1. Early Versus Delayed Laparoscopic Cholecystectomy for Acute

Early versus delayed laparoscopic cholecystectomy for acute

cholecystitis (Review)

Gurusamy KS, Samraj K

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2009, Issue 1

http://www.thecochranelibrary.com

Early versus delayed laparoscopic cholecystectomy for acute cholecystitis (Review)

Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

11DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

13AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

14ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

14REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

17CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

23DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Early versus delayed LC (number of people randomised), Outcome 1 Bile duct injury. . 25

Analysis 1.2. Comparison 1 Early versus delayed LC (number of people randomised), Outcome 2 Bile leak requiring

ERCP. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

Analysis 1.3. Comparison 1 Early versus delayed LC (number of people randomised), Outcome 3 Intra-abdominal

collections requiring percutaneous drainage. . . . . . . . . . . . . . . . . . . . . . . . 27

Analysis 1.4. Comparison 1 Early versus delayed LC (number of people randomised), Outcome 4 Superficial infection. 28

Analysis 1.5. Comparison 1 Early versus delayed LC (number of people randomised), Outcome 5 Deep infection. . 29

Analysis 1.6. Comparison 1 Early versus delayed LC (number of people randomised), Outcome 6 Conversion to open

cholecystectomy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

Analysis 2.1. Comparison 2 Early versus delayed LC (number of people operated), Outcome 1 Bile duct Injury. . . 31

Analysis 2.2. Comparison 2 Early versus delayed LC (number of people operated), Outcome 2 Bile leak requiring ERCP. 32

Analysis 2.3. Comparison 2 Early versus delayed LC (number of people operated), Outcome 3 Intra-abdominal collections

requiring percutaneous drainage. . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

Analysis 2.4. Comparison 2 Early versus delayed LC (number of people operated), Outcome 4 Superficial infection. . 34

Analysis 2.5. Comparison 2 Early versus delayed LC (number of people operated), Outcome 5 Deep infection. . . 35

Analysis 2.6. Comparison 2 Early versus delayed LC (number of people operated), Outcome 6 Conversion to open


Analysis 3.1. Comparison 3 Early versus delayed LC - risk difference, Outcome 1 Bile duct injury. . . . . . . . 37

Analysis 3.2. Comparison 3 Early versus delayed LC - risk difference, Outcome 2 Bile leak requiring ERCP. . . . 38

Analysis 3.3. Comparison 3 Early versus delayed LC - risk difference, Outcome 3 Intra-abdominal collections requiring

percutaneous drainage. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

Analysis 3.4. Comparison 3 Early versus delayed LC - risk difference, Outcome 4 Superficial infection. . . . . . 40

Analysis 3.5. Comparison 3 Early versus delayed LC - risk difference, Outcome 5 Deep infection. . . . . . . . 41

Analysis 3.6. Comparison 3 Early versus delayed LC - risk difference, Outcome 6 Conversion to open cholecystectomy. 42

Analysis 4.1. Comparison 4 Early versus delayed LC (high-quality trials), Outcome 1 Bile duct injury. . . . . . 43

Analysis 4.2. Comparison 4 Early versus delayed LC (high-quality trials), Outcome 2 Bile leak requiring ERCP. . . 43

Analysis 4.3. Comparison 4 Early versus delayed LC (high-quality trials), Outcome 3 Intra-abdominal collections requiring

percutaneous drainage. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

Analysis 4.4. Comparison 4 Early versus delayed LC (high-quality trials), Outcome 4 Superficial infection. . . . . 45

Analysis 4.5. Comparison 4 Early versus delayed LC (high-quality trials), Outcome 5 Deep infection. . . . . . . 45

Analysis 4.6. Comparison 4 Early versus delayed LC (high-quality trials), Outcome 6 Conversion to open cholecystectomy. 46

Analysis 5.1. Comparison 5 Early (< 4 days of onset of symptoms) versus delayed LC, Outcome 1 Bile duct injury. . 46

iEarly versus delayed laparoscopic cholecystectomy for acute cholecystitis (Review)


