Perioperative blood transfusion is associated with post-operative infectious complications in patients with Crohn’s disease
Perioperative blood transfusion is associated with post-operative infectious complications in patients with Crohn's disease
Nan Lan 1
Luca Stocchi 0
Yi Li 0
Bo Shen 1
0 Department of Colorectal Surgery, Digestive Disease and Surgery Institute, The Cleveland Clinic Foundation , Cleveland, OH , USA
1 Center for Inflammatory Bowel Disease, and Digestive Disease and Surgery Institute, The Cleveland Clinic Foundation , Cleveland, OH , USA
Background: We have previously demonstrated that blood transfusion (BT) was associated with post-operative complications in patients undergoing surgery for Crohn's disease (CD), based on our institutional data registry. The aim of this study was to verify the association between perioperative BT and infectious complications in CD patients enrolled in the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database. Methods: All CD patients undergoing surgery between 2005 and 2013 were identified from NSQIP. Variables were defined according to the ACS NSQIP guidelines. The primary outcome was infectious complications, including superficial, deep and organ/space surgical site infection, wound dehiscence, urinary tract infection, pneumonia, systemic sepsis and septic shock. Multivariate analyses were performed to assess the risk factors for post-operative infections. Results: All 10 100 eligible patients were included and 611 (6.0%) received perioperative BT. BT patients were older, lighter in weight and more likely to be functionally dependent. BT patients were more likely to have post-operative infectious complications than those without BT, including superficial surgical site infection (SSI) (10.8% vs 7.4%, p¼0.002), deep SSI (3.3% vs 1.6%, p¼0.003), organ/space SSI (14.2% vs 5.4%, p<0.001), pneumonia (3.8% vs 1.3%, p<0.001), urinary tract infection (3.9% vs 2.2%, p¼0.006), sepsis (11.5% vs 4.5%, p<0.001) and sepsis shock (3.1% vs 0.8%, p<0.001). Multivariate analysis showed that intra- and/or post-operative BT was an independent risk factor for post-operative infectious complications (odds ratio [OR] ¼ 2.2; 95% confidence interval [CI]: 1.8-2.7; p<0.001) and the risk increased with each administered unit of red blood cell (OR ¼ 1.3, 95% CI: 1.2-1.5). Other independent factors were history of smoking, chronic heart disease, diabetes, hypertension and the use of corticosteroids. Pre-operative BT, however, was not found to be a risk factor to post-operative infections. Conclusions: Intra- and/or post-operative, not pre-operative, BT was found to be associated with an increased risk for postoperative infectious complications in this CD cohort. Therefore, the timing and risks and benefits of BT should be carefully balanced.
blood transfusion; Crohn's disease; infectious complications; surgical outcomes
The clinical course of Crohn’s disease (CD) is often
unpredictable. Most patients do require surgery, sometimes repeatedly, to
correct or reduce clinical symptoms and improve patient’s
quality of life (QOL) [
]. Investigators have attempted to identify the
risk factors associated with post-operative adverse outcomes,
such as infection and anastomotic leak, believing that risk
factor modification could result in reduced morbidity, length of
hospital stay and mortality, and improved patient’s QOL [
Purported risk factors for post-operative infections include
weight loss and the use of corticosteroids or anti-tumor
necrosis factor (TNF) biological agents [
]. Blood transfusion (BT),
on the other hand, has been also found to be associated with
multiple adverse surgical outcomes such as venous thrombosis,
infections and increased 5-year mortality [
mechanisms include the disruption of coagulation factors,
altered balance between anti- and pro-inflammatory factors [
and the release of cytokines from apoptic white blood cell
(WBC) in allogeneic blood [
]. Biological factors in the blood
may also influence the innate immunity making patients
susceptible to infections [
]. It appears that BT carries a significant
risk for infections and profound immunosuppression [
BT is still a common practice for patients with severe
]. While aiming to correct patient’s anemic state, the
effect BT might have on possible consequent surgery is often
overlooked. The actual risk of BT remains controversial [
even though extensive research has been conducted in some
major operations such as cardiac surgery [
] as well as
cancer-related surgery [
]. As for CD surgical patients, BT
has been reported to be associated with an increased risk of
post-operative endoscopic and surgical recurrence of CD [
as well as septic complications . Our previous institutional,
registry-based study showed that BT was associated with both
infectious and noninfectious outcomes [
]. These studies,
however, were mostly conducted in a single institution and
they usually combine all perioperative (pre-, intra- and post-)
transfusion for analysis. Since CD patients are inherently
susceptible to postsurgical complications, it would be important to
clarify the possible and specific risk factors that might lead to
an unsatisfying surgical outcome on a larger scale. Therefore
the aims of this study were: (i) to identify the rate of transfusion
among CD patients undergoing surgery and adverse outcomes
associated with BT and (ii) to assess the risk factors, including
perioperative BT, for post-operative infectious complications,
by using the American College of Surgeons National Surgical
Quality Improvement Program (ACS NSQIP).
