CLB-08999; No.

of pages: 6; 4C:
Clinical Biochemistry xxx (2015) xxxxxx

Contents lists available at ScienceDirect

Clinical Biochemistry
journal homepage: www.elsevier.com/locate/clinbiochem

Does the addition of RDW improve current ICU scoring systems?

Sarah Loveday a, Leanne Sinclair b, Tony Badrick a,c,
a
b
c

Faculty of Health Sciences and Medicine, Bond University, Robina, Australia

Wesley Laboratory, Sullivan Nicolaides Pathology, Taringa, Australia
RCPAQAP, Sydney, Australia

a r t i c l e

i n f o

Article history:
Received 27 February 2015
Received in revised form 31 March 2015
Accepted 2 April 2015
Available online xxxx
Keywords:
APACHE
RDW
ICU scoring systems

a b s t r a c t
Background: The aim of this study was to evaluate whether the addition of red blood cell distribution width
(RDW) improves the prognostic value of current intensive care unit (ICU) scoring systems, namely APACHE III.
Design and Methods: All patients admitted to a mixed ICU in Brisbane between June 2013 and July 2014 for
whom RDW was available were included in the study. Analyses included descriptive statistics, linear regression
correlation, and receiver operating characteristic (ROC) curves.
Results: The study included 708 patients for whom both ICU mortality prediction and RDW were available. In
univariate analysis higher RDW values were associated with increased hospital mortality. Adding RDW to
APACHE III increased the area under the ROC marginally (from 0.9586 to 0.9613). RDW was not correlated
with C-reactive protein, white cell count, or patient's length of stay in ICU.
Conclusion: RDW was an independent predictor of mortality. The addition of RDW to APACHE III improved
its mortality prediction marginally. The underlying mechanism of RDW elevation warrants further investigation.
2015 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Background
ICU scoring systems use physiological parameters to predict patient
mortality. A small number of studies have validated the usefulness of including RDW in ICU scoring systems owing to its prognostic value. A summary of the key issues and ndings of current studies is provided below.
ICU scoring systems
ICU scoring systems are a means of quantifying the severity of illness
in critical patients [1]. Scoring systems, though not typically used clinically in the decision to withhold or withdraw treatment, are essential
in improvement of clinical decisions [2,3]. Their uses include: predicting
patient outcome; monitoring treatment efcacy; optimizing the use of
resources; and comparing performance within clinical trials and across
different centres [3,4]. The Acute Physiologic and Chronic Health Evaluation (APACHE) is one of the most commonly used ICU scoring systems,
predicting mortality based upon data collected on the day of ICU admission [4].
APACHE was the rst scoring system proposed to predict mortality
[5]. Developed in the 1980s with data from two American ICUs, it
included 33 physiological variables in addition to an assessment of
chronically ill health [5,6]. Subsequent revisions have been made since
its inception to improve APACHE's mortality prediction [7]:
Corresponding author at: Suite 201, level 2, 8 Herbert Street, St Leonards, Sydney
Australia 2065.
E-mail address: tony.badrick@rcpaqap.com.au (T. Badrick).

APACHE II (1985) physiologic values reduced to 12; inclusion of

age, chronic health status, and 56 disease groups (allowing outcome
comparisons among ICUs that were adjusted for differing patient
case-mix).
APACHE III (1991) data elements selected based upon a scientic
evaluation of their impact on severity; the number and weightings
of physiologic variables were changed; the measurement of chronic
health status was revised with co-morbidities reduced from 16 to 7;
the number of disease groups expanded from 56 to 78; terms for
admission source were added; a variable for operative status was
included in the model; and additional equations were constructed for
use with patients undergoing coronary artery bypass grafting surgery.
APACHE III-i (1998) the number of disease groups increased to 94.
APACHE III-j (2001) a variable that rescaled the PaO2:FiO2 ratio was
included, and this variable along with age had spline terms added.
APACHE IV (2006) updated to reect changes in protocols and practices within ICUs; number of disease groups increased from 94 to 116.
In future versions of APACHE, Cerner intend to include additional
chronic health items and laboratory measurements, and eventually
genomic information [7].
The potential use of RDW in ICU scoring systems
A routine full blood count (FBC) reports RDW as a measure of the
variation in the size of the red blood cells in a patient [810]. No clinical
scenarios result in an RDW less than the lower limit, 11.0%, but many
disease processes can elevate the RDW above the upper limit, 14.5%

http://dx.doi.org/10.1016/j.clinbiochem.2015.04.002
0009-9120/ 2015 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Please cite this article as: Loveday S, et al, Does the addition of RDW improve current ICU scoring systems?, Clin Biochem (2015), http://
dx.doi.org/10.1016/j.clinbiochem.2015.04.002

