Acta Biomed 2018; Vol. 89, Supplement 9: 119-134
DOI: 10.23750/abm.v89i9-S.7905
© Mattioli 1885
Review
Conservative treatment of acute appendicitis
Federico Coccolini1, Paola Fugazzola1, Massimo Sartelli2, Enrico Cicuttin1, Maria Grazia
Sibilla1, Gioacchino Leandro5, Gian Luigi de’Angelis3, Federica Gaiani3, Francesco di Mario3,
Matteo Tomasoni1, Fausto Catena4, Luca Ansaloni1
Emergency, General and Trauma Surgery dept., Bufalini hospital, Cesena, Italy; 2 General Surgery Department, Macerata Hospital, Macerata, Italy; 3 Gastroenterology and Digestive Endoscopy Unit, University Hospital of Parma, University of Parma,
Parma, Italy; 4 General and Emergency Surgery dept., Maggiore hospital, Parma, Italy; 5 National Institute of Gastroenterology
“S. De Bellis” Research Hospital, Castellana Grotte, Italy
1
Summary. Acute appendicitis has been considered by surgeons a progressive disease leading to perforation
for more than 100 years. In the last decades the theories about this concept gained attention, especially in
adults. However, appendectomy for acute appendicitis remains the most common urgent/emergent surgical
procedure. At present, accumulating evidences are showing the changing in clinical practice towards the nonoperative management of several cases of acute appendicitis either non-complicated or complicated. The present review aims to show the literature results regarding the non-operative management of acute appendicitis
in non-complicated and in complicated cases. (www.actabiomedica.it)
Key words: appendicitis, conservative, complicated, uncomplicated, review, adult, children, treatment
Background
The acute appendicitis has been considered by
surgeons a progressive disease leading to perforation
for more than 100 years. In the last decade the theories
challenging of this concept gained attention especially
in adults. However appendectomy for acute appendicitis remains the most common urgent/emergent surgical procedure in children. The first report of operative treatment for AA has been reported in 1735 when
Claudius Amyand treated an inflamed appendix during the course of a hernia operation in an 11-year-old
boy. The perforated appendix was situated in the hernia sac. The abscess was opened, and the boy recovered
and was discharged a month after the operation. Unfortunately, the hernia recurred (1). The first reported
appendectomy for suspected AA was performed by the
Scotsman Robert Lawson Tait in 1880 (2). His intervention precedes Charles McBurney who presented
his first series in 1889 and Abraham Groves (3, 4).
Five years later, McBurney published his article on the
surgical procedure that bears his name. Some authors
however suggested that the grid-iron incision was first
performed by Louis L. McArthur (5, 6). The open appendectomy through a McBurney incision remained
the method of choice to treat AA until Karl Semm in
1980 performed the first laparoscopic appendectomy
(7). Successively Ure et al. published in 1991 the first
series of laparoscopic appendectomies in children (8).
Conservative treatment of acute appendicitis during
the years
Searching for the first case of nonoperative treatment of AA, it could be suggested that it is as old as
man itself. The first report of a suspected spontaneous
resolution of AA was published in 1910 by Smith and
Wood Jones. They described the case of a young Nubian woman where the appendix was found attached
with a thick adhesive band to the left pelvic wall suggesting that she had survived appendiceal rupture with
abscess formation (9). The bizarre aspect of the report
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is that at the time of diagnosis, she was an uneviscerated mummy from the Byzantine era. In 1930 Bailey proposed his non-operative treatment algorithm
(10) and in 1959 Coldrey described for the first time
a large series of 471 patients treated non-operatively
with intravenous antibiotics (11). The recurrence rate
was 48/470 (10.2%) with 1 death, 9 patients requiring
abscess drainage, and 48 cases requiring a subsequent
appendectomy. Another series from China reported
500 patients with the clinical diagnosis of AA (12).
Of these, 425 had conservative treatment with Chinese traditional medicine and antibiotics were given
to some. 7 recurrences have been reported. Conservative treatment has also been reported from doctors in
service aboard of the U.S. Navy and the Soviet fishing
fleet ships (13, 14). The Russian one is a review of conservative treatment in 252 patients with AA on vessels
of the Kalingrad fishing industry from 1975 to 1987.
In this series Gurin et al. (14) reported a recovery rate
of 84.1% with only the use of antibiotics. The authors
found no difference in outcomes based on presenting
symptoms or age, but they suggested that conservative treatment was as more effective as earlier it starts.
In fact it showed to be most effective if administered
within 12 h from symptom onset, ideally within the
first 6 h. Moreover they reported the best effect when
early intervention with antibiotics was combined with
antihistamines and spasmolytics. All these aforementioned trials however dealed with a non-confirmed
diagnosis, a poor follow-up. For these reasons these
experiences did not receive much attention (15).
Reason for treating conservatively acute appendicitis
It is general opinion that the appendix has no significant function in humans. De Coppi et al. in 2006
showed that the vermiform appendix was capable of
producing mesenchymal stem cells (16). They found
that appendix-derived mesenchymal stem cells are
present in the vermiform appendix. These cells can differentiate into osteoblasts, lipoblasts, and myoblasts,
depending on the stimulation. They suggested the possibility that vermiform appendix acts like a reservoir
for stem cells capable of bowel repair trough life. From
North Carolina many articles have been published on
F. Coccolini, P. Fugazzola, M. Sartelli, et al.
this topic (17). Some authors moreover suggested the
possibility that appendix deserve as a reservoir for bacteria of the gut flora, and it is necessary to recolonize
the bowel after bacterial infections. Appendectomy either open either laparoscopic is still associated with a
significant morbidity and mortality despite advances in
surgery and care. Blomqvist et al. analyzed a Swedish
cohort of 117,424 patients who underwent appendectomy (1987-1996) analyzing the 30-day postoperative
mortality ratio (18). They reported a 3.5-fold excess
mortality after surgical intervention for non-perforated appendicitis and a 6.5-fold excess mortality in
perforated ones. In patients with a discharge diagnosis
of nonspecific abdominal pain the mortality rate after negative appendectomy was increased by 9.1-fold.