Patients and methods
The ACS NSQIP is a national database prospectively collecting
data from hundreds of centers voluntarily participating in the
program across the USA. The data were collected by an assigned
trained Surgical Clinical Reviewer on randomly assigned
patients per database protocol. The number and types of variables
collected will differ from hospital to hospital, depending on the
hospital size, patient population and quality improvement
focus. The data include demographic, clinical and laboratory
information, along with surgical outcome variables including
30day post-operative complications. Patients with the diagnosis of
CD were extracted between 2005 and 2013. This study was
approved by the Cleveland Clinic Institutional Review Board.
Inclusion and exclusion criteria
All patients with CD were identified by using the International
Classification of Disease, 9th revision (ICD-9) via
ICD9¼555.XXX. All surgical procedures related to CD were included
in this study. Exclusion criteria were: (i) patients without
complete data on BT and post-operative follow-up and (ii) patients
with ongoing infection(s) upon admission that included
pneumonia, wound infection and sepsis.
According to the ACS NSQIP guideline descriptions, there were
three variables in the database that concerned transfusion:
(i) transfusion of more than four units of red blood cell (RBC)
within 72 hours before surgery, (ii) the number of RBC units
given intra-operatively and (iii) occurrence of transfusion for
bleeding. Transfusion of four units or more RBC in 72 hours
before surgery was regarded as pre-operative BT for analysis. The
number of RBC units given intra-operatively was an old variable
recorded in a limited number of patients before 2009 and was
the only quantified BT-related variable available in the
database. The occurrence of transfusion for bleeding, which was
defined as any transfusion given from the time patients enter the
operating room (intra-operative) up to 72 hours post-operatively
(post-operative), was regarded as intra- and/or post-operative BT
for analysis. No variables were documented in the database for
transfusions occurring outside the 72-hour range before and
Demographic information, including age, gender, height and
weight, were extracted from the database. Height and weight
were used to calculate the body mass index (BMI) for each
patient. The ethnicity of the patients was classified into the
following categories according to the NSQIP guideline: African
American, American Indian or Alaska Native, Asian, Hawaiian
or Pacific Islander, White and unknown. Functional health
status was defined as the patient’s ability to perform daily
activities with or without the help of others. Daily activities include:
bathing, feeding, dressing, toileting and mobility. Patients who
required assistant with some or all daily activities were
regarded as functionally dependent and patients who did not
require assistance from another person for any daily activities
were regarded as functionally independent. The American
Society of Anesthesiology (ASA) Physical Status Classification of
the patient’s present physical condition was also extracted. It
was rated on a scale from 1 to 5, 1 being normal healthy patients
and 5 being a moribund patient who might not survive without
the operation. Patients’ clinical histories were also extracted
from the data, along with previous surgical history and
The primary outcome was infectious event after surgery, which
includes superficial, deep and organ/space surgical site
infection (SSI), wound dehiscence, urinary tract infection (UTI),
pneumonia, systemic sepsis and septic shock. Secondary outcome
included other post-operative adverse outcomes such as the
length of hospital stay, unplanned tracheal intubation,
ventilator usage exceeding 48 hours, acute renal failure, cardiac arrest
that required cardiopulmonary resuscitation (CPR), any
thromboembolic events and unplanned return to the operation room
for surgical exploration.
Categorical variables were summarized as percentages.
Quantitative variables were summarized as mean 6 standard deviation.