Analysis 5.2. Comparison 5 Early (< 4 days of onset of symptoms) versus delayed LC, Outcome 2 Bile leak requiring

ERCP. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47

Analysis 5.3. Comparison 5 Early (< 4 days of onset of symptoms) versus delayed LC, Outcome 3 Intra-abdominal

collections requiring percutaneous drainage. . . . . . . . . . . . . . . . . . . . . . . . 47

Analysis 5.4. Comparison 5 Early (< 4 days of onset of symptoms) versus delayed LC, Outcome 4 Superficial infection. 48

Analysis 5.5. Comparison 5 Early (< 4 days of onset of symptoms) versus delayed LC, Outcome 5 Deep infection. . 48

Analysis 5.6. Comparison 5 Early (< 4 days of onset of symptoms) versus delayed LC, Outcome 6 Conversion to open


Analysis 6.1. Comparison 6 Early (including studies with > 4 days but < 7days of onset of symptoms) versus delayed LC,

Outcome 1 Bile duct injury. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49


Outcome 2 Bile leak requiring ERCP. . . . . . . . . . . . . . . . . . . . . . . . . . 50


Outcome 3 Intra-abdominal collections requiring percutaneous drainage. . . . . . . . . . . . . . 50


Outcome 4 Superficial infection. . . . . . . . . . . . . . . . . . . . . . . . . . . . 51


Outcome 5 Deep infection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51


Outcome 6 Conversion to open cholecystectomy. . . . . . . . . . . . . . . . . . . . . . 52

Analysis 7.1. Comparison 7 Early versus delayed LC (surgical experience: 25 to 50 laparoscopic cholecystectomies),

Outcome 1 Bile duct injury. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52


Outcome 2 Bile leak requiring ERCP. . . . . . . . . . . . . . . . . . . . . . . . . . 53


Outcome 3 Intra-abdominal collections requiring percutaneous drainage. . . . . . . . . . . . . . 53


Outcome 4 Superficial Infection. . . . . . . . . . . . . . . . . . . . . . . . . . . . 54


Outcome 5 Deep infection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54


Outcome 6 Conversion to open cholecystectomy. . . . . . . . . . . . . . . . . . . . . . 55

55ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

59APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

60FEEDBACK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

62WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

62HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

62CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

63DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

63INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iiEarly versus delayed laparoscopic cholecystectomy for acute cholecystitis (Review)


[Intervention Review]

Early versus delayed laparoscopic cholecystectomy for acutecholecystitis

Kurinchi Selvan Gurusamy1, Kumarakrishnan Samraj2

1University Department of Surgery, Royal Free Hospital and University College School of Medicine, London, UK. 2Department of

General Surgery, John Radcliffe Hospital, Oxford, UK

Contact address: Kurinchi Selvan Gurusamy, University Department of Surgery, Royal Free Hospital and University College School of

Medicine, 9th Floor, Royal Free Hospital, Pond Street, London, NW3 2QG, UK. [email protected].

Editorial group: Cochrane Hepato-Biliary Group.

Publication status and date: Edited (no change to conclusions), published in Issue 1, 2009.

Review content assessed as up-to-date: 9 August 2006.

Citation: Gurusamy KS, Samraj K. Early versus delayed laparoscopic cholecystectomy for acute cholecystitis. Cochrane Database ofSystematic Reviews 2006, Issue 4. Art. No.: CD005440. DOI: 10.1002/14651858.CD005440.pub2.


A B S T R A C T

Background

Gallstones are present in about 10% to 15% of the adult western population. Between 1% and 4% become symptomatic in a year.

Cholecystectomy for symptomatic gallstones is mainly performed after the acute cholecystitis episode settles because of the fear of

higher morbidity and conversion from laparoscopic cholecystectomy to open cholecystectomy during acute cholecystitis.

