Study

First author, year

Appropriate and clearly focused question?

Yes/no/unclear

Comprehensive and systematic literature search?

Yes/no/unclear

Description of included and excluded studies?

Yes/no/unclear

Description of relevant characteristics of included studies?

Yes/no/unclear

Appropriate adjustment for potential confounders in observational studies?

Yes/no/unclear/not applicable

Assessment of scientific quality of included studies?

Yes/no/unclear

Enough similarities between studies to make combining them reasonable?

Yes/no/unclear

Potential risk of publication bias taken into account?

Yes/no/unclear

Potential conflicts of interest reported?

Yes/no/unclear

Georgiou, 2017

Yes

Yes

No

Yes

No

Yes

Unclear*

Yes

SR, study B, C: no; study A, D: unclear

Sallinen, 2016

Yes

Yes

No

No

Not applicable

Yes

Unclear*

Yes

Yes

Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Georgiou, 2017

PS., study characteristics and results are extracted from the SR (unless stated otherwise)

SR and meta-analysis of RCTs and cohort studies

Literature search up to October 2015

A: Hartwich, 2015

B: Minneci, 2014

C: Svensson, 2015

D: Tanaka, 2015

Study design: SR of parallel RCT (A), prospective cohort (B, C, D)

Setting and Country: Department of Paediatric Surgery and Urology, Southampton Children’s Hospital, Southampton, United Kingdom

Source of funding:

SR: No external funding

Individual studies:

A: NR

B: supported by the National Institutes of Health, intramural funding from the Research Institute at Nationwide Children’s Hospital,

and the National Center for

Advancing Translational Sciences.

C: Supported by the Crown Princess Lovisa’s Foundation and the Hirsch

Foundation grants.

D: NR

Inclusion criteria SR:

1. types of studies: any study design

reporting nonoperative treatment of acute uncomplicated appendicitis in children;

2. types of participants: children

(<18 years of age)

Exclusion criteria SR:

studies that

reported NOT as treatment of

complicated appendicitis (such as perforated appendicitis, ruptured

appendicitis, appendicitis with

an abscess, or appendix mass),

studies that included a mixed

population of adults and children, or studies that reported NOT as treatment of acute appendicitis

only in children with malignancy.

10 studies included in the original SR. However, we excluded six studies that were either non-comparative or retrospective.

Important patient characteristics at baseline:

N (I/C)

A: 24/ 50

B: 37/ 65

C: 24/ 26

D: 78/ 86

Age (years)

A: mean (SEM) (I/C) 13 (0.6)/ 12 (0.5)

B: median (IQR) (I/C) 11 (10-14)/ 12 (9-13)

C: mean (range) 11 (6-15)

D: mean (range) 10 (5-15)

Groups comparable at baseline? Unclear, only one study was randomised, with

the remainder using treatment cohorts assembled according to

patient and physician choice.

Describe intervention:

A:

Intravenous antibiotics

Piperacillin-tazobactam, 0.3 days (2 doses, 8 hours)

Oral antibiotics

Amoxicillin-clavulanic acid, 7 days

B:

Intravenous antibiotics

Piperacillin-tazobactam; or ciprofloxacin,

Metronidazole, to complete 10-d

total course

Oral antibiotics

Amoxicillin-clavulanic

acid; or ciprofloxacin,

metronidazole, 9 days

C:

Intravenous antibiotics

Meropenem, metronidazole, 2 or more days

Oral antibiotics

Ciprofloxacin, metronidazole, 8 days

D:

Intravenous antibiotics

Cefmetazole for 2 days; if no decrease of white

blood cell count over 25%:

ampicillin-sulbactam, ceftazidime or meropenem

or imipenem-cilastatin, gentamicin, mean 6.6 days

Oral antibiotics

Not specified

Describe control:

Appendectomy

End-point of follow-up:

A: 14 months (mean)

B: 21 months (median)

C: 12 months

D: I: 4.5 years, C: 3.3 years (median)

For how many participants were no complete outcome data available?