This mortality rate may only partially be explained by
an underlying condition that was concealed by the appendectomy. Also Flum and Koepsell found a threefold increase in mortality after negative appendectomy
compared with appendectomy for AA (19). Different
studies reported an increased SBO (small bowel obstruction) rate in the years after appendectomy. During
a 30-year follow a Swedish report showed that 1.3%
of patients subjected to an appendectomy had a SBO
compared with 0.2% of controls (20). Others have
reported rates of SBO between 0.16 and 10.7% after
appendectomy (21, 22). Leung et al recently reported
as the incidence of SBO after appendectomy at 2.8%,
and the incidence of reoperation for SBO after appendectomy to be 1.1% during the 5-year follow-up (23).
Sakorafas et al. recently reported reduced cost, morbidity, and abdominal pain associated with non-operative
treatment (15). Svensson et al. described that centers
with restrictive indications for exploration have fewer
patients with non-perforated appendicitis, compared
with centers with a more active attitude to exploration
(24). This could suggest that many patients with AA
would potentially have spontaneous resolution of their
disease. The experience of a hospital in which patients
with suspected appendicitis were admitted to five units
on a strict 24-hours rotation, three with a conservative
approach and two with an active approach to exploration by Howie et al. in 1964. On one hand the active
units removed a significantly greater average number of
inflamed appendices per unit (72 vs. 46, p<0.0001). On
the other hand the conservative units removed fewer
Management of acute appendicitis
normal appendices (16.7 compared with 34% for the
radical units, p<0.0001). Luckman in 1989 suggested
that perforated and non-perforated appendicitis could
be two separate entities. Lastly a meta-analysis by Andersson et al showed as the incidence of perforated appendicitis did not correlate with the rate of negative
appendectomy and as a counterpart that the incidence
of uncomplicated appendicitis correlated directly with
the rate of negative appendectomy and inversely with
diagnostic accuracy.
Uncomplicated acute appendicitis
Definition:
Uncomplicated appendicitis is defined as appendicitis without neither perforation nor appendiceal abscess nor mass formation.
Literature evidence:
Randomized controlled trials: Many different prospective and retrospective observational trials comparing conservative treatment of uncomplicated AA have
been published during the years. A few randomized
controlled trials have also been published increasing
the data level of evidence. For this reason the present
review will focus on higher level of evidence data.
The first prospective randomized trial on acute
appendicitis was presented in 1995.
Eriksson and Granström randomized 40 patients
to either operation or conservative treatment (25).
Methods: Randomization of patients admitted
with history and clinical signs of acute appendicitis.
Ultrasonography and laboratory tests: white blood cell
count and C reactive protein to identify patients with
a high probability for acute appendicitis.
Participants: Patients with typical history and
clinical signs, positive findings at ultrasound, and either increased white blood cell count and C reactive
protein values or high C reactive protein or white blood
cell count on two occasions within a four hour interval. Initial randomization of 20 patients in each group,
but one patient from the antibiotic group developed
increased abdominal pain and generalized peritonitis
and had surgery, and subsequent data were discounted.
Interventions: The conservative group underwent
cefotaxime 2 g 12 hourly and tinidazole 800 mg for two
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days. Patients were discharged after two days with oral
ofloxacin 200 mg twice daily and tinidazole 500 mg
twice daily for eight days. Patients were excluded from
the study in the event of increased abdominal pain and
generalized peritonitis and this case they underwent
surgical intervention. The surgery arm underwent antibiotics for 24 hours only in the event of bowel perforation or in cases of abdominal spillage. They were
discharged when conditions were satisfactory and/or
when patients wished to return home. Histology were
obtained for all specimens. All patients were seen for a
follow-up visit at 6th, 10th, and 30th day after admission and underwent blood tests for white blood cell
count and C reactive protein, pain scores and temperature were evaluated and recorded. Abdominal and rectal examination were performed on days 6th and 10th.
Stools were examined for Clostridium difficile toxin at
day 30th. Ultrasonography was performed on days
10th and 30th.
Outcomes: Pain scores (every six hours using a
VAS), morphine consumption, white blood cell count
and temperature, positive diagnosis at surgery, hospital
stay, wound infection, and recurrent appendicitis were
evaluated.
Results: One out of 20 patients needed operation
due to failure of conservative treatment, 3 out of 20
appendectomies were negative and 7 out of 19 patients
treated conservatively had recurrence of symptoms and
surgical intervention within 1 year. Non-operatively
treated patients had a faster decrease of C-reactive
protein, a lower morphine consumption, and a lower
pain score compared with the patients who underwent
initial operation. The authors state that 40 out of 45
consecutive patients (27 men and 13 women between
18 and 75 years of age) were included in the trial, and
only 5 declined participation. In the surgery group, two
had mesenteric lymphadenitis and one had Campylobacter enteritis. All patients in this trial had an ultrasound diagnosis of appendicitis but, despite this 17 out
of 20 patients who underwent operation had AA.
Styrud et al. randomized 252 men: 128 to conservative treatment and 124 to open appendectomy
(26).
Methods: Patients were randomized to either surgery or antibiotic treatment. Patients were monitored at
the end of the first and sixth week and of the first year.
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Participants: Male patients, between 18 and 50
years of age, admitted to six different hospitals. No
women were enrolled by decision of the local ethics
committee. All patients with suspected appendicitis
with a C-reactive protein concentration >10 mg/L and
with no clinical signs of perforation.
Interventions: The antibiotics arm underwent
intravenous cefotaxime 2 g 12 hourly and tinidazole
800 mg daily for two days. Patients were discharged
after two days with oral ofloxacin 200 mg and tinidazole 500 mg twice daily for 10 days. If symptoms
didn’t improve within first the 24 hours, appendectomy was performed. All conservatively treated patients
with a suspected recurrence of appendicitis underwent
surgery. Patients randomized to surgery had open or
laparoscopic operations at the surgeon’s discretion. All
removed specimens were sent for histology.
