MAJOR ARTICLE
Perioperative Blood Transfusion Is Predictive
of Poststernotomy Surgical Site Infection: Marker
for Morbidity or True Immunosuppressant?
Thomas R. Talbot,1 Erika M. C. D’Agata,1,a Vicki Brinsko,2 Byron Lee,4 Theodore Speroff,1,3,5 and William Schaffner1,3
Departments of 1Medicine, 2Infection Control, and 3Preventive Medicine and Centers for 4Clinical Improvement and 5Health Services Research,
Vanderbilt University School of Medicine, Nashville, Tennessee
To analyze risk factors for the development of adult poststernotomy surgical site infections (SSIs), we performed
a retrospective case-control study at a tertiary care hospital. Case patients with poststernotomy SSI between
June 1999 and January 2001 were matched to control subjects without poststernotomy SSI according to date
of procedure and age. Data were collected on known SSI risk factors. Of 711 procedures, we identified 38
cases with SSI and 114 matched controls. Univariate analysis revealed that receipt of transfused blood (odds
ratio [OR], 3.19; 95% confidence interval [CI], 1.54–6.62), diabetes (OR, 2.90; 95% CI, 1.27–6.59), length of
stay before hospitalization (OR, 1.19 per day; 95% CI, 1.02–1.37 per day), and American Society of Anesthesia
score (OR, 2.19; 95% CI, 1.04–4.64) were significantly associated with SSI. Multivariate analysis revealed that
transfusion (OR, 3.21; 95% CI, 1.41–7.31) and diabetes (OR, 3.65; 95% CI, 1.42–9.36) were predictors for SSI.
The exact role of blood transfusion in the pathogenesis of SSI, whether as a direct immunosuppressant or a
surrogate marker for morbidity, remains unresolved.
Surgical site infections (SSIs) have been associated with
increased morbidity and mortality and excess health
care costs [1]. Identification of factors that increase the
risk for SSIs following surgery is a key step in the reduction of morbidity and mortality. In particular, the
ascertainment of any modifiable risk factors would play
an essential role in the future reduction of SSI risk.
Some previous investigations have noted an association between blood transfusion and postoperative in-
Received 21 November 2003; accepted 14 January 2004; electronically published
28 April 2004.
fection [2–8], yet the controversial role of blood transfusion as a risk factor for such infections has received
only modest attention among infectious diseases (ID)
and infection control (IC) specialists. From mid-1999
through late 2000, we investigated median sternotomy
SSIs in adult cardiothoracic patients at our hospital. In
a retrospective case-control study, operative transfusion
of blood was significantly predictive of SSI in a multivariate analysis. We present the results of our investigation primarily as a means to highlight the potential
risk of blood transfusion for the development of SSIs
and to encourage ID and IC practitioners to further
investigate this potential risk factor.
Presented in part: 13th Annual Meeting of the Society for Healthcare
Epidemiology of America, Arlington, VA, 5–8 April 2003 (abstract 111).
Financial support: Vanderbilt Department of Preventive Medicine and Center for
Clinical Improvement.
a
Present affiliation: Department of Medicine, Beth Israel Deaconess Medical
Center, Harvard Medical School, Boston, MA.
Reprints or correspondence: Dr. Thomas R. Talbot, A-4103C Medical Center
North, 1161 21st Ave. S, Vanderbilt University Medical Center, Nashville, TN 37232
(tom.talbot@vanderbilt.edu).
Clinical Infectious Diseases 2004; 38:1378–82
2004 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2004/3810-0008$15.00
1378 • CID 2004:38 (15 May) • Talbot et al.
PATIENTS AND METHODS
Study design. A matched case-control study was conducted at a 658-bed tertiary care center at Vanderbilt
University (Nashville, TN). Eligible patients were adults
118 years of age who had undergone median sternotomy for coronary artery bypass grafting (CABG), valve
repair and/or replacement, or both between June 1999 and
January 2001.
