Introduction
Leakage from an esophagogastric or esophagojejunal anastomosis after esophagectomy
or gastrectomy is associated with a high postoperative mortality rate and an impaired
quality of life during long-term follow-up [1]
[2]
[3]
[4]
[5]
[6]. Leakage rates vary between 3 % and 25 % after esophagectomy [7]
[8]
[9]
[10] and between 3 % and 11 % after total gastrectomy [3]
[5]
[11]
[12]. There is a lack of consensus regarding the management of leakage from an esophageal
anastomosis because of the rarity of this complication, substantial variability in
the severity of the clinical manifestations of the anastomotic dehiscence, and above
all the existing literature, which mainly consists of small, single-institution series
containing a multiplicity of confounders. As a result, there is only weak evidence
in favor of any of the alternative therapeutic options.
Owing to the high rates of mortality and morbidity following traditional open surgical
interventions for anastomotic leakage [9]
[13], several minimally invasive endoscopic methods, which include esophageal stents,
clips, fibrin glue, and endoluminal vacuum therapy, have been advocated and introduced
[14]
[15]
[16]. Experiences of stent therapy, which is an established therapeutic option for various
other causes of gastrointestinal leakage, including spontaneous or iatrogenic perforation,
have been described in a few series containing sufficient numbers of patients [17]
[18]; success rates ranging from 54 % to 77 % have been reported [14]
[19]
[20]
[21]. Most publications have, however, reported experiences based on a small number of
cases in which the focus has been on the clinical characteristics of the anastomotic
leaks and the outcomes, without further analysis of the factors associated with positive
or negative outcomes. The significant variations in reported success rates after stent
treatment, in addition to the diverse clinical presentations and therapeutic outcomes,
emphasize the need for a complementary analysis of the role of stent therapy in the
management of esophageal anastomotic leakage. Herein, we report a single-center experience
of stent treatment for esophagogastric and esophagojejunal anastomotic leakage that
ranges over more than a decade, with a focus on assessing the risk for failure of
the SEMS-based therapeutic concept.
Material and methods
Patient inclusion
Beginning in 2003, all patients with a leak from the esophagus were initially approached
and evaluated for temporary closure with a self-expandable metallic esophageal stent
(SEMS). Until 2014, all patients at the Karolinska University Hospital with a leak
from an esophagogastric or esophagojejunal anastomosis were identified. Data regarding
the characteristics of the patients and leaks and the treatment outcomes were compiled.
All included patients had undergone surgery for malignant or benign disease with esophagectomy
and esophagogastric anastomosis, gastrectomy and esophagojejunal anastomosis, or esophagogastrectomy
and esophagojejunal anastomosis. Gastrectomy also included proximal gastrectomy/distal
esophagectomy with jejunal interposition (Merendino procedure). Patients who had gastrojejunal
or esophagocolonic leaks were not included in this study. Patients were identified
through the hospital databases Vis-Portalen, TakeCare, and Orbit.
Definition of anastomotic leakage and management
In case an anastomotic leak was clinically suspected during the postoperative period,
the patient underwent either acute endoscopy or, more often, endoscopy preceded by
computed tomography with native-phase images and then imaging after the oral intake
of water-soluble contrast medium to document and characterize the dehiscence. Anastomotic
leakage was defined by the presence of extraluminal collections of air or contrast,
excessive amounts of bile-stained fluid, or a combination of these. A diagnosis of
leakage could also be established if blue-stained output from a drain or a cervical
incision was observed after the patient had orally ingested methylene blue.
If further evaluation of the leakage or any type of intervention was indicated, the
patient underwent endoscopy under general anesthesia. During the study period, sealing
of the perforation with an esophageal stent was the preferred primary strategy whenever
feasible. A fully or partially covered SEMS was inserted over a guidewire under fluoroscopic
guidance. Over the 10-year period, different types of stents were used. When needed,
double stents were deployed for better coverage of the defect. After a stent had been
inserted, computed tomography was again performed in most cases to exclude persistent
leakage. All patients received broad-spectrum antibiotics and often also antifungal
drugs.