Outcomes: Hospital stay, sick leave, diagnosis at operation, recurrences, and complications were evaluated.
Results: Of the 128 patients treated non-operatively 18 required operation due to failure of antibiotic
therapy. Of the 124 appendectomies, 4 were negative.
16 out of 110 conservatively treated patients had a recurrence within 1 year. 17 patients experienced complications in the open appendectomy group.
In 2009, Hansson et al. in a large randomized trial
published the results of 369 patients where 202 were
randomized to conservative treatment and 167 to surgical intervention (27). The trial protocol accepted a
crossover after randomization, but before initiation of
treatment. For this reason 119 patients were treated
conservatively and 250 were operated.
Methods: Three centers participated to the study;
one hospital enrolled patients to be used as a reference cohort for comparison and the other two centers enrolled patients into the study and control arms.
Allocation were done by date of birth. Questionnaire
was sent to all patients after one and 12 months. All
patients who didn’t answer to the questionnaire were
contacted by telephone.
Participants: Patients were enrolled if they had
positive history, clinical signs, laboratory tests, and, in
some cases, ultrasonography, computed tomography,
and gynecological examination.
Interventions: The conservative treatment arm
underwent intravenous cefotaxime 1 g twice daily and
F. Coccolini, P. Fugazzola, M. Sartelli, et al.
metronidazole for at least 24 hours. Patients who improved were discharged 24 hours later with oral ciprofloxacin 500 mg twice a day and metronidazole 400
mg three times a day for 10 days. If there was no improvement the intravenous treatment was prolonged.
The surgery arm underwent open or laparoscopic appendectomy with a single dose antibiotic prophylaxis,
and postoperative antibiotic treatment when the appendix was gangrenous or perforated. All specimens
were sent for histological examination.
Outcomes: Treatment efficacy, complications, recurrences and reoperations, length of antibiotic treatment, abdominal pain after discharge from hospital,
length of hospital stay, and sick leave were evaluated.
Moreover the total costs for the primary hospital stay
were analyzed for each patient.
Results: Based on per-protocol analysis, 11 out of
119 patients in the conservative treatment arm needed
early operation, 27 out of the 250 appendectomies
were negative, and 15 out of the 108 conservatively
treated patients had a recurrence within 1 year. Serious
complications rate were three times more frequent in
the surgery arm.
In 2011, a Vons et al. published the results of a
randomized trial in which 239 adult patients were randomly assigned 120 to conservative treatment and 119
to surgical intervention (28).
Methods: The study is an open label, non-inferiority, randomized controlled trial to which participated six academic centers. Patients in both treatment
groups were assessed twice a day after admission and
were discharged after resolution of pain, fever, and any
digestive symptoms. All patients were seen on days
15th, 30th, 90th, 180th, and 360th.
Participants: All included patients were adults
over 18 years with suspected AA, who had diagnosis of
uncomplicated appendicitis by computed tomography
(CT). Included patients were randomized to appendectomy or antibiotic treatment. Patients who were
allergic to antibiotics or iodine, had been on antibiotics before admission, were receiving steroid or anticoagulants, had a history of inflammatory bowel disease,
were pregnant, had blood creatinine of ≥200 μmol/L,
or were unable to understand the protocol or consent
form were not included into the study.
Interventions: The patients included into the anti-
Management of acute appendicitis
biotics arm underwent intravenous or oral amoxicillin
plus clavulanic acid (3 g per day if <90 kg or 4 g for
patients >90 kg) for 48 hours. If there was no resolution of symptoms after 48 hours patients underwent
appendectomy. Patients were discharged with antibiotics and reviewed on day 8th if there was resolution of
the symptoms. CT was done in presence of persistent
pain or fever or if there was a suspicion for the necessity of appendectomy. If not, antibiotics continued for
another 8 days. If symptoms persisted on day 15th, appendectomy was done. Patients enrolled in the surgery
arm underwent open or laparoscopic appendectomy.
Amoxicillin plus clavulanic acid 2 g was administered
at the time of induction of general anesthesia. Antibiotics were given postoperatively only if the appendicitis was complicated. Histology was obtained for all
specimens.
Outcomes: The primary endpoints was: occurrence
of peritonitis within 30 days of initial treatment, diagnosed either at appendectomy or postoperatively
by CT. The secondary endpoints were number of days
with a post-intervention VAS pain score ≥4, length of
stay, absence from work, incidence of complications
other than peritonitis within one year, and recurrence
of appendicitis after antibiotic treatment (considered
as appendectomy done between 30 days and one year
of follow-up, with a confirmed diagnosis of AA).
Results: There were 14 early failures and only 1 out
of 119 negative appendectomy. Of 120 patients enrolled into the conservative treatment group 30 had an
operation within the first year and 26 had appendicitis.
Malik and Bari published a trial where 80 patients
were randomized 40 to conservative treatment and 40
to surgical intervention (29). This article was retracted
from the Journal of Gastrointestinal Surgery in 2011
(31). The editors state that significant portions of the
article were published earlier in other studies (25, 30).
Methods: This is a monocentric randomized controlled trial. Patients were evaluated during the followup at the 7th, 12th, 30th day, blood sample (WBC and
CRP levels), pain (VAS) and oral temperature was
registered. Patient with recurrent appendicitis within
one year were readmitted.
Interventions: The patients enrolled to conservative treatment arm underwent intravenous ciprofloxacin 500 mg every 12 h and 500 mg of metronidazole
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administered intravenously every 8 h for a period of 2
days. After the discharge were administered a 7-day
oral therapy with 500 mg of ciprofloxacin twice a day,
and 600 mg of tinidazole twice a day. Patients randomized to the surgery arm received a preoperative antibiotic prophylaxis with cephalosporin and tinidazole
that was protracted for 48 hours in the event of bowel
perforation or abdominal spillage. cephalosporins and
imidazole. For each patient the pain was registered
every 6 hours using VAS and oral temperature was
measured twice daily. Histology was obtained for all
specimens. Patients from both groups were discharged
once conditions were satisfactory.