Case patient selection. Cases were defined as eligible patients who received a diagnosis of sternal wound SSI using
standardized definitions from the National Nosocomial Infection Surveillance (NNIS) system, a partnership between participating hospitals and the Centers for Disease Control and
Prevention (CDC) [9]. Cases were identified through standard
active surveillance by IC practitioners, as well as through active
reporting from cardiothoracic case managers and laboratory
reports of positive results of cultures of sternal wound specimens. SSIs were classified as either soft-tissue infections (superficial or deep infection) or mediastinitis [9].
Control subject selection. Controls were chosen among
eligible patients with no evidence of SSI by standard surveillance and chart review. Controls were matched to cases
by date of procedure and age (5 years), with a 1:3 ratio of
cases to controls.
Data collection. A single IC practitioner and a trained
assistant abstracted data from the charts of all cases and controls. Chart abstractions by the assistant were reviewed by the
IC practitioner for accuracy. Risk factor data included patient
demographic information (age, weight, and sex), comorbid illnesses or risk factors (diabetes mellitus, chronic obstructive
pulmonary disease, American Society of Anesthesiology [ASA]
score [10], and tobacco use), procedural characteristics (CABG
or non-CABG; recurrent procedure; preoperative length of stay;
specific surgical personnel; total number of operating room
personnel; use of internal mammary artery, radial artery, or
saphenous vein; number of bypass grafts; duration of extracorporeal bypass; duration of surgery; interval between patient
entry into the operating room and the first incision; and the
suture type used), preoperative skin preparatory information
(type of skin preparatory agent and individual who performed
skin preparation), antibiotic administration (type of antibiotic
given before, during, and after the operation, and number of
total doses administered perioperatively), and units of blood
transfused during the procedure. Initiation of antibiotic prophylaxis was classified as appropriate if administration occurred
⭐30 min prior to the initial incision [11].
Statistical analysis. Baseline characteristics between the 2
groups were compared using Student’s t test and the Wilcoxon
rank sum test for continuous variables and x2 analysis and
Fisher’s exact test for categorical variables. Univariate relationships between predictor variables and sternal SSI were analyzed
using conditional logistic regression. Multivariate forward stepwise conditional logistic regression analysis with a significance
level of .05 for entry into the model was then performed to
identify the significant predictors of sternal SSI. All analyses
were conducted using Stata, version 7.0 (Stata).
RESULTS
During the study period, 711 median sternotomy procedures
were performed on adults, among whom 39 cases with sternal
SSI (5.5%) and 114 matched controls (16%) were identified.
Medical records for 1 case could not be located, resulting in
exclusion. Of the 38 cases with sternal SSI, soft-tissue infections
(superficial or deep) were diagnosed in 18 (47%), and mediastinitis was found in 20 (53%). Gram-positive organisms alone
were found in 20 cases (52%) (Staphylococcus aureus in 8,
Staphylococcus epidermidis in 3, enterococcal species in 1, and
mixed gram-positive bacteria in 8), a gram-negative organism
(Enterobacter aerogenes) was the sole pathogen isolated from 1
case, and mixed bacteria were isolated from 2 cases (5%). Culture results were negative for 6 cases (18%), and samples were
not obtained for culture for 9 cases (24%).
Univariate analysis identified several variables significantly
associated with adult sternal wound SSI: history of diabetes
mellitus, ASA score, preoperative length of stay, and receipt of
transfused blood (table 1). In a multivariate analysis using forward stepwise conditional logistic regression, blood transfusion
(OR, 3.21; 95% CI, 1.41–7.31) and a history of diabetes (OR,
3.65; 95% CI, 1.42–9.36) were significant predictors of an increased SSI risk.
DISCUSSION
Our investigation found that receipt of transfused blood, along
with a history of diabetes mellitus, was predictive of the development of SSI following median sternotomy in adults. The
association of diabetes and SSI was expected, because numerous
studies have identified an increased risk of wound infections
in diabetic patients [11]. The finding that receipt of transfused
blood may be associated with an increased SSI risk in cardiothoracic patients was unexpected but not altogether surprising,
because multiple studies have shown a relationship between
perioperative blood replacement and postoperative infection
risk. The association between SSI and blood transfusion has
not, however, received attention similar to that of other, more
established SSI risk factors, because the role of blood transfusion in the pathogenesis of postoperative infections is controversial and has been debated for 120 years.