Tests for association between groups and categorical variables
were performed using the chi-square method and Fisher’s exact
test. For quantitative variables, the means were compared by
Student’s t-tests or Wilcoxon rank sum tests. P<0.05 was accepted
as statistically significant. Comparisons of infection rates were
conducted between those with any BT and those without. Along
with BT, other factors were also evaluated by univariate and
multivariate analyses to identify whether BT was an independent risk
factor for infection-related outcome. The relationship between the
number of units of packed-RBC transfused and infection was also
be examined by logistic analysis.
Demographic and clinical data
A total of 10 100 patients were extracted from the ACS NSQIP
database and 611 (6.0%) of them underwent perioperative BT.
The mean age for the whole cohort was 42.0615.2 years and
patients with BT were older than those without BT (46.3616.5 vs
41.7615.1 years, p<0.001). BMI was 23.966.1 kg/m2 in patients
with BT and 24.966.7 kg/m2 in those without BT (p<0.001). Of
the whole cohort, 27 (4.4%) patients with BT and 124 (1.3%)
patients without BT were functionally dependent (p<0.001).
Regarding the ASA Classification, patients without BT were
more often found to be classified into Levels 1 and 2, while
patients with BT were more often found to be Levels 3 and 4
Patients with BT had a longer mean total surgery time than
controls (2146115 vs 159695 minutes, p<0.001). Transfused patients
had a longer total hospital stay than controls (12.4612.1 vs
7.667.0 days, p<0.001). Patients with BT were associated with
an increased rate of superficial SSI (10.8% vs 7.4%, p¼0.002),
deep SSI (3.3% vs 1.6%, p¼0.003), organ space SSI (14.2% vs 5.4%,
p<0.001), pneumonia (3.8% vs 1.3%, p<0.001), UTI (3.9% vs 2.2%,
p¼0.006), sepsis (11.5% vs 4.5%, p<0.001) and sepsis shock (3.1%
vs 0.8%, p<0.001), as compared with those without BT (Table 1).
The rate for wound disruption, however, was comparable
between the two groups (1.6% vs 1.0%, p¼0.103). In addition,
patients with transfusion were also at risk of suffering
thromboembolic complications such as pulmonary embolism
(1.3% vs 0.4%, p¼0.003) and deep vein thrombosis (3.1% vs 0.8%,
p<0.001). A higher risk for respiratory dysfunction was also
found in those with BT. Patients with BT were more likely to
undergo unplanned tracheal intubation (3.3% vs 0.7%, p<0.001) and
to have ventilators for more than 48 hours (3.6% vs 0.6%,
p<0.001) (Table 1).
Risk factors for post-operative infections
In the whole cohort, 1850 patients (18.3%) were found to have
post-operative infections. The infection rate in patients with
pre-operative BT was 30.3% (23/76), while it was 32.9% (187/568)
in patients with intra-/post-operative BT. Possible variables
associated with post-operative infections were analysed (Table
2). A significant difference was found in the history of chronic
illnesses, such as diabetes (27.9% vs 18.0%, p<0.001), chronic
obstructive pulmonary diseases (25.9% vs 18.2%, p¼0.02), chronic
heart diseases (63.6% vs 18.3%, p¼0.001) and hypertension
(22.0% vs 17.6%, p<0.001). Patients being dependent on overall
health status (32.5% vs 18.1%, p<0.001), having a weight loss of
more than 10% (21.3% vs 18.1%, p¼0.02), higher ASA level (8.0%
vs 16.3% vs 23.2% vs 23.0% vs 0.0%, p<0.001) or worse wound
classification (11.2% vs 16.7% vs 21.4% vs 23.1%, p<0.001) were
also more susceptible to infection. In addition, the use of
corticosteroids (19.9% vs 17.2%, p¼0.001), smoking (22.3% vs 16.9%,
p<0.001), peripheral vascular disease (40.9% vs 18.3%, p¼0.01)
and bleeding disorders (24.7% vs 18.2%, p¼0.02) were also found
to be more common in patients with post-operative infections.
