CRITICAL APPRAISAL

OF JOURNAL REPORT

G A BR I EL , J EBE LI N E BE I
PEL A G I O , C A S S A N D R A
V I LL A N U EVA , M A R I ELL E I R I S
2 NOV 2020
Antibiotics-first strategy for uncomplicated acute
appendicitis in adults is associated with increased rates of
peritonitis at surgery. A systematic review with meta-
analysis of randomized controlled trials comparing
appendectomy and non-operative management with
antibiotics
MAURO PODDA,*NICOLA CILLARA, SALOMONE DI SAVERIO, ANTONIO
LAI, FRANCESCO FEROCI, GIANLUIGI LURIDIANA, FERDINANDO
AGRESTA, NEREO VET TORET TO, ON BEHALF OF THE ACOI (ITALIAN
SOCIETY OF HOSPITAL SURGEONS) STUDY GROUP ON ACUTE
APPENDICITIS
 INTRODUCTION
Acute appendicitis (AA)
o among the most common causes of lower abdominal pain leading patients to ER
o most common diagnosis made in young patients admitted to hospital for acute
abdominal pain
o highest incidence: second decade of life
o Significant debate: uncomplicated (non-perforated) AA should be operated or not
o “Jerusalem guidelines”: antibiotic therapy can be successful in selected patients
with uncomplicated appendicitis who wish to avoid surgery, and accept the risk
up to 38% recurrence
 RESEARCH OBJECTIVES

o Up-to-date reassessment of the current available evidence on the antibiotic

approach to uncomplicated AA when compared to the standard surgical
treatment with particular focus on safety and efficacy

o Discuss the limitations of published randomized trials, potentially limiting

a more widespread diffusion of the antibiotic-first treatment.
 METHODOLOGY
Materials and Methods
A. Search methods for identification of randomized controlled trials (RCTs)
 PubMed
o Systemic literature search was performed using:  EMBASE
 Medline
 Google Scholar
 Cochrane Central Register
of Controlled Trials
databases for studies
comparing antibiotic
therapy (AT) and Surgical
therapy (ST)
B. Selection of studies
o RCTs comparing AT and ST as primary treatment for uncomplicated AA in
adults were included, irrespective of language or publication status
 o Inclusion Criteria:
Author (Year) Inclusion Criteria

Eriksson S. et al. (1995) Adult patients with typical history of AA and clinical signs, positive findings
following US, and either increased WBC and CRP values or elevated WBC and CRP
levels as measured on two separate occasions within a 4-h interval

Styrud J. et al. (2006) Male patients (18-50 y/o) admitted for suspected AA with CRP level >10 mg/l in
whom perforation was not suspected

Turhan AN. et al. (2009) Patients with AA, confirmed by physical examination, blood cell count
(leukocytosis), abdominal US and CT scan

Vons C. et al. (2011) All adults examined in the emergency department and suspected to have an AA
were assessed for possible inclusion in the study. After informed consent was
obtained, a CT scan was done. Diagnosis of uncomplicated appendicitis was
assessed by CT imaging

Salminen P. et al. (2015) Patients aged 18-60 years admitted to the emergency department with clinical
suspicion of uncomplicated acute appendicitis, confirmed by a CT scan.
 o Studies not reporting data on the selected outcomes of
o Exclusion Criteria: interest
o Articles in which the outcomes of interest could not be
calculated
o Studies not specifying the patients selection criteria
o Studies not reporting the specific antibiotics used for the
AT
o Studies that only included pediatric patients
o Non-human studies

C. Types of outcome measures

C1. Primary Outcomes
o Treatment efficacy (for AT) based on 1 year follow-up
o Treatment efficacy (for ST)-AA confirmed at the time of the surgical operation and
resolution of symptoms after surgical treatment
o Recurrence at 1 year follow up
o Complicated appendicitis with peritonitis identified at the time of surgical operation
o Overall post-intervention complications
C2.Secondary outcomes
o Length of primary hospital stay
o Period of sick leave, intended as “absence from work”

