laparoscopic versus open appendectomy in adults with complicated appendicitis- systematic review and...

7/30/2019 Laparoscopic Versus Open Appendectomy in Adults With Complicated Appendicitis- Systematic Review and Meta-A

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Laparoscopic Versus Open Appendectomy in Adultswith Complicated Appendicitis: Systematic Review

and Meta-analysis

Georgios Markides Daren Subar

Kallingal Riyad

Societe Internationale de Chirurgie 2010

Abstract

Background The goal of the present study was to criti-cally review and identify the strength of available evidence

in the literature on the use of laparoscopic appendectomy

(LA) in complicated appendicitis (CA).

Methods The Cochrane Library and Controlled Trials

Registry, MEDLINE (Ovid), PubMed, Web of knowledge,

and SCOPUS databases were electronically searched, using

the keywords appendectomy, laparoscopy, appen-

dicitis. complicated appendicitis. gangrenous appen-

dicitis, perforated appendicitis, with English language

as a limit. Backward chaining was also employed. The

NHS Public Health Resource Unit Critical Appraisal Skills

Programme Tools were used for critical appraisal.

Results Twelve retrospective case-control studies were

included in the review. Overall methodological quality was

moderate to poor, with heterogeneity, absence of random-

ization and blinding, and presence of important methodo-

logical flaws. Meta-analysis showed that LA in CA has

reduced surgical site infection (SSI) rates compared to

open appendectomy (OA), odds ratio (OR) 0.23, 95%

confidence intervals (CI): 0.140.37 (level 3a evidence),

and no difference with regard to intra-abdominal abscess

(IAA) complication rates OR: 1.02, 95% CI 0.561.86

(level 3a evidence).Conclusions When compared to OA, laparoscopic

appendectomy is advantageous in CA with regard to SSIs,

with no significant additional risk of IAA (level 3a

evidence).

Introduction

Evidence-based practice is the cornerstone for best medical

practice. It is the process of systematically finding,

appraising and using contemporaneous research findings as

the basis of clinical decisions [1]. In the face of a clinical

problem such as the choice between laparoscopic appen-

dectomy (LA) and open appendectomy (OA) best evidence

derived from level 1 quantitative research like well-

designed randomized double-blinded control trials should

be used to decide on the best management. In the absence

of such trials, evidence from lower down in the hierarchical

evidence ladder should be carefully considered.

Acute appendicitis is a surgical condition with incidence

of 1.17 per 1,000 [2] and lifetime risk of 8.6% in males and

6.7% in females [3]. Complicated appendicitis (CA) occurs

once the appendix has become gangrenous and/or has

perforated with various degrees of peritonitis. The rate of

CA is slowly increasing [4] and has been reported at an

incidence of 1230% [5]. It is associated with higher

morbidity rateswound infection rates 20% versus 5% in

noncomplicated appendicitis (nCA) [6]and mortality

rates5% versus 0.8% in nCA [7].

Since 1894, after the description of a series of case

studies by McBurney, OA via the McBurney approach has

been the gold standard procedure for appendectomy [8]. In

the early 1980s Semm [9] described the first laparoscopic

G. Markides (&)

Department of General Surgery, Royal Oldham Hospital,

Oldham, UK

e-mail: [email protected]

D. Subar

Department of General Surgery, Stepping Hill Hospital,

Stockport, UK

K. Riyad

Department of General Surgery, Royal Blackburn Hospital,

Blackburn, UK

123

World J Surg

DOI 10.1007/s00268-010-0669-z


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appendectomy. Subsequent technological advances and

improvement of surgical laparoscopic techniques and

expertise have given ground for trying to introduce this

procedure as the mainstay of treatment for appendicitis. A

recent systematic review and meta-analysis has shown that

the advantages of LA in nCA appear to focus on the

reduction of postoperative pain, wound infection rates, and

in-hospital stay compared to OA, and that it has distinctdiagnostic advantages in females of reproductive age [10].

The use of LA in CA though has been controversial and

associated with increased rates of intra-abdominal abscess

(IAA) complications [10, 11]. More recent studies have

refuted the above finding, suggesting reduced postoperative

wound infection rates of LA compared to OA in CA, and

are actually recommending LA as the mainstay of treat-

ment for these patients [12, 13]. The aim of the present

study was therefore to systematically review the literature

on the effectiveness of LA in relation to conventional OA

in the management of adult patients with complicated acute

appendicitis, with a subsequent meta-analysis.

Methods

Types of studies

Our search included both randomized controlled trials and

observational studies. Eligibility criteria included all stud-

ies comparing LA to OA in adult patients with CA, with (a)

postoperative surgical site infection (SSI) rates, and/or (b)

postoperative IAA rates, and/or (c) postoperative analgesia,

and/or time to oral intake, and/or length of stay in hospital,

as end points. Studies with insufficient data to form 2 9 2

tables for use in odds ratio (OR) analysis and 95% confi-

dence interval (CI) or studies not providing adequate data

to obtain mean values and standard deviation for continu-

ous variables were excluded from the relevant calculations.

Search and selection strategies

The Cochrane Library and Controlled Trials Registry,

MEDLINE (Ovid) (1966November 2008), PubMed,

EMBASE (1966November 2008), Web of knowledge,

and SCOPUS databases were electronically searched for

appendectomy, laparoscopy, laparoscopic appendec-

tomy, and appendicitis, complicated appendicitis,

gangrenous appendicitis with perforated appendicitis.

