Introduction
In acute pancreatitis, 15 % to 20 % of patients develop necrosis of pancreatic parenchyma
and/or peripancreatic tissue, indicating a severe course of the disease [1]
[2]
[3]. Approximately one-third of these patients develop infected pancreatic necrosis
(IPN), a life-threatening local condition that is a prerequisite for subsequent systemic
complication, namely organ failure [4]. Both local and systemic complications account for high morbidity and mortality
that usually is fatal without therapeutic intervention.
Therapeutic procedures, notably open surgery, are accompanied by high mortality rates,
particularly when carried out in the first 14 days after onset of the disease [5] Postponing the intervention 4 weeks, after the necrotic collection is demarcated
and encapsulated, decreases mortality rate [6]
[7].
In parallel to a delayed practice, a paradigm shift in the therapy of pancreatic necrosis,
away from open surgery to an interventional step-up approach, has taken place in the
last two decades [8].
But in one-quarter of patients, infected pancreatic necrosis can occur during the
first 14 days after onset of the disease [9], and early intervention is potentially inevitable.
Current guidelines consider the early infection of pancreatic necrosis and recommend
deferring a therapeutic intervention for at least 4 weeks after onset of pancreatitis
but advise therapy in case of progressive deterioration of the patient [10].
However, most of the current data are based on surgery and consensus data for optimal
timing of the endoscopically based approach are sparse [11]. This retrospective two-center study evaluated early direct endoscopic necrosectomy
using lumen apposing metal stents (LAMS) in case of proven or suspected super-infection
in comparison to a delayed practice.
Patients and methods
Between June 2012 and February 2018, all patients endoscopically treated with direct
endoscopic necrosectomy after LAMS placement in two German tertiary referral centers
were screened with regard to the interval between the first proof of necrosis and
the first endoscopic intervention. All patients with an endoscopic treatment within
the first 30 days after first proof of necrosis were included in the study. The patient
cohort consisted of 49 patients (37 male, 12 female) with a median age of 52.2 years.
The etiology of pancreatitis was alcoholic (n = 17), biliary (n = 15), hypertriglyceridemia
(n = 1), post-ERCP-pancreatitis (n = 3), after surgery (n = 1) and unknown (n = 12)
([Table 1]).
Table 1
Patient characteristics.
|
Patients (n)
|
49
|
|
Age [median (95 %CI)]
|
52.2 (48–59)
|
|
male
|
37 (75.5 %)
|
|
Female
|
12 (24.5 %)
|
|
Etiology
|
|
Alcoholic
|
17 (34.7 %)
|
|
Biliary
|
15 (30.1)
|
|
Post-ERCP
|
3 (6,1 %)
|
|
Hypertriglyceridemia
|
1 (2,0 %)
|
|
After surgery
|
1 (2,0 %)
|
|
Uunknown
|
12 (24.5 %)
|
|
Maximum diameter of necrosis (mm) (95 %CI)
|
80 (70–90)
|
ERCP, endoscopic retrograde cholangiopancreatography.
All patients gave written consent, all procedures performed in the study were ethically
in accordance with the 1964 Helsinki Declaration and its later amendments.
Pancreatic necrosis was diagnosed by contrast-enhanced computed tomography (CT) and
evaluated with endoscopic ultrasound (EUS). Infected necrosis was confirmed by the
presence of gas in the CT scan or was suspected based on clinical and biochemical
markers of persistent infection or sepsis, despite maximal therapy in the intensive
care unit and without evidence for another infection source.
Technical success was defined as the ability to position and deploy the stent. Clinical
success was defined as the resolution of the necrotic collection associated with the
recovery of the patient. The periods in the Intensive Care Unit (ICU) and Intermediate
Care Unit (IMU) were recorded and C-reactive-protein (CRP) was measured as a marker
of inflammatory activity. Concerning adverse events (AEs), bleeding with the need
for intervention, perforation, and stent dislocation were recorded. Transfer to surgery
was judged as a failure of the procedure.