S. Loveday et al. / Clinical Biochemistry xxx (2015) xxxxxx

Table 1
Mechanisms associated with elevated RDW [16].

Table 3
Statistical signicance of RDW in predicting mortality.

Mechanisms associated with elevated RDW

Study

Statistical signicance

[13]
[8]

RDW N 15.8% OR 1.53 (95% CI 1.032.28; P b 0.035)

RDW 13.314.0% OR 1.19 (95% CI 1.081.30; P b 0.0001);
RDW 14.014.7% OR 1.28 (95% CI 1.161.42; P b 0.0001);
RDW 14.715.8% OR 1.69 (95% CI 1.531.87; P b 0.0001);
RDW N 15.8% OR 2.62 (95% CI 2.392.88; P b 0.0001);
All relative to patients with RDW 13.3%
Mortality rate per RDW tertile: tertile I = 11.2%, tertile II = 18.8%,
tertile III = 33.8%; all P b 0.001
Per 1% increase in RDW OR 1.10 (95% CI 1.061.15; P b 0.0001)
Per femtolitre of RDW OR 1.04 (95% CI 1.021.06; P b 0.001)
OR 1.1 (95% CI 1.031.16; P b 0.002)

Cigarette smoking
Nutritional deciencies
Obesity
Oxidative stress
Physical inactivity/sedentary lifestyle
Increased circulating immature red blood cells
Impaired iron metabolism
Increased blood viscosity and other thrombotic mechanisms
Suppressed bone marrow function
Haemolysis
Abnormal haemoglobin variants
Neurohormonal and endocrine system activation
Diminished capacity for systemic repair, recovery and defense
Tissue hypoxia/hypoxemia
Physiologic impairments associated with ageing
Chronic hyperglycemia
Shorter telomere length

[8], as indicated in Table 1. RDW has been proposed for inclusion to

improve the mortality prediction of APACHE as it has been shown as a
prognostic indicator of mortality in cases of: bacteremia; respiratory
disease; renal and liver disease; bone marrow disease; acute cerebral
infarction; community-acquired pneumonia; and cardiovascular disease including coronary disease, myocardial infarction, heart failure,
stroke, peripheral artery disease and pulmonary hypertension [2,8,
1114]. As this parameter is already determined as part of the FBC no
additional costs would be associated with its measurement for inclusion
in ICU scoring systems.
ICU specic studies
ICU specic investigations of the prognostic power of RDW on
patient mortality originate from Turkey [13] China [4,14], the United
States of America [8,15] and the Netherlands [9]. Table 2 lists a brief
summary of these studies' ndings.
Method of evaluation
The authors appropriately evaluate the relationship between RDW
and mortality by utilizing regression analysis. Each study was able to
show, with statistical signicance, that the odds of mortality are greater
when RDW is elevated, regardless of how the study populations were
stratied or adjusted (Table 3).

[4]
[15]
[9]
[14]

Zhang et al. [14] and Hunziker et al. [15] whereas Wang et al. [4]
excluded patients if they had a history of recent blood transfusion
(less than 2 weeks); Meynaar et al. [9] excluded patients who had
received a blood transfusion in the preceding three months; and Bazick
et al. [8] included patients who had received transfusion 48 h before
critical care initiation. Exclusion of patients with recent transfusion is
an important consideration when investigating whether the addition
of RDW improves ICU scoring systems, as this parameter is not typically
included in the calculation. RDW may be increased by transfusions [9],
which may subsequently skew the relationship between RDW and mortality if blood transfusion is not an independent predictor of mortality
[17], or strengthen it if patients who receive transfusions have an
increased mortality rate [18,19]. The investigation of populations
stratied by transfusion history is warranted to validate whether such
a phenomenon exists.
Different patient populations also exist between studies because of
the patient types within the different hospital settings. Hunziker et al.
[15] included all adult patients admitted to ICU including medical, cardiac, surgical, and cardiothoracic; Meynaar et al. [9] did not include cardiac surgery and neurosurgery patients; and Wang et al. [4] did not
include any surgery patients at all. This is an important consideration
as heterogeneity may lower the discriminating power of RDW, hence
further studies are warranted to investigate whether analysis restricted
to certain subgroups can improve the diagnostic performance of RDW
[14]. Future studies in the improvement of ICU scoring systems by the
addition of RDW must include all types of ICU patients to reect the
utility of current scoring systems.
Differences also exist in the type of data recorded and the adjustments made in each study. Whilst all studies recorded age, sex and

