Introduction
Appendicitis is a common abdominal surgical emergency condition that occurs most often
between the ages of 10 and 20 years, with a male:female ratio of 1.4:1 [1]. Abraham Groves performed the first recorded appendectomy in 1883 [2]. A century later in 1983, Semm first introduced laparoscopic appendectomy [3]. While appendectomy remains the most effective treatment in cases of uncomplicated
appendicitis, it causes complications and carries the risk of negative appendectomy
(removal of a normal appendix) [4].
Endoscopic retrograde appendicitis therapy (ERAT) is a new and minimally invasive
alternative method for the diagnosis and treatment of acute appendicitis. Liu et al.
first introduced and implemented the technique in 2012 [5]. ERAT is inspired by endoscopic retrograde cholangiopancreatography (ERCP) technology.
The basic principle involves the use of an endoscope with a transparent cap at its
distal end to intubate the appendix and thereby decompress the lumen; the appendix
cavity is fully drained using a Seldinger technique. The novel technique requires
direct endoscopic imaging or fluoroscopic endoscopic retrograde appendicography (ERA)
to distinguish between suspected acute appendicitis and actual acute appendicitis.
For patients with uncomplicated acute appendicitis, we performed ERAT to relieve the
appendiceal lumen obstruction. Studies have shown that up to 93.8 %–95 % of uncomplicated
acute appendicitis did not have a recurrence following ERAT [6]
[7].
To date, there are no reports comparing ERAT with laparoscopic appendectomy for uncomplicated
acute appendicitis. Therefore, we conducted this noninferiority retrospective study
to assess the feasibility of ERAT compared with laparoscopic appendectomy in patients
who were hospitalized with acute appendicitis.
Methods
Patient selection
Following approval by the institutional review board, we retrospectively reviewed
data of patients admitted to The First Affiliated Hospital of Zhengzhou University
between April 2017 and March 2020 for treatment for appendix disease.
The inclusion criteria for this study were patients aged 18–60 years with uncomplicated
acute appendicitis (appendix > 6 mm in diameter with wall thickening, along with periappendiceal
edema and/or a small collection of fluid, without appendiceal stones, perforation,
abscess, or suspected tumor) confirmed by computed tomography (CT), and opting for
laparoscopic appendectomy or ERAT.
We excluded patients who had any of the following: 1) age younger than 18 years or
older than 60 years; 2) complicated acute appendicitis found on preoperative examination
or intraoperatively. Patients with suspected tumors were excluded if any of the following
criteria applied: 1) CT scan showed an appendix > 5 mm with thickened or irregular
walls; 2) colonoscopy for ERAT showed an involuted, mass-like protrusion, mucus, or
polyp-like tissue at the opening of the appendix; 3) ERA showed a filling defect in
the appendiceal lumen that remained after repeated flushing, with confirmed absence
of fecal stone. Patients were also excluded if they could not be contacted during
the follow-up period. Both ERAT and laparoscopic appendectomy procedures were carried
out independently by experienced doctors or by beginners under the supervision of
an experienced doctor.
We gathered the following clinical data: age, sex, body temperature, white blood cell
count, C-reactive protein (CRP), level of abdominal pain (resulting in presentation
to hospital), procedure duration, length of hospital stay, comorbidities, and adverse
events. The visual analog scale (VAS) was applied to assess the level of abdominal
pain (0–10 cm line; 0 = no pain; 0.1–3.0 = mild pain; 3.1–7.0 = moderate pain; 7.1–9.9 = severe
pain; 10 = unbearable pain). All enrolled patients were followed up by telephone and/or
medical records.
Description of ERAT technique
Preparation for ERAT included bowel cleansing using either 2 L polyethylene glycol
electrolyte solution or low-pressure cleansing enemas (300–500 mL per enema) given
five times. For patients with mild/moderate symptoms, the oral preparation was given
4–6 hours before the procedure. For clinically severe cases or patients with anorexia
or nausea/vomiting, low-pressure cleansing enemas were given about 30 minutes prior
to endoscopy [8].
The ERAT procedure was performed as described previously [5]. 1) An endoscope with a transparent cap attached to the tip was inserted to the
cecum to the level of Gerlach’s valve. 2) Gerlach’s valve was then pushed aside using
the transparent cap, and the appendix was intubated using the guidewire–catheter technique.