D. Statistical analysis, data synthesis and reporting of the results

o Meta-analysis: in accordance with the recommendations of Preferred Items for
Systematic Reviews and Meta-analyses (PRISMA) statement
o Statistical analysis was performed using Reviewer Manager software
 PRIMARY OUTCOME MEASURES
TREATMENT EFFICACY BASED ON 1 YEAR FOLLOW-UP
RECURRENCE AT 1 YEAR FOLLOW UP
COMPLICATED APPENDICITIS WITH PERITONITIS
IDENTIFIED AT TIME OF SURGICAL OPERATION
OVERALL POST-INTERVENTION COMPLICATIONS
 
 
POST-INTERVENTION COMPLICATIONS OF PATIENTS WHO
UNDERWENT APPENDECTOMY
HIGHER RATE IN ST GROUP (98.3% vs 75.9%, P < 0.0001)
22.5% of patients treated with antibiotics
HIGHER RATE IN AT group (19.9% vs 8.5%, P ¼ 0.02). RESULTS
 
No statistically significant differences were found when 5 RCTs
comparing AT and ST groups (4.3% vs 10.9%, P ¼ 0.32) Total: 1,351
  (AT Group: 632; ST
No statistically significant differences were found when Group: 719)
comparing AT and ST groups (15.8% vs 10.9%, P ¼ 0.35)

SECONDARY OUTCOME MEASURES

 
LENGTH OF HOSPITAL STAY No statistically significant differences were found when
  comparing AT and ST groups (3.24 ± 0.40 vs 2.88 ± 0.39, P
  ¼ 0.13)
   
PERIOD OF SICK LEAVE No statistically significant differences were found when
  comparing AT and ST groups (8.91 ± 1.28 vs 10.27 ± 0.24, P
¼ 0.06).
 
DISCUSSION
Acute appendicitis
 one of the most common indications for urgent abdominal surgery
 treatment of choice (traditionally): appendectomy
 majority of patients with uncomplicated AA can be treated with an AT-first
approach (avoiding ST)  conflicting data about rates of efficacy of AT (esp
long-term outcomes)

Each of the trials published in the literature show several limitations:

o patient selection bias
o definition of primary endpoints
o lack of a standardized CT/US diagnosis
 o standardized pathologic criteria for the diagnosis of potentially clinically significant
appendicitis
 difficult to achieve meaningful conclusions about the real effectiveness of the AT
approach when compared to ST

 AT was associated with a significant lower treatment efficacy based on one year
follow-up when compared to ST
o confirmed previous data published in other systematic reviews and meta-analyses:
A. Wilms et al. (2011) concluded that ST remains the standard of care for AA due to
the higher success rate (97.4%) when compared to AT (73.4%)
B. Mason et al. in 2012: Same conclusion; non-operative management was
associated with significantly fewer complications, better pain control and shorter
sick leave than AT
 A higher rate of complicated appendicitis with peritonitis identified at the time
of surgical operation in the AT group was found
• majority in patients with persistent appendicitis (62%)
• lack of accuracy on the diagnostic process
• complicated appendicitis might already have been present in a percentage of
patients at the time of randomization (Vons et al)

 Time to the administration of antibiotics in case of suspected AA : role in the

effectiveness of the treatment.
• most effective when administered within 12 h of symptom onset, and even
more within the first 6 h
 No statistically significant differences were found for overall post-intervention
complications (wound infections, incisional pain, mild obstructive symptoms)
• advantages of the antibiotic-first approach:
• lower rates of major and minor complications
• shorter length of primary hospital stay
• early return to daily normal activity