Exclusion parameters, included data and adjustments

Differences exist between the studies in regard to the exclusion
parameters utilised. For example, Bazick [8] excluded patients with
white blood cell counts N 150 109 L (as it would interfere with RDW
determination) but other studies did not. Surprisingly, there was no
mention of transfusion history in some studies Topeli et al. [13],

Table 2
Current study ndings linking RDW to mortality.

Table 4
Adjustments in multivariate analysis.
Study Adjustments
[8]
[15]
[9]
[14]

DeyoCharlson index, age, sex, race, coronary artery bypass grafting, myocardial
infarction, haematocrit, WBC, MCV, BUN, sepsis, creatinine
SAPS, age, gender, haematocrit, different comorbidities
APACHE II score, age, admission type, mechanical ventilation
DeyoCharlson Index

Study Signicant nding

[13]
[8]
[4]
[15]
[9]
[14]

Elevated ICU RDW (N15.8) is an independent factor associated with increased

hospital mortality.
RDW is a particularly strong predictor of all cause mortality 30 days
following ICU admission.
There is a signicantly graded increase in ICU mortality rate across
increasing RDW tertile.
RDW is signicantly associated with ICU mortality.
Increased RDW is an independent prognostic factor for hospital mortality in
critically ill patients.
RDW is signicantly associated with hospital mortality after ICU discharge.

Table 5
Patient inclusion and admittance data.
Study

Number of patients included

Patient admission date to ICU

[13]
[8]
[4]
[15]
[9]
[14]

702
51,413
602
17,922
2915
1539

January 2003 to December 2005

1997 to 2007
January 2009 to March 2010
January 2001 to December 2008
May 2005 to December 2011
October 2009 to December 2012

Please cite this article as: Loveday S, et al, Does the addition of RDW improve current ICU scoring systems?, Clin Biochem (2015), http://
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S. Loveday et al. / Clinical Biochemistry xxx (2015) xxxxxx

Table 6
Population characteristics.
Summary statistics

Total population

Survived ICU

Died in ICU

Gender

1058
Patients
650
Male
408
Female
133
Ward
855
OT/Recovery
42
Accident & Emergency
28
Other Hospital
275
Cardiovascular
154
Gastrointestinal
27
Gynaecological
5
Haematological
17
Metabolic
60
Musculoskeletal/skin
209
Neurological
6
Other medical disorder
42
Renal/Genitourinary
200
Respiratory
57
Sepsis
5
Trauma
1
Undened/Unknown
66.1 (15.5)
2.4 (3.5)
13.3 (5.6)
0.1450 (0.1600)
45.0 (18.6)
25.2 (12.3)
0.1070 (0.1483)
14.5 (2.0)

1031
Patients
635
Male
396
Female
115
Ward
850
OT/Recovery
40
Accident & Emergency
26
Other Hospital
269
Cardiovascular
154
Gastrointestinal
27
Gynaecological
3
Haematological
17
Metabolic
60
Musculoskeletal/Skin
207
Neurological
6
Other medical disorder
41
Renal/Genitourinary
198
Respiratory
44
Sepsis
4
Trauma
1
Undened/Unknown
66.0 (15.4)
2.3 (3.4)
12.9 (5.1)
0.1320 (0.1368)#
43.6 (16.1)
24.4 4.4 (11.0)
0.0943 (0.1200)
14.5 (2.0)##

27
15
12
18
5
2
2
6
2
2
1
2
13
1

Source

ICU Diagnosis

Age
Length of ICU stay
APACHE II
APACHE II ROD
APACHE III
SAPS II
SAPS II ROD
RDW

Patients
Male
Female
Ward
OT/Recovery
Accident & Emergency
Other Hospital
Cardiovascular
Haematological
Neurological
Renal/Genitourinary
Respiratory
Sepsis
Trauma

71.4 (17.8)
4.3 (4.1)
27.1 (7.1)
0.6014 (0.2367)^
99.7 (26.7)
57.1 (16.7)
0.5913 (0.2718)
16.7 (2.2)^^

907 patients.
708 patients.
#
882 patients.
##
599 patients.
^
25 patients.
^^
19 patients.