3) Under radiographic surveillance, the lumen of the appendix was then imaged with
a water-soluble contrast agent to observe the morphology and internal diameter of
the appendiceal lumen, and to evaluate whether there is filling defects of leakage of the contrast agent, to confirm whether have the appendiceal
stones or appendiceal perforation. Appendiceal stones are commonly found in the appendiceal cavity and should be removed
with mesh baskets, balloons, etc. 4) The appendiceal lumen was then repeatedly flushed
with 50–100 mL of saline. 5) For patients with a large amount of pus or narrowing
of the appendiceal lumen, a 7–8.5-Fr plastic stent (5–7 cm length; Cook Medical, Bloomington,
Indiana, USA) was placed over the guidewire under X-ray surveillance to drain the
pus and support the luminal stenosis to continuously reduce the pressure in the appendiceal
lumen. After 2–4 weeks, patients underwent abdominal radiography to determine whether
the stent should be removed. In some patients, the stent may dislodge on its own.
Endoscopic images of the ERAT procedure are shown in [Fig. 1].
Fig. 1 The endoscopic retrograde appendicitis therapy (ERAT) procedure. a Appendiceal orifice. b Appendiceal lumen cannulation. c Filling defect in the appendiceal lumen visible on imaging (red arrows). d Flushing out of pus or appendiceal fecal stone. e Stent placement. f Radiograph after ERAT (red arrow indicates the stent).
Primary and secondary outcomes
The primary outcome was the rate of curative treatment. In the ERAT group, we defined
curative treatment as successful appendiceal intubation and no recurrence of appendicitis
during the 1-year follow-up period. In the laparoscopic appendectomy group, we identified
curative treatment as a successful appendectomy without converting to open appendectomy.
Secondary outcomes included duration of treatment, rate of postoperative pain relief
from moderate/severe to mild/no pain within 6 hours of treatment, length of hospital
stay, short-term (within 30 days) adverse events, and long-term (> 30 days) adverse
events. Overall adverse events included both short-term and long-term adverse events.
In the ERAT group, short-term adverse events included recurrent appendicitis, gastrointestinal
perforation, fever, bleeding and blood transfusion, abdominal abscess, contrast allergy,
and systemic adverse events (pulmonary embolism, stroke, cardiac events, acute renal
failure, and sepsis). Long-term adverse events included recurrent appendicitis, abdominal
pain, diarrhea, constipation, and appendiceal tumors. In the laparoscopic appendectomy
group, short-term adverse events included incisional infection, incisional pain, anastomotic
leak, abdominal abscess, anesthesia-related events, and systemic adverse events. Long-term
adverse events included bowel obstruction, abdominal pain, incisional hernia, diarrhea,
and constipation. The definitions of adverse events are shown in Table 1 s in the online-only Supplementary material.
Sample size calculation
In this study, we assumed a 99 % success rate for uncomplicated acute appendicitis
in the laparoscopic appendectomy group and a 95 % success rate in the ERAT group.
A noninferiority margin of 11 % was used to calculate the sample size, meaning that
the lower pass limit for ERAT would be 88 %. We estimated that a sample size of 74
patients per group would give an 80 % power to establish whether ERAT was noninferior
to laparoscopic appendectomy regarding treatment success, using a one-sided significance
α level of 0.05. The calculation was performed using Proc Power version 9.4 (SAS Institute
Inc., Cary, North Carolina, USA) [9].
Statistical analysis
Propensity score matching (PSM) was used to minimize selection bias. The propensity
score was estimated by logistic regression, with treatment as the dependent variable
and independent variables, including sex and age. We matched patients 1:1 using the
nearest-neighbor matching algorithm without replacement, with the caliper value fixed
at 0.1 for the propensity matching scores [10]. Continuous variables (procedure duration, length of hospital stay, age, time to
recurrence, and hospitalization cost) were expressed as medians with 95 % confidence
intervals (CIs) and interquartile ranges (IQRs), and categorical variables were expressed
as frequency and percentages with 95 %CIs. The Mann–Whitney U test was applied for continuous variables. The Pearson’s chi-squared test or Fisher’s
exact test were used for categorical variables. We computed the cumulative incidence
of recurrent appendicitis in the ERAT group using the Kaplan–Meier approach. We performed
PSM and all calculations using Stata/SE 15.0 (Stata Corp., College Station, Texas,
USA). All tests were two-sided. P values of < 0.05 were considered statistically significant.
