ARTICLE
Auteur(s) : Urs
Zingg1, Jens Forberger2, Daniel M
Frey1, Adrian J Esterman3, Daniel
Oertli1, Beatrice Beck-Schimmer4, Andreas
Zollinger5
1Department of Surgery, University Hospital
Basel, Basel, Switzerland
2Department of Surgery, Triemli City Hospital
Zurich, Zurich, Switzerland
3School of Nursing and Midwifery, University
of South Australia, Adelaide, Australia
4Institute of Anaesthesiology, University Hospital
Zurich, Zurich, Switzerland
5Institute of Anaesthesiology and Intensive
Care Medicine, Triemli City Hospital Zurich, Zurich,
Switzerland
accepté le 26 Novembre 2009
Open, right-sided, transthoracic esophagectomy with one-lung
ventilation (OLV) is one of the standard surgical approaches for
curative treatment of esophageal cancer (abdomino-thoracic or
thoraco-abdomino-cervical esophagectomy). The OLV leads to a
complete collapse of the right lung with subsequent shunting of
blood and the risk of hypoxemia.
The procedure triggers a massive inflammatory reaction, with
production of various cytokines such as the pro-inflammatory
interleukin-6 (IL-6) and IL-8, and the anti-inflammatory
cytokines IL-10 and IL-1 receptor antagonist (IL-1RA) [1,
2]. Increased concentrations of these interleukins have been
measured in bronchoalveolar lavage (BAL) fluid, peripheral blood,
and in the pleural space [3, 4]. Increased levels of
anti-inflammatory cytokines in bronchoalveolar fluid have been
reported to correlate with the development of acute respiratory
distress syndrome (ARDS), and low concentrations of
anti-inflammatory cytokines were associated with poor prognosis in
patients with ARDS [5, 6].
In esophagectomy, pulmonary complications are frequent with
rates of up to 40% [7]. Impaired respiratory mechanics due to
thoracotomy and laparotomy, pre-existing pulmonary co-morbidity,
and the inflammatory reaction with release of oxygen radicals and
resultant lung injury are possible explanations for these
complications.
Although a few studies have addressed the production of
cytokines and the inflammatory reaction in esophagectomy, the
mechanisms are still not well understood. The influence of the OLV
on the inflammatory cascade is unclear and the data on the
inflammatory reaction in the ventilated left and collapsed right
lung, respectively, are scarce. Different mechanisms may induce
lung injury associated with OLV, such as ischemia/reperfusion
injury in the collapsed lung, ventilator-induced injury, hyperoxia,
volume overload and increased capillary stress in the ventilated
lung [8-10]. Cree et al. demonstrated significantly higher
IL-8 levels in the BAL fluid after surgery compared to the
peripheral blood, but did not show a difference between the
collapsed and ventilated lung groups [4]. However, the BAL fluid
samples were taken from different patients. As cytokine production
varies substantially between patients, this might have introduced a
selection bias.
The aim of this study was to analyze the character and time
course of the inflammatory reaction, represented by the
concentrations of IL-6, IL-8, IL-10 and IL-1RA in BAL fluid
from the ventilated left and collapsed right lungs, in the
peripheral blood, and in the right pleural space in patients
undergoing transthoracic esophagectomy for cancer.
Patients and methods
From the 1st January 2006, all patients undergoing
transthoracic esophagectomy for cancer at the Triemli Hospital
Zurich and the University Hospital Basel were assessed for
eligibility to be included in a prospective, randomized,
double-blind trial to analyze the influence of n-acetylcysteine
(NAC) on pulmonary morbidity (trial ongoing). The trial has been
registered by the National Library of Medicine, at
www.clinicaltrials.gov with the number NCT00512265. The study was
approved by the Ethics committees of the two participating
hospitals. Informed consent was obtained from all patients. In the
first 30 patients included in the NAC trial, cytokine analysis
was performed for this study. One patient was excluded as an
intra-operative decision was made to perform a transhiatal
esophagectomy, resulting in data from 29 patients being
available for analysis.