The search was limited to studies published in the English

language, and was completed with reference follow-up.

The citations and/or abstracts or full text of all potentially

relevant studies were independently reviewed and selected

by two reviewers, and any disagreements were resolved

with discussion.

Data abstraction and validity assessment

Data on study methodology, participant characteristics,

intervention characteristics, and primary outcomes were

independently extracted and tabulated by two reviewers

with a predefined data extraction form. Attempts to contact

authors were made if there were missing data or unclear

information in the studies, and data were adjustedaccordingly. The studies were subsequently assessed

independently by two reviewers for methodological quality

using the Critical Appraisal Skills Tools for randomized

controlled trials and case-control studies [14, 15], with

criteria marked as met, unclear, and not met. Overall risk of

bias was assessed with established methods and graded as

A (low risk), B (moderate risk), and C (high risk) [16].

Data analysis

The RevMan 5 statistical package [17] was employed to

perform odds ratio (OR) analysis and to assess statisticalheterogeneity via I2, with statistical significance at p\ 0.05

and I2\ 30%, respectively, and to assess publication bias

via funnel plot graphical representation. Meta-analysis was

conducted with the Mantel-Haenszel statistical method for

dichotomous variables, and Inverse Variance was used for

continuous variables. Separate analyses were performed for

each bias risk group and for all groups combined together.

Final recommendations were graded based on the Oxford

Centre of Evidence Based Medicine level of evidence and

grades of recommendation guidelines [18].

Results

The initial literature search identified 381 studies. Based on

the inclusion criteria, 362 studies were excluded, with a

selection of 19 studies for more detailed review. Seven of

those studies were subsequently excluded [1925] (Fig. 1),

including one conference abstract with limited study meth-

odology information, leaving 12 retrospective observational/

case-controlled studies for systematic review. A summary of

the studies methodology, intervention characteristics, and

measured outcomes is provided later in Tables 1, 2 and 3.

Discussion

Summary of studies

Randomization, concealment of allocation, and blinding

are inherently absent from the methodological design of the

included studies. In the absence of a standardized care

protocol, patients were allocated to either operative group

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based on the surgeons discretion. This is an important bias

because it reflects the surgeons experience with LA, the

presence of co-morbidities, and the patients clinical con-

dition, all of which may have influenced placement into

either of the patient group [2628].

Another of the problems encountered in the appraisal of

the studies is the case definition for CA. Most studies

define this as a perforated appendix with or without abscess

formation, with or without peritonitis. Four of the studies

[13, 2931] include gangrenous appendix in their case

definition, presumably because it is difficult macroscopi-

cally to distinguish between a perforated and a nonperfo-

rated gangrenous appendix, allowing for variation in the

interpretation of results between these groups of studies.

Initial diagnosis of CA in all but two cases [12, 30] is made

subjectively based on clinical opinion, and macroscopic

histological confirmation is provided in only four of the

studies [13, 3133]. Validity of the case definition in the

remaining studies is therefore compromised. In an attempt

to avoid this problem, Fukami et al. [12] used CT (com-

puted tomography) scanning to confirm CA prior to group

allocation. A drawback of this definition though would be

that patients with perforation but minimal abdominal fluid

that cannot be diagnosed by CT scanning were excluded

from the study thus creating a potential selection bias and

less general applicability of the studys results (reduced

external validity). An alternative is provided by Yau et al.

[30], who diagnose CA laparoscopically first and then

proceed to separate the two groups. This appears to be a

reasonable way to reach a good case definition, as the

diagnostic effects of an initial laparoscopy in suspected

appendicitis have been well established [10]. It does though

introduce the bias of an initial diagnostic laparoscopy.

Two of the studies [34, 35] do not report any patient

characteristics and should be viewed with great caution

with regard to generalizing their results to a normal pop-

ulation. In the remaining studies statistical testing of these

independent variables varies significantly (Table 1) with

external validity implications. Yau et al. [30] are the only

authors who used exclusion criteria regarding age. It is

difficult to judge from the reported ages how big the

pediatric contribution is to these studies, as some infor-

mation is presented as median age standard deviation

and some as mean age, rather than medians with the

interquartile ranges. From a cautious review, it appears that

the majority of patients included are adults as the range of

reported median and mean ages is 3648 and 3040 years,

respectively, between groups. The exception to this is the

study by Pokala et al. [29], which reports the inclusion of

24 pediatric cases in a total study population of 104. In

recognition of that, the authors later test the two popula-

tions separately, but they potentially compromise the sig-

nificance of the studys findings because of a change in the

patient number group ratio (from 43:61 to 28:52).