Outcomes: hospital stay, complications, pain, analgesic consumption, inflammatory laboratory tests, and
body temperature were evaluated.
Results: In the conservative treatment group the
85.0% and in the surgical treatment group 92.5% patients were successfully cured within two weeks without major complications. The mean duration of pain
was 23 hours in antibiotic arm and 21.3 hours in surgery arm. The mean hospital stay was 2.3 days in antibiotic arm and 1.2 days in surgery arm. 2 out of 40
patients in the conservative treatment arm failed and
undergone surgery during the first admission and 4 out
of the remaining 38 undergone appendectomy during
the first year.
Systematic reviews and meta-analyses:
There are several systematic reviews with metaanalysis published about the comparison between conservative and surgical treatment of AA.
Varadhan et al analyzed three trials (25-27, 32).
Their analysis showed a trend toward a reduced risk
of complications in the antibiotic-treated group [RR
(95%CI): 0.43 (0.16, 1.18) p=0.10], without prolonging the length of hospital stay [mean difference (inverse
variance, random, 95% CI): 0.11 (-0.22, 0.43) p=0.53].
In their analysis 350 patients were randomized to the
antibiotic group, among them the 68% (238 patients)
were treated successfully with antibiotics alone and the
15% (38 patients) were readmitted. The remaining 112
patients (32%) who were randomized to conservative
treatment crossed over to surgery. At 1 year followup analysis, 200 patients in the conservative treatment
group remained asymptomatic. Authors concluded
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that “that although antibiotics may be used as primary
treatment for selected patients with suspected uncomplicated appendicitis, this is unlikely to supersede appendectomy at present”.
Ansaloni et al. included four trials in their study,
including the discussed Malik and Bari’s trial (2529, 33). Efficacy was significantly higher for surgery (OR=6.01, 95% CI=4.27-8.46). No differences
were found in the numbers of perforated appendix
(OR=0.73, 95% CI=0.29-1.84) and patients treated
with antibiotics (OR=0.04, 95% CI=0.00-3.27). Complication rates were significantly higher for surgery
(OR=1.92, 95% CI=1.30-2.85). They conclude that
“although a nonsurgical approach in AA can reduce
the complications rate, the lower efficacy prevents antibiotic treatment from being a viable alternative to
surgery”.
Liu and Fogg included six trials in their metaanalysis (25-29, 33-35). They found a non-operative
management failure rate of 6.9% and a 14.2% recurrence rate. They conclude that appears to be safe to
treat AA with antibiotics. One appendectomy patient
had a recurrence. A normal appendix was found in
7.3% of patients at appendectomy. Complications rate
was lower with antibiotic treatment than with appendectomy (OR 0.31; 95% CI 0.19-0.49, p<0.05).
The Cochrane collaboration published its review
in December 2011 (36). The authors included five trials (25, 26, 28, 29, 34) excluding the Hansson et al. trial as it was considered a low quality trial. The primary
reason was the cross-over between the groups driven
by patient or surgeon preference. Malik and Bari and
Turhan et al trials were included in the review (34, 29).
It should be mentioned that the Turhan et al trial is
difficult to be considered a real randomized trial.
Authors found that the 73.4% (95% CI 62.7 and
81.9) of patients who underwent conservative treatment and the 97.4% (95% CI 94.4 and 98.8) of patients who underwent surgical intervention were successfully treated within two weeks and had no major
complications (including recurrence) within the first
year. Patients who undergone surgical intervention experienced a shorter hospital admission OR 0.66 (95%
CI 0.44 to 0.87). However the duration of sick leave
periods is significantly shorter in patients treated with
antibiotics with an OR of 0,69 (95%CI -1.65 to 0.27).
F. Coccolini, P. Fugazzola, M. Sartelli, et al.
The authors concluded that appendectomy remains
the gold standard, as a counterpart initial antibiotic
therapy was not inferior to operation based on a 20%
non-inferiority margin.
Fitzmaurice et al. published their systematic review with the aim to evaluate the evidence to challenge initial operation as the gold standard treatment
for AA in adults (37). By searching in the literature
they found 13 trials (1999-2009). Most of them were
considered of low level of evidence. They included four
randomized controlled trials (26-29, 38). Fitzmaurice
et al did not find enough evidence to challenge initial
operation as the gold standard treatment for AA in
adults.
Mason et al. published their meta-analysis of five
randomized trials (25-29, 39). In 2008 Mason has already published a review supporting the conservative
treatment of AA showing as many of the treated patients (up to 70%) would not require surgical intervention (40). The aforementioned meta-analysis revaluate
the evidence of the necessity of a blind assessment of
the outcome. Authors proposed as the most important factor is the choice of treating AA with antibiotic
is the safety of treatment. They focused on the lower
complication rate of patients treated with antibiotics with an OR of 0.54 (95% CI 0.37-0.78, p=0.001).
Patients treated with antibiotics experienced a reduction in sick leave/disability SMD -0.19 (95% CI
-0.33, -0.06, p=0.005) and in pain medication utilization SMD -1.55 (95% CI -1.96, -1.14, p<0.0001). The
failure rate is higher in conservative treatment with an
OR of 6.72 (95% CI 0.08, 12.99, p<0.0001). Author
conclude that “the conservative treatment is associated
to fewer complication, better pain control and shorter
sick leave disease, but has inferior efficacy because of
the high rate of recurrence”.
Varadhan et al published their meta-analysis as an
update to their previous review (32, 41). They excluded
the trial by Malik and Bari and Turhan et al included
on an intention to treat basis data by Hasson et al. excluding the cross-over of patients (27, 29, 34). They
showed as non operative management was associated
with a significantly lower complication rate (RR 0.69;
95% CI 0.54-0.89; P=0.004). A secondary analysis,
excluding the crossover of patients between the two
interventions after randomization from Hasson et al,
Management of acute appendicitis
confirmed the relative risk reduction RR 0.61 95% CI
0.40-0.92; P=0.02). The authors found no differences
neither in the duration of hospital stay nor in the incidence of complicated appendicitis. This is the only of
the published meta-analysis concluding that: “Antibiotics are both effective and safe as primary treatment
for patients with uncomplicated acute appendicitis.