Neoadjuvant treatment, surgery and anesthetic
procedure
All patients with advanced tumors (T3 and/or N+) received
neoadjuvant treatment. This usually entailed chemotherapy with
5-fluorouracil and cisplatin, and a radiation dose of
45-50 Gray. Surgery was performed 6-8 weeks after
completion of the combined pre-treatment.
Esophagectomies were performed using the abdomino-thoracic
(Ivor-Lewis resection) and the thoraco-abdomino-cervical (3-stage)
approach in 23 and six patients, respectively. In the latter
group, the cervical phase was performed simultaneously to the
abdominal phase, thus not prolonging the procedure. In all
patients, the stomach was used as conduit for reconstruction. The
anastomosis was either stapled or hand-sewn, according to the
surgeon’s preference. Two thoracic drains (28 French anterior
and 32 French posterior), were inserted into the thoracic
cavity before closure of the thoracotomy. The posterior drain was
left in place for a minimum of five days. A contrast swallow
was performed on postoperative day five.
Anesthetic procedures were standardized for all patients
including the use of double-lumen endobronchial tubes under
fiber-optic control to allow single lung ventilation and the use of
thoracic epidural catheters with continuous infusion of local
anesthetics both intraoperatively (ropivacaine 0.3%), and up to
five days postoperatively (bupivacaine 0.125%). Total intravenous
anesthesia was applied using bolus doses of fentanyl and continuous
infusions of propofol and remifentanil intraoperatively, and
tempered until endotracheal extubation. Muscle relaxation
(intraoperatively only) was achieved using bolus doses of
rocuronium. One-lung ventilation during thoracotomy followed the
principles of a lung protective strategy, using pressure-limited or
pressure-controlled ventilation modes with tidal volumes of <
7 mL/kg body weight, positive end-expiratory pressure of
3-5 cm H2O and limiting peak inspiratory pressures
to < 30 cm H2O. The inspired oxygen
concentration on the ventilated lung was set to 100% at the
beginning and gradually reduced thereafter based on the arterial
oxygen tension measured by repeated blood gas analyses [11-13].
Extubation was performed on the morning of the first postoperative
day, with the exception of six patients who were extubated within
four hours of completion of surgery.
Continuous monitoring included ECG analysis, measurement of
arterial oxygen saturation with pulse oxymetry and invasive
arterial as well as central venous pressure monitoring. Blood
samples were drawn intermittently, at predefined time points, for
blood gas and further laboratory parameter analysis.
BAL, pleural lavage and peripheral blood samples
Bilateral BAL was performed after intubation, at the completion of
surgery and prior to extubation. In the six patients that were
extubated within four hours postoperatively, only the first two
bilateral BALs were performed (at intubation and end of surgery).
The bronchoscope was wedged in the lower bronchus of both lungs and
a lavage with 50 mL of sterile saline was performed. The BAL
fluid was immediately centrifuged at 2,000 rpm for
15 minutes and the supernatant stored at - 20°C.
Pleural samples were obtained after amending the initial
protocol following the first 12 patients. To analyze the
pleural inflammatory reaction, lavage of the pleural space after
thoracotomy and before closure of the thoracotomy with 100 mL
of sterile saline was performed. On day 1-3, pleural fluid samples
were taken in a standardized way directly from the pleural tubes.
The fluid was processed as described above for the BAL samples.
Peripheral venous blood samples were obtained at the same time
as the BAL, and pleural fluid samples on the day of surgery and on
day 1-3. Again, the samples were processed as described.
Cytokine assays
The concentrations of IL-6, IL-8, IL-10 and IL-1RA in the BAL,
pleural space and blood samples were determined using enzyme-linked
immune-sorbent assays (ELISA, R & D Systems, Minneapolis, MN,
USA). To standardize the BAL fluid samples for optimal comparison,
we extrapolated the results retrieved in the ELISA to a sample
volume of 10 mL.