Intervention characteristics

The level of surgical experience and the learning curve are

two important independent variables requiring consider-

ation. A higher surgical level of experience in LA could

mean a reduced number of converted cases to OA and

potentially lower complication rates. Even though the

Potentially relevant studies identifiedand screened for retrieval

n = 381

Studies retrieved for more detailedevaluation

n= 19

Studies excluded n = 362Not satisfying eligibility criteria

Potentially appropriate studies to beincluded in the meta-analysis

n= 17

Studies included in meta-analysisn = 12(retrospective case-control

studies)

Studies with usable information, byoutcome,

n= 12

Studies excluded n = 2

Retrospective case-series n = 2

Studies withdrawn, by outcome, n = 0

Studies excluded from meta-analysis n = 5Serious methodological flaw with high

bias risk directly affecting outcomen=4

Inadequate data for analysis n=1

Fig. 1 Article selection flow

chart

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Table1

Summaryofstudies

Study

Exposure

measurement

Samplesize

Inclusioncriteria

Independentvariables

Conversionrate&ITT

Findings

Katsunoetal.[31]

Retrospective

case

notereview

LAn=

146

OAn=

84

May1995May

2007

Allpatientswith

CAfrom

hospitalrecord

s

NSbetweengroups:age,

gender,co-morbiditiesnot

tested

3.4%ITTnotused

SSbetwee

ngroups:lowerrateof

SSIs,lo

ngerOT,analgesicuse,

TTOI,pLOSinLAgroup,

NSbetweengroups:IAA,other

post-op

complications

Fukamietal.[12]

Retrospective

case

notereview

LAn=

34

OAn=

39

Jan1999Dec2004

AllCApatients

undergoing

OAinfirst3yearsandallCA

patientsunderg

oingLAin

last3years


gender,obesity,co-

morbidities

0%N/A

SSbetwee

ngroups:lowerrateof

SSIs,analgesicuse,TTOI,

duration

ofdrainage,pLOSin

LAgroup

NSbetweengroups:OT,IAA,

hernia,fistulaformation

Kirshteinetal.[13]Retrospective

case

notereview

LAn=

50

OAn=

98

Jan2005Aug2005

Allpatientswith

CAfrom

hospitalrecord

s

Sbetweengroups:more

femalesofreproductiveage,

higherco-morbidity,obese

andunknownabdominal

pain

ptsinLAgroup

16%ITTnotused

(conversionstreatedas

separategroup)

NSbetweengroups:OT,TTOI

(solids),pLOS,SSI,IAA

Pokalaetal.[29]

Retrospective

case

notereview

LAn=

43

OAn=

61

Jan2003Feb2006

Allpatientswith

CAfrom

hospitalrecord

s

Sbetweengroups:more

pediatriccasesinLAgro

up

(separateanalysiscontacted),

NSbetweengroups:gende

r,

ASAgroup

18.6%ITTused

SSbetwee

ngroups:longerOT,

higherIAArateinLAgroup

NSbetweengroups:overall

complic

ationsandSSI

Yauetal.[30]

Retrospective

case

notereview

LAn=

175

OAn=

244

Jan1999Jan20

04

Allpatientswith

CAfrom

hospitalrecord

s


gender

13.7%ITTused

SSbetwee

ngroups:shorterOT,

LOSan

dSSIinLAgroup

NSbetweengroups:IAArates

Linetal.[37]

Retrospective

case

notereview

LAn=

99

OAn=

130

Jan2001Dec2003

Allpatientswith

CAfrom

hospitalrecord

s


gender

8%ITTused

SSbetwee

ngroups:longerOT,

shorter

antibioticrequirements,

shorter

TTOIandLOS,lower

SSIinLAgroup

NSbetweengroups:postoperative

analgesia,reoperationrates,IAA

Gulleretal.[35]

NISdatabase

LAn=

1,763

OAn=

12,644

1997

Allpatientswith

appendicitis

fromU.S.nationaldatabase

stratificationfo

rCA

Notreported

Notgiven

SSbetwee

ngroups:shorterLOSin

LAgroup

NSbetweengroups:SSI,post-

operativ

ecomplications

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Table1

continued

Study

Exposure

measurement

Samplesize

Inclusioncriteria

Independentvariables

Conversionrate&ITT

Findings

Soetal.[36]

Retrospective

case

notereview

LAn=

85

OAn=

146

Jan1992Jun19

99

Allpatientswith

perforated

appendicitis


gender

40%ITTused

SSbetwee

ngroups:less

postoperativeanalgesiaand

complic

ations,reducedTTOI

andLOSinLAgroup

NSbetweengroups:OT

Piksunetal.[32]

Prospectivecase

notecollection

LAn=

28

OAn=

24

52prospectivepatients

Nottested

36%ITTnotused,

groupstested

individually

NSbetweengroups:OT,IAA,

SSI,pLOS

Wullsteinetal.[34]Retrospective

case

notereview

LAn=

217

OAn=

82

Aug1989Mar1

999forOA

Allpatientswith

CA

19911999LA

Notreported

21%(3560%in1991;

23.4%in19981999)

ITTused

SSbetwee

ngroups:SSIlower

inLA

NSbetweengroups:IAA

Stoltzingetal.[33]Retrospective

case

notereview

LAn=

80

OAn=

45

Jul1991Jun1999

Allpatientswith

perforated

appendix

NSbetweengroups:

age,gender,BMI

45%(16%inlatter

years)ITTnotused

SSbetwee

ngroups:SSI

NSbetweengroups:OT,LOS,

IAA

Khalilietal.[44]