Initial antibiotic treatment merits consideration as a
primary treatment option for early uncomplicated appendicitis”.
An interesting prospective non-randomized
study recently published by Di Saverio et al. evaluate
the question from a different point of view (95). Randomized trials that assign patients with suspected AA
to either surgical or nonsurgical treatment group show
a relapse rate of approximately 14% at 1 year. Authors
suggested that would be useful to determine the relapse rate of patients treated according to the results
of a thorough clinical evaluation, including physical
examination and laboratory results (all characteristics
used to determine the Alvarado score (101)) and radiological evaluation. Only clinical signs and symptoms and laboratory values, as included in the Alvarado and Appendicitis Inflammatory Response (AIR)
(96) scores, were routinely evaluated in patients with
suspected AA. If this clinical evaluation is effective,
authors would expect patient selection to be better
than chance and the relapse rate to be below 14%.
Authors suggested that once established the utility of
this evaluation, it would be possible to begin to identify those components that have predictive value. This
would be a first step toward developing an accurate
diagnostic-therapeutic algorithm, possibly functional
for avoiding the risks and costs of needless surgery.
Authors also suggest that observational studies have
a role in research on the benefits and harms of medical interventions. Randomized trials cannot answer
all important questions about a given intervention.
For example, observational studies are more suitable
for detecting rare or late adverse effects of treatments
and are more likely to provide an indication of what
is achieved in daily medical practice (97). This single-cohort, prospective, observational study has been
registered on ClinicalTrials.gov database (identifier
NCT01096927) (98) and published in the protocol
form (99). All patients presented to the emergency
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department with right iliac fossa (RIF) pain and suspected AA had the following tests: complete blood
cell count with differential and C-reactive protein. An
attending/consultant surgeon conducted an assessment of the right lower quadrant pain suspected of
being appendicitis and rule out the presence of acute
appendicitis and need for operation; they eventually underwent additional abdominal US and eventual
completion with an abdominal CT scan if requested
by the attending/consultant surgeon. Those patients
not needing immediate surgery were treated with a
5- to 7-day course of amoxicillin and clavulanate at
dosage of 1 g orally thrice daily.
The aim of the study were to evaluate the outcome of patients treated non-operatively with antibiotics and to assess the reliability of the initial clinical
evaluation in predicting which non-operatively treated
patients should have been treated surgically. The primary outcomes were 1- Short-term efficacy of antibiotic treatment evaluated as failure of non-operative
management with 7 days of amoxicillin and clavulanic
acid therapy and defined as readmission due to lack
of clinical improvement and/or worsening abdominal
pain and/or localized/diffuse peritonitis. 2- Long term
efficacy of antibiotic treatment defined as the efficacy
of antibiotic therapy for right lower quadrant pain suspected of being AA defined as an incidence of recurrences of clinical episodes of appendicitis up to followup at 2 years (at 7 days, 15 days, 6 months, 1 year, and
2 years). 3- Long-term efficacy of antibiotic treatment
(no need for surgery) defined as the efficacy of antibiotic therapy for right lower quadrant pain suspected of
being AA defined as definite improvement without the
need for surgery up to follow-up at 2 years (at 7 days,
15 days, 6 months, 1 year, and 2 years). 4- Safety of
antibiotic treatment defined as the incidence of major
side effects/drug- or treatment-related complications
(i.e., allergy or other treatment related complications
such as abscess formation).
Secondary outcomes were as follows:
1- Minor complications 2- Abdominal pain after
discharge: assessed at 5, 7, and 15 days. 3- Length of
hospital stay. 4- Outpatient clinic follow-up defined as
the number of follow-up appointments scheduled in
the outpatient clinic. 5- Sick leave. 6- Cost analysis.
An additional objective was to identify clinical, labo-
126
ratory, and imaging findings that were predictive of
failure of non operative management with antibiotics
and/or relapse of appendicitis and need for appendectomy within 2 years.
The inclusion criteria were as follows: age more
than 14 years, lower abdominal pain/RIF pain, clinical diagnosis/suspicion made by an attending general
surgeon, of AA, confirmed by at least 1 validated score
(Alvarado and/or AIR scores):
- Alvarado score 5 to 6 (equivocal for AA)
- Alvarado score 7 to 8 (probable AA)
- Alvarado score 9 (highly probable AA)
- AIR score 3 to 4 (low probability)
- AIR score 5 to 8 (indeterminate group)
Exclusion criteria: diffuse peritonitis, antibiotic
(penicillin) documented allergy, ongoing/previously
started antibiotic therapy, previous appendectomy,
positive pregnancy test, inflammatory bowel disease
history or suspicion of it recurrence.
Clinical diagnosis or clinical suspicion of non perforated AA not requiring immediate surgery was made
by an attending surgeon and rigorously assessed and
validated on the basis of routine use of clinical scores.
Suspected AA was defined as patient presenting with
RIF pain and the absence of a definite alternative diagnosis of a gastrointestinal disease, urinary tract disease
or an obstetric-gynecological cause. Patients needing
immediate surgery were defined as those with diffuse
peritonitis and/or signs of severe abdominal sepsis and
also those with clinic-radiological (US or CT scan)
evidence of an intra-abdominal collection/abscess or
free perforation. Sepsis was defined by the presence
of systemic inflammatory response syndrome (100) in
the presence of a known or strongly suspected intraabdominal infection/collection or free perforation. Patients who did not undergo surgery were physically examined 5 days later. If their condition did not improve
or worsened, they were admitted for surgical appendectomy. This study gave interesting results. In 2010,
a total of 159 patients with a mean AIR (Appendicitis
Inflammatory Response) score of 4.9 and a mean Alvarado score of 5.2. The follow-up period was 2 years.