Statistical analysis
Comparison of data between the groups was undertaken using
Chi-square tests for categorical data, and Wilcoxon signed rank
tests for continuous data. To analyze the influence of time on the
cytokine response, a regression model using an interaction term for
group and time was developed. Postoperative morbidity was
classified as surgical, pulmonary or medical. Surgical morbidity
included anastomotic leak, thoracic empyema, chyle leak and
rethoracotomy or relaparotomy. An anastomotic leak was defined as
contrast extravasation during a contrast swallow study. Pulmonary
morbidity included postoperative pneumonia, pleural effusion
requiring intervention, and ARDS. Medical morbidity included
cardiac complications such as arrhythmias needing intervention, or
renal failure.
An analysis to assess whether the concentrations of cytokines in
the different compartments were different in patients with and
without complications was performed. This analysis was stratified
according to the type of complication: complications that were
results of the change of the immune system such as pulmonary and
medical complications, pulmonary complications alone and the major
surgical complication, anastomotic leakage. Atrial fibrillation was
included in the complications that were the result of changes in
the immune system [14].
Data are presented as mean values with standard deviation (SD)
or median values with inter-quartile range (IQR), as appropriate.
Statistical significance for each model was set at p < 0.05.
Statistical analyses were performed with SPSS®, Version
16 for Windows and GraphPad InStat Version 3.1a for Macintosh
(GraphPad Software, San Diego California USA).
Results
Patients, pathology and morbidity
There were 26 men and 3 women in the study group. The
mean age was 63.1 years (SD 9.6 years) and mean body mass
index was 25.8 (SD 4.0). Preoperative spirometry showed a mean
forced expiratory volume (FEV1) of 2.8 liters (SD
0.8 liters) and a mean vital capacity (VC) of 4.1 L (SD
0.8 L). The mean percentage FEV1/VC was 69.7% (SD 11.7%). The
mean cardiac ejection fraction was 58.6% (SD 8.3%). Six patients
(20.7%) had pulmonary co-morbidities, five patients (17.2%) cardiac
co-morbidities, six patients (20.7%) presented with non-insulin
dependent diabetes and one patient (3.5%) with pre-existing renal
impairment.
There were 19 patients with adenocarcinoma and 10 with
squamous cell carcinoma. Seventeen patients received neoadjuvant
radio-chemotherapy and 12 patients proceeded directly to
surgery. An abdomino-thoracic technique was used in
23 patients, and a thoraco-abdomino-cervical technique in six
patients. No difference in duration of surgery or blood loss
occurred between these different techniques (median
270 minutes in both techniques, p = 0.333; 500 mLs versus
400 mLs, p = 0.609). The International Union Against Cancer
(UICC) stages were as follows: four patients (14%) with stage 0,
seven patients (24%) with stage I, nine patients (31%) with stage
IIA, six patients (21%) with stage IIB and three patients (10%)
with stage III.
There was one, in-hospital death on postoperative day 30. This
involved a patient with an anastomotic leak and mediastinitis.
Morbidity is shown in table 1. The six
anastomotic leaks included two cervical and four intra-thoracic.
Both cervical leaks were treated conservatively; three patients
with intra-thoracic leaks underwent re-thoracotomy and suture
repair.
Fifteen patients received NAC, and 14 received the placebo
(glucose 5%). No significant differences in cytokine concentration
in BAL fluid, peripheral blood and pleural fluid between patients
with and patients without NAC were detected.
Table 1 Morbidity shown as medical, surgical and
pulmonary morbidity
|
Surgical morbidity total - No - Yes
|
21 8
|
|
Leak - No - Yes
|
23 6
|
|
Rethoracotomy - No - Yes
|
25 4
|
|
Relaparotomy - No - Yes
|
27 2
|
|
Pulmonary morbidity total - No - Yes
|
12 17
|
|
Effusion - No - Yes
|
22 7
|
|
Pneumonia - No - Yes
|
16 13
|
|
ARDS - No - Yes
|
28 1
|
|
Medical morbidity total - No - Yes
|
22 7
|
BAL fluid cytokine assay
Both lungs were affected by the surgical procedure. The cytokine
response showed substantial variability for the individual patients
(figure 1A-F).