Retrospective

case

notereview

LAn=

77

OAn=

122

Jan1994Aug1997

Allpatientswith

acute

appendicitis

Notreported

ITTnotused

SSbetwee

ngroups:OT

NSbetweengroups:LOS,IAA

LAlaparoscopicappendectomy,ASAAmericanSocietyofAnesthesiologistsscore,BMIbodymassindex,OAopen

appendectomy,CAcomplicatedappendic

itis,uCAuncomplicated

appendicitis,

ITTintentiontotreat,

SSstatisticallysignificant,

NSstatisticallynonsignificant,

OToperatingtime,TTOItim

etooralintake,

LOSlengthofstayinhospital,pLOSpostoperative

lengthofstayinhospital,

SSIsurgicalsiteinfection,IAAintra-abdominalabscess

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Table2

Summaryofstudiesinterventioncharacteristics

Study

CAdiagnosis

Surgeons

LA

OA

Primarywound

closure

Antibiotic

Proce

dure

Meso-appendix&

appendixresection

Retrieval

bag

Procedure

Katsunoetal.

[31]

Intraoperative

1experienced

surgeon?

surgicaltrainees

3trochars,10-5-

5m

m,

?typeof

endoscope

Coagulation?

suture

loopsorstaples

Use

d

McBurneysor

paramedian

Yes

Preoperativeand

postoperativeuseas

clinicallyindicated

Fukamietal.

[12]

CTscan

6experiencedsurgeons

forLA,atleast2other

surgeonsforOA

3trochars,10-10-

5m

m,flexible

end

oscopeused

Electrocauteryor

ultrasound

dissector?

endolinear

cutter

Use

d

McBurneysor

paramedian

Yes

Preoperativeand

postoperativeuseas

clinicallyindicated

Kirshteinetal.

[13]

?clinical

9surgeons?experience

3trochars,45deg

end

oscope

Coagulationor

clips?

sutureloopsor

staples

Use

din

67%

Gridironor

paramedian

Secondary

closurein

contaminated

cases

Preoperativeand

postoperativeuseas

clinicallyindicated

Pokalaetal.[29]Clinical?

CTsca

n

confirmationofCA

Notreported

Notr

eported

Notreported

Notre

ported

Notreported

Notreported

Notreported

Yauetal.[30]

Laparoscopically

Surgicalresidentsat

least3yearsexperience

3trochars,10-5-

5m

m,

?typeof

endoscope

Electrocauteryor

ultrasound

dissector?

suture

loops

Use

d

Gridiron

Notreported

Preoperativeand

postoperativeuseas

clinicallyindicated

Linetal.[37]

Intra-abdominalpus

4experiencedsurgeons

3trochars,10-3-

3m

m,

?typeof

endoscope

Electrocauteryorclipsor

harmonic

scalpel?

clipsor

endoloop

Use

d

McBurneys,

paramedianor

midline

Yes

Preoperativeand

postoperativeuseas

clinicallyindicated

Gulleretal.[35]?clinical

Notreported

Notr

eported

Notreported

Notre

ported

Notreported

Notreported

Notreported

Soetal.[36]

Clinical

?number,lessexperienced

surgeons(n\

20)

associatedwithhigher

conversionrates

3trochars,12-5-

5m

m,

?typeof

endoscope

Electrocautery,clipsor

stapler?

endoloopor

stapler

Use

d

usually

Gridironor

midline

Yesbutin4

cases

Preoperativeand

postoperativeuseas

clinicallyindicated

Piksunetal.[32]?clinical

12surgeons?experience

3trochars,10-5-

12mm,

?typeof

endoscope

?clips?

stapler

Use

d

Notgiven

Yes

Preoperativeand

postoperative5daysand

thenasclinically

indicated

Wullsteinetal.

[34]

?clinical

?surgeons

3trochars,12-5-

12mm,

?typeof

endoscope

Clipsorstapler?

clips

orendoloop

Use

d

McBurneys

Notreported

Preoperativeand

postoperativeuseas

clinicallyindicated

?experience

Learningcurve

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finding is not statistically tested, So et al. [36] do actually

report that less experienced laparoscopic surgeons (per-

forming fewer than 20 laparoscopic procedures) had a

higher rate of conversion. Trying to compensate for this

problem and only allowing experienced surgeons to per-

form LA, though, would positively bias the results in favor

of LA and reduce external validity. This is because in the

normal hospital environment of a general hospital there is avariation in the level of laparoscopic experience among

both senior surgeons and trainees. As OA is a procedure

performed both during day and night by all these levels of

surgeons, LA should be assessed under similar

circumstances.

Similarly, a surgeon at the start of his or her learning

curve in performing LA, would be more likely to have a

higher rate of conversion to OA, as well as a higher rate of

complications. Including a large number of these cases in

the analysis sample could potentially bias the results

against LA. Such a learning curve is reported by Katsuno

et al. and Wullstein et al. [31, 34]. The inclusion of thisindividual surgeon learning curve in the studies under

some circumstances may be acceptable and can be

assumed to represent a normal variation around hospitals

as inexperienced surgeons learn LA. This though should

only occur after a plateau has been reached where, theo-

retically, all the senior surgeons in an institution have

mastered the art of laparoscopy. Results from studies near

the introduction of LA would therefore be mostly appli-

cable to clinical practice during that particular time period,

with recent results being more applicable to current prac-

tice. The earlier studies included in the present appraisal,

such as the ones by So et al. [36] and Wullstein et al. [34],

both of which include an early institutional learning curve

from the early 1990s and should therefore be reviewed

carefully with regard to current practice.