RDW, additional information gathered was typically dependent on the

physiological scoring system used in the hospital setting: APACHE II
[4,9,13]; DeyoCharlson Index [4,8,14,15]; or SAPS Hunziker et al.
[15]. Additionally, the data utilized in making adjustments is unclear in
some studies [4,13] whereas other studies specied this explicitly
(Table 4).

conclusions can be drawn. For example, Hunziker et al. [15] noted that
their patient-history lacked transfusion information hence they were
unable to correct for this factor. Potential bias due to lack of information
can be overcome, in part, by using multivariate analysis, as in Zhang
et al. [14], but ultimately gaps in patient data limit the accuracy and
application of the models developed.

Number of patients in study

Addition of RDW to ICU scoring systems

Peduzzi et al. [20] stipulate that the minimum number of patients

required in a study, N, is dependent upon the smallest proportion of
negative (or positive) cases in the population, p, and the number of covariates, k, such that N = 10 k/p. It is unclear whether the current studies
have included sufcient patients for a statistically valid prediction
(Table 5); those with larger studies, Bazick et al. [8] and Hunziker et al.
[15], appear more reliable.

Some studies have investigated whether the addition of RDW

improves ICU scoring systems. Combining RDW and APACHE II score
increases the area under the ROC (AUROC) for predicting ICU mortality
as shown by Wang et al. [4] (from 0.832 0.020 to 0.885 0.017;
P b 0.05) and Meynaar et al. [9], albeit marginal (from 0.845 to 0.849,
P b 0.001). SAPS is also improved by the addition of RDW as shown by
Hunziker et al. [15] (AUROC from 0.793 to 0.805; P b 0.001). However,
these studies do not utilize the most recent ICU scoring systems developed, which have superior accuracy for outcome prediction [9,15],
hence further investigation with current scoring systems is required.

Missing information
Retrospective observational studies utilize previously recorded data.
Consequently, data necessary to understand the pathophysiology
underlying RDW differences (e.g. reticulocyte count, iron studies, transfusion history) may be lacking for all or a proportion of patients [9,15].
Lack of information limits what adjustments can be made and what

Table 7
RDW as a predictor of mortality in all ICU patients.

Materials and methods

The aim of the study was to determine whether the addition of RDW
to the current ICU scoring system utilized by The Wesley Hospital,

Table 8
RDW as a predictor of mortality in ICU patients with normal MCVs.

Parameter

Number

Hospital mortality

Parameter

Number

Hospital mortality

RDW b13.1
RDW 13.113.9
RDW 13.915.3
RDW 15.3

161
164
188
195

0 (0.0%)
1 (0.6%)
3 (1.6%)
15 (7.7%)

RDW b13.1
RDW 13.113.9
RDW 13.914.9
RDW 14.9

120
122
110
151

0 (0.0%)
1 (0.8%)
2 (1.8%)
10 (6.6%)