 In patients who underwent surgery after failure of the AT, rates of

complications were similar in both groups
• decision to delay appendectomy can be safely made with low risk of
developing postoperative complications following delayed surgery
 The inferiority of non-operative therapy vs appendectomy could also be related to
the type of antibiotic used.
 NOTA (Non Operative Treatment for AA) study:
• if patients are correctly addressed to the proper treatment option, AT for
suspected acute appendicitis is:
• safe and effective
• low recurrence rates (13.8%)
• short sick leave time (5.8 days)
• positive impact on human and surgical operating room utilization, as well as on
social and health care costs
LIMITATIONS
• small number of well-designed randomized controlled trials that have published
on this subject to date
• missing or unclear data regarding randomization methods, allocation sequence
generation
• the impossibility to take measures to effectively blind both patients and
investigators to the administered treatment
• the majority of the appendectomies for patients enrolled in this meta-analysis
were performed using the open approach
 CONCLUSION
• Appendectomy still remains undoubtedly the most effective treatment for
patients with uncomplicated acute appendicitis because of its high efficacy
and low complication rates.
• Researchers suggested that when antibiotic therapy is considered, patients
should be accurately selected and assessed, and choice of most appropriate
treatment option should be carried out through a precise clinical evaluation.
• AT strategy should be accurately explained and discussed with the patient
and informed consent must be obtained.
Section A: Are the results of the review valid?

1. Did the review address a clearly focused question?

 YES
• POPULATION: Patients with uncomplicated acute appendicitis
• INTERVENTION: Antibiotic therapy for uncomplicated AA
• COMPARISON: Surgical therapy- Appendectomy
• OUTCOME MEASURES:
• primary outcome measures
• Secondary outcomes
2. Did the authors look for the right type of papers?
 YES
• randomized controlled trials (RCTs) comparing AT and ST as primary
treatment for uncomplicated AA in adults were included in the systematic
review and meta-analysis
 Is it worth continuing?

3. Do you think all the important, relevant studies were included?

 YES
• A systematic literature search was performed using different databases.
• The search was also extended to related articles suggested by the databases and
supplemented with manual searches for reference lists of all relevant articles
• RCTs comparing AT and ST as primary treatment for uncomplicated AA in adults
were included, irrespective of language or publication status
4. Did the review’s authors do enough to assess quality of the included
studies?
 YES
Two reviewers (MP and NC) independently considered the eligibility of
potential titles and extracted data. Discrepancies were resolved with the
involvement of a third party (SDS). The risk of bias for the trials enrolled in the
meta-analysis was evaluated according to the Cochrane Handbook for Systematic
Reviews of Interventions.

5. If the results of the review have been combined, was it reasonable to

do so?
 YES
Section B: What are the results?

6. What are the overall results of the review?

 Higher rate of treatment efficacy* based on 1 year follow-up was found in
ST group, recurrence at 1 year was reported in 22.5% of patients treated
with antibiotics.
 Rate of complicated appendicitis with peritonitis identified at time of
surgical operation was higher in AT group.
 No statistically significant differences were found when comparing AT and
ST groups for the outcomes of overall post-intervention complications,
post-intervention complications based on the number of patients who
underwent appendectomy, length of hospital stay, and period of sick leave.
7. How precise are the results?

 95% Confidence Interval

 The researches used PRISMA flow chart for systemic search and selection
of articles for review and meta-analysis.
 The study also included the risk for bias.
 The researchers clearly showed the significant differences when comparing
AT and ST groups for the outcome of interest over rate of efficacy and all
post-intervention complications.
Section C: Will the results help locally?

8. Can the results be applied to the local population?

 YES
• Appendectomy remains undoubtedly the most effective treatment, but the
researchers suggested that when Antibiotic therapy is considered, patient
should be accurately selected and assessed, and must be carried out through a
precise clinical evaluation.
9. Were all important outcomes considered?
 YES
The research stated all important primary outcomes such as: treatment
efficacy based on 1 year follow up, reoccurrence at 1 year follow up,
complications identified during surgical operation and overall post-
intervention complications
Secondary outcomes are also stated by the researchers.
These are: length of primary stay and period of sick leave.
10. Are the benefits worth the harms and costs?
 NO
2 cited advantages of antibiotic management: shorter length of hospital stay and
early return to daily normal activities
 can also be achieved using laparoscopic appendectomy, which is a minimally
invasive surgical technique that has significant reduction to postoperative pain
and might result to earlier recovery from surgery in the near future

 Excessive delay in deciding the failure of NOM and/or underestimating the

patients who are not improving solely with antibiotics may lead to higher
incidence of peritonitis and delay in surgical source control of the intra-
abdominal infection
THANK YOU