A tailored approach for optimizing drainage was applied; methods used included percutaneous
drainage, drainage via the cervical incision, drainage of the pleural spaces and mediastinum
via thoracotomy or thoracoscopy, and trans-hiatal drainage via laparotomy. Patients
received parenteral or enteral nutrition until the leakage was considered to be under
control. Extraction of the stent, repeated endoscopic inspection of the leak, and
the application of a new stent were regularly performed based on clinical developments
and the patient’s recovery. Stents were not used in patients with minor subclinical
leakage that was judged to be manageable with drainage alone, typically via the cervical
incision in those with a proximal neck anastomosis. The SEMS-based concept was not
followed in the most severe clinical situations; if signs of conduit necrosis were
observed, immediate surgical intervention and conduit takedown were required.
Definition of treatment failure
Failure was defined as a need for reoperation because of uncontrolled sepsis and mediastinitis
(usually rescue esophagectomy with end-esophagostomy) or as death resulting from leakage
or the development of an esophagotracheal fistula that did not heal after repeated
attempts at management with esophageal stents, usually combined with tracheal stents,
and therefore required surgical reconstruction at a later stage [22]. Persistent leakage after stenting in which the leakage and infection could be managed
successfully with drainage procedures and antibiotics and eventually healed was accordingly
not considered a failure.
Possible risk factors
The following variables were analyzed as possible risk factors for unsuccessful or
failed stent therapy: age; sex; American Society of Anesthesiologists (ASA) physical
status classification; smoking; alcohol abuse; cardiovascular disease, pulmonary disease,
or diabetes; maximal physical performance on a preoperative bicycle test; indication
for surgery (malignant vs. benign disease); prior neoadjuvant treatment; type of resection;
type of reconstruction; level of anastomosis; time from surgery to the diagnosis of
leakage and stenting; sealed leakage after index stent insertion; number of endoscopic
reinterventions (to control leakage); development of esophagotracheal fistula; body
mass index (BMI) and C-reactive protein (CRP) level; albumin and creatinine levels
preceding stent insertion.
Secondary outcomes and descriptive data
These included the following: frequency of treatments other than SEMS placement as
up-front therapy, days in intensive care unit (ICU), days in hospital, need for ventilator
support or hemodialysis, and in-hospital mortality in the successful and failed treatment
groups, respectively.
Cardiopulmonary exercise testing
At the time of the study, nearly all patients for whom esophagectomy was planned underwent
a physical endurance exercise test as a part of their routine preoperative assessment.
This test is performed with the patient on a stationary ergometer; after an initial
period of unloaded pedaling, a continuous, incremental increase in resistance is applied.
The patient’s blood pressure, pulse oximetry reading, and electrocardiogram are monitored
during the test period, and the end of the test is determined by the patient’s physical
endurance. Typical reasons for stopping the test include leg pain, shortness of breath,
and in some cases chest pain, which indicates ischemic heart disease. The results
of the test are given as maximal performance during exercise in watts. Physical performance
was interpreted by the department of clinical physiology, and results were divided
into six categories based on age-, weight-, and sex-matched control variables: good,
ordinary, slightly decreased, moderately decreased, very decreased, and extremely
decreased. Data were then made dichotomous by assigning a score of 1 for a performance
below good and a score of 0 for a performance above good and were analyzed by receiver
operating characteristics, which yielded a cutoff value of 75.5 %.
Statistics and ethics
Numeric data were presented as median and interquartile range (IQR). For the estimation
of risk for failed SEMS therapy and outcome data, variables were analyzed with simple
logistic regression. Variables with a P value below 0.10 in simple logistic regression, as well as patient age and CRP level,
were further analyzed with multivariable logistic regression, which was conducted
by using a logistic regression model with odds ratios and 95 % confidence intervals
presented as a measure of effect size. Patients who had undergone an esophagectomy
were also analyzed as a separate group because some variables were applicable only
to this group. Variables regarding overall treatment outcome were analyzed with Fisher’s
exact test, a chi-squared test, or a Mann – Whitney U test. This study was approved by the Stockholm Ethics Committee (2013/2266 – 31 /4).
Results
Preoperative characteristics of the patients
Between January 2003 and April 2014, 266 esophagogastric anastomoses and 181 esophagojejunal
anastomoses were performed. Of these, 97 were cervical anastomoses, 189 were intrathoracic,
and 161 were abdominal. Anastomotic leakage occurred in 80 patients (18 %): 33 with
cervical, 28 with thoracic, and 19 with abdominal anastomoses. The overall frequency
of leakage was 22 % for esophagogastric anastomoses and 12 % for esophagojejunal anastomoses.