The study showed a short-term (7 days) non operative
management failure rate of 11.9%. All patients with
initial failures were operated within 7 days. At 15 days,
no recurrences were recorded. After 2 years, the overall
F. Coccolini, P. Fugazzola, M. Sartelli, et al.
recurrence rate was 13.8% (22/159); 14 of 22 patients
were successfully treated with further cycle of amoxicillin/clavulanate. No major side effects occurred.
Abdominal pain was assessed by the Numeric Rating
Scale and the visual analog scale with a median score
of 3 at 5 days and 2 after 7 days. Mean length of stay
of non operatively managed patients was 0.4 days, and
mean sick leave period was 5.8 days. Long-term efficacy of non operative management was 83% (118 patients recurrence free and 14 patients with recurrence
non operatively managed). None of the single factors
forming the Alvarado or AIR score were independent
predictors of failure of non operative management or
long-term recurrence. Alvarado and AIR scores were
the only independent predictive factors of non operative management failure after multivariate analysis, but
both did not correlate with recurrences. Overall costs
of non operative management and antibiotics were
€316.20 per patient. Authors concluded that antibiotics for suspected AA are safe and effective and may
avoid unnecessary appendectomy, reducing operation
rate, surgical risks, and overall costs. After 2 years of
follow-up, recurrences of non operatively treated right
lower quarter abdominal pain are less than 14% and
may be safely and effectively treated with further antibiotics.
Doubtful issues:
It has already been observed by Fitz that AA may
takes various different clinical courses, mainly three:
spontaneous resolution, persistent inflammation without perforation and perforation. With the advent of
ultrasonography and CT, spontaneous resolution rate
has been reported in the range of 3.6% to 20.0% in
many cases reports, (42-44) and in large case series
(45-50, 52). Case reported demonstrate as the typical symptoms of AA corroborated by imaging studies,
appear to resolve completely in 24 to 48 hours without treatment. So on it could be speculated as the real
challenge is to differentiate since the beginning those
patients who are likely to resolve spontaneously the
AA episode and those who will not. If an appendectomy results in a inflamed appendix that is considered
sufficient to justify the surgical intervention (45). We
must keep in mind however that the absence of inflammatory infiltrate extending into the muscularis
Management of acute appendicitis
propria, with only mucosal or sub-mucosal involvement has no definitive significance. This inflammatory
pattern in fact is commonly observed in the incidentally removed appendix (45, 53). So on the appendix reported as inflamed would comprise a lot of not “really
inflamed” appendix (53) giving partial and incorrect
results and leading sometimes to misinterpretation of
data. Livingston et al showed that ‘‘there was a sudden
reversal of the long term decreasing trend in the rate
of nonperforating appendicitis coincident with more
frequent use of CT imaging and laparoscopic appendectomy’’ (54). Anderson corroborated this statement
by demonstrating that the increment in use of CT scan
has leaded in last decade to an increase in the number
of detected appendicitis (55). Moreover Petrosyan et al
evaluated the direct correlation between appendectomy and CT scan. In fact at the increase of the number
of patients with a CT scan increased also the number
of patients who undergone appendectomy, and this
phenomenon was especially pronounced in patients
with low Alvarado scores (56). As a counterpart patients without CT scan are more likely to be treated
without appendectomy. This confirm the trend toward
overdiagnosis of AA by CT scan. Kirshenbaum et al.
in fact reported an highest spontaneous resolution rate
(up to 20%) if AA is diagnosed by CT scan (52).
As a consequence of all the aforementioned data,
Liu et al suggested that the idea that appendicitis
could be a condition that has a continuous spectrum
from non-perforated to perforated, and from uncomplicated to complicated appendicitis, may be incorrect.
They suggested the existence of several distinct types
of appendicitis, each with varied pathophysiology and
clinical courses (35).
127
Ongoing randomized trials:
open label, non-inferiority multicenter trial to compare antibiotic therapy (ertapenem) with emergency
appendectomy in the treatment of uncomplicated AA.
Inclusion criteria are: signed informed consent,
age between 18 and 60 years. CT scan diagnosis of uncomplicated AA. Exclusion criteria are: age <18 years
or >60 years, pregnancy or lactating, allergy to contrast
media or iodine, renal insufficiency, serum creatinine >
150 μmol/l, metformin medication, peritonitis, inability to co-operate and give informed consent, serious
systemic illness, complicated AA in a CT scan (appendicolith, perforation, peri appendicular abscess or
suspicion of a tumor).
The primary endpoint is the success of the randomized treatment. In the antibiotic treatment arm
successful treatment is defined as the resolution of
AA resulting in hospital discharge without the need
for surgical intervention and no recurrent appendicitis
during a minimum follow-up of one-year (treatment
efficacy). Treatment efficacy in the operative treatment
arm is defined as successful appendectomy evaluated to
be 100%. Secondary endpoints are post-intervention
complications, overall morbidity and mortality, the
length of hospital stay and sick leave, treatment costs
and pain scores (VAS, visual analogue scale). 610 adult
patients (aged 18-60 years) with a CT scan confirmed
uncomplicated AA will be enrolled from six hospitals
and randomized by a closed envelope method in a 1:1
ratio either to undergo emergency appendectomy or
to receive ertapenem (1 g per day) for three days continued by oral levofloxacin (500 mg per day) plus metronidazole (1.5 g per day) for seven days. Follow-up
will be performed by a telephone interview at 1 week,
2 months and 1, 3, 5 and 10 years. Both the primary
and secondary endpoints will be evaluated at each time
point.