The assay of the pro-inflammatory cytokines of the bilateral BAL
fluids showed significantly higher concentrations on the ventilated
left side at the time of extubation (table
2).
The anti-inflammatory response was seen as regards IL-1RA, but
not IL-10, and was mostly restricted to the left lung. Again, the
response was most marked at the time of extubation.
The regression model using an interaction term for group and
time showed that there was a significant effect in the time
progression for IL-6 (p = 0.003), IL-8 (p = 0.002) and
IL-1RA (p = 0.001), respectively, but not for IL-10 (p =
0.572).
Taking the cytokine concentration at intubation as a baseline,
the ratios of cytokine increase showed a substantial increase in
pro-inflammatory cytokines, especially IL-6, whereas the increase
in anti-inflammatory cytokines was less pronounced (table 2).
Table 2 Comparison of the cytokine levels in the BAL
fluid from the right and left lung
|
BAL from collapsed right lung
|
Ratio of cytokine response in collapsed right
lung*
|
BAL from ventilated left lung
|
Ratio of cytokine response in ventilated left
lunga
|
P valueb BAL from right lung compared to BAL
from left lung
|
|
IL-6 (pg/mL), Median (IQR)
|
|
- At intubation - End of surgery - Before extubation
|
54 (17-113) 959 (135-2,297) 428 (174-1,217)
|
12.1 6.4
|
48 (29-114) 669 (328-1,391) 1045 (137-5,829)
|
9.4 12.8
|
0.598 0.258 0.044
|
|
IL-8 (pg/mL), Median (IQR)
|
|
- At intubation - End of surgery - Before extubation
|
2015 (498-3,681) 4933 (1,738-21,384) 11515 (4,397-18,807)
|
3.9 4.1
|
2,077 (1,152-4,398) 5,472 (1,540-11,437) 23,097 (7,696-62,921)
|
2.3 6.6
|
0.745 0.150 0.038
|
|
IL-10 (pg/mL), Median (IQR)
|
|
- At intubation - End of surgery - Before extubation
|
0 (0-7) 35 (0-79) 0 (0-9)
|
2.5 0
|
0 (0-8) 15 (0-33) 3 (0-25)
|
2.1 1.3
|
0.715 0.063 0.117
|
|
IL-1RA (pg/mL), Median (IQR)
|
|
- At intubation - End of surgery - Before extubation
|
5838 (2035-12379) 11390 (5659-40199) 10,245 (6,689-18,663)
|
2.4 2.6
|
6519 (2,600-12,402) 8775 (3,029-23,165) 33,780 (9,041-109,282)
|
1.1 3.2
|
0.745 0.089 0.092
|
Blood cytokine assay
Of the pro-inflammatory cytokines, only IL-6 increased in the
blood, while IL-8 showed little change (table 3). Of the anti-inflammatory cytokines, both
IL-10 and IL-1RA increased in the blood. The increase was
already observed by the end of surgery, i.e. only a few hours after
the surgical trauma had occurred. The ratio calculation showed that
IL-6 and IL-1RA increased most noticeably (table 3).