A total of 46 patients (58 %), 41 men and 5 women, received stents as primary treatment
for anastomotic leakage. The vast majority, 43 patients, had undergone surgery because
of malignancy. Neoadjuvant treatment was given to 18 patients (42 % of all those with
cancer). Esophagotracheal fistula developed in 13 of the 266 patients who underwent
esophagectomy (5 %).
Stent treatment
In total, 29 of the 46 patients (63 %) who received a temporary SEMS recovered successfully
and were able to leave the hospital with a patent anastomosis. The overall in-hospital
mortality rate in this group was 0 % if only leakage-related mortality is considered.
However, 1 patient in the success group spent 111 days in the hospital, and the leakage
was sealed after 56 days. This patient had a previous history of both pulmonary and
cardiovascular disease, and the cause of death was respiratory and cardiac failure
that was not associated with the leakage or the ensuing mediastinal infection. In
17 patients (37 %), SEMS therapy failed ( [Table1], [Table 2]). No statistically significant differences between the success and failure groups
were noted regarding age, sex, comorbidities or tumor characteristics, type of resection,
method of reconstruction, anatomical level of the anastomosis, or need for endoscopic
reintervention after primary stenting. The median times between surgery and insertion
of a SEMS, as well as the times between the diagnosis of leakage and stent insertion,
were similar in the success and the failure groups. In the success group, the leak
healed after a median (IQR) of 34 (17 – 50) days ([Table 3]). In the failure group, 11 patients (65 %) died as a direct consequence of leakage
and uncontrolled sepsis. Accordingly, the overall mortality rate in the 46 patients
in whom SEMS was applied as first-line treatment was 26 %.
Table 1
Variables for all patients included in a study of risk factors for failure of stent
placement for anastomotic leakage.
|
Variables
|
Stent and recovery, n = 29 (63 %)
|
Stent and failure, n = 17 (37 %)
|
Unadjusted odds ratio
|
95 % CI
|
P value
|
Adjusted odds ratio[1]
|
95 % CI
|
P value
|
|
Lower
|
Upper
|
Lower
|
Upper
|
|
Age, median (IQR), y
|
63 (39 – 77)
|
65 (52 – 78)
|
1.023
|
0.954
|
1.097
|
0.528
|
|
|
|
|
|
Sex ratio, M:F
|
27:2
|
14:3
|
0.346
|
0.052
|
3.316
|
0.343
|
|
|
|
|
|
ASA score, median (IQR)
|
2 (1 – 3)
|
2 (1 – 2)
|
0.710
|
0.319
|
1.578
|
0.400
|
|
|
|
|
|
BMI, median (IQR) (n = 31)
|
28 (25 – 30)
|
25 (21 – 28)
|
0.887
|
0.753
|
1.044
|
0.150
|
|
|
|
|
|
Smoker, n (%)
|
10 (34)
|
11 (65)
|
3.483
|
0.993
|
12.223
|
0.051
|
2.146
|
0.244
|
18.887
|
0.492
|
|
T stage, n (%) (n = 41)
|
|
|
1.422
|
0.616
|
3.284
|
0.410
|
|
|
|
|
|
T1 – 2
|
12 (46)
|
4 (26)
|
|
|
|
|
|
|
|
|
|
T3 – 4
|
14 (54)
|
11 (74)
|
|
|
|
|
|
|
|
|
|
Neoadjuvant therapy, n (%) (n = 42)
|
12 (44)
|
6 (40)
|
0.833
|
0.231
|
3.003
|
0.780
|
|
|
|
|
|
Resection type, n (%)
|
|
|
0.684
|
0.174
|
2.689
|
0.586
|
|
|
|
|
|
Esophagectomy
|
20 (69)
|
13 (77)
|
|
|
|
|
|