Laboratory results showed significant differences in
hypoalbuminemia (21.3% vs 18.0%, p¼0.001), low hematocrit (19.1% vs
17.5%, p¼0.04) and high alkaline phosphatase (23.7% vs 18.4%,
p<0.001). Both emergency surgery (22.4% vs 18.1%, p¼0.03) and
open surgery (20.8% vs 14.0%, p<0.001) were more susceptible to
Multivariate analysis was conducted with the inclusion of all
variables that were found to be statistically significant in the
univariate analysis (Table 3). The results showed that intra-/
post-operative BT was independently related to infections with
an odds ratio (OR) of 2.1 and 95% confidence interval (CI) of 1.7–
2.6. Pre-operative transfusion, on the other hand, was not found
to be a risk factor (OR¼1.1, 95% CI: 0.7–2.0). Other risk factors
were a history of smoking (OR¼1.4, 95% CI: 1.2–1.6), chronic
heart diseases (OR¼4.7, 95% CI: 1.0–21.3), diabetes (OR¼1.7;
95% CI: 1.2–2.3), the use of corticosteroids (OR¼1.2, 95% CI: 1.1–
1.4) and a dependent health status (OR¼1.8, 95% CI: 1.2–2.6).
Laparoscopic surgery (OR¼0.7, 95% CI: 0.6–0.8) was found to be a
Assessment of dose-dependency between BT and postoperative infectious complications
The above data showed that intra- and/or post-operative
transfusion had an adverse impact on infectious complication of CD
surgery. The only quantified variable available in the database was
the number of RBC infused intra-operatively which could be found
in 3648 cases. There were a total of 218 patients that received
intra-operative transfusion (Table 4). After assessing all BT data
available with logistic regression, we found that the overall OR for
infection was 1.3 (95% CI: 1.2–1.5) for each increase in units of
blood infused intra-operatively, suggesting that the adverse effect
on the infectious complication was dose-dependent.
The prospectively maintained national database has provided a
powerful tool to sort out the controversy in the association
between BT and post-operative infectious complications. This is
especially important in patients with CD, as those patients are
prone to the development of those complications. We found that
patients with BT were older and more likely to have a lower BMI.
Those with concomitant chronic illness were more likely to need
BT as well. BT patients seemed to have a longer operative time
and a longer total hospital stay. BT itself was found to be
significantly associated with infectious outcome along with
thromboembolism, respiratory failure, renal failure and cardiac arrest. In
multivariate analysis, we confirmed that intra-/post-operative BT
was an independent risk factor and the association of intra- and/or
post-operative infection appeared to be dose-dependent.
Pre-operative BT, however, was not found to be a risk factor.
CD patients were susceptible to post-operative infections.
There were many known risk factors that could further increase
the odds. In general, patients with penetrating disease or with
unfavorable biochemistry parameters such as
hypoalbuminemia and anemia were often at risk of developing infections after
]. Furthermore, pre-operative medications such
as corticosteroids, biologics and even narcotic use were cited to
increase the incidence of infectious complications [
Complex surgery and a longer duration of surgery were all
relevant factors that might lead to infection [
In addition, previously published data suggest that BT was also
related to post-operative infectious complications, longer hospital
stay and overall higher morbidity and mortality in surgical non-CD
]. On the other hand, the frequency of BT has still
American Indians or Alaska native
Native Hawaiian or Pacific Islander
History of smoking
History of alcohol use
Functional health status
Chronic obstructive pulmonary disease
History of ascites
Chronic heart disease
Weight loss >10%
Percutaneous coronary intervention
Previous cardiac surgery
Peripheral vascular disease
Transient ischemic attack
Stroke with neurological damage
Stroke without neurological damage
remained high among surgical non-CD patients [
preoperative anemia and perioperative bleeding complications could
lead to adverse outcomes, they were often managed by BT. A
recent study conducted among hepatopancreaticobiliary surgery
reported an average triggering level for transfusion in anemic
patients was hemoglobin (Hb) of 7.7 g/dL and the average target
was 9.3 g/dL. They suggested that, by using a restricted transfusion
policy (Hb<8 g/dL), BT would be avoided in about 20–25% patients
without increasing the risk for morbidity [
]. Another study from
the same group that consisted of cardiothoracic and
gastrointestinal procedures also pointed out that patients with restricted
perioperative transfusion strategy (Hb<7 g/dL, mean target Hb was
9.1 g/dL) did not increase risk for ischemic complications, as
compared with a more liberal triggering level (Hb 7 g/dL, mean target
Hb was 9.3 g/dL). Therefore, due to frequent complications seen in
transfused patients, a more restrictive transfusion practice may be
safe and efficient [
]. Most publications agreed that patients
undergoing BT were more likely to experience complications and that
the triggering level of Hb and target of transfusion should be