Table 3 Comparison of the cytokine levels in the pleura
fluid with the levels in the peripheral blood. The pleural samples
were taken immediately after the thoracotomy and before closure of
the thoracotomy. On day 1-3, the pleural and peripheral blood
samples were taken at the same time
|
Pleural fluid
|
Ratio of cytokine response in pleural fluid*
|
Peripheral blood
|
Ratio of cytokine response in peripheral
blooda
|
P valueb pleural fluid versus blood
|
|
IL-6 (pg/mL), Median (IQR) - At thoracotomy/intubation - End of
surgery - Day 1 - Day 2 - Day 3
|
399 (0-702) 1,799 (659-3,046) 52,124 (27,311-68,355) 26,755
(16,796-41,109) 10,583 (7,047-28,171)
|
2.5 103.3 39.1 19.5
|
0 (0-12) 134 (76-208) 146 (98-224) 86 (56-145) 51 (24-98)
|
11.1 11.9 4.9 4.2
|
< 0.001 < 0.001 < 0.001 < 0.001 < 0.001
|
|
IL-8 (pg/mL), Median (IQR) - At thoracotomy/intubation - End of
surgery - Day 1 - Day 2 - Day 3
|
28 (0-216) 222 (31-319) 705 (296-1,232) 589 (230-1,289) 417
(201-951)
|
1.1 6.6 5.3 2.9
|
0 (0-22) 10 (0-48) 0 (0-45) 0 (0-28) 0 (0-38)
|
1.1 1.4 1.3 1.2
|
0.040 < 0.001 < 0.001 < 0.001 < 0.001
|
|
IL-10 (pg/mL), Median (IQR) - At thoracotomy/intubation - End of
surgery - Day 1 - Day 2 - Day 3
|
0 (0-25) 10 (0-44) 317 (237-392) 234 (152-285) 155 (106-217)
|
0.8 11.9 9.4 7.3
|
15 (0-258) 75 (38-276) 62 (12-323) 46 (6-281) 57 (6-317)
|
1.2 1.3 1.4 1.4
|
0.022 < 0.001 0.051 0.098 0.855
|
|
IL-1RA (pg/mL), Median (IQR) - At thoracotomy/intubation - End of
surgery - Day 1 - Day 2 - Day 3
|
62 (0-803) 1137 (319-1,837) 7152 (3,834) 5314 (11,758) 3807
(3,457-8,991)
|
3.0 24.9 5.9 4.3
|
63 (0-780) 5,053 (1,048-11,533) 961 (357-1,502) 436 (171-1,297) 397
(145-2,085)
|
9.8 1.6 1.1 1.7
|
0.380 < 0.001 < 0.001 < 0.001 < 0.001
|
Pleural fluid cytokine assay
All cytokines increased substantially after surgery. The highest
concentrations of all cytokines were measured on day one
post-surgery, and decreased thereafter. The ratio calculation
showed that all cytokines increased substantially, more than in the
BAL fluid or in the blood. IL-6 and IL-1RA showed the greatest
change, with day one ratios of 103 and 25, respectively.
Comparison of cytokine concentrations in the pleural fluid and the
peripheral blood revealed higher levels in the pleural fluid for
all cytokines throughout the measurement period, with the exception
of IL-10 (table 3).
Patients with complications versus patients without
At no time was any significant difference in interleukin levels, in
any compartment, observed in patients with and without
complications that were the results of changes in the immune
system. Also, no difference between patients with pulmonary
complications or anastomotic leak in any of the compartments was
detected.
Patients receiving neoadjuvant radiochemotherapy versus
patients who did not
A comparison of the initial inflammatory status of the
17 patients who received neoadjuvant radio-chemotherapy
compared with the 12 patients that proceeded directly to
surgery is shown in table 4.
Table 4 Comparison of basic serum cytokine levels in
patients who underwent neoadjuvant radio-chemotherapy, and patients
who proceeded directly to surgery
|
Neoadjuvant treatment n = 17
|
No neoadjuvant treatment n = 12
|
P valuea
|
|
IL-6 (pg/mL), Median (IQR)
|
3 (0-18)
|
0 (0-0)
|
0.040
|
|
IL-8 (pg/mL), Median (IQR)
|
0 (0-50)
|
0 (0-0)
|
0.088
|
|
IL-10 (pg/mL), Median (IQR)
|
50 (0-694)
|
12 (0-32)
|
0.262
|
|
IL-1RA (pg/mL), Median (IQR)
|
139 (0-1,586)
|
43 (0-263)
|
0.510
|
Discussion
In all patients, both lungs were affected. There was a difference
between pro-inflammatory cytokine concentrations in BAL fluid of
the ventilated left and the collapsed right lung. The
concentrations of the pro-inflammatory cytokines IL-6 and
IL-8 were significantly higher in the ventilated left lung
before the delayed extubation. The ratio analysis showed that
IL-6 demonstrated the most pronounced increase. The
anti-inflammatory response was represented by changes in IL-1RA
levels, whereas no notable increase in IL-10 occurred. There
was also a significant influence of time in the concentrations of
IL-6, IL-8 and IL-1RA, indicating that both the time course
and extent of the inflammatory response are different in the two
lungs. To our knowledge, no other study has analyzed cytokine
levels and time course during OLV, in both lungs, in the same
patient. Cree et al. examined ventilated left and collapsed
right lungs of two different groups of patients and found no
significant difference in cytokine concentrations [4]. However, as
these and other authors state, cytokine concentrations vary
considerably between patients, thus inflicting a bias [4, 5]. Our
data support this statement. Furthermore, the different time
courses of the cytokine concentrations may represent the different
mechanisms that trigger the inflammatory reaction. The increase in
concentrations of the pro-inflammatory cytokines IL-6 and
IL-8 take longer and are more pronounced in the ventilated
left lung compared to the collapsed right lung. A similar
finding was described in two groups of patients with a low and high
ratio of OLV to total ventilation time (< 35% and > 35%),
respectively [15]. These authors showed non-significant, higher BAL
fluid IL-6 concentrations in the group with a low OLV to total
ventilation time ratio. In contrast to our results, these authors
did not show any differences in IL-8 concentrations.