|
|
|
|
Total gastrectomy
|
9 (31)
|
4 (24)
|
|
|
|
|
|
|
|
|
|
Reconstruction type, n (%)
|
|
|
0.684
|
0.174
|
2.689
|
0.586
|
|
|
|
|
|
Esophagogastrostomy
|
20 (69)
|
13 (77)
|
|
|
|
|
|
|
|
|
|
Esophagojejunostomy
|
9 (31)
|
4 (24)
|
|
|
|
|
|
|
|
|
|
Level of anastomosis, n (%)
|
|
|
|
|
|
|
|
|
|
|
|
Neck
|
7 (24)
|
7 (41)
|
|
|
|
|
|
|
|
|
|
Mediastinum
|
13 (45)
|
6 (36)
|
0.462
|
0.111
|
1.921
|
0.288
|
|
|
|
|
|
Abdomen
|
9 (31)
|
4 (24)
|
0.444
|
0.092
|
2.150
|
0.313
|
|
|
|
|
|
CRP, median (IQR), mg/L (n = 42)
|
221 (131 – 307)
|
275 (227 – 333)
|
1.006
|
0.999
|
1.013
|
0.104
|
|
|
|
|
|
Time between surgery and insertion of stent, median (IQR), days
|
10 (8 – 15)
|
10 (5 – 17)
|
0.984
|
0.910
|
1.064
|
0.684
|
|
|
|
|
|
Persistent leakage after primary stent, n (%)[2]
|
6 (21)
|
9 (53)
|
12.000
|
1.990
|
72.352
|
0.007
|
11.570
|
1.032
|
129.712
|
0.047
|
|
Endoscopic reinterventions, n (%)
|
15 (52)
|
10 (59)
|
1.333
|
0.398
|
4.470
|
0.641
|
|
|
|
|
CI, confidence interval; ASA, American Society of Anesthesiologists; BMI, body mass
index; CRP, C-reactive protein.
1 Adjusted for age, smoking, and CRP level at baseline.
2 Confirmed with computed tomography after stent placement.
Table 2
Variables for the patients undergoing esophagectomy.
|
Variables
|
Stent and recovery, n = 20 (61 %)
|
Stent and failure, n = 13 (39 %)
|
Unadjusted odds ratio
|
95 % CI
|
P value
|
Adjusted odds ratio[*]
|
95 % CI
|
P value
|
|
|
|
Lower
|
Upper
|
Lower
|
Upper
|
|
CPET performance below cutoff (75.5 %; n = 32)
|
7 (37)
|
10 (77)
|
7.500
|
1.196
|
47.049
|
0.032
|
7.907
|
1.084
|
57.650
|
0.041
|
|
Esophagotracheal fistula
|
3 (15)
|
10 (77)
|
18.889
|
3.183
|
112.093
|
0.001
|
21.387
|
3.233
|
141.487
|
0.002
|
|
Neoadjuvant treatment
|
|
|
6.667
|
0.487
|
91.331
|
0.155
|
|
|
|
|
|
Chemotherapy
|
5 (63)
|
1 (20)
|
|
|
|
|
|
|
|
|
|
Chemoradiotherapy
|
3 (38)
|
4 (80)
|
|
|
|
|
|
|
|
|
CPET, cardiopulmonary exercise testing.
* Adjusted for age and smoking.
Table 3
Postoperative data for all patients.
|
Variables
|
Stent and recovery, n = 29 (63 %)
|
Stent and failure, n = 17 (17 %)
|
P value
|
|
Time to recovery, median (IQR), days
|
34 (17 – 50)
|
–
|
|
|
Time to change of treatment strategy, median (IQR), days
|
–
|
99 (10 – 513)
|
|
|
Endoscopic reintervention(s), n (%)
|
15 (52)
|
10 (59)
|
0.641
|
|
Drainage via laparotomy, n (%) (n = 45)
|
8 (28)
|
4 (25)
|
0.762
|
|
Drainage via thoracotomy, n (%) (n = 45)
|
2 (7)
|
4 (25)
|
0.174
|
|
Days in hospital, median (IQR)
|
54 (31 – 71)
|
61 (40 – 107)
|
0.232
|
|
Days in intensive care unit, median (IQR)
|
12 (1 – 23)
|
23 (13 – 38)
|
0.010
|
|
Ventilator support, n (%)
|
19 (66)
|
16 (94)
|
0.036
|
|
Dialysis, n (%)
|
2 (7)
|
5 (29)
|
0.083
|
|
In-hospital mortality, n (%)
|
1 (3)
|
11 (65)
|
< 0.001
|
|
Second-line treatment, n
|
|
|
|
|
Acute rescue esophagectomy
|
|
5
|
|
|
Delayed colonic interposition
|
|
3
|
|
|
Endoluminal vacuum therapy
|
|
1
|
|
|
Esophagojejunal anastomosis
|
|
1
|
|
IQR, interquartile range.