(intervention/control)

A: 3/ 1

B: 2/ 9

C: 0/ 0

D: 29/ 26

Outcome measure-1 morbidity

Defined as complications including complicated appendicitis and postoperative complications

Effect measure: RR (95% CI):

A: Not estimable

B: 0.35 (0.04, 2.89)

C: 3.24 (0.14, 75.91)

D: 0.55 (0.05, 5.96)

Pooled effect (random effects model):

0.64 (95% CI 0.16 to 2.64) favoring conservative treatment

Heterogeneity (I²): 0%

Outcome measure-2 Reintervention in conservative treatment group

A: 7 (33.3%) of the 21

B: 9 (24.3%) of the 37

C: 9 (37.5%) of the 24

D: 17 (21.8%) of the 78

Outcome measure-3 Recurrent appendicitis after initial success in conservative treatment group

A: 2 (9.5%) of the 21

B: 7 (20%) of the 35

C: 2 (8.7%) of the 23

D: 22 (28.6%) of the 77

Outcome measure-4 Success rate

Defined as no complications and no recurrences within 1 month after hospital discharge

Effect measure: RR (95% CI):

A: 0.87 (0.74, 1.02)

B: 0.91 (0.81, 1.02)

C: 0.92 (0.80, 1.06)

D: 0.94 (0.88, 1.00)

Pooled effect (random effects model):

0.82 (95% CI 0.88 to 0.97) favoring conservative treatment

Heterogeneity (I²): 0%

Data were extracted from individual studies.

Facultative:

Author’s conclusion

Current data suggest that nonoperative treatment is safe. It appears effective as initial treatment in 97% of children with acute uncomplicated appendicitis, and the rate of recurrent appendicitis is 14%. Longer-term clinical outcomes and cost-effectiveness of nonoperative treatment compared with appendicectomy require

further evaluation, preferably in large randomized trials, to reliably inform decision-making.

Personal remarks

Large clinocal heterogeneity was found between the included studies such as type of antibiotics administered, duration of antibiotic administration and different inclusion and exclusion criteria.

Sallinen, 2016

PS., study characteristics and results are extracted from the SR (unless stated otherwise)

SR and meta-analysis of RCTs

Literature search up to December 2015

A: Eriksson, 1995

B: Salminen, 2015

C: Styrud, 2006

D: Vons, 2011

Study design: SR of parallel RCTs

Setting and Country: Helsinki University Hospital and University of Helsinki, Helsinki, Finland

Source of funding:

The Academy of Finland (number 276046), competitive

Research Funding of the Helsinki and Uusimaa Hospital

District, Jane and Aatos Erkko Foundation, and Sigrid Jusélius Foundation. V.S. also received funding from

Vatsatautien tutkimussäätiö Foundation and Mary and Georg Erhnrooth’s Foundation.

A: Karolinska

Institute, Swedish

Hoechst, Pfizer,

Mutual Group Life

Insurance Company

Förenade Liv

No conflict of interest

B: Government

research grant (EVO

Foundation)

awarded to Turku

University Hospital

C: Swedish

Society of Medicine,

Karolinska Institute,

Wallenius Corporation,

Aventis Pharma

D: French

Ministry of Health,

Programme

Hospitalier de

Recherche Clinique

2002

Inclusion criteria SR: RCTs that compared antibiotic treatment with appendicectomy

in patients with suspected acute non-perforated

appendicitis

Exclusion criteria SR: Studies

with a very high risk-of-bias, in which both the description of methods and the baseline characteristics indicated that many patients randomized were not included.

5 studies included, including the RCT among children of Svensson, 2015. This study is included in the review of Georgiou, 2017 and described above.

Important patient characteristics at baseline:

N, age

A: 41 patients, 18-75 yrs

B: 530 patients, 18-60 yrs

C: 252 men, 18-50 yrs

D: 243 patients, 18-68 yrs

Groups comparable at baseline? Unclear

Describe intervention:

A:

Intravenous antibiotics

Cefotaxime 2 g twice daily and tinidazole 800mg

once daily for 2 days

Oral antibiotics

Ofloxacin 200mg and

tinidazole 500mg

twice daily for 8 days

B:

Intravenous antibiotics

ertapenem

sodium 1 g once daily

for 3 days

Oral antibiotics

Levofloxacin 500mg once daily and metronidazole

500mg three times per day for 7 days

C:

Intravenous antibiotics

Cefotaxime 2 g twice daily and tinidazole 800mg

once daily for 2 days

Oral antibiotics

Ofloxacin 200mg and

tinidazole 500mg twice daily for 10 days

D:

Amoxicillin plus clavulanic

acid 3–4 g per day for

8–15 days, intravenously to those with nausea or

vomiting, and orally to

all others

Describe control:

A: Open appendicectomy

(100%). Antibiotics given only to patients with

perforation or abdominal spillage.