Results
Patient characteristics
From the inpatient database of The First Affiliated Hospital of Zhengzhou University,
we extracted data of 2880 patients with suspected acute appendicitis between April
2017 and March 2020. Of these patients, we excluded 356 patients who were younger
than 18 years, 297 patients who were older than 60 years, 103 patients with perforation
on CT, and 176 patients with periappendiceal abscess on CT. A total of 1948 patients
with uncomplicated acute appendicitis were confirmed by CT and opted for treatment.
Then we excluded 918 patients who were treated with antibiotics, 3 patients with periappendiceal
abscess diagnosed during laparoscopic appendectomy, 5 patients with perforation diagnosed
during laparoscopic appendectomy, 2 patients with carcinoid tumors confirmed by postoperative
pathology, 543 patients with chronic appendicitis confirmed by postoperative pathology,
and 55 patients who could not be contacted (lost to follow-up). We identified 422
eligible patients for matching (ERAT 79; laparoscopic appendectomy 343). Propensity
score matching yielded 78 patient pairs ([Fig. 2]). Fig. 1 s presents the distribution of the propensity scores in the laparoscopic appendectomy
and ERAT groups. [Table 1] shows the characteristics of the matched patients.
Fig. 2 Flow diagram of the entire and matched cohorts.
Table 1
Baseline patient characteristics after propensity score matching.
|
Variable
|
ERAT (n = 78)
|
Laparoscopic appendectomy (n = 78)
|
P value
|
|
Sex, male, n (%)
|
40 (51.3)
|
41 (52.6)
|
0.86
|
|
Age, median (IQR), years
|
30 (21–35.3)
|
30 (22.8–34.3)
|
0.35
|
|
Temperature[1] > 37.2℃, n (%)
|
33 (42.3)
|
31 (39.7)
|
0.74
|
|
VAS[2] for pain, n (%)
|
|
|
29 (37.2)
|
35 (44.9)
|
0.33
|
|
|
49 (62.8)
|
43 (55.1)
|
|
|
CRP[3] > 5 mg/L, n (%)
|
63 (80.8)
|
57 (73.1)
|
0.25
|
|
Leukocytes count[4] > 10 × 109/L, n (%)
|
67 (85.9)
|
61 (78.2)
|
0.21
|
ERAT, endoscopic retrograde appendicitis therapy; IQR, interquartile range; PSM, propensity
score matching; VAS, visual analog scale; CRP, C-reactive protein.
1 Baseline temperature reference: 36.3–37.2℃.
2 0 = no pain; 0.1–3.0 = mild pain; 3.1–7.0 = moderate pain; 7.1–9.9 = severe pain;
10 = unbearable pain.
3 Baseline CRP reference: 0–5 mg/L.
4 Baseline leukocytes count reference: 0–10 × 109/L.
Primary outcome
In the ERAT group, three endoscopists performed ERAT for patients with uncomplicated
acute appendicitis. Overall, 76 patients (97.4 %; 95 %CI 91.1 % to 99.3 %) underwent
successful appendiceal intubation and 2 patients (2.6 %; 95 %CI 0.7 % to 8.9 %) were
referred for surgery because of failed intubation during the ERAT process. In total,
70/76 patients (92.1 %; 95 %CI 83.8 % to 96.3 %) with uncomplicated acute appendicitis
did not require surgical intervention during the 1-year follow-up period after ERAT.
With a predetermined 11 % noninferiority margin for this study, we were able to demonstrate
that ERAT was noninferior to laparoscopic appendectomy. A total of 28 patients (36.8 %;
95 %CI 26.9 % to 48.1 %) underwent saline flushing of the appendiceal lumen and placement
of a stent, and 48 patients (63.2 %; 95 %CI 51.9 % to 73.1 %) underwent saline flushing
of the appendiceal lumen alone. In the laparoscopic appendectomy group, all patients
received laparoscopic surgical resection successfully. Intraoperative abdominal tubes
were placed in three patients and removed after 24 hours of observation. Postoperative
pathology confirmed uncomplicated acute appendicitis in all 78 patients, including
58 (74.4 %; 95 %CI 63.7 % to 82.8 %) with acute simple appendicitis and 20 (25.6 %;
95 %CI 17.3 % to 36.3 %) with acute suppurative appendicitis.
