Evaluation of serial C-reactive protein measurements after surgical treatment of pleural empyema.

Abstract

Serial C-reactive protein measurements have been used to diagnose and monitor the response to therapy in patients with pneumonia and other infectious diseases. Nonetheless, the role of C-reactive protein measurement after surgical treatment for pleural empyema is not well defined. The aim of this study is to describe the behavior of C-reactive protein levels after the surgical treatment of pleural empyema and to correlate this parameter with the patient's prognosis.
We retrospectively analyzed the records of patients with pleural empyema treated by either chest-tube drainage or surgery from January 2006 to December 2008. C-reactive protein levels were recorded preoperatively and 2 and 7 days postoperatively. The clinical outcome was binary: success or failure (mortality or the need for repeated pleural intervention).
The study group comprised fifty-two patients. The median C-reactive protein values were as follows: 146 mg/L (pre-operative), 134 mg/L (post-operative day 2), and 116 mg/L (post-operative day 7). There was a trend toward a decrease in these values during the first week after surgery, but this difference was only statistically significant on day 7 after surgery. Over the first week after surgery, the C-reactive protein values decreased similarly in both groups (successful and failed treatment). No correlation between the preoperative C-reactive protein level and the clinical outcome was found.
We observed that, in contrast to other medical conditions, C-reactive protein levels fall slowly during the first postoperative week in patients who have undergone surgical treatment for pleural empyema. No correlation between the perioperative C-reactive protein level and the clinical outcome was observed.

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CLINICAL SCIENCE
Evaluation of serial C-reactive protein measurements
after surgical treatment of pleural empyema
Israel Lopes Medeiros,IRicardo Mingarini Terra,IIEsther Mihwa Choi,IIPaulo Manuel Pego-Fernandes,II
Fabio Biscegli JateneII
IMessejana Hospital, Fortaleza/CE, Brazil.IIHospital das Clı ´nicas, Heart Institute (InCor), Faculdade de Medicina da Universidade de Sa ˜o Paulo, Sa ˜o Paulo/
SP, Brazil.
OBJECTIVE: Serial C-reactive protein measurements have been used to diagnose and monitor the response to
therapy in patients with pneumonia and other infectious diseases. Nonetheless, the role of C-reactive protein
measurement after surgical treatment for pleural empyema is not well defined. The aim of this study is to describe
the behavior of C-reactive protein levels after the surgical treatment of pleural empyema and to correlate this
parameter with the patient’s prognosis.
METHODS: We retrospectively analyzed the records of patients with pleural empyema treated by either chest-tube
drainage or surgery from January 2006 to December 2008. C-reactive protein levels were recorded preoperatively
and 2 and 7 days postoperatively. The clinical outcome was binary: success or failure (mortality or the need for
repeated pleural intervention).
RESULTS: The study group comprised fifty-two patients. The median C-reactive protein values were as follows:
146 mg/L (pre-operative), 134 mg/L (post-operative day 2), and 116 mg/L (post-operative day 7). There was a trend
toward a decrease in these values during the first week after surgery, but this difference was only statistically
significant on day 7 after surgery. Over the first week after surgery, the C-reactive protein values decreased similarly
in both groups (successful and failed treatment). No correlation between the preoperative C-reactive protein level
and the clinical outcome was found.
CONCLUSIONS: We observed that, in contrast to other medical conditions, C-reactive protein levels fall slowly
during the first postoperative week in patients who have undergone surgical treatment for pleural empyema. No
correlation between the perioperative C-reactive protein level and the clinical outcome was observed.
KEYWORDS: Pleural Empyema; C-Reactive Protein; Treatment Outcome; Surgery.
Medeiros IL, Terra RM, Choi EM, Pego-Fernandes PM, Jatene FB. Evaluation of serial C-reactive protein measurements after surgical treatment of
pleural empyema. Clinics. 2012;67(3):243-247.
Received or publication on October 23, 2011; First review completed on November 29, 2011; Accepted for publication on November 29, 2011
E-mail: rmterra@uol.com.br
Tel.: 55 11 2661-5248
INTRODUCTION
C-reactive protein (CRP) is an acute-phase protein pro-
duced primarily in the liver in response to cytokine release;
elevated levels of serum CRP are observed with most
invasive infections (1). Several studies have investigated the
role of serial CRP measurements in the diagnosis of sepsis
and infection and in monitoring the response to therapy (2).
In patients with community-acquired pneumonia, for
instance, CRP has been proven to be a valuable marker of
disease severity; in addition, the identification of the CRP
response pattern after antibiotic therapy can be useful in the
assessment of an individual’s clinical course (3-5).