In the patients in the failure group, in whom the SEMS strategy was abandoned, the
second-line treatment was initiated after a median (IQR) of 99 (10 – 513) days ([Table 3]). Second-line treatment consisted of reoperation with elective colonic interposition
in 3 cases, rescue esophagectomy with end-esophagostomy in 5 cases, and endoluminal
vacuum therapy in 1 case. In 1 patient, a metastatic cancer was discovered during
the in-hospital stay, and a decision was made to discontinue ICU treatment. Another
patient, in whom an esophagotracheal fistula developed, underwent reoperation on 2
separate occasions. First, an attempt was made to reconstruct the esophagogastric
anastomosis and suture the fistula. Because of recurrence of the fistula, reconstruction
with an esophagojejunal anastomosis was subsequently performed by using a free transplanted
jejunal graft. In 7 of the patients who died, a major change in treatment strategy
was not considered possible because of their extremely poor clinical status, and 4
patients died despite second-line treatment.
Risk factors for stent treatment failure
Failure of the SEMS strategy was related to persistent leakage after the index stent
insertion in simple logistic regression analysis (P = 0.007). For patients who had undergone esophagectomy, the development of a esophagotracheal
fistula postoperatively and a reduced physical exercise capacity preoperatively were
both statistically significant risk factors for SEMS failure (P = 0.001 and P = 0.032, respectively). In the multivariable logistic regression analyses, adjustments
were made for CRP level at baseline, smoking status, and age, after which persistent
leakage after initial SEMS remained a statistically significant risk factor for failure
(P = 0.047). In the corresponding analysis for patients with an esophagectomy, both
reduced physical exercise capacity and esophagotracheal fistula remained statistically
significant risk factors (P = 0.041 and P = 0.002, respectively) after adjustment for age and smoking status. However, it was
not possible to adjust for sex in any of the analyses because of a skewed distribution
with only 2 women in the success group (7 %) and 3 in the failure group (18 %).
Treatments other than placement of a self-expandable metal stent
A total of 34 patients (43 %) did not receive a SEMS as primary treatment. The reasons
for applying alternative treatments were as follows: 13 patients had a cervical anastomosis
that was primarily treated with débridement of the cervical wound because the esophagogastric
anastomosis was considered too proximally located to allow a SEMS to be successfully
deployed, and 9 patients had subclinical leakage that was assessed as best managed
by conservative means. In 4 patients who presented with extensive leakage, with or
without dramatic clinical deterioration, SEMS was not considered justified and immediate
surgical intervention was mandated. Another 8 patients demonstrated signs of conduit
necrosis at the emergency endoscopy in the near vicinity of or including the anastomosis
and required rescue surgery. The overall in-hospital mortality rate of those patients
in whom SEMS placement was not suitable was 18 %.
Discussion
During the studied decade, we consistently and prospectively applied an esophageal
SEMS-based strategy as a part of the multimodal first-line treatment of dehiscence
of either an esophagogastric or esophagojejunal anastomosis. Therefore, the current
study for the first time provides a comprehensive analysis of how often such a therapeutic
strategy can be used and its results. The focus of the study was on risk factors for
the failure of this therapeutic concept, which we defined as a radical change of treatment
strategy because of uncontrolled mediastinitis, which in this setting meant emergency
esophagectomy with end-esophagostomy, or as death resulting from leakage and uncontrolled
sepsis. We have shown that in patients in whom the leakage was controlled with the
SEMS concept, the in-hospital mortality rate was low. The majority of patients who
did not receive a SEMS had cervical anastomoses, which could be carefully managed
by externalization and drainage through a wide opening of the neck incision, allowing
direct cleansing. In total, 43 % of the patients did not receive a SEMS as primary
therapy, of whom 12 % required an emergency operation because of severe mediastinitis.
The other main circumstance in which SEMS treatment was inappropriate was conduit
necrosis.