Intraoperative and postoperative outcomes
The median procedure time was 50 minutes (95 %CI 50 to 55) in the laparoscopic appendectomy
group, which was significantly longer than that of the ERAT group (40 minutes [95 %CI
35 to 45]; P < 0.001; difference 10 minutes [95 %CI 6 to 15]). A total of 72 patients (94.7 %;
95 %CI 87.2 % to 97.9 %) had VAS ≤ 3 6 hours after treatment in the ERAT group compared
with 65 patients (83.3 %; 95 %CI 73.5 % to 90.0 %) in the laparoscopic appendectomy
group, with a statistical difference between the two groups (P = 0.02; difference 11.4 percentage points [95 %CI 1.7 to 21.1]). The median hospital
length of stay was 4 days (95 %CI 3 to 4) in the laparoscopic appendectomy group,
which was significantly longer than the hospital stay in the ERAT group (2 days [95 %CI
2 to 2]; P < 0.001; difference 2 days [95 %CI 1 to 2]). [Table 2] shows the main outcomes of the two matched groups.
Table 2
Outcomes of the two matched groups.
|
ERAT (n = 76)
|
Laparoscopic appendectomy (n = 78)
|
Difference
|
P value
|
|
Procedure time, median [95 %CI], minutes
|
40 [35 to 45]
|
50 [50 to 55]
|
–10 [–15 to –6]
|
< 0.001[6]
|
|
Hospital length of stay, median [95 %CI], days
|
2 [2 to 2]
|
4 [3 to 4]
|
–2 (–2 to –1)
|
< 0.001[6]
|
|
Curative treatment rate, n (%) [95 %CI]
|
70 (92.1) [83.8 to 96.3]
|
78 (100) [100 to 100]
|
–8 (–7.9) [–14.0 to –1.8]
|
0.01[6]
|
|
VAS for pain ≤ 3 at 6 hours after treatment, n (%) [95 %CI]
|
72 (94.7) [87.2 to 97.9]
|
65 (83.3) [73.5 to 90.0]
|
7 (11.4) [1.7 to 21.1]
|
0.02[6]
|
|
Overall adverse event rate, n (%) [95 %CI]
|
14 (18.4) [9.7 to 27.1]
|
19 (24.4) [14.8 to 33.9]
|
–5 (–5.9) [–18.9 to 7.0]
|
0.37
|
|
Recurrence of appendicitis, n (%) [95 %CI]
|
6[1] (7.9) [3.7 to 16.2]
|
0
|
6
|
0.01[6]
|
|
Overall short-term adverse event rate, n (%) [95 %CI]
|
5[2] (6.6) [1.0 to 12.2]
|
6 (7.7) [3.6 to 15.8]
|
–1 (–1.1) [–9.2 to 7.0]
|
0.79
|
|
|
0
|
2 (2.6) [0.7 to 8.9]
|
–2
|
0.50
|
|
|
0
|
1 (1.3) [0.2 to 6.9]
|
–1
|
> 0.99
|
|
|
0
|
3 (3.8) [1.3 to 10.7]
|
–3
|
0.25
|
|
|
2 (2.6) [0.7 to 9.1]
|
0
|
2
|
0.24
|
|
|
1 (1.3) [0.2 to 7.1]
|
0
|
1
|
0.49
|
|
Overall long-term adverse event rate, n (%) [95 %CI]
|
9[4] (11.8) [4.6 to 19.1]
|
13 (16.7) [10 to 26.5]
|
–4 (–4.8) [–15.8 to 6.2]
|
0.49
|
|
|
5 (6.6) [2.8 to 14.5]
|
4 (5.1) [0.2 to 10.0]
|
1 (1.5) [–6.0 to 8.9]
|
0.75
|
|
|
0
|
9[5] (11.5) [6.2 to 20.5]
|
–9
|
0.003[6]
|
ERAT, endoscopic retrograde appendicitis therapy; CI, confidence interval; VAS, visual
analog scale.