Randomization of surgeons laparoscopic experience in

the LA group should therefore be the most appropriate

approach. The number of surgeons performing each pro-

cedure should also be sufficient that individual surgeon

bias is not introduced, affecting the results and external

validity. In the studies included herein there is a wide

variation in the numbers of recruited surgeons and their

laparoscopic experience, both between groups and between

studies (Table 2). The effect of this performance bias can

potentially be seen in the studies by Yau et al. [30] and Lin

et al. [37], groups that only use experienced laparoscopic

surgeons in their studies, reporting relatively low conver-

sion rates compared to the other studies (Table 1). A lower

conversion rate could mean an underestimation of wound

infections in the LA group because the use of intention to

treat (ITT) analysis places patients undergoing LA that

required conversion to OA, which means a bigger

abdominal wall incision, into the LA group. In theseTable2

continued

Study

CAdiagnosis

Surgeons

LA

OA

Primarywound

closure

Antibiotic

Proce

dure

Meso-appendix&

appendixresection

Retrieval

bag

Procedure

Stoltzingetal.

[33]

Clinical

?surgeons

3trochars,10-5-

12mm,

?typeof

endoscope

Electrocautery,clipsor

stapler

Use

d

Pararectalincision

orlowermidline

laparotomy

Notreported

Preoperativeand

postoperativeuseas

clinicallyindicated

?experience

Learningcurve

Khalilietal.[44]Clinical

Notreported

Notr

eported

Notreported

Notre

ported

Notreported

Notreported

Notreported

CTcrosstomographyscan,

CAcomp

licatedappendicitis,uCAuncomplicatedappe

ndicitis

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Table3

Summaryofstudiesmeasuredoutcomes

Study

OT(min)

Postoperative

analgesia(days)

TTOI(days)

LOS(days)SSI

IAA

Otherpostoperative

complications

Follow-up

Notes

Katsunoetal.[31]

LA:117*

OA:96

impentazosine,

LA:0.8,OA:1.2

POlaxoprofen

sodium,LA:4.2,

OA:6.4*

LA:2.7*,

OA:3.6

LA:8.9

*,

OA:1

6.6

LA:24%*,

OA:6.4%

LA:4.3%,

OA:4.8%

Smallbowelobstruction,

LA:2/146,OA:4/84

Enteritis

,OA:1/84

Pneumonia,OA:2/84

1appt

?timing

Oralintakecommenced

afterbo

welsopened,1

experiencedsurgeonwithteam,

learningcurveincluded

Fukamietal.[12]

(n=73)

LA:97.9,

OA:92

impentazosine,

LA:0.7,OA:0.9

prdiclofenac,LA:

2.1,OA:7.5*

LA:2.6*,

OA:5.1

LA:11.7*,

OA:2

5.8,

pLOS

LA:8.8%*,

OA:

48.6%

LA:5.9%,

OA:5.1%

Hernia,LA:1/34

Fistula,OA:1/39

36patients

?timing

43.6%OAptsperformed

underspinalanaesthesia

Kirshteinetal.[13]

(n=90)

LA:45,

OA:34

Notreported

Tosolids,

LA:1,OA:

1

LA:5,OA:

4,pLOS

LA:2%,

OA:2%

LA:7%,

OA:6%

Abdominalwall

haematoma,LA:1/42

Pulmonaryemboli,OA:

1/48

Wounddehiscence,OA:

1/48

30days

ITTanalysisnotused?

Signific

antlymorefemalesof

reprodu

ctiveage&higher

co-morbidityinLAgroup

Pokalaetal.[29]

(n=104)

LA:101*,

OA:82

Notreported

Postoperative

ileus,LA:

14%,OA:

11%

LA:6,OA:

6

LA:2.3%,

OA:8.2%

LA:14%*,

OA:0%

Smallbowelobstruction,

LA:1/43,OA:1/61

Medical

complications,

LA:2/43,OA:4/61

Mortality,OA:1/61

30days

24/104w

erepaediatric

patients

Yauetal.[30]

(n=224)

LA:55*,

OA:70

Notreported

NotmeasuredLA:5*,

OA:6

LA:0.6%*,

OA:10%

LA:5.7%,

OA:4.3%

Notreported

2835

days

Linetal.[37]

(n=229)

LA:96*,

OA:68

impethidine,LA:

1.7,OA:1.5

LA:3.2*,

OA:5

LA:6.3

*,

OA:9

.3

LA:15%*,

OA:40%

LA:3%,

OA:4%

Intra-abdominalbleeding,

LA:1/99

Enterocutaneousfistula,

OA:3/130

1follow-

upvisit

Verysignificantselection

bias-lowsocioeconomicstatus

&high

co-morbidityptsforOA

Gulleretal.[35]

(n=8,839)

Not reported

Notreported

Notreported

LA:3.7

*,

OA:5

,

MedV

NS,p=

0.8

NS

Nopvalue

provided

NotreportedforsubgroupsNo

Stratified

analysisused

Ptcharac

teristicsunavailable

Soetal.[36]

(n=231)

LA:73,

OA:71

impethidine,LA:

2.9,OA:3.2

ponaproxen,LA:

4,OA:2.9

LA:3.9*,

OA:4.6

LA:5.2

,

OA:5

.9

LA:14%,

OA:25%

LA:0%,

OA:1.4%

Re-operation,LA:4/85,

OA:14/146

30day

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Table3

continued

Study

OT(min)P

ostoperative

a

nalgesia(days)

TTOI(days)

LOS(days)SSI

IAA

Otherpo

stoperative

complica

tions

Follow-up

Notes

Piksunetal.[32]

(n=42)

LA:115,

OA:106

N

otreported

LA:22%,

OA:38%

OA:9.2

,

OA:1

0.5

LA:0%,

OA:14%

LA:28%,

OA:29%

Notrepo

rted

No

5perforatedcasesconverteddue

tolackofsurgicalexperience

ITTanaly

sisnotusedfor10

convertedcases

Wullsteinetal.[34]

(n=299)

Not reported

N

otreported

Notreported

Not reported

LA:10.5%*,

OA:34%

LA:4.6%,

OA:6%

Trocharhernia,

LA:2/217

Haemato

ma,

LA:2/217,OA:1/82

Fistula,LA:1/217,

OA:1/82

No

Ptcharacteristicsunavailable

Highinitialconversionrate(27%

total)learningcurve

Stoltzingetal.[33]

(n=125)

LA:75,

OA:70,

Conv:

90,MedV

N

otreported

Ileus,LA:

5%,OA:

2%

Total,L

A:

10,OA:

11,Co

nv:

11,MedV

LA:11%,

OA:18%,

some

laparot-

omies

LA:6%,

OA:4%

Mortality,OA:

5/45

No

Significan

tselectionbiasas

initially

ptswithsuspectedCA

selected

forOA?

longer

symptom

durationinLA

Khalilietal.[44]

(n=276)

LA:86,

OA:70

N

otreported

Notreported

LA:6.3,

OA:6

.4

Not reported

LA:5%,

OA:5%

Notrepo

rted

No

ITTnotu

sed.Ptcharacteristics

unavaila

ble

imintramuscular,prperrectum,po

peroral,

PRNpro-re-nata(asrequired),M

edVmedianvalue

*Statisticallysignificantdifference

(p\

0.05)

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studies recommendations would strongly favor LA over

OA.

Standardization of the laparoscopic and open interven-

tions within studies can reduce internal validity errors and

improve the studies external validity [38]. All of the nine

studies that give information on the interventions report the

number and size of trochars used with small inter-study

variation (Table 2). The type of endoscope used is onlyreported by Fukami et al. [12]. Even though the rigid

endoscope is the most commonly used instrument for these

operations, failure to disclose the type used may affect the

studys external validity, as other centers may use different

types of endoscopes. Indeed, Fukami et al. [12] describe

LA in CA with a flexible endoscope at very good success

rates and reduced complication rates.

The method of ligation and resection of the meso-

appendix and the appendix is also reported (Table 2) with

some interstudy and intrastudy variation that can affect the

rates of intra-abdominal complications and comparison

within and between studies. A systematic review is beingconducted by the Cochrane group comparing all the sur-

gical techniques used to close the appendix base, and these

findings should provide some evidence of the significance

of variations in these studies.

The use of a retrieval bag for the removal of the per-

forated or gangrenous appendix from the abdominal cavity

can, theoretically, limit the spread of infection within the

abdominal cavity and at the abdominal skin wound site. All

of the studies report use of the retrieval bag. Fukami et al.

[12], however, used this technique in only 28 of their 42

LA cases. This variation could introduce a significant bias

with regard to the findings of the study, as one of the main

assessment areas between LA and OA is postoperative

complications. The authors themselves note that 4 of the 6

LA infective complications in their series occurred in

patients undergoing LA where the retrieval bag was not

used. The inclusion of these cases in the LA versus OA

comparison of a small number of infective complications

might have introduced a significant alteration to the actual

results, with a potential type I statistical error. So et al. [36]

find themselves in a similar situation.

In the studies being considered, for OA the conventional

approach is described by almost all authors, using a

McBurneys, a Gridiron, or a paramedian incision

(Table 2). There is some variation in the approach to either

primary or secondary closure of the skin wounds. A recent

systematic review and meta-analysis of such variation did

not show any difference in the postoperative rates of sur-

gical site infection (SSI) between the two closure tech-

niques [39]. Kirshtein et al. [13] and So et al. [36]

selectively use secondary closure in patients with a con-

taminated abdomen, whereas other authors report per-

forming only primary closure. Similar variability appears

to exist in the use of a drain when an intra-abdominal

abscess (IAA) is encountered.

All of the studies advocated the use of antibiotics in CA,

which involves one preoperative dose followed by regular

intravenous antibiotics until the patients condition clini-

cally improves and antibiotics are not required. In the

absence of a clear care pathway, the decision to stop

antibiotic administration becomes subjective and depen-dent to individual clinicians opinion and may introduce

bias within the studies and affect external validity. One of

the studies [37] does cite a basis for the cessation of anti-

biotic treatment, which is the resolution of pyrexia or

negative microbiology culture results. The use of a protocol

with a fixed duration of antibiotic treatment, as reported in

the study by Piksun et al. [32], could directly affect one of

the study outcomespostoperative length of hospital stay

(pLOS), eliminating any potentially significant pLOS

benefits gained from LA. In addition, a wide range of broad

spectrum antibiotics are used between studies, so it is not

possible to achieve direct absolute comparison betweenstudy findings.