Objectives

The aim was to compare the early laparoscopic cholecystectomy (less than seven days of onset of symptoms) versus delayed laparoscopic

cholecystectomy (more than six weeks after index admission) with regards to benefits and harms.

Search methods

We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL)

in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded until November 2005.

Selection criteria

We considered for inclusion all randomised clinical trials comparing early versus delayed laparoscopic cholecystectomy for acute

cholecystitis.

Data collection and analysis

We collected the data on the characteristics of the trial, methodological quality of the trials, mortality, morbidity, conversion rate,

operating time, and hospital stay from each trial. We analysed the data with both the fixed-effect and the random-effects models using

RevMan Analysis. For each outcome we calculated the odds ratio (OR) with 95% confidence intervals (CI) based on intention-to-treat

analysis.

Main results

We included five trials with 451 patients randomised: 223 to the early group and 228 to the delayed group. Surgery was performed

on 222 patients in the early group and on 216 patients in the delayed group. There was no mortality in any of the trials. Four of the

five trials were of high methodological quality. There was no statistically significant difference between the two groups for any of the

1Early versus delayed laparoscopic cholecystectomy for acute cholecystitis (Review)


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outcomes including bile duct injury (OR 0.63, 95% CI 0.15 to 2.70) and conversion to open cholecystectomy (OR 0.84, 95% CI 0.53

to 1.34). Various other analyses including ’available case analysis’, risk difference, statistical methods to overcome the ’zero-event trials’

showed no statistically significant difference between the two groups in any of the outcomes measured. A total of 40 patients (17.5%)

from the delayed group had to undergo emergency laparoscopic cholecystectomy due to non-resolving or recurrent cholecystitis; 18

(45%) of these had to undergo conversion to open procedure. The total hospital stay was about four days shorter in the early group

compared with the delayed group.

Authors’ conclusions

Early laparoscopic cholecystectomy during acute cholecystitis seems safe and shortens the total hospital stay. The majority of the

outcomes occurred rarely; hence, the confidence intervals are wide. Therefore, further randomised trials on the issue are needed.

P L A I N L A N G U A G E S U M M A R Y

Early laparoscopic cholecystectomy during acute cholecystitis is safe and shortens the total hospital stay

Cholecystectomy for symptomatic gallstones is mainly performed after an acute cholecystitis episode settles. The main reason is the

fear of higher morbidity and conversion from laparoscopic cholecystectomy to open cholecystectomy during acute cholecystitis. This

systematic review of five randomised trials shows that there is no significant difference in the complication rate or the conversion rate

in regard to the time when the laparoscopic cholecystectomy is performed during acute cholecystitis versus performed 6 to 12 weeks

after the symptoms settle. No mortality was reported in any of the trials. Early laparoscopic cholecystectomy during acute cholecystitis

appears to be safe and shortens the total hospital stay.

B A C K G R O U N D

About 10% to 15% of the adult western population have gall-

stones (Janzon 1985; Jørgensen 1987; NIH 1992; Muhrbeck

1995; Halldestam 2004). Between 1% and 4% become symp-

tomatic in a year (NIH 1992; Halldestam 2004). More than half

a million cholecystectomies are performed per year in the United

States alone (NIH 1992). Regional differences exist in the chole-

cystectomy rates (Mjäland 1998). Laparoscopic cholecystectomy,

which was introduced in 1987, is now the preferred method of

cholecystectomy (NIH 1992; Fullarton 1994; Bakken 2004).

There is a considerable controversy regarding the timing of laparo-

scopic cholecystectomy in acute cholecystitis. While early open

cholecystectomy has no increased morbidity or mortality over de-

layed open cholecystectomy (Papi 2004) and delayed cholecystec-

tomy increases the risks of further gallstone related complications

(Lawrentschuk 2003; Papi 2004), there are concerns about higher

morbidity rates in laparoscopic cholecystectomy performed as an

emergency procedure (Cuschieri 1991; Wilson 1991; Kum 1996)

and about the higher conversion rate to open procedure during

the acute phase (Cheema 2003; Livingston 2004). While one of

the main reasons for conversion in early laparoscopic cholecystec-

tomy is inflammation obscuring the view of Calot’s triangle (Peng

2005), the main reason for conversion in the delayed group is fi-

brotic adhesions (Lo 1998; Peng 2005). Severe inflammation is

also one of the important reasons for bile duct injury (Richardson

1996). There are also reports that the hospital stay is longer in

early performed cholecystectomy (Lo 1996).