restricted. However, not many studies were conducted in CD surgical
The results of our study were mostly consistent with
previously published data in non-CD patients, except that the CD
patients had a relatively lower BT rate (6%) than other diseases
]. Our study confirms that the overall post-operative
infection rate in CD patients undergoing surgery was higher in the
BT group than in the non-BT group. Although many studies
have shown the association between BT and overall infection,
there is scant literature on the association between BT and
specific infections. Our study showed that the association extended
to each infection subgroup, including local infections like SSI as
well as systemic infections like pneumonia, UTI, sepsis and
sepsis shock. The results suggest that the impact of BT was
systematic. Bernard et al. showed that BT of two units as compared
with to that of one unit further increased the odds for 30-day
mortality, morbidity, pneumonia and sepsis/shock [
study also showed an increase in the risk of infections with
increased units of blood transfused intra-operatively, delineating
a dose–response relationship. But, differently from the previous
studies, we included all perioperative infections for analysis. In
addition, we analysed pre-operative and intra- and/or
post-operative BT separately. Our results showed that intra- and/or
postoperative BT, not pre-operative BT, was an independent risk
factor for the adverse complications. One possible explanation
is that the purpose of pre-operative BT in the majority of
patients was to correct anemia, which might have improved the
patient’s overall health status and better prepared them for
surgery. The patients requiring pre-operative transfusion were also
those who tended to have a more severe disease presentation
and were therefore prone to having a worse outcome. In this
way, pre-operative transfusion may be a confounding factor
that might result from the patient’s overall worse health status.
The mechanism of transfusion-associated post-operative
infection remains to be clarified. The most commonly cited is
transfusion-induced immunosuppression [
]. In surgical
patients, interleukin (IL)-6 and IL-6 soluble receptor are highly
up-regulated when they receive BT, suggesting that BT may
enhance IL-6 along with IL-2 response [
]. The role of
allogeneic leukocytes in the immunomodulation and in the
development of post-operative infectious complications has
also been investigated. Despite careful process and separation,
transfused RBC may not be completely free of WBC or WBC
products . However, the results of several randomized trials
of WBC-depleted transfusions were inconclusive in this aspect
]. CD patients are often in an immunosuppressive state,
from the underlying disease and concurrent use of
immunosuppressive agents , which makes them even more susceptible
to transfusion-related post-operative infections.
The findings of this study have clinical implications. This
was the largest study to date for the evaluation of the effect of
BT on post-operative infectious complications in CD patients.
The ACS NSQIP has provided a national perspective on the
outcomes of these patients. We demonstrated that intra- and/or
post-operative BT was a risk factor for infectious complications
after the surgery for CD. The risks and benefits of transfusions
intra- and/or post-operatively should be carefully balanced,
especially in the current era of extensive use of biological agents
in CD. On the other hand, the benefits of correcting anemia with
pre-operative BT may be justified.
There are several limitations to the study. The database only
tracked patients up to 30 days post-operatively and the
available number of variables was limited. Many long-term
consequences, such as post-operative recurrence of CD, which could
have been associated with BT, were not documented in the
database. Second, the units of RBC transfused in the
perioperative period were only found in some patients before 2009 in the
database, resulting in a much smaller sample size for this
particular endpoint. Third, there was no documentation on
whether the blood was autogenic or allogeneic. Patients’ low Hb
level that triggered transfusion and the target Hb were not
included. Other factors that might have contributed to
post-operative infectious complications, such as the use of anti-TNF or
narcotics, were not included in the database.
In conclusion, BT was shown to be associated with multiple
adverse outcomes, especially infections. As patients with CD
undergoing surgery are prone to the development of
post-operative infectious complications, the risks and benefits of
intraand/or post-operative BT should be carefully balanced.
The American College of Surgeons National Surgical Quality
Improvement Program and the hospitals participating in
the ACS NSQIP are the source of the data used herein; they
have not verified and are not responsible for the statistical
validity of the data analysis or the conclusions derived by
the authors. This report was presented as a poster at the
American College of Gastroenterology annual scientific
meeting October 2015, Honolulu, Hawaii.
Conflict of interest statement: none declared.
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