Endoscopic procedure
Indication for endoscopic therapy was infected pancreatic necrosis with clinical signs
of sepsis. In the case of infected necrosis, a lumen apposing metal stent (Hot-Axios
Stent, Boston Scientific, Marlborough, Massachusetts, United States, or NAGI Stent,
Taewoong Medical, Wolgot-Myeon, South Korea) was implanted via the transgastral or
transduodenal access.
The two stent designs used are 15 mm in diameter and 10 mm in length (Boston Scientific)
and 16 mm in diameter and 20 mm in length (Taewoong medical). In the case of the Hot
Axios stent, the drainage of the necrotic cavity was carried out by direct puncture
using the electrocautery delivering. In the case of the other stent design, the puncture
was performed with a 19G EUS needle (Echotip, Cook Medical, Bloomington, Indiana,
United States or Expect, Boston Scientific, Marlborough, Massachusetts, United States).
Then a 0.035-inch guidewire (Jagwire Boston Scientific, Marlborough, Massachusetts,
United States) was pushed forward, building two loops in the necrotic area. Subsequently,
the access to the necrotic cavity was achieved using a cystotome (Ring-Knife, MTW,
Wesel, Germany or Boston Scientific, Marlborough, Massachusetts, United States). Thereafter,
the access was dilated (CRE Balloon Dilation Catheter, Boston Scientific, Marlborough,
Massachusetts, United States), and the stent was deployed. The fluid content of the
necrosis was preserved for microbiological testing.
All interventions were performed under monitored anesthesia using propofol or general
anesthesia. Concomitant antibiotics (piperacillin/tazobactam or imipenem/cilastin)
were administered. In the case of cardiopulmonary instability due to sepsis, the first
necrosectomy procedure was postponed for two or three days after stent insertion and
was carried out after the recovery of the patient. Otherwise, the first direct endoscopic
necrosectomy was performed during the same session immediately after stent placement
([Fig. 1], [Fig. 2]). Sequential endoscopic necrosectomies were performed at intervals of 2 to 3 days
until the complete resolution of the necrotic debris ([Fig. 3], [Fig. 4]). In five cases (8 %), a second lumen-apposing metal stent was added because of
the extent of the necrotic collection. In seven patients (12 %) additional external
drainage after the initial endoscopic access was required due to the extension of
the necrosis to the lesser pelvis ([Fig. 5], [Fig. 6]).
Fig. 1 Performing direct endoscopic necrosectomy via transduodenal access, contrast agent
is applied to visualize the necrotic cavity.
Fig. 2 First necrosectomy after LAMS placement with the help of an endoscopic snare.
Fig. 3 Necrotic cavity after first necrosectomy.
Fig. 4 Necrotic cavity after last endoscopic necrosectomy.
Fig. 5 Extensive pancreatic necrosis reaching the pelvis before therapy.
Fig. 6 Pancreatic necrosis 8 weeks after therapy.
Statistical analysis
Statistics were performed with SPSS version 24 (IBM, United States). The 95 % confidence
interval (CI) of the median was calculated using Bootstrapping. The Wilcoxon signed-rank
test was used for continuous variables to investigate differences between paired values.
The Mann Whitney U test was used for independent values. For binominal variables,
chi-square was chosen to examine differences between groups. P < 0.05 indicated statistical significance.
Results
All 49 patients received a median of four necrosectomies (3–5) after a median of 7
days (3–11) after the first proof of necrosis ([Table 2]).