Only about 30% of the laparoscopic cholecystectomies in the

United States are performed during acute cholecystitis (Livingston

2004). Only 20% of surgeons in the United Kingdom perform

laparoscopic cholecystectomy during acute cholecystitis (Senapati

2003). We have not been able to identify any Cochrane review

comparing early and delayed laparoscopic cholecystectomy in pa-

tients with acute cholecystitis. We identified three previous meta-

analyses related to the topic. Two of these (Papi 2004; Shikata

2005) included both open and laparoscopic cholecystectomy for

comparison. The first (Papi 2004) included only two trials. The

second meta-analysis included three trials. Both these meta-anal-

yses (Papi 2004; Shikata 2005) included a trial by Chandler et

al (Chandler 2000) that in fact examined two different surgical

strategies for early treatment. The most recent meta-analysis by

Lau et al (Lau 2006) also included three studies. One of these was

the study by Serralta et al (Serralta 2003) in which the allocation

was by surgeon’s experience and hence is not a randomised trial

at all. However, all three meta-analyses found no significant dif-

ference in the morbidity between early and delayed laparoscopic

cholecystectomy in patients with acute cholecystitis.



O B J E C T I V E S

To assess the benefits and harms of early laparoscopic cholecys-

tectomy compared with delayed laparoscopic cholecystectomy in

patients with acute cholecystitis. The following null hypothesis

was tested: there is no difference in outcome between early and

delayed laparoscopic cholecystectomy in acute cholecystitis.

M E T H O D S

Criteria for considering studies for this review

Types of studies

We included all randomised clinical trials, which compare early

versus delayed laparoscopic cholecystectomy in acute cholecystitis

(irrespective of language, blinding, or publication status).

Quasi-randomised trials (where the method of allocating partici-

pants to a treatment are not strictly random, for example, date of

birth, hospital record number, alternation) were not included.

Types of participants

Patients with acute cholecystitis who are about to undergo laparo-

scopic cholecystectomy.

Types of interventions

We included only trials comparing early versus delayed laparo-

scopic cholecystectomy (irrespective of the size and the number

of ports or abdominal lift or open or closed method of induc-

tion of pneumoperitoneum). Early laparoscopic cholecystectomy

is defined as laparoscopic cholecystectomy performed within seven

days of onset of symptoms. Delayed laparoscopic cholecystectomy

is defined as laparoscopic cholecystectomy, which was intended to

be performed after six weeks of index admission.

Types of outcome measures

Primary outcomes

1. Morbidity.

i) Complications (pancreatitis, recurrent episodes of

cholecystitis, obstructive jaundice).

ii) Surgery related morbidity (bile duct injury, bile leak,

reoperation rate, infection, bleeding).

2. Conversion to open cholecystectomy.

3. Mortality.

Secondary outcomes

1. Hospital stay.

2. Operating time.

Other outcome measures mentioned by individual trials were

recorded for each trial. The data of the above outcome measures

were extracted. In addition, the data on language of publication

and inclusion and exclusion criteria for each study were extracted.

Search methods for identification of studies

See: Hepato-Biliary Group strategy (Gluud 2006).

We searched The Cochrane Hepato-Biliary Group Controlled TrialsRegister, the Cochrane Central Register of Controlled Trials (CEN-TRAL) in The Cochrane Library, MEDLINE, EMBASE, and Sci-ence Citation Index Expanded. We have given the search strategies

and the time span of the searches in Appendix 1.

We did not apply any language or publication status restrictions.