The APPAC trial:
The APPAC trial aims to provide level I evidence
to support the hypothesis that approximately 75-85%
of patients with uncomplicated AA can be treated
with effective antibiotic therapy avoiding unnecessary
appendectomies and the related operative morbidity,
also resulting in major cost savings (registration: Clinicaltrials.gov NCT01022567) (57). The APPAC trial is
designed to be a randomized prospective controlled,
The ASAA trial:
The ASAA-Study (Antibiotics vs. Surgery in
Acute Appendicitis) is an intention to treat prospective randomized controlled study which aims to
compare the antibiotic therapy and the surgery in the
treatment of uncomplicated acute appendicitis (registration: EudraCT 2011-002977-44). Preliminary
agreement has been reached over Andersson’s score as
the most comprehensive diagnostic tool for patients
128
suspected to suffer of AA. According to the Andersson’s score 3 groups have been individuated. Group 1:
patients with very low probability to suffer from AA
and group 3: patients with very high probability to suffer from AA. The group 2 includes patients with intermediate probability to suffer from AA; in this group
we added ultrasound to better discern the presence of
AA. Patients which require immediate surgery and
group 1 or 2 patients with negative ultrasound and/or
positive gynecological consultation are excluded. Of
the remaining patients, those who meet the inclusion
criteria are randomized. In order to perform a noninferiority analysis between antibiotics and surgery the
population size was calculated as 110 patients in each
arm.
Inclusion criteria are: all the patients between 18
and 65 years old admitted to the hospital with a first
episode of suspected AA diagnosed by Andersson’s
score combined with abdominal ultrasound (see below,
at the population study section, for details). Exclusion
criteria are: patients with any potential immunodeficiency status (diseases or syndromes, neoplasm in the
last five years), diabetes, assumption of antibiotics for
different infectious disease or surgery in the last 30
days, allergy to antibiotics established in the study protocol, no acceptance of study protocol, pregnancy or
delivery in the last 6 months, ASA IV or V, no Italian
or English fluently speakers.
The primary endpoints are: absence of symptoms
and normalization of laboratory test after 2 weeks, no
major complications or recurrence within 1 year. The
secondary endpoints are: reintervention for bowel occlusion or intraperitoneal abscess, bowel occlusion
longer than 48 hours, incisional hernia or wound dehiscence, recurrence of AA, wound infection, negative
appendectomy, hospital stay, work absence and evaluation of pain (VAS at admission time, twice a day
during the entire admission beginning since 24 hours
from the intervention or the first antibiotic dose).
In the antibiotic arm will be administered to the
patients Ertapenem e.v. infusion 1g for day for 3 consecutive days followed by Amoxicillin plus Clavulanic
acid per os 1gr 3 times day for seven days. In the surgery arm will be administered Amoxicillin plus Clavulanic acid e.v. 2 gr followed by surgery.
F. Coccolini, P. Fugazzola, M. Sartelli, et al.
Complicated acute appendicitis
Introduction and definition:
Complicated appendicitis is defined as appendicitis complicated by a local or contained perforation
with an appendiceal abscess or mass formation.
Literature evidence:
Conservative treatment of complicated AA may
include radiologic-guided drainage of a peri-appendiceal abscess. After successful conservative management, some centers are used to proceed with elective
interval appendectomy. At present no consensus exists
among surgeons regarding the optimal treatment for
patients with complicated AA (58).
Randomized controlled trials: at the best of our
knowledge no randomized trials exist comparing conservative and surgical treatment of complicated AA in
adults.
Systematic review and meta-analysis: one systematic review with meta-analysis have been published by
Similis et al. (58) . The following outcomes were evaluated to compare patients in the conservative treatment
group and those in the surgery one: 1 - duration of
hospital which means the mean duration of hospital
stay during the first hospital admission and the overall
duration of hospital stay. The overall duration of hospital stay included hospitalizations for interval appendectomy and eventual complications. 2 - duration of
antibiotic therapy which means the average number of
days the patient had intravenous antibiotic therapy as
an inpatient but excluded any oral courses completed
after discharge. 3 - complications rate divided into
overall complications rate and wound infection rate.
Wound infection is defined as superficial or deep after wound closure but excluded any abscess formation.
Abdominal/pelvic abscess defined as a collection of
fluid in the pelvis or abdomen diagnosed on radiologic
imaging or at reoperation or at interval appendectomy, ileus or bowel obstruction diagnosed after CT or
postoperatively, pneumonia, sepsis/diffuse peritonitis,
deep venous thrombosis/pulmonary embolism, death,
adhesions, and fistula formation. The authors choose
these particular complications because they were the
129
Management of acute appendicitis
most commonly reported by the different studies to
compare the 2 groups. 4 – reoperation rate considers
all the reoperations needed as a result of postoperative
complications after interval appendectomy or acute
appendicitis during the same and/or during any other
hospital readmissions (58).
This review included a total of 17 studies published between 1969 and 2007 (59-75) considering
the management either of adult either of pediatric
patients. 16 non-randomized retrospective trials (5975) and 1 non-randomized prospective trials (74). The
analysis was performed on 1,572 patients, of which
847 (53.9%) patients received conservative treatment
and 725 (46.1%) patients underwent acute appendectomy for complicated appendicitis. Of the 847 patients
who received conservative treatment, 483 proceeded to
have interval appendectomy. The duration of intravenous antibiotics given to patients, which was found to
be similar between conservative treatment and acute
appendectomy (WMD, 1.02; 95% CI, --1.30--3.34;
P =.39). No difference was found in the duration of
first hospitalization (WMD, 0.49; 95% CI, --2.70-3.69; P =.76). No difference was found in the overall duration of hospitalization (WMD, 0.04; 95%CI,
--3.87--3.95; P = .98). Complications comparing the
2 treatment approaches were found to be more common in the acute appendectomy group compared with
the conservative treatment group (OR, 0.24; 95% CI,
0.13--0.44; P<.001). A greater incidence of ileus/bowel obstruction was found in the acute appendectomy
group (OR, 0.35; 95% CI, 0.17--0.71; P=.004). The
acute appendectomy group was found to have a greater
rate of abdominal/pelvic abscess formation (OR, 0.19;
95% CI, 0.07--0.58; P = .003). Wound infection was
found to be more common in the acute appendectomy
group (OR, 0.28; 95% CI, 0.13-- 0.60; P=.001). No
difference was shown between the 2 groups when comparing pneumonia (OR, 1.11; P=.89), sepsis/diffuse
peritonitis (OR, 0.54; P=.36), deep venous thrombosis/pulmonary embolism (OR, 0.37; P=.20), mortality
(OR, 0.70; P=.67), adhesions (OR, 3.35; P=.39), and
fistula formation (OR, 0.22; P=.07). Reoperation was
found to be greater in the acute appendectomy group
(OR 0.17; 95% CI, 0.04--0.75; P=.02).