Pleural empyema (PE) is a severe infectious condition
associated with significant morbidity and mortality, parti-
cularly in elderly and immunocompromised populations
(6,7). The main goal of surgery for the treatment of PE is to
prevent pleural sepsis. The failure of surgical treatment is
frequently determined by the presence of fever, leukocy-
tosis, and the presence of residual pleural pus that is
confirmed radiologically (8). However, these signs are not
specific and can be misleading. Therefore, an accurate
laboratory marker capable of identifying persistent infection
and the necessity of a second surgery would be clinically
useful. Due to the features already reported in other
conditions, it was hypothesized that CRP could serve as
such a marker; nevertheless, to date, few studies have
evaluated the time course and clinical relevance of changes
in the CRP levels in patients undergoing surgery for PE
(9,10).
The primary endpoint of this study was to evaluate the
decrease in CRP levels during the first week after surgical
treatment for pleural empyema. The secondary endpoint
Copyright ? 2012 CLINICS – This is an Open Access article distributed under
the terms of the Creative Commons Attribution Non-Commercial License (http://
creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-
commercial use, distribution, and reproduction in any medium, provided the
original work is properly cited.
No potential conflict of interest was reported.
CLINICS 2012;67(3):243-247 DOI:10.6061/clinics/2012(03)07
243

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was to correlate the preoperative CRP levels and the CRP
levels from the first postoperative week with the final
outcome of PE surgical treatment.
METHODS
We retrospectively analyzed the medical records of all
patients with pleural empyema treated by either chest tube
drainage or surgery from January 2006 to December 2008 in
a tertiary teaching hospital. Empyema was defined as
pleural effusion that met one or more of the following
criteria: (1) grossly purulent fluid; (2) positive fluid culture
or positive Gram stain for bacteria; and (3) a pH less than
7.20, a lactate dehydrogenase (LDH) level greater than
1,000 IU/L and a glucose level less than 40 mg/dL. In our
facility, video-assisted thoracic surgery (VATS) is consid-
ered the standard procedure for empyema management;
nonetheless, patients with a thick pleural peel (.2 cm)
usually undergo open decortication, and those patients in
poor clinical condition undergo chest tube drainage as the
primary treatment. Patients with chronic empyema that is
not suitable for decortication – mostly because the patient is
in poor clinical condition — undergo open-window thor-
acostomy (11) and were not considered for participation in
the present study. The ethics committee of our institution
approved the study, and informed consent was waived
because the study was a retrospective review of patient
charts.
At our hospital, the level of C-reactive protein is
measured by nephelometry. The normal range for this
assay is less than 10 mg/L; levels were first routinely
measured in patients with pleural empyema in 2006.
Nevertheless, some wards in our hospital did not start to
routinely use CRP until 2007; therefore, some patients did
not undergo CRP measurement during the study period.
Patients in whom the serum CRP levels were not quantified
were deemed to have incomplete records and were
excluded from the analysis. The CRP levels were recorded
for all patients preoperatively and on the 2ndand 7thdays
postoperatively. We chose the 2ndand the 7thpostoperative
days to analyze the serum CRP levels to minimize the
number of missing data because CRP measurements are
performed as part of a routine protocol in both the ICU and
the clinical ward.
The following data were also collected for each patient:
age, sex, comorbidities, etiology of the empyema (pneumo-
nia, tuberculosis, thoracic surgery, trauma), treatment
modality (tube thoracostomy, VATS, open decortication),
axillary temperature, white blood cell count (WBC),
requirement for a second surgical procedure and mortality.
The clinical outcome was binary: success or failure. We
considered treatment failure to be mortality during the first
30 days after surgery (or during the same hospitalization
period) and/or the requirement for a second surgical
intervention (VATS, decortication, open drainage) due to
persistent sepsis. During the study period, fever, the white
blood cell count, hemodynamic parameters, and radiologi-
cal results were the factors taken into account when
considering whether to perform an additional pleural
intervention.
Continuous variables are presented as the median
(interquartile range) unless otherwise stated. The Shapiro-
Wilkes test was used for the assessment of normality.
Comparisons between groups of continuous data were
performed using the nonparametric Mann-Whitney U-test
and the Wilcoxon signed-rank test. A comparison of CRP
values over time was performed using the nonparametric
bidirectional Friedman test. To compensate for the multiple
testing situation, the p-value was adjusted using the
Bonferroni test. For comparisons among three groups, a p-
value below 0.016 was considered statistically significant.