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Brisbane, would improve its mortality prediction. Deidentied laboratory and ICU data was gathered for all patients admitted to ICU from July
1st 2013 to June 30th 2014. The ICU provided data for all 1058 patients
admitted in this time period with measurements taken within the rst
24 h after patients were admitted to ICU. A single laboratory provided
data for 989 of these patients, including measurements within the rst
24 h after patients were admitted to ICU and measurements taken up
until the patients left ICU. The datasets were merged using date of
birth and gender as common identiers, as all ICU patients were determined to have unique dates of birth with respect to their ICU number,
and patients were excluded if mortality prediction or RDW was not
available. This resulted in a total of 708 patients for whom both ICU
mortality prediction and RDW were available. A summary of the patient
population is provided in Table 6.
Whilst ICU calculates APACHE II, APACHE III and SAPS II scores, only
the most current scoring system, APACHE III, is investigated in this
study.
To adjust for patients who may have an elevated RDW due to recent
transfusion, nutritional deciencies, haemoglobinopathies, etc., a population subset was created to minimize confounding effects. This subset
included only those patients with a normal mean cell volume (MCV),
between 85 and 95 inclusive to exclude those patients with an elevated
RDW due to B12/folate deciency or iron deciency anaemia.
Univariate analysis, using quartiles, was undertaken to assess the
prognostic power of RDW and RWD + APACHE III score. Descriptive
statistics were calculated online (http://www.calculatorsoup.com/
calculators/ statistics/descriptivestatistics.php) with counts determined
using Microsoft Excel 2010.
To assess the accuracy of the APACHE III score in predicting mortality, the AUROC was calculated. Similarly, the accuracy of RDW to predict
mortality and the accuracy of RDW + APACHE III score to predict
mortality was assessed by calculating the AUROC. ROCs were determined by calculating the sensitivity and specicity at every threshold
(708 data points for the entire population, 503 data points for the normal population); AUROCs were calculated using the trapezoidal rule.
(Calculations performed in Microsoft Ofce 2010 from rst principles.)
Finally, to investigate the cause of RDW elevation, RDW and white
cell count (WCC), and RDW and C-reactive protein (CRP), were correlated. All cell counts and derived parameters were performed on the same
analyser for the entire period (Sysmex XN-1000, Sysmex Corporation,
Japan). To assess the prognostic value of RDW on length of stay (LOS),
RDW and LOS were correlated. A further investigation in how RDW
changes over a patient's LOS was also included for those patients who
died in ICU, for whom serial RDW measurement was obtained, compared
to similarly matched patients who survived ICU. Graphical data generated
in Microsoft Excel 2010.
Results
Univariate analysis, using quartiles, indicated that as RDW increased
so too did mortality for all ICU patients (Table 7) and for those with
normal MCVs (Table 8). Similarly, as RDW + APACHE III score
increased, so too did mortality in both patient groups (Tables 9 and 10),
suggesting both RDW and RDW + APACHE III score are good predictors
of mortality.
The AUROC analysis revealed that RDW is a better prognostic predictor of mortality in patients with a normal MCV and that the addition of
Table 9
RDW + APACHE III score as a predictor of mortality in all ICU patients.
Parameter

Number

Hospital mortality

RDW + APACHE III b47.4

RDW + APACHE III 47.457.0
RDW + APACHE III 57.070.0
RDW + APACHE III 70.0

176
177
177
178

0 (0.0%)
1 (0.6%)
0 (0.0%)
18 (10.1%)

Table 10
RDW + APACHE III score as a predictor of mortality in ICU patients with normal MCVs.
Parameter

Number

Hospital mortality

RDW + APACHE III b46.4

RDW + APACHE III 46.455.7
RDW + APACHE III 55.768.5
RDW + APACHE III 58.5

125
124
130
124

0 (0.0%)
1 (0.8%)
0 (0.0%)
12 (9.7%)

RDW to APACHE III score increased mortality prediction (more so in the

population of all patients than the subset of patients with a normal
MCV Table 11).
When assessing the entire population for whom data is available,
there were no signicant correlations found between RDW and WCC
(Fig. 1), RDW and CRP (Fig. 2) or RDW and LOS (R2 = 0.02037, data
not shown). Fig. 3 shows the lack of correlation between RDW and
LOS for surviving patients to compare with the results of Zhang et al.
[14].
Quantifying how RDW changes over a patient's LOS revealed that the
greatest rates of change occurred in survivors (Fig. 4).