Table 2
Intervention characteristics, clinical outcomes, and adverse events.
|
n = 49
|
|
Technical success rate
|
100 %
|
|
Clinical success rate
|
87.8 %
|
|
Mortality
|
8.2 %
|
|
Period until intervention (d) median (95 % CI)
|
7 (3–11)
|
|
necrosectomies
|
4 (3–5)
|
|
ICU treatment, n (%)
|
21(43 %)
|
|
ICU days, median (95 %CI)
|
5 (3–9)
|
|
IMC treatment, n (%)
|
33 (67 %)
|
|
IMC days, median (95 %CI)
|
3(2–4)
|
|
Follow-up(months), median (95 %CI)
|
14 (10–18)
|
|
CRP pre (mg/L), median (95 %CI)
|
241 (182.8–288.9)
|
|
CRP post (mg/L), median (95 %CI)
|
23.3(18–60)
|
|
WBC pre (T/µL), median (95 %CI)
|
15.1(13.6–17.5)
|
|
WBC post (T/µL), median (95 %CI)
|
7.9(6.5–9.3)
|
|
Adverse events
|
6 (12.2 %)
|
|
Bleeding
|
2 (4.1 %)
|
|
Perforation
|
2 (4.1 %)
|
|
Dislocation
|
4 (8.2 %)
|
ICU, intensive care unit; IMC, intermediate care unit; CRP, C-reactive protein; WBC,
white blood cell.
Technical success was defined as the ability to deploy the stent in the correct position;
this was achieved in all 49 patients (100 %). The clinical success rate of the procedure
defined as clinical resolution of the necrotic collection was 87.8 %; the mortality-rate
accounted for 8.2 %.
The median CRP-level as a marker for systemic inflammation was 241 mg/L (182.8–288.9)
and 23.3 mg/L (18–60) before and after therapy (P < 0.001) ([Table 2]).
The median time period for the 21 (43 %) patients who received intensive care was
5 days (3–9) in the ICU, time spent in the IMC was a median 3 days (2–4).
Adverse events
One perforation combined with significant bleeding occurred and was handled endoscopically
using an over-the-scope-clip (OTSC, Ovesco, Tuebingen, Germany). Two further clinically
significant hemorrhages took place. One was managed endoscopically, the second patient
was transferred to surgery because of recurrent hemorrhage in the necrotic cavity
and died in the course of the disease due to multiple organ failure. Three stent dislocations
occurred during endoscopic debridement. Those were successfully repositioned ([Table 2]). The median follow-up time was 14 months (10–18).
Discussion
In the course of acute necrotizing pancreatitis, the Atlanta classification distinguishes
between the acute necrotic collection containing a various amount of fluid and necrotic
tissue which is a criterion of an early stage of the disease and the walled-off necrosis
consisting of necrotic material within an enhancing wall of reactive tissue which
usually occurs in a later course of the disease [1] This encapsulated collection has a defined wall and matures over a time period ≥ 4
weeks after onset of pancreatitis. Infected pancreatic necrosis is predominantly an
attribute of this late phase of necrotizing pancreatitis. But in 25 % of cases, infection
of necrosis occurs within the first 14 days before the walled-off necrosis has fully
matured [9].
In the case of early infected pancreatic necrosis, current guidelines recommend postponing
the first intervention for 4 weeks after the onset of pancreatitis, if it is tolerated
by the patient [12]
[13]. After demarcation of the infected tissue, drainage or debridement are supposed
to be easier performed with fewer complications.
Different surgical based studies had shown an improved outcome by delaying the intervention
for ≥ 4 weeks [5]
[6]
[7]
[8]. Particularly stable patients might benefit from conservative treatment with antibiotics
to delay the required intervention and give the necrotic collection time to evolve
and demarcate.
In contrast, in the case of unstable, rapidly deteriorating patients, earlier intervention
is inevitable. In this early stage of the disease, data about timing of the first
intervention are sparse. A survey of 116 international pancreatologists showed a disagreement
among the participants regarding the timing of invasive interventions: in the case
of early infected necrosis, 55 % of respondents would postpone the intervention under
antibiotic therapy, whereas 45 % prefer immediate intervention [11].
The current European Society for Gastrointestinal Endoscopy guideline deliberates
the early intervention in case of septic aggravation of the patient if a delay is
not tolerable due to the patient's condition [10]. In our study, the patients received the first transluminal therapy after a median
of 7 days (3–9, 95 % CI) after the first proof of necrosis.