A number of factors may be responsible for the development and
severity of inflammatory reactions during OLV. The
ischemia/reperfusion in the collapsed lung triggers an inflammatory
response that may lead to lung injury [9]. In the ventilated lung
during OLV, high oxygen concentrations are necessary to maintain
adequate oxygenation, producing reactive oxygen species and
subsequently triggering an inflammatory reaction [8, 16].
Additionally, mechanical ventilation can cause mechanical stress on
alveolar walls known as barotrauma or volutrauma, initiating a
cytokine response [17-19]. Our findings indicate that the
inflammatory reaction in the ventilated left lung is more
pronounced and prolonged compared to the collapsed right lung.
These findings underline the importance of improving the
mechanical ventilation in OLV in order to attenuate the
inflammatory reaction and to protect the left lung. Although the
principles of a lung protective ventilation strategy were followed
in this study (lower tidal volumes, positive end-expiratory
pressure and limited peak airway pressures), the inflammatory
response to mechanical ventilation appears to be substantial.
A number of studies have analyzed the influence of protective
ventilation strategies on the cytokine reaction, with inconsistent
results [18, 20-22]. A recent trial in patients with ARDS,
showed that tidal volumes as low as 4.2 ± 0.3 mL/kg
body weight further enhances lung protection as compared with tidal
volumes of 6.3 + 0.2 mL/kg [23]. It remains to be examined
whether or not such a ventilation strategy would also be beneficial
regarding cytokine release during OLV. Furthermore, promising
results were obtained in a study comparing two-lung, high-frequency
jet ventilation with standard OLV in patients undergoing
transthoracic esophagectomy [24]. The two-lung jet-ventilated
patients showed a lower PCO2 with adequate oxygenation.
However, no measurements to analyze the inflammatory reactions were
performed.
In the blood, the pro-inflammatory reaction was mainly
represented by the increase in IL-6, but not IL-8 levels. The
latter was elevated but only locally in the BAL fluid and the
pleural fluid. Both anti-inflammatory cytokines were increased in
the blood, with the increase in IL-1RA being more pronounced.
Interestingly, the systemic reaction occurred had already at the
end of surgery and was this very fast since it was observed only a
few hours after the surgical and anesthetic trauma. Transthoracic
esophagectomies have been shown to trigger higher interleukin
concentrations in the peripheral blood compared to
pancreaticoduodenectomies or transhiatal esophagectomies [25, 26].
The intrathoracic phase of the operation seems to be responsible
for the more severe inflammatory response. In addition, the
systemic response may be attenuated by the suppression of
circulating white blood cells such as monocytes or T-helper
lymphocytes [27]. Whether the production of IL-10 is less
attenuated in the peripheral blood, leading to the higher
concentrations compared to those found in the BAL fluid, is
unclear. Van Sandick et al. showed a depression of
IL-10 production in vitro in patients undergoing esophagectomy
[27].