We used multiple logistic regression to investigate the
association between the outcome of interest and the CRP
levels. We included age, sex, and comorbidities (chronic
cardiac disease, chronic renal failure, diabetes mellitus,
systemic arterial hypertension, chronic pulmonary disease,
malignant neoplasm, and immunosuppression) in the base-
line model. Age and the CRP level were entered into the
model as continuous variables, whereas the other variables
were coded as binary variables. We could not find CRP
values on some patients’ charts; three pre-operative mea-
surements (5.8%) and four measurements taken on post-
operative day 7 (7.7%) were missing. We assumed that these
data were randomly missing and dealt with them using
multiple imputation, in which each missing value was
replaced with the group’s mean. Statistical analyses were
performed using SPSS 17.0 (SPSS Inc., Chicago, Ill).
RESULTS
Sixty-nine patients with pleural empyema underwent
pleural surgical procedures at our institution during the
study period. All of these patients were considered for
inclusion, but 17 patients were eventually excluded due to
incomplete registration information. Therefore, the study
group comprised 52 cases. The demographic and clinical
characteristics of the patients are presented in Table 1.
The C-reactive protein values before surgery varied from
3.67 to 434.0 mg/L (median=146.0 mg/L). Only one patient
hada normal preoperative CRP level (3.67 mg/L), buthe had
already been taking intravenous antibiotics for a week before
the surgery; all others had preoperative CRP levels far above
thenormal limit of 10 mg/L. These values tendedto decrease
during the first week after surgery, but this difference was
only statistically significant on day 7 after surgery, as shown
in Figure 1. Subgroup analysis showed that in patients
undergoing open decortication, the fall in the CRP level was
faster. This decrease was noted as soon as day 2 after surgery
(pre-op: 199.7 mg/L; postoperative day 2: 90.6 mg/L; POD 7:
Table 1 - Characteristics of the patient population.
Age (years){
Sex (male/female)
Etiology of empyema
48.0¡15.7
36/16
Pneumonia 82.7%
Thoracic surgery 7.7%
Tuberculosis 3.8%
Other* 5.8%
VATS 76.9%
Open decortication 13.5%
Tube thoracostomy 9.6%
Treatment of empyema
Comorbidities
Systemic arterial hypertension
Malignant neoplasm
Diabetes mellitus
Chronic cardiac disease
Chronic pulmonary disease
Chronic renal failure
Immunosuppression
34.6%
26.9%
13.5%
11.5%
9.6%
7.7%
3.8%
{Mean ¡ std. deviation *Trauma, malignant pleural effusion.
C-reactive protein and pleural empyema
Medeiros IL et al.
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100.0 mg/L; p=0.018). Moreover, in patients undergoing
chest tube drainage and VATS, the fall in CRP was not
statistically significant on either POD 2 or POD 7.
Nine patients died (17.3%), and six patients required a
second surgery (11.5%). All deaths were caused by septic
shock and occurred on average 25 days after surgery. Only
two patients died during the first postoperative week, and,
interestingly, both displayed a drop in CRP levels – 19% and
50% - relative to the preoperative values. No patient
underwent a second pleural intervention during the first
postoperative week.
We divided the patients into two groups: successful
treatment (69.2%) and failure (30.8%). Over the first week
after surgery, the CRP values decreased to a similar extent
in both groups (p=0.64; Figure 2). The CRP values and WBC
of success and failure groups were not significantly different
before surgery or at postoperative days 2 and 7 (Table 2).
We were unable to find any association between the
preoperative or first postoperative week CRP levels (POD 2,
POD 7) and the clinical outcome (death and/or reoperation).
Multivariatelogisticregressionrevealedthat only thepresence
of chronic renal failure (p=0.008) and chronic pulmonary
disease (p=0.029) were independently associated with an
increased risk of death and/or reoperation in these patients.
DISCUSSION
This study showed that, in a population of patients with
PE surgically treated in a tertiary hospital, the CRP levels
fall slowly during the first week after surgery and are
significantly reduced on POD 7. We also noticed that the
CRP levels and the WBC, measured before surgery and on
POD 2 and POD 7, were not associated with outcome
(mortality and/or reoperation).
C-reactive protein is an acute-phase protein synthesized
by the liver in response to tissue damage. Interleukin-6
(IL-6) is thought to be the primary trigger of CRP release,
although tumor necrosis factor alpha (TNFa), interleukin-1
(IL-1), and other cytokines are thought to be involved. The
secretion of CRP begins within 4-6 hours of the stimulus,
doubling every 8 hours and peaking at 36-50 hours. After
the disappearance or removal of the stimulus, the CRP level
falls rapidly, as it has a half-life of 19 hours. However, the
CRP level can remain elevated, even for very long periods, if
the underlying cause of the elevation persists (1). The
evaluation of a single CRP measurement is useful in
the diagnosis of sepsis and as a prognostic marker.
Nevertheless, following its evolution over the duration of
a hospital stay can be more helpful in diagnosis and in the
monitoring of the response to therapy.