At this particular time, most of the necrotic collections are not expected to be encapsulated.
With regard to the previously published data, one would anticipate an increase in
complication rate and eventually, mortality. In our study, despite postponing the
intervention, the mortality rate was 8.2 %, which is comparable to previous studies
ranging from 7.5 % to 19 % [8]
[14]
[15]. These results suggest that early intervention is tenable when it is essential due
to the clinical deterioration of the patient.
This is in contrast to earlier surgically based studies showing that postponing the
interventions decreases mortality [6]
[7]
[16]. Surgical necrosectomy of infected and not demarcated pancreatic necrosis resulted
in distinct inflammatory stress leading to organ failure and increased mortality.
But our data indicate that these surgical results are not entirely applicable to an
endoscopically based approach.
Our results support the assumption that endoscopic intervention produces a minor inflammatory
stimulus in comparison to surgery, which leads to a weakened systemic inflammatory
response and enables intervention in the early phase of the disease, particularly
when clinical deterioration due to infected pancreatic necrosis necessitates early
intervention. In principle, this is in accordance with the results by Bakker et al.,
who demonstrated a reduction in the systemic inflammatory response in patients treated
with endoscopic intervention [17].
Bang et al. compared an endoscopic transluminal approach with minimally invasive surgery
and demonstrated a significantly lower rate of SIRS (20.6 % vs. 65.6 %), and significantly
fewer patients with new-onset SIRS (5.6 % vs. 56.3 %) 72 hours after endoscopic intervention
[18]. This study included a high portion of patients in American Society of Anesthesiologists
Class 3 and 4, and one- quarter of patients received their first endoscopic intervention
within 4 weeks after the onset of pancreatitis. The low mortality rate of 8 % in this
study is in line with our study, which showed that an early timed endoscopic intervention
is not only justifiable but often mandatory in patients with sepsis.
Our findings are also in line with the study by Trikudanathan et al., who compared
an early (< 4 weeks) to a standard (≥ 4 weeks after onset of disease) endoscopically
focused approach for necrotizing pancreatitis [19]. They found no difference in complication rates between the two patient groups and
a slight increase in mortality for the early intervention (13 % vs. 4 %). The authors
concluded that the early timed intervention is justified when the indication for it
is strong.
Yan et al. compared immediate direct endoscopic necrosectomy after LAMS placement
with necrosectomy after 1 to 2 weeks to allow the cystenterostomy to mature to reduce
complications. They found no significant difference in procedure-related AEs between
immediate and delayed intervention (7.5 % vs. 9.4 %) and demonstrated earlier resolution
of pancreatic necrosis in the case of immediate necrosectomy [20].
This is consistent with our data showing comparable complication rates ([Table 2]).
Four stent dislocations (8.2 %) occurred in this study. All incidents happened during
the performance of necrosectomy. The stents were able to be retracted in the correct
position using endoscopic forceps. LAMS offer the ability to enter the necrotic cavity
easily without prior dilation. Stent dislocation during necrosectomy can be expected
and does not imply an adverse outcome for the patient because it is recognized immediately.
The perforation rate (4.1 %) is in line with a systematic review, which included 455
patients in 14 studies (4 %) [21]. The bleeding risk was 5 % in our study, in contrast to 18 % in that review. This
represents a complication rate associated with the early endoscopically based intervention
comparable to a traditionally timed intervention.
Our results are limited by the low number of patients and the retrospective data analysis.
It may be considered a strength that all patients with infected pancreatic necrosis
and early endoscopic therapy admitted were included during the mentioned period. The
study represents the entire patient population rather than a case series with selected
patients suitable for endoscopic intervention.
Conclusion
In conclusion, our data show that in the case of infected pancreatic necrosis, endoscopic
therapy can be performed earlier than 4 weeks if a patient’s clinical status necessitates
intervention. Further studies should be performed to delineate the optimal timing
of endoscopic intervention.