Discussion
The results are consistent with previous studies that have shown
that mortality is greater when RDW is elevated. Univariate analysis
also revealed that mortality increases when RDW + APACHE III score
increases.
The addition of RDW to APACHE III score increased mortality prediction marginally as quantied by AUROC analysis. Interestingly, RDW
was found to be a better prognostic predictor of mortality in patients
with a normal MCV than in the entire population, whereas APACHE
III and RDW + APACHE III score were better predictors in the entire
population when compared to the normal population.
The lack of correlation between RDW and WCC, and RDW and CRP
is consistent with the ndings of Maynaar et al. [9], supporting the conclusion that RDW is not a result of inammation. It is important to note
that CRP was only available for 86 patients, all of whom were survivors,
and some of whom had multiple serial CRP/RDW paired scores included
to give the 142 data points analysed. A possible association between
RDW and sepsis warrants further investigation as it was found to be
the most prevalent diagnosis of patients who died in ICU.
The nding of Zhang et al. [14] that RDW and LOS are correlated was
not supported. Neither the entire population nor the subset of survivors
in the total population showed a correlation between RDW and LOS.
Zhang et al. [14] had also reported that repeated measurements of
RDW provide no additional prognostic value in critically ill patients.
Quantifying how RDW changes over a patient's LOS revealed the greatest
rates of change, as either an increase or decrease, occurred in survivors,
potentially providing additional prognostic value and warranting further
investigation.
The strengths of the study are that differences in parameter measurement, by other laboratories or point of care devices, is minimized
as data from only one laboratory was used and patients without RDW
recorded in the laboratory data were excluded. Results from the laboratory are valid as blood samples are processed immediately on site before
any signicant changes in MCV, and hence RDW, occur.
Table 11
Improvement in APACHE III ROC with addition of RDW.
Parameter

RDW
APACHE III
RDW + APACHE III

AUROC
All patients

Normal MCV

0.8114
0.9586
0.9613

0.8124
0.9443
0.9466

Please cite this article as: Loveday S, et al, Does the addition of RDW improve current ICU scoring systems?, Clin Biochem (2015), http://
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S. Loveday et al. / Clinical Biochemistry xxx (2015) xxxxxx

Fig. 1. Lack of correlation between RDW and WCC.

Several weaknesses and limitations exist in this study. Firstly, the

limiting nature of a retrospective study resulted in small and biased
populations in some analyses such as RDW and CRP correlation and
how RDW changes over LOS. Confounded by data storage issues, a larger
dataset including patients admitted prior to 2013 was not accessible.
Also, data pertaining to the cause of elevated RDW is lacking, such as
reticulocyte count, serum B12 and iron studies, as these are not part of
routine biochemistry or full blood count; transfusion history was not
available either. Secondly, the accuracy of the APACHE scores generated
from ICU is inherently erroneous as not all parameters are recorded in
the same manner for all patients. For example, blood gases recorded
1 h prior to ICU admission are used when no blood gas was taken
in the rst 24 h, and only the highest value of a parameter being
measured/recorded instead of both the highest and lowest. Thirdly,
statistical analyses do not include multivariate analysis, condence
intervals or P-values.
Analysis of larger datasets with sufcient statistical rigour is required
to validate the ndings of this study. Subsequent analysis of subgroups
within heterogeneous ICU populations also warrants further study. To
better understand the dynamic changes that occur in RDW over ICU
LOS, RDW values prior to ICU admission should be included to assess

if/when an acute change occurs. Thus the usefulness of RDW could also
be extended further to predict ICU admission. Additionally, parameters
not utilized in the APACHE scoring system warrant further investigation
to understand the pathophysiology underlying RDW differences and to
identify other potential indicators of mortality.

Conclusion
RDW was found to be an independent predictor of mortality in ICU
patients. The addition of RDW to APACHE III improves its mortality
prediction marginally. No correlation was found between RDW and
WCC, CRP or LOS. Further investigations are warranted to understand
the cause of elevated RDW and how RDW changes over hospital and
ICU LOS.

Acknowledgements
The authors would like to thank Dr Ranald Pasoce, Director of
Intensive Care, The Wesley Hospital, Brisbane.

Fig. 2. Lack of correlation between RDW and CRP.

Please cite this article as: Loveday S, et al, Does the addition of RDW improve current ICU scoring systems?, Clin Biochem (2015), http://
dx.doi.org/10.1016/j.clinbiochem.2015.04.002

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Fig. 3. Lack of correlation between RDW and LOS.

Fig. 4. Change in RDW over length of stay.

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Please cite this article as: Loveday S, et al, Does the addition of RDW improve current ICU scoring systems?, Clin Biochem (2015), http://
dx.doi.org/10.1016/j.clinbiochem.2015.04.002