Some studies have shown that in patients with commu-
nity-acquired pneumonia, a decrease of 50% or more in the
CRP level at day 4 (after starting antibiotics) is usually
observed in patients in whom treatment has been success-
ful. Therefore, the CRP level after the start of antibiotic
administration seems to be a good marker of prognosis (3,4).
In our study, CRP was not so useful during the first week
after the surgical treatment of PE: a significant decrease
(40%) in the CRP level was only observed at day 7 after
surgery.Similar results were
et al. (9), who analyzed 22 patients undergoing surgery for
pleural empyema. The CRP values decreased slowly: on day
7, only 12 patients had CRP values of 100 mg/L or below.
Furthermore, CRP measurement could not discriminate
between patients with and without sepsis during the
postoperative period. The authors suggested that procalci-
tonin is a more appropriate laboratory parameter than CRP
when monitoring the postoperative course of these patients.
The slow decline of the CRP level observed in our study
after surgical treatment of PE might be explained by two
technical features of this type of therapy. First, the sur-
gery itself can lead to substantial elevation of the CRP
obtainedbyCarboni
Figure 1 - CRP changes during the first postoperative week.
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concentration (1), which could counter-balance the decrease
in the CRP level induced by the control of sepsis and
therefore contribute to the slow postoperative fall in CRP
levels. In the study by Icard et al. (10), which evaluated the
utility of CRP measurements for empyema diagnosis after
pneumonectomy, even in patients without postoperative
complications, there was a rapid postoperative rise in the
CRP levels until a peak or plateau was reached within 3 to 6
days, followed by a progressive decline to a value of less than
75 mg/L on day 9 and less than 50 mg/L on day 12. Second,
the surgery for pleural empyema frequently does not remove
all of the infected tissue. This surgery allows for the
debridement and removal of adhesions, which allows for
adequate drainage of the pleural space, but complete
resolution of the infection may take several days. Moreover,
full lung expansion – one of the goals of therapy – is not
frequent after video thoracoscopy or chest tube drainage in
patients with malignant pleural effusion (12); we would
expect a similar trend after PE treatment. One fact that
reinforcesthehypothesis ofslowintrapleuralsepsiscontrol is
the observation that CRP levels fall faster after open
decortications; an open technique would allow for more
effective cleaning of the pleural cavity, and, therefore, a faster
decrease in the CRP level.
The main limitation of our study is the retrospective
design based on chart review, which resulted in many losses
due to incomplete registries. The small sample size is also a
limitation in terms of obtaining significant results. Given the
limited number of missing data (,10%) and the fact that
these data were missing at random, the imputation method
(in which each missing value is replaced with the mean of
the group) may lead to an overestimation of the association
of interest. Another significant limitation is the fact that
some patients had already had some sort of medical
treatment prior to the surgical treatment, many of them
elsewhere. This prior treatment may have interfered with
the preoperative CRP levels measured in the present study.
Our data suggest that neither the preoperative nor the
first postoperative week CRP serum levels in patients who
underwent an invasive treatment for pleural empyema
correlate with the final outcome (reoperation or death).
Finally, we observed that, in contrast to the case for other
medical conditions, CRP levels fall slowly during the first
postoperative week in patients who undergo surgical
treatment for PE. We should expect a slow decline during
the first several days after surgery, and a significant 40%
difference – relative to the preoperative values – will be
reached on approximately the seventh day.
Figure 2 - The CRP pattern of change according to outcome.
Table 2 - CRP and WBC values in patients in which treatment was successful or failed.
Successful treatment group (n=36) Treatment failure group (n=16)p-value
CRP before surgery
CRP on POD 2
CRP on POD 7
WBC before surgery
WBC on POD 2
WBC on POD 7
149.0 (111.2-187.7)
134.0 (86.9-172.0)
116.0 (82.0-154.0)
11.87(7.53-16.52)
11.98 (10.01-16.81)
9.65 (6.89-11.68)
145.0 (92.1-230.4)
131.9 (96.4-163.7)
116.0 (73.2-171.5)
12.02 (8.84-16.08)
13.73 (6.51-17.30)
9.66 (7.23-14.30)
0.835
0.781
0.843
0.905
0.736
0.912
CRP: C-reactive protein (mg/L); WBC: white blood cell count (x 1,000/mm3); POD: postoperative day.
Values are expressed as the median (interquartile range: 25-75).
C-reactive protein and pleural empyema
Medeiros IL et al.
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AUTHOR CONTRIBUTIONS
Medeiros IL, Terra RM contributed to the study design, data collection
and manuscript writing. Choi EM contributed to data collection and
manuscript writing. Pego-Fernandes PM contributed to study design, data
analysis and manuscript revision. Jatene FB contributed to study design
and manuscript revision.
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