Assessment of bias risk

All the studies appear to be using reasonable statistical tests

with Students t-test measurement for continuous normally

distributed variables such as operating time and 2 9 2 chi

square analysis or Fishers exact test for categorical data

[40, 41]. Significance is tested at 5%. Intention to treat

(ITT) analysis is appropriately used in all but four of the

studies [13, 3133], introducing attrition bias into these

studies [42]. The number of participants in these studies is

relatively small and unequal owing to the lack of true

randomization between the two operative groups, with the

exception of the study by Guller et al., which is based on a

stratification sample from a nationwide database [35].

None of the studies uses a power analysis, and therefore the

possibility of significant type II error is present [43].

The lack of randomization and the presence of selection,

performance, and measurement bias in all of the studies

affect their methodological validity (Table 4). Significant

problems, such as selection bias, absence of patient char-

acteristics, absence of ITT analysis, and absence of any

intervention characteristics, would only allow for classifi-

cation of findings/conclusions into level 3a to 3a evidence

with regard to practice recommendation [18].

Measured outcomes

The main outcomes measured for assessing the efficacy of

LA against OA in CA in the studies appraised, with short-

term follow-up of up to 45 weeks, are shown on Table 3.

All of the studies, although they agreeon the type of

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Fig. 3 Time to oral intake meta-analysis (all available data)

Fig. 2 Operative time meta-analysis (all available data)

Table 4 Results of studies risk of bias after critical review

Study Center Selection

bias

Performance

bias

Attrition

bias

Selective

reporting bias

Detection

bias

Statistical

bias

External

validity/bias

Overall

bias

BC D ID ITT SM PA

Katsuno et al. [31] One M M U M NM M U M NM U B

Japan

Fukami et al. [12] One M U NM M M M U M NM U B

Japan

Kirshtein et al. [13] One NM M NM M NM M U M NM M C

Israel

Pokala et al. [29] One NM U U M M M U M NM U C

US

Yau et al [30] One U U U M M M U M NM U B

Hong Kong

Lin et al. [37] One NM U M M M M U M NM M C

Taiwan

Guller et al. [35] [1,000 hospitals U U NM M U M U M NM U C

US

So et al. [36] One U U NM M M M U M NM M B

Singapore

Piksun et al. [32] One U M NM M NM M U M NM M C

Italy

Wullstein et al. [34] One U U U M M M U M NM M C

Germany

Stoltzing et al. [33] One M NM NM M NM M U M NM NM C

Germany

Khalili et al [44] One U U NM M NM M U M NM U B

US

BC baseline characteristics, D diagnosis, ID incomplete data, SMstatistical methods, PA power analysis, M met, Uunclear, NMnot met, A low

risk, B moderate risk, C high risk

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outcomes measured, fail to define these outcomes, allowing

for the widespread introduction of detection bias and

deficiencies in internal and external validity. Important

measurement outcomes such as in-hospital and out-of-

hospital costs, as well as other life quality issues, such as

time to return to normal daily activities and work and

cosmesis have not been assessed. In addition, long-term

follow-up of patients is lacking, and complications such ashernias and intestinal obstruction lack evaluation.

It is important to note the significant mortality rate of

11% in OA in the study by Stoltzing et al., something that

might be attributable to the initial selection bias of the

study, which during its initial period required that patients

with suspected CA were placed in the OA group. At the

same time, the ASA score between LA and OA patients has

not been statistically verified for absence of bias in either

group.

Operating time

The lack of an operating time (OT) definition may

potentially create internal and external validity problems

surrounding this outcome. Most studies suggest that there

is no significant statistical difference in OT between LA

and OA. Four of the studies considered here report sig-

nificantly longer OT in LA compared to OA [2931, 37],

whereas Fukami et al. [12] report a shorter OT for LA, but

with the presence of reduced external validity because only

experienced laparoscopic surgeons participated in this

study. Meta-analysis of the four studies [31, 36, 37, 44] that

report data in mean SD values indicates that OT is

longer in LA by 12.8 min (p\ 0.01, 95% CI 8.417.3), butwith a significant statistical heterogeneity of I2 = 86%

(Fig. 2). Exclusion of the study by So et al. from the

analysis significantly improves heterogeneity to 36%, but

with no significant change in the final result (mean OT

longer in LA: 21.4 min, 95% CI 15.427.3, p\ 0.01).

Conclusions remain the same when only studies with

moderate bias (group B) or all studies are included in the

analysis (level of evidence 3a).

Postoperative analgesia

Regarding postoperative analgesia, one of the importantadvantages of LA, this is measured in four of the studies

[12, 31, 36, 37], as the use of intramuscular and per-rectal

or oral analgesic use. Three of the studies [12, 31, 36]

conclude that there is significantly less use of postoperative

Fig. 5 Surgical site infection rate meta-analysis (all studies included)

Fig. 4 Length of hospital stay meta-analysis (all available data)

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analgesia by LA patients. All three of these studies state

that analgesia is given as required (PRN), whereas Linet al. [37] do not define analgesia use. The use of PRN

analgesia may have some drawbacks as it depends on

patient understanding and lack of embarrassment with

regard to its use, as well as staff being available to

administer it. A more objective scoring system for the

assessment of postoperative pain would potentially be a

more accurate way of measuring this outcome. No data

meta-analysis was therefore performed for this outcome.