1 Two patients experienced recurrence of appendicitis within 30 days after ERAT, and
four patients had recurrence of appendicitis > 30 days after ERAT.
2 Including two patients with recurrent appendicitis within 30 days after ERAT.
3 Baseline temperature, reference: 36.3℃–37.2℃. Both patients had body temperatures < 38℃.
4 Including four patients with recurrent appendicitis > 30 days after ERAT.
5 Three patients with Grade 1 diarrhea ( < 4 stools/day) and six patients with Grade
2 diarrhea (4–6 stools/day).
6 Significant difference between the two groups.
Short- and long-term adverse events
The median follow-up time was 1 year. The overall short-term adverse event rate was
7.7 % (95 %CI 3.6 % to 15.8 %) in the laparoscopic appendectomy group and 6.6 % (95 %CI
1.0 % to 12.2 %) in the ERAT group, with no significant difference between the two
groups. In one patient in the ERAT group, ERA showed a fecal stone in the distal appendiceal
cavity. The contrast agent diffused into the abdominal cavity, thus confirming the
appendiceal perforation. With the patient’s consent, we placed two abdominal drains
and administered peritoneal flushing. The patient recovered with no intra-abdominal
abscesses or other adverse events, and was discharged after 7 days of conservative
antibiotic treatment. A month later, we successfully performed ERAT once again using
ultrafine choledochoscopy (SpyGlass; Boston Scientific Corp., Marlborough, Massachusetts,
USA) to break the fecal stone before removing it. The patient had no recurrence during
the follow-up period. Two patients (2.6 %; 95 %CI 0.7 % to 9.1 %) in the ERAT group
developed fever after treatment and recovered following conservative antibiotic treatment.
During the 1-year follow-up period, there were no deaths in either group, no bowel
obstruction or hernia in the laparoscopic appendectomy group, and no appendiceal tumors
in the ERAT group. The overall long-term adverse event rate was 16.7 % (95 %CI 10.0 %
to 26.5 %) in the laparoscopic appendectomy group and 11.8 % (95 %CI 4.6 % to 19.1 %)
in the ERAT group (P = 0.49; difference 4.8 percentage points [95 %CI –6.2 to 15.8]). Five patients (6.6 %;
95 %CI 2.8 % to 14.5 %]) in the ERAT group had varying degrees of abdominal pain 2
months after treatment, three had spontaneous resolution of symptoms, and two went
to the hospital for examination. One patient was diagnosed with enteritis and the
other with pelvic infection; both patients recovered after conservative treatment.
In the laparoscopic appendectomy group, three patients (3.9 %; 95 %CI 1.3 % to 10.7 %])
had Grade 1 diarrhea (< 4 stools/day) and six patients (7.7 %; 95 %CI 3.6 % to 15.8 %])
had Grade 2 diarrhea (4–6 stools/day), all of whom recovered after symptomatic treatment.
Recurrence in the ERAT group
There was no recurrence of appendicitis in patients who had stents placed, whereas
appendicitis recurred in six patients (7.9 %; 95 %CI 3.7 % to 16.2 %]) without stents.
Among the patients with recurrent appendicitis, two of them recurred within 30 days.
The overall median recurrence time was 50 days (IQR 25–127). One patient underwent
laparoscopic surgery 4 months after ERAT and recovered well after surgery. Postoperative
pathology confirmed chronic appendicitis. The other five patients had recurrence of
uncomplicated appendicitis. We performed ERAT again for one of them and placed a stent
for adequate drainage; four other patients received antibiotic therapy. None of the
five patients experienced recurrence during the follow-up period. [Fig. 3] shows the cumulative incidence of recurrent acute appendicitis in the ERAT group.
Fig. 3 Kaplan–Meier graph for time to recurrence after endoscopic retrograde appendicitis
therapy at 1-year follow-up.