B: Open (94%) or

laparoscopic (6%)

appendicectomy with prophylactic antibiotics. Postoperative antibiotics given only in patients with

suspected wound infection

C: Open (94%) or laparoscopic (6%)

appendicectomy.

D: Open (34%) or laparoscopic (66%) appendicectomy

with single-dose prophylactic antibiotics.

End-point of follow-up:

A: 1 year

B: 1 year

C: 1 year

D: 1 year

For how many participants were no complete outcome data available?

(intervention/control)

Loss to follow-up at 1 year was substantial, varying from 7 to 22 per cent, and was similar in

the two groups within each study, although unclear

in the study of Styrud, 2006.

Outcome measure-1 morbidity

Defined as major complications at 1 year conditions requiring endoscopic, radiological or

surgical intervention, or causing organ dysfunction or

death, such as appendiceal perforation, as well as deep

infections, incisional hernias and adhesive bowel obstruction not requiring intervention.

Effect measure RR (95% CI):

A: 1.00 (0.07, 14.90)

B: 0.52 (0.19, 1.37)

C: 1.13 (0.39, 3.27)

D: 0.45 (0.22, 0.90)

Pooled effect (random effects model):

0.58 (95% CI 0.36 to 0.95) favoring conservative treatment

Heterogeneity (I²): 0%

Defined as minor complications at 1

year, such as superficial wound infections, diarrhoea and abdominal discomfort

Effect measure : RR (95% CI):

A: 0.20 (0.01, 3.92)

B: 0.12 (0.05, 0.29)

C: 0.23 (0.08, 0.66)

D: 1.87 (0.17, 20.36)

Pooled effect (random effects model):

0.22 (95% CI 0.09 to 0.57) favoring conservative treatment

Heterogeneity (I²): 38%

Outcome measure-2 Reintervention in conservative treatment group within 1 year*

A: 8 of the 20

B: 70 of the 257

C: 31 of the 128

D: 44 of the 120

Outcome measure-3 Recurrent appendicitis (I/C)

Defined as a recurrent appendicitis between 1-12 months*

Effect measure RD (95% CI):

A: 0.35 (0.13, 0.57)

B: 0.21 (0.16, 0.26)

C: 0.13 (0.07, 0.18)

D: 0.25 (0.17, 0.33)

Pooled effect (random effects model):

0.21 (95% CI 0.14 to 0.28) favoring conservative treatment

Heterogeneity (I²): 71%

Outcome measure-4 Success rate *

Defined as patients who were treated successfully with antibiotics only and had

none of the following: failure of antibiotic therapy or

symptom recurrence needing appendicectomy, and/or

developing any post-therapeutic and postoperative complications.

In the appendicectomy group,

this was defined as patients who were successfully treated

with appendicectomy and had none of the following: no

appendicitis on histology and/or developing any posttherapeutic and postoperative complications including readmission’.

Effect measure RR (95% CI):

A: 0.76 (0.53, 1.11)

B: 0.87 (0.79, 0.96)

C: 0.78 (0.71, 0.87)

D: 0.83 (0.73, 0.96)

Pooled effect (random effects model):

0.83 (95% CI 0.78 to 0.88) favoring conservative treatment

Heterogeneity (I²): 0%

*Data were extracted from individual studies.

Facultative:

Author’s conclusion

The choice of medical versus surgical management in patients with clearly uncomplicated appendicitis is value- and preference-dependent, suggesting a change in practice towards shared decision-making is necessary.

Level of evidence: GRADE (per comparison and outcome measure)

Major complications: Low

Minor complications: Very low

Recurrence: high

Heterogeneity: Large clinical heterogeneity was found between the included studies such as type of antibiotics administered, duration of antibiotic administration and different inclusion and exclusion criteria

Study reference

(first author, year of publication)

Bias due to a non-representative or ill-defined sample of patients?