At the heart of the debate lies a central question: does transfusion lead to direct immunosuppression (i.e., to transfusionassociated immunomodulation [TRIM] [8]) that increases
one’s risk for SSI, or does the receipt of blood products merely
identify individuals with greater underlying comorbidity and,
therefore, greater inherent risk for infection? This debate, however, has been largely confined to the surgical and transfusion
medicine communities, with less attention devoted to this subject in the ID and IC literature.
Many observational studies and multiple randomized con-
Blood Transfusion and Surgical Site Infections • CID 2004:38 (15 May) • 1379
Table 1. Baseline characteristics of case patients with poststernotomy surgical site infection and control subjects that were determined to be significantly
different by univariate analysis.
Variable
Cases
(n p 38)
Controls
(n p 114)
OR (95% CI)
47.4
25.4
2.90 (1.27–6.59)
History of diabetes, % of patients
Duration of hospitalization before
operation, days
ASA score
a
Blood transfusion, units
2.6 3.7
1.5 2.2
1.19 (1.02–1.37)
3.68 0.5
3.48 0.5
2.19 (1.04–4.64)
1.74 2.1
0.76 1.2
3.19 (1.54–6.62)
NOTE. Data are mean values SD , unless otherwise indicated. ASA, American Society of
Anesthesiology.
a
ORs calculated for blood transfusion as a binary variable (presence or absence of transfusion).
trolled trials have described the potential association between
transfusion and an increased risk of postoperative SSI [2, 5, 8,
12, 13]. This association has been noted with a variety of surgical procedures (colorectal, general abdominal, orthopedic,
trauma, head and neck, and cardiothoracic surgery [6, 7, 12,
14–18]). Donated WBCs have been implicated as a source of
transfusion-induced immunosuppression, and several clinical
trials have compared the receipt of standard whole blood– or
buffy coat (BC)–depleted products with the receipt of WBCdepleted products. BC-depleted blood, although containing
∼70% fewer WBCs than whole blood, still has a higher WBC
count than WBC-depleted blood [19, 20]. Other trials have
compared the receipt of autologous and allogeneic blood products, postulating that the effects of nonnative WBCs found in
allogeneic blood will not occur after transfusion of native autologous WBCs. Results of these randomized clinical trials have
failed, however, to provide a consensus answer to the association between transfusion and postoperative infection (table 2).
In addition, many investigations have used nonstandardized
and subjective definitions of infection outcomes [6, 7, 21]; have
failed to take into account many, if not all, known risk factors
for postoperative infection; and have utilized only univariate
analyses [3, 4, 22].
With a growing yet discrepant body of literature on the sub-
Table 2. Comparison of randomized clinical trials investigating the association between postoperative infection (PI) and perioperative
blood transfusion (BT).
Study
Initial no.
of subjects
a
[3]
215
b
Surgical procedure
Elective colorectal
Blood products compared
NNIS system
definitions for
PI outcomes
Multivariate
analysis of
PI outcomes
Association
between
BT and PI
detected
No
No
Yes
Whole vs. WBC depleted
[23]
475
Elective colorectal
Allogeneic vs. autologous
No
No
No
[14]
120
Elective curative colorectal cancer resection
Allogeneic vs. autologous
No
Yes
Yes
[19]
871
Elective colorectal adenocarcinoma resection
BC depleted vs. WBC depleted
No
Yes
Yes
[4]
60
Elective colorectal
Whole vs. WBC depleted
No
No
Yes
[20]
589
Elective colorectal
BC depleted vs. WBC depleted
No
No
Yes
[24]
697
Elective colorectal adenocarcinoma resection
BC depleted vs. WBC depleted
No
Yes
Yes
[21]
231
Unilateral total knee replacement
Allogeneic vs. autologous salvaged blood
No
No
Yes
[25]
50
Aortic aneurysm repair
Allogeneic vs. autologous salvaged blood
No
No
c
No
[22]
914
Cardiothoracic (CABG and/or valve surgery)
BC depleted vs. WBC depleted
Yes
No
No
e
[26]
279
Colorectal
WBC/BC depleted vs. BC depleted vs.
no transfusion
No
No
[27]
145
Aortic
Allogeneic vs. autologous
No
No
NOTE.
a
b
c
d
e
f
BC, buffy coat; CABG, coronary artery bypass grafting; NNIS, National Nosocomial Infection Surveillance.