Both of us, independently of each other, identified the trials for

inclusion. We resolved any differences in opinion through discus-

sion.

References of the identified trials were also searched for identifying

further trials.

Data collection and analysis

We assessed the methodological quality of the trials independently,

without masking of the trial names. We sought any unclear or

missing information by contacting the authors of the individual

trials. We resolved any differences by discussion.

Assessment of methodological quality

We followed the instructions given in the Cochrane Reviewer’s

Handbook (Higgins 2005).

Due to the risk of overestimation of intervention effects in ran-

domised trials with unclear or inadequate methodological quality

(Schulz 1995; Moher 1998; Kjaergard 2001), we looked at the

influence of methodological quality of the trials on the trial results

by evaluating the reported randomisation and follow-up proce-

dures in each trial. We assessed generation of allocation sequence,

allocation concealment, and follow-up.

Generation of the allocation sequence

• Adequate, if the allocation sequence was generated by a

computer or random number table. Drawing of lots, tossing of a

coin, shuffling of cards, or throwing dice was considered as

adequate if a person who was not otherwise involved in the

recruitment of participants performed the procedure.

• Unclear, if the trial was described as randomised, but the

method used for the allocation sequence generation was not

described.

• Inadequate, if a system involving dates, names, or

admittance numbers were used for the allocation of patients.



These studies are known as quasi-randomised and were excluded

from the review.

Allocation concealment

• Adequate, if the allocation of patients involved a central

independent unit, on-site locked computer, or sealed envelopes.

• Unclear, if the trial was described as randomised, but the

method used to conceal the allocation was not described.

• Inadequate, if the allocation sequence was known to the

investigators who assigned participants or if the study was quasi-

randomised.

Follow-up

• Adequate, if the numbers and reasons for dropouts and

withdrawals in all intervention groups were described or if it was

specified that there were no dropouts or withdrawals.

• Unclear, if the report gave the impression that there had

been no dropouts or withdrawals, but this was not specifically

stated.

• Inadequate, if the number or reasons for dropouts and

withdrawals were not described.

Blinding was not assessed since we expected that there were no

double-blind trials. However, we registered if trials used blinded

assessment of outcomes. There were no trials which used blinded

assessment of outcomes.

Statistical methods

We performed the meta-analyses according to the recommenda-

tions of The Cochrane Collaboration (Higgins 2005).

We used the software package RevMan Analyses 1.0 (RevMan

2003) provided by The Cochrane Collaboration for analysis. For

dichotomous variables, we calculated the odds ratio with 95% con-

fidence interval. We used the random-effects model (DerSimonian

1986) and the fixed-effect model (DeMets 1987).

We performed subgroup analyses depending on the methodologi-

cal quality of the trials in order to compare the intervention effect

in trials with adequate methodological quality to that of trials with

unclear or inadequate methodological quality. We also performed

sub-group analyses to determine whether trials, which included

only patients with less than four days of symptoms were different

to those, which included patients with symptoms for seven days.

We also performed subgroup analysis to determine whether the

results varied with surgical experience.

We explored the heterogeneity using the chi-squared test with sig-

nificance set at P value 0.10 and measured the quantity of hetero-

geneity using I2 (Higgins 2002).

We performed all the analyses based on the intention-to-treat prin-

ciple (Newell 1992). We also performed the available case analy-

sis (Higgins 2005) to check whether the results changed. We also

performed a sensitivity analysis with and without empirical con-

tinuity correction factors as suggested by Sweeting et al (Sweeting

2004) for ’zero-event trials’. We performed this using StatsDirect

2.4. We also calculated the risk difference between the interven-

tion groups in order to take into account the ’zero-event trials’

using RevMan 2003.

We used a funnel plot to explore publication bias and other bias

(Egger 1997; Macaskill 2001). We used asymmetry in funnel plot

of study size against treatment effect to identify bias. We also

performed linear regression approach described by Egger et al (

Egger 1997) to determine the funnel plot asymmetry. We used

StatsDirect 2.4 for this purpose.