(unlikely/likely/unclear)

Bias due to insufficiently long, or incomplete follow-up, or differences in follow-up between treatment groups?

(unlikely/likely/unclear)

Bias due to ill-defined or inadequately measured outcome?

(unlikely/likely/unclear)

Bias due to inadequate adjustment for all important prognostic factors?

(unlikely/likely/unclear)

Lee, 2017

Likely

Unclear, only total number lost to follow-up reported

Unlikely

Unlikely

Gorter, 2018

Unlikely

Unlikely

Unlikely

Likely

Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Lee, 2017

Type of study: prospective, nonrandomized patient-preference study

Setting: Harbor-UCLA Medical Center

Country: Canada

Source of funding: Not reported

Inclusion criteria: age 3–17 years; ≤ 5 days of abdominal pain; radiographic evidence of nonperforated appendicitis (ultrasound or CT); evaluation by a surgeon confirming clinical suspicion of nonperforated

appendicitis; willingness to participate. Imaging confirmation of appendicitis was

not required if the attending pediatric surgeon diagnosed the patient with nonperforated appendicitis (pediatric appendicitis

score ≥ 6)

Exclusion criteria: age < 3 years; positive pregnancy

test; history of immunodeficiency or cirrhosis; cognitive impairment;

inability to follow-up; diffuse peritonitis; evidence of severe sepsis/septic

shock on clinical evaluation; intravenous antibiotics within 24 h of presentation; evidence of intraabdominal abscess greater than 5 cm or

perforated appendicitis on imaging; or clinical concern for perforated

appendicitis

N total at baseline:

Intervention: 51

Control: 32

Important prognostic factors²:

For example

Age, median (IQR):

I: 10 (7-13)

C: 11 (8-15)

Sex:

I: 59 % M

C: 53% M

Hours of symptoms median (IQR):

I: 24 (24-48)

C: 24 (24-48)

Groups comparable at baseline? Yes

NB. Multivariate analysis failed to identify any

significant predictors of failure.

Describe intervention (treatment/procedure/test):

Patients choosing NOM received intravenous antibiotics (ceftriaxone/

metronidazole or ciprofloxacin/metronidazole if penicillin allergic).

Patients with clinical improvement were started on liquids and had

their diet advanced. When tolerating a diet and having completed at least one dose of intravenous antibiotics, patients were switched to

oral amoxicillin-clavulanate, ciprofloxacin/Flagyl, or cefdinir/Flagyl. Patients

were subsequently discharged with oral antibiotics to complete a

10-day total course.

Describe control (treatment/procedure/test):

Appendectomy

Length of follow-up:

10 to 14 days, 30 days, 3 months, and 1 year after discharge.

Loss-to-follow-up:

The percentage of patients lost to phone follow up was 5% (4/83) at 2 weeks, 13% (11/83) at 30 days, 33% (28/33) at 3 months, and 40% (21/52) at 1 year.

Incomplete outcome data:

Not reported.

Outcome measures and effect size (include 95%CI and p-value if available):

Outcome measure-1 morbidity

Defined as complications including negative appendectomy, the need

for intraoperative drain placement, the development of an intraabdominal abscess, postoperative ileus prolonging admission, representation to the emergency department for pain control, readmission

or reoperation, diarrhea resulting in termination of antibiotics at 7 days (instead of 10 days), superficial surgical site infection, or other

wound complication

I: 9/ 51

C: 6/ 32

Outcome measure-2 Reintervention (initial failure + recurrence)

I: 25 (49%) of the 51

Outcome measure-3 Recurrent appendicitis after initial success

I: 9 (17.6%) of the 51

Outcome measure-4 Success rate

Defined as no complications and no recurrences within 1 month after hospital discharge

NR

Author’s conclusion

When expanding the inclusion criteria for children with presumed uncomplicated appendicitis, NOM was associated with high failure and recurrence rates. These high rates may be because of the inclusion of patients with complicated appendicitis and patients with an appendicolith. Even in this setting of less restrictive exclusion criteria, NOM remained cost neutral.

Gorter, 2018

Type of study: multicentre-prospective cohort study

Setting: two academic

(tertiary referral) centres and two large general hospitals in the

Netherlands.

Country: The Netherlands

Source of funding: This research did not receive any specific grant from funding

agencies in the public, commercial or not-for-profit sectors.

