lv
aria
ble
s,an
dth
ein
dep
end
ent
t-te
stw
asu
sed
for
con
tin
uo
us
var
iab
les
O. Okoye et al.
123
TBI outcomes have used varying definitions of anemia,
resulting in a lack of consensus management guidelines.
Carlson et al. [9] studied the impact of anemia and trans-
fusions on the neurological outcomes in TBI patients,
establishing that a hematocrit\30 % was associated with a
significantly higher discharge GCS and Glasgow Outcome
Scale (GOS) scores. Contrary to this, Steyerberg et al.
performed a post-hoc analysis of several randomized con-
trolled trials (RCTs) and concluded that a lower Hb was
associated with poor outcomes at 3–6 months [17]. Salim
et al. [12] demonstrated that anemia as low as 9 g/dl was
safe and only associated with increased morbidity and
mortality in the presence of pRBC transfusion in patients
with TBI. The results of the current study show that anemia
down to 8 g/dl is not associated with a negative impact on
morbidity or mortality.
There is increasing evidence that blood transfusions in
critically injured patients may not be associated with a
negligible risk. The CRIT trial, which reviewed data from
284 ICUs, identified pRBC transfusion as a significant risk
factor for mortality in the ICU [18]. The same was true for
the subgroup analysis of trauma patients in 111 ICUs [19].
The TRICC trial demonstrated a significant in-hospital
survival advantage in patients randomized to the transfu-
sion-restrictive strategy [1]. In a prospective study of
15,534 patients over a 3-year period at a level 1 trauma
center, blood transfusion was identified as a strong inde-
pendent predictor of mortality and ICU admission [13].
The mechanism of this transfusion-related risk is likely
multifactorial, including an immunomodulatory pathway
ultimately leading to an increased risk of infectious com-
plications, prolonged mechanical ventilation, and organ
dysfunction [20, 21]. Available in vitro studies show that
pRBC reduce T cell proliferation in a dose-dependent
manner [22]. This finding is supported by the results of a
large registry analysis of 29,829 trauma patients over
15 years in Germany, which found that incremental units
of pRBC transfusion were associated with a significantly
increased risk of developing sepsis [23]. Transfusion-rela-
ted acute lung injury (TRALI) is now the most common
cause of transfusion-related mortality reported to the Food
and Drugs Administration [24].
In TBI patients, concerns about anemia-related cerebral
hypoperfusion and hypoxia complicate decision-making.
Recent literature has failed to show any benefit of a more
liberal transfusion strategy in this population [25, 26]. Data
in both multi-system trauma and isolated TBI patients
suggest that pRBC transfusions are linked with adverse
outcomes. Carlson et al. noted that increasing pRBC unit
transfusions negatively impacted discharge GCS and GOS
significantly [9]. These findings are echoed by Salim
et al.’s analysis of the impact of pRBC transfusions in
anemic TBI patients [12].Ta
ble
2R
isk
of
dev
elo
pin
gco
mp
lica
tio
ns
Acu
tere
nal
fail
ure
AR
DS
Sep
sis
AO
R(9
5%
CI)
p-V
alu
eA
OR
(95
%C
I)p
-Val
ue
AO
R(9
5%
CI)
p-V
alu
e
Hb
B8
6.7
(0.4
,1
31
.7)
0.2
08
0.0
00
.99
82
.2(0
.4,
14
.3)
0.3
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The impact of anemia in moderate to severe traumatic brain injury
123
The present study is a 7-year review of 812 patients who
sustained isolated TBI. Our aim was to examine the out-
comes associated with varying degrees of anemia, as well
as the impact of red blood cell transfusion in this patient
cohort.
Here, pRBC transfusion was associated with a five-fold
increase in septic complications. No difference in the
incidence of ARDS or ARF was noted between the groups;
however, the numbers of these complications were low.
Transfusion had no effect on mortality in this population.
Anemia at cut-points of 10 and 9 g/dl was associated
with increased length of both hospital and ICU stay. This is
consistent with previous studies in this population [12, 26].
No difference in LOS was observed in the 8 g/dl group.
This is presumably due to the lack of power.
TBI patients in our study demonstrated a 40 % inci-
dence of anemia (Hb B10 g/dl), consistent with previously
reported rates of 40–50 % [27]. Numerous mechanisms
contribute to the development of anemia in critically ill
patients, including: repeated blood draws [28–30], blunted
response of erythrocytes to erythropoietin [31–33], and
impaired iron metabolism [34, 35]. These patients had an
average of four blood draws in the first 24 h, translating to
45–60 ml of phlebotomized whole blood. This volume and
sampling practice is consistent with findings from other
institutions [2], and remains a target for reducing the
incidence of anemia in the ICU.
In summary, anemia in the presence of TBI is a common
problem facing physicians caring for victims of neuro-
trauma. This study was limited by its retrospective nature
and the inability to report on the neurological outcomes of
patients. The low sample size in the Hb \8 cohort did not
allow for a robust multivariate analyses, and the results
reported in that group may be imprecise. Another limita-
tion of the study is the inability to determine the rationale
for packed cell transfusions in non-anemic patients. These
transfusions were probably given for active bleeding or
drops in hemoglobin treated before the next day. The ret-
rospective nature of this study does not allow for distin-
guishing a clear cause and effect relationship between
transfusions and the patient outcomes. Within these limi-
tations however, the use of a restrictive transfusion policy
in patients with TBI is supported by the results.
Conflict of interest We confirm that the manuscript has been read
and approved by all named authors and that there are no other persons
who satisfied the criteria for authorship but are not listed. We further
confirm that the order of authors listed in the manuscript has been
approved by all of us. We wish to confirm that there are no known
conflicts of interest associated with this publication and there has been
no significant financial support for this work that could have influ-
enced its outcome.
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The impact of anemia in moderate to severe traumatic brain injury
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