In 58 % of the cases, SEMS was applied as first-line therapy with the objective of
sealing the leak. We were able to demonstrate several risk factors for failure of
this treatment strategy in patients with esophagogastric or esophagojejunal anastomotic
leakage. Persistent leakage after the first stent placement was identified as an independent
risk factor for failure in the whole cohort, which we believe is of clinical significance.
This strongly suggests that endoscopic reintervention with adjustment or change of
stent should always be considered in a patient in whom signs of continuous leakage
develop if there is proof of a sealed leak after the first stent insertion. We therefore
suggest that radiologic monitoring after stent placement be done routinely because
such information is crucial for important decisions that need to be taken later during
the course of treatment.
In the esophagectomy group, additional risk factors, not applicable to the gastrectomy
group, were analyzed. The formation of an esophagotracheal fistula emerged as an independent
risk factor for the failure of stent-based treatment. The currently reported incidence
of airway fistulization is 5 % for all esophagogastric anastomoses, which is within
the range reported in the few larger series on this devastating complication [21]
[23]. Our experience of treating this specific complication with SEMS, usually applying
a dual-SEMS strategy, has been presented before [22]. When an esophagotracheal fistula develops after placement of a stent over an anastomotic
leak, it cannot be ruled out that the airway fistula has been caused by pressure from
the esophageal stent on the very frail pars membranacea of the trachea. Esophagotracheal
fistulas also develop in the absence of stents, and with the currently available data,
it is not possible to identify cases in which there is a risk for inducing the formation
of an esophagotracheal fistula with a SEMS. In the multivariable logistic regression
analyses, adjustments were made for CRP level at baseline, smoking status, and age,
and reduced physical working capacity, as assessed during the preoperative work-up,
remained a statistically significant risk factor after these adjustments. However,
it was not possible in any of the analyses to adjust for sex because of a skewed distribution
with only 2 women in the success group (7 %) and 3 in the failure group (18 %).
Significant clinical experience and research suggest that patients with a poor physical
performance status preoperatively have an increased risk for mortality after esophagectomy
[24]
[25]
[26], which is related to a generally poor outcome after surgery and susceptibility to
complications. This was the main reason why we analyzed the possible influence of
reduced physical performance on the risk for failure after SEMS treatment of an already
established postoperative complication. In fact, this emerged as an independent risk
factor, which may improve the risk stratification of patients eligible for esophagectomy.
Given the observations presented herein, it may be suggested that rescue esophagectomy
be considered at an early time in patients with a reduced physical performance when
anastomotic leakage develops that does not promptly respond to SEMS treatment.
This study has some weaknesses that need to be carefully considered. First of all,
despite the fact that we tried to follow a predefined management strategy, the study
was retrospective, and as such, some vital information may have avoided detection.
Moreover, in 43 % of the patients, stents were not applied as a primary treatment.
On the other hand, and as presented previously, there were relevant reasons for not
doing so. The lower mortality rate among the patients who did not receive a stent
implies that their cases were less complicated. Lastly, the patient cohort is by necessity
heterogeneous, given that it includes both patients with esophagogastric and patients
with esophagojejunal anastomoses. Because of the limited number of patients, further
subgroup studies would have introduced a significant risk for loss of power, which
is why we completed a similar analysis of risk factors in those who underwent esophagectomy
alone.
Whenever a SEMS-based strategy is followed in a clinical situation as demanding as
the one currently presented, the team has to be prepared to undertake repeated endoscopic
reinterventions to control ongoing or recurrent leakage. In this context, it should
be emphasized that the frequency of reintervention did not emerge as a statistically
significant risk factor when the success and failure groups were compared. However,
the conclusions that can be drawn from the present study are that SEMS can be applied
up front in patients with esophagogastric or esophagojejunal anastomotic leakage as
part of a carefully processed treatment strategy. Treatment failure must be vigorously
searched for, and the main risk factors for failure are continued leakage from the
anastomosis and the development of an airway fistula. If these events occur in a patient
with a reduced physical capacity preoperatively, aggressive therapeutic alternatives
have to be promptly instituted. Currently, it appears that emergency esophagectomy
may have been delayed in some of our patients because the second-line treatment was
initiated after a median (IQR) of 99 (10 – 513) days. Future clinical research must
better document the options that can add to the efficacy of SEMS (e. g., vacuum therapy)
and optimize timing of the switch to second-line treatment.