Randomization occurred after decision was made to transfuse.
Used mortality as the primary outcome; rates of infectious complications only were compared between the 2 groups.
Infection outcome was defined as the development of systemic inflammatory response syndrome or sepsis.
On the basis of results of intention-to-treat analysis.
Between the 2 transfusion groups.
Between the transfusion and nontransfusion groups.
1380 • CID 2004:38 (15 May) • Talbot et al.
d
No; Yes
No
f
ject, the association between blood transfusion and SSI remains
unresolved. The occurrence of TRIM, seen particularly in recipients of allogeneic transfusions of WBC-containing blood
products, has been supported by animal and human studies.
Transfusion-related decreases in cell-mediated immune function, macrophage inhibition, and a reduction of CD4 helper
lymphocyte levels have been demonstrated using various mouse
models [4, 5]. Although limited, human studies also have
shown significant decreases in natural killer cell activity, lymphocyte proliferation due to phytohemagglutinin, and the CD4:
CD8 cell ratio, as well as significant increases in soluble IL-2
receptor and IL-6 levels following transfusion with whole blood,
compared with such findings in subjects who received WBCdepleted blood or who did not receive a transfusion [3, 4].
These investigations support the biological plausibility of transfusion acting as an immunosuppressant.
There were some limitations to our investigation. Because
of the retrospective nature of the study, several known risk
factors for infection could not be studied, such as past tobacco
or concurrent corticosteroid use or perioperative glucose levels.
We were also unable to analyze risk with regard to certain
aspects of the surgical procedure because of the relatively small
numbers in each subgroup (i.e., valve replacement and CABG
vs. CABG alone) and incomplete documentation (i.e., method
of hair removal). Another potential limitation involves the large
number of risk factors entered into the univariate statistical
model. With 25 variables in the model, statistical chance alone
dictates that 1 or 2 factors may be significant. The association
between transfusion and SSI, and, in particular, transfusion’s
potential role as an immunosuppressant, is biologically plausible, and the association between transfusion and SSI remained
significant after multivariate analysis. Therefore, it is unlikely
that this association was simply a product of chance alone.
Finally, although data were not available on the type of blood
transfused (e.g., allogeneic vs. autologous) or the specific WBC
status of the units transfused in the study cohort, since 1998,
all allogeneic and most autologous units of transfused blood
at our institution were WBC depleted. Thus, it is highly likely
that all transfusions received in our study were leukocyte
depleted.
In the latest CDC guidelines for the prevention of SSIs, perioperative transfusion is briefly mentioned as a proposed SSI
risk factor [11]. Although physicians generally weigh the risks
and benefits of blood transfusion prior to administration of
blood products, if blood replacement therapy were to be documented as a unique risk factor for infection, this finding might
lead to further prudence and more-widespread use of bloodsparing techniques. In addition, universal reduction of leukocytes in all units of donated blood in the United States has
now been proposed to eliminate the potential immunosuppressive effects of transfusion, a decision that has been met
with controversy [8]. Critics argue that more-definitive answers
with regard to the role of transfusion and TRIM in posttransfusion morbidity are needed before embarking on this expensive process. A larger study involving standardized NNIS outcome definitions, appropriate multivariate techniques, and all
known risk factors for postoperative infection is now needed
to further investigate the role of transfusion in postoperative
infection.
Acknowledgments
We thank the Vanderbilt University Infection Control staff,
including Valerie Thayer, Kathie Wilkerson, and Peggy Connolly; the members of the Department of Cardiac Surgery; and
the Centers for Clinical Improvement and Health Services Research for their support of this study.
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