Discussion
The appendix is a lymphoid organ, the tissue of which begins to appear at birth and
is fully developed by 12–20 years of age. The structure has an immune function, as
evidenced by the fact that it can be a good host for biofilms that are essential for
beneficial microorganisms [11]. In addition, a comprehensive study found that appendectomy was associated with
a higher risk of Crohn’s disease [12]. In 2009, a study from China demonstrated that the appendix may have a protective
effect against colon cancer, and that appendectomy may be a risk factor for the development
of colorectal cancer [13]. Furthermore, the appendix is closely associated with intestinal microecology. In
2014, Japanese researchers compared rats with and without appendectomy, and found
that the appendix provides immune cells to the intestine and plays a role in maintaining
intestinal bacterial homeostasis [14].
In recent years, appendectomy has been challenged as the “gold standard” for the management
of acute appendicitis because of postoperative complications and a high rate of resection
of the normal appendix [15]
[16]
[17]
[18]. The most recent guidelines recommend antibiotic treatment as a good option for
patients with uncomplicated appendicitis [19]. The Appendicitis Acuta (APPAC) study showed that 73 % of the 256 patients with
uncomplicated acute appendicitis treated with antibiotics did not require surgical
therapy during a 1 -year follow-up period [20]. In addition, a comprehensive review and meta-analysis showed that antibiotics could
be a viable and effective treatment option for image-proven uncomplicated appendicitis
[21]. Nevertheless, the use of antibiotics in treating uncomplicated acute appendicitis
faces unavoidable problems: patients with appendiceal fecaliths are at higher risk
of acute peritonitis because of complications of appendiceal perforation and have
a higher recurrence rate after antibiotic treatment [20]. ERAT is useful for patients with appendiceal fecoliths, as it can flush the fecoliths
out and remove the obstruction, thus relieving symptoms and considerably reducing
the recurrence rate of appendicitis [22]. Another advantage of ERAT over antibiotics for uncomplicated acute appendicitis
is that ERAT rapidly eliminates painful symptoms, whereas patients experience varying
levels of pain during antibiotic treatment. The curative treatment rate of ERAT in
the current study was better than the rate with antibiotic treatment in previous studies
of uncomplicated acute appendicitis [23]
[24]
[25]
[26]
[27]. Further prospective studies are needed to compare ERAT and antibiotic treatment
for uncomplicated acute appendicitis.
Although appendectomy is a routine surgical procedure, there remains a risk of surgical
adverse events and negative appendectomy. Common complications include incisional
infection (6 %), abdominal infection (1.6 %–3 %), small-bowel adhesion obstruction
(0.4 %–1.3 %), incisional hernia (0.4 %), and other complications such as interstitial
pneumonia (2.5 %), urinary tract infection (1.1 %), and cardiovascular accidents (1.1 %)
[28]. In our study, nine cases of diarrhea occurred after laparoscopic appendectomy surgery,
which might be because of the imbalance of intestinal flora after appendectomy. Further
exploration of changes in gut flora after ERAT and laparoscopic appendectomy may clarify
the cause of diarrhea and bowel dysfunction. The six patients with recurrence in the
ERAT group were treated with appendix flushing without stent placement for drainage.
Interestingly, one patient with recurrence chose ERAT again and the condition did
not recur after stent placement, suggesting that adequate drainage may be an effective
means of reducing recurrence of appendicitis. Therefore, exploring and differentiating
the population at high risk of recurrence after ERAT is a key direction for future
research. The median length of hospital stay in the ERAT group was shorter than that
in the laparoscopic appendectomy group. In China, patients usually choose to remain
in hospital for an observation period of 2–4 days after laparoscopic or open surgery.
However, this study still has its limitations, including the retrospective design,
relatively small sample size, and potential selection bias, in particular the possibility
that healthier patients could have been selected for ERAT (unmeasured confounders).
There are also issues that the study was not designed to investigate; for example,
ERAT may exacerbate perforation, cancer diagnosis may be missed, and some patients
need to undergo multiple colon examinations.
In conclusion, ERAT could be an effective and minimally invasive alternative approach
for the treatment of uncomplicated acute appendicitis, with rapid postoperative abdominal
pain relief, preservation of the appendix, and fast recovery, enabling daily life
to return to normal as soon as possible. To further evaluate the safety and efficacy
of ERAT, a comprehensive international, multicenter, randomized controlled prospective
study is urgently needed.