Time to oral intake

Time to oral intake (TTOI) is measured in six of the studies[12, 13, 31, 32, 36, 37], and two of the studies report the

presence of ileus [29, 33] (Table 4). One variation between

studies in this outcome was the measurement by Kirshtein

et al. of time to solid oral intake [13] rather than any oral

intake. Four of the six studies reporting on TTOI individ-

ually report a significantly shorter TTOI in the LA group.

Meta-analysis of data from the three studies [31, 36, 37]

providing mean SD values (Fig. 3) shows a significant

difference between the two procedures, with mean differ-

ence of TTOI of 0.8 days (p\ 0.01, 95% CI: 0.51.15)

shorter for LA and not significant statistical heterogeneity,

both when only group B or all studies are included in theanalysis (level of evidence 3a).

Length of hospital stay

Similarly, length of stay in hospital (LOS) is only defined

as postoperative length of stay by Fukami et al. [12] and

Kirshtein et al. [13]. Giving results on total length of stay

would introducesignificant bias, as preoperative time is not

an intervention outcome. Five of the studies [12, 30, 31, 35,

37] individually report LOS as shorter in LA. Four studies

providing mean SD values were included in this out-come meta-analysis (Fig. 4), showing a significantly

shorter mean LOS for LA of 1.1 day (p\ 0.01, 95% CI

0.51.6), but with unacceptably high statistical heteroge-

neity (I2 = 92%), and no change in findings when only

group B studies are included in the analysis (level of evi-

dence 3a).

Surgical site infection and intra-abdominal abscess rates

The important outcomes of SSI and IAA are measured in

all of the identified studies. Unfortunately, the great

majority of studies do not explicitly state how the diagnosiswas reached in each of these cases. A diagnosis of SSI

would more accurately require positive organism culture

confirmation rather than just a clinical diagnosis, and IAA

diagnosis should be reached via imaging studies. None of

the studies include the odds ratio in terms of the rate of

each complication, and all of them only report significance

levels.

The great majority of studies agree that there is reduced

rate of SSI in LA and no significant difference in IAA rates

between LA and CA, whereas So et al. [36] only report a

combined reduced incidence in LA. Guller et al. are the

only authors to suggest no difference in the rate of SSIbetween the two procedures.

Meta-analysis of the SSI rates reported (Fig. 5) indicates

that this complication occurs significantly less frequently in

LA than in OA: OR 0.43 (95% CI 0.340.55) with sig-

nificant statistical heterogeneity (I2 = 73%) when all

studies are used for the analysis, and OR values of 0.23

(95% CI 0.140.37) when only group B studies are used,

with moderate statistical heterogeneity I2 = 61% (level of

evidence 3a).

Fig. 6 Intra-abdominal abscess rate meta-analysis (all studies included)

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Meta-analysis of IAA rates (Fig. 6) shows no significant

difference between the two procedures: OR 1.24 (95% CI

0.841.84), with no statistical heterogeneity when all

studies are used and OR 1.02 (95% CI 0.561.86) when

only group B studies are used, with no statistical hetero-

geneity (level of evidence 3a).

Conclusions

With this systematic review and meta-analysis of reports

from the medical literature we have tried to identify the

best and most up-to-date evidence in regards to LA and OA

in the management of adult patients with CA. Overall the

quality of the studies found was intermediate to poor, with

heterogeneity achieving only low grades of evidence rec-

ommendation. The absence of randomization and blinding

and the presence of important methodological flaws intro-

duce a number of systematic errors and significantly reduce

the studies rigor. There appears to be a genuine attempt to

justify the efficacy of LA in the majority of studies, but

their retrospective nature and lack of care pathway stan-

dardization decreases their internal and external validity,

restricting general interpretation and application of their

results.

A cautious interpretation of the findings, having con-

sidered all their deficiencies, indicates that LA may have a

lower incidence of SSI than OA (level 3a evidence). There

appears to be no difference with regard to IAA complica-

tion rates (level 3a evidence), the main LA drawback, as

previously suggested. An important parameter neglected by

these studies though is the long-term complications. Thereported findings provide the initial framework for higher

level studies on LA versus OA in CA, making it possible to

obtain better evidence on the subject and possibly gain a

significant benefit from the adoption of a new procedure as

the gold standard. Blinded randomized controlled trials

comparing LA and OA in CA would be the next step.

These are feasible as they have been performed in nCA in

the past, comparing the two procedures. Similar studies can

be conducted for CA, taking into consideration the prob-

lems with current evidence as identified through this

review.

In current clinical practice LA can be used in CAaccording to the surgeons discretion and laparoscopic

experience. It should, however, be remembered that lapa-

roscopy is a fairly new intervention requiring significant

resources and surgical expertise to reach maximum effi-

ciency. Industrialized countries appear to be meeting these

technical and surgical criteria, but developing and third-

world countries may find a high level of practice difficult to

achieve. In those instances conventional OA should be the

surgical treatment of choice.

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