Inclusion criteria:

All patients were contacted who were eligible for

the multicentre-prospective cohort study conducted between September

2012 and June 2014. In summary, all children aged 7–17 years old with a simple appendicitis confirmed by

imaging studies were eligible for inclusion.

Exclusion criteria:

Children with signs of severe general illness, with a faecalith, or with sonographic

features of complex appendicitis, significant comorbidity, and those with a known type 1 allergy for the antibiotics used.

N total at baseline:

Intervention: 25

Control: 19

Important prognostic factors²:

For example

Age, median (IQR):

I: 14 (10-17)

C: 14 (7-17)

Sex:

I: 60 % M

C: 74% M

Simple appendicitis

I: 25 (100%)

C: 15 (79)

Groups comparable at baseline? Yes

Describe intervention (treatment/procedure/test):

Study participants were admitted to the pediatric (surgical) ward and received

intravenous (IV) antibiotics (amoxicillin/clavulanic

acid 250/25 mg/kg 4 times daily; maximum

6,000/600 mg/d and gentamicin 7 mg/kg once

daily) for ≥48 hours. During the first 24 hours, no

oral intake was permitted and IV fluids were given.

Every 6 hours, clinical reevaluation was performed

systematically to identify signs of clinical deterioration at an early stage. If the clinical condition was improved (no fever, normal heart rate, normal daily activity, less pain) after 24 hours, a normal diet was started. After 48 hours, ultrasonography

was repeated. If the patient met the criteria for

improvement described herein, treatment was

switched to oral antibiotics (amoxicillin/clavulanic

acid 500/125 mg 3 times daily). The patient was

kept in the hospital for another 24 hours to ensure

adequate oral intake of the antibiotics and to

observe the clinical status. If the clinical course was favorable, the patient was discharged after 72 hours from admission with oral antibiotics for another 4 days. The following criteria of improvement were used: body temperature < 38^◦C, visual analog scale/comfort scale < 4, adequate oral

intake, able to mobilize, lower level of C-reactive

protein, amount of leukocytes less than at admission, and no signs of complex appendicitis on

repeat ultrasonography.

If after 48 hours the patient did not meet these

criteria for improvement, IV administration was

continued for another 24 hours with reevaluation.

Describe control (treatment/procedure/test):

Patients who were eligible for initially nonoperative treatment according to the study protocol, but who,

or whose parents in case the child was below 12 years of age, declined participation, all underwent immediate appendectomy with pre-, peri- and postoperative care according to the national Dutch protocol. Appendectomies were performed by multiple (paediatric) surgeons or by surgical trainees under direct supervision, all with extensive experience in treating children with appendicitis.

Length of follow-up:

I: 25 (16-36) months

C: 26 (17-34) months

Loss-to-follow-up:

No children were lost to

follow-up in either group.

Incomplete outcome data:

Not reported.

Outcome measures and effect size (include 95%CI and p-value if available):

Outcome measure-1 morbidity

Complications were defined as:

- Allergic reaction to antibiotics administered;

- Readmission to an emergency department or hospital for indications other than recurrent appendicitis, but potentially related to the appendicitis;

- Need for subsequent invasive interventions other than appendectomy, but related to appendicitis or to a postappendectomy

complication;

- Complications associated with immediate or delayed appendectomy being surgical site infection (SSI); intraabdominal abscess (IAA);

stump leakage and stump appendicitis; secondary or prolonged bowel obstruction; anaesthesia-related complications; incisional

hernia; urinary tract infection and pneumonia.

I: 3 (12%)

C: 2 (11%)

Outcome measure-2 Reintervention (appendectomy)

I: 6 (24%)

Outcome measure-3 Recurrent appendicitis after initial success

I: 3 (12%)

Outcome measure-4 Success rate

NR

Author’s conclusion

Outcome of initially nonoperative treatment for acute simple appendicitis in children is similar to the outcome in those who undergo immediate appendectomy. Initially nonoperative management seems to be able to avoid appendectomy in 3 out of 4 children.

Personal remarks:

In the two patients that underwent an interval appendectomy

histopathological examination showed a noninflamed appendix. Reason

to perform interval appendectomy was on parental request in one

patient and on doctor’s request in another patient.