The inflammatory response in the compartment where the surgery
is performed, i.e. the right sided thoracic cavity, has not
previously been studied in detail. Two studies analyzed the
concentrations of the pro-inflammatory cytokines IL-6 and
IL-8 in pleural drainage fluid and peripheral blood, and found
significantly higher levels in the pleural samples [3, 28]. Our
results are consistent with these reports. To our knowledge, no
study has analyzed the time course of anti-inflammatory cytokines
in the pleural space. Both IL-10 and IL-1RA concentrations
were markedly higher in the pleural fluid compared to the
peripheral blood. The concentrations of the anti-inflammatory
cytokines increase until day one after surgery, which is then
followed by a subsequent, slow decrease. On day three, the
concentrations were clearly still higher than at the beginning of
the surgery. This may be influenced by the thoracic drains, which
stayed in place for a minimum of five days.
The analysis of the patients with complications versus patients
without complications did not reveal any differences at any time
point or for any cytokine type. We were not able to reproduce the
findings of Szczesny et al., who demonstrated IL-6 and
IL-1 in pleural fluid to be a marker for postoperative
complications in a small cohort of 27 patients undergoing
lobectomy or pneumonectomy [29]. The groups in their study showed
significant differences in age (patients with complications were
older), and length of surgery (longer in patients with
complications). Although the authors argue that these factors are
non-immunological, we believe that they still might have had an
influence as the immune response might be less pronounced in older
patients and longer operation times might have had an influence on
the time course and extent of the immune response.
Pulmonary complications per se were not associated with an
altered inflammatory response. A subclinical anastomotic leak
may also increase the pleural inflammatory response. However, the
comparison between the patients who were diagnosed with an
anastomotic leak and those without did not reveal any differences
in cytokine concentrations. As the groups were small, no definite
conclusion can be drawn.
The patients of this study were also enrolled in a prospective
randomized trial analyzing the effect of NAC on pulmonary
morbidity. Fifteen patients received NAC and 14 did not. This
might have influenced the inflammatory response and needs to be
acknowledged as a limitation. However, there are no data on the
effect of NAC in esophagectomy. We compared the patients with and
without NAC and found no differences in the cytokine response in
any compartment. Thus, we believe that NAC has not biased the
results.
A number of patients underwent neoadjuvant radio-chemotherapy.
The interval between pretreatment and surgery was 6-8 weeks.
We performed a sub-analysis comparing the initial blood cytokine
levels in patients with and without neoadjuvant treatment. The
results showed no statistical difference in the cytokines except
for IL-6, which was most likely caused by a type 1 error.
Literature on the perioperative inflammatory response after
neoadjuvant treatment is scarce. Endo et al. assessed cytokine
production in patients with small lung cell cancer who underwent
preoperative chemotherapy with cisplatin and docetaxel and found an
increased cytokine production during the perioperative period [30].
As the numbers in our study are small, careful interpretation of
these results is necessary and further studies are needed to
analyze the impact of neoadjuvant treatment on the perioperative
cytokine response.
Conclusion
The findings of this study underline the complexity of the
inflammatory reaction associated with transthoracic esophagectomy.
The response of pro- and anti-inflammatory cytokines arises in both
the ventilated left and the collapsed right lungs. The response is
more pronounced on the ventilated left side, and the time courses
are significantly different. In the blood, the pro-inflammatory
IL-6, and both anti-inflammatory cytokines increased. The response
occurred early after the surgical and anesthetic trauma. All
cytokines increased in the pleural cavity.
Acknowledgments
The authors thank Ms. C. Booy and Ms. L. Reyes for their skillful
laboratory work, Dr. R. Whitfield, MBBS, FRACS, for help in
preparation of the manuscript in English, and Mr. Eric Smith, BSc.
for support with the figures and the statistical analysis.
Disclosure. The study was supported by departmental
grants from the Institute of Anesthesiology, Triemli City Hospital
Zurich and Department of Surgery, University Hospital Basel,
Switzerland.
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