This meta-analysis showed that conservative
management of complicated AA, with or without in-
terval appendectomy, is associated with a decreased
complication and reoperation rate. Moreover the conservative treatment of AA has similar duration of hospital stay and duration of intravenous antibiotics. The
authors however suggest the needing for subsequent
studies (58).
Conservative treatment acute appendicitis in
pediatric patients
Uncomplicated acute appendicitis
A different discussion should be reserved to the
management of AA in pediatric patients. The vast
majority of published data presented discussed almost exclusively about adult patients. Only one pilot
randomized controlled trial exists (102) comparing
appendectomy with non-operative treatment in children with uncomplicated AA. In this trial, 92% of
patients treated with antibiotics had initial resolution
of symptoms and only 1 patient (5%) had recurrence
of AA during follow-up. These results suggested that
non-operative treatment of AA in children is feasible and safe. Some other randomized controlled trial
about this topics are in progress (103-106). Similarly,
some meta-analysis and cohort studies (76, 77, 107109) suggested the possibility to successfully use the
non-operative treatment of uncomplicated AA with
a reported success rate ranged from 74% to 97% and
a recurrence rate of 14%. These studies reported the
same complications rate in the surgery group and in
the non-operative group. The reported long term efficacy of non-operative management ranged from 73
and 82%. Although scarce, present literature supports
the feasibility of non-operative management of acute
uncomplicated appendicitis in children. Higher quality prospective randomized controlled trials with larger
sample sizes are required to establish its utility.
Complicated acute appendicitis
No consensus exists among pediatric surgeons
regarding the optimal treatment complicated AA in
children (78). The advent of broad-spectrum antibiotics leads some surgeons to suggest the possibility to try
130
to apply the non-operative management in cohort of
children (79-87). As a counterpart a little evidence exists about the possibility to determine which children
are most likely to benefit from this approach. In fact,
the term “complicated acute appendicitis” includes
different clinical entities: the gangrenous appendicitis,
the perforated appendicitis, the phlegmon and the appendicular abscess.
The existing literature that try to determine the
real efficacy of the non-operative management in patients with perforated AA has no possibility to reduce
the heterogeneity of data and the incompleteness of
them. For this it’s impossible to differentiate the real
clinical status of patients treated with conservative
management and those treated with appendectomy
and no definitive data could be obtained.
Literature reports that 30 to 60% of children with
AA have already developed appendicular perforation at the moment of the child presentation to the
surgeon (88, 89). The surgeon at that moment could
choose between three main options: immediate appendectomy and non-operative management with or
without drainage of a peri-appendiceal abscess. After
successful conservative management, once the child
is returned to normal activity many surgeons suggest
interval appendectomy.. Several reports demonstrated
good outcomes in series of children with perforated
appendicitis, without abscess, phlegmon, or mass,
treated non-operatively with intravenous broad-spectrum antibiotics (79, 80, 82, 84, 87, 90-92). As already
stated before the majority of these series are affected
by significant selection bias, most commonly due to
the undefined clinical status at presentation which has
determined the treatment choice. All the published
series proposed retrospectively collected data where
diagnosis was based on different combinations of clinical suspicion, abdominal US and CT scan. The success
rate of non-operative is reported in 62 to 100% of cases. To overcome some of the limitations of these retrospective studies, Blakely et al. performed a prospective,
randomized controlled trial comparing non-operative
treatment to early appendectomy in 131 unselected
children with perforated AA without evidence of abscess or mass (93). The protocol fixed the date of interval appendectomy following successful non-operative
treatment after 6 to 8 weeks. The 89% of the children
F. Coccolini, P. Fugazzola, M. Sartelli, et al.
who underwent early appendectomy for suspected
perforated appendicitis had this as a final diagnosis.
The primary outcome was time away from normal activities. It has been demonstrated to be significantly
shorter in the group who underwent early appendectomy compared with those who underwent non-operative management and who returned for interval appendectomy. The adverse events rate were significantly
more common in the non-operative management arm.
On the basis of these findings the authors propose a
clear preference for early appendectomy for perforated
AA. A subsequent paper with a cost-analysis based on
this trial showed a significant cost-benefit to early appendectomy (94).
Another randomized controlled trial (110) focusing on children with appendicitis with abscess, didn’t
find advantages between initial laparoscopic appendectomy versus initial non-operative management and
interval appendectomy in terms of total hospitalization, recurrent abscess rate or total charges. An analysis
of the studies that included only pediatric patients in
a meta-analysis about appendicitis complicated with
abscess or phlegmon revealed that, compared with the
non-operative group, the early appendectomy group
had a greater rate of overall complications, wound infections and abdominal/pelvic abscess formation. No
differences were found between the two groups in the
duration of first hospitalization, ileus/bowel obstruction and reoperations. Similar results emerged in another recent meta-analysis (111) about pediatric patients with complicated appendicitis.
Finally a meta-analysis (112) of the two randomized controlled trials about complicated acute appendicitis found that for children with perforated appendicitis and no abscess at presentation, it appears
that early appendectomy is favored, while for children
with an intra-abdominal abscess at presentation, the
controversial question of early versus interval appendectomy is still alive because there is no convincing
evidence suggesting major differences between the two
surgical approaches. More high quality randomized
studies are needed to demonstrate the risks and benefits of operative and nonoperative approaches to complicated appendicitis.
Management of acute appendicitis
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Correspondence:
Federico Coccolini MD,
General, Emergency and Trauma Surgery, Bufalini Hospital,
Viale Ghirotti 268, 47521 Cesena, Italy
Tel. +39- 0547 354771
E-mail: federico.coccolini@gmail.com