R E S U L T S

Description of studies

See: Characteristics of included studies; Characteristics of excluded

studies.

We identified a total of 4886 references through the electronic

searches of The Cochrane Hepato-Biliary Group Controlled Tri-als Register and the Cochrane Central Register of Controlled Trials(CENTRAL) in The Cochrane Library (n = 742), MEDLINE (n =

1263), EMBASE (n = 1627), and Science Citation Index Expanded(n = 1254). We excluded 754 duplicates and 4104 clearly irrele-

vant references through reading abstracts. Twenty-eight references

were retrieved for further assessment. No references were identi-

fied through scanning reference lists of the identified randomised

trials. Of the 28 references, we excluded three because of the rea-

sons listed under the table ’Characteristics of excluded studies’ and

18 because they were clearly irrelevant. In total, seven publications

describing five randomised trials fulfilled the inclusion criteria.

All the five were completed trials and could provide data for the

analyses (Lai 1998; Lo 1998; Davila 1999; Johansson 2003; Kolla

2004). Details of the trials are shown in the table ’Characteristics

of included studies’.

Participants

A total of 451 participants with acute cholecystitis were ran-

domised in the five trials. The number of participants in each trial

ranged from 40 to 145. We were not able to extract relevant data

on the percentage of sex of the participants from one trial (Davila

1999). The percentage of females was 57.3% in the remaining

trials. The mean age was 57 years.

Experimental intervention

Early laparoscopic cholecystectomy was conducted within seven

days of onset of symptoms in all trials. The timing is described in

the ’Characteristics of included studies’ table.



Control intervention

Delayed laparoscopic cholecystectomy was conducted at least six

weeks after the onset of symptoms in all trials. The timing is

described in the ’Characteristics of included studies’ table.

Concomitant intervention

The way the common bile duct stones were dealt with in each

study is given in Table 1.

Outcome measures

The primary outcome measures reported by all the included trials

were the complications and conversion rate in each group. The

complications reported were bile duct injury, bile leak, infection,

and conversion in all the trials. Two trials (Lo 1998; Johansson

2003) reported recurrent cholecystitis, and one trial (Lo 1998)

reported cholangitis during the waiting time for delayed laparo-


The other outcome measures reported by the trials were operating

time (all the included trials), hospital stay (all the included trials),

quality of life (Johansson 2003), and pain (Lo 1998; Kolla 2004)

in each of the two groups.

Risk of bias in included studies

Four out of the five trials (80%) had adequate generation of the

allocation sequence, adequate allocation concealment, and ade-

quate follow-up and were of high methodological quality compo-

nents (Lai 1998; Lo 1998; Johansson 2003; Kolla 2004). These

same four trials performed analyses following the intention-to-

treat principle. Two trials (40%) reported on sample-size calcula-

tions (Lai 1998; Lo 1998).

Information is not available for one study (Davila 1999) regarding

the methodological quality components, intention-to-treat prin-

ciple, and sample size calculation, in spite of attempts to contact

the authors of the study.

Effects of interventions

Five trials including 451 patients were included for this review:

223 patients were randomised to the early group and 228 patients

to the delayed group. Two hundred twenty-two patients in early

group and 216 patients in delayed group underwent surgery.

Bile duct injury

There was no statistically significant difference between the two

groups for this most feared complication (OR 0.63, 95% CI 0.15

to 2.70). There was no change in the results by adopting the

random-effects model, available case analysis, calculating the risk

difference, or by using empirical correction factors for zero-event

trials described in the section ’zero-event trials’. The bile duct

injury rate was 0.5% in the early group versus 1.4% in the delayed

group (Table 2).

Bile leak requiring endoscopic retrograde

cholangiopancreatography

Bile leak requiring endoscopic retrograde cholangiopancreatogra-

phy was higher in the early group (3.2%) than the delayed group

(0%). However, this was only statistically significant using the

fixed-effect model (OR 5.78, CI 1.00 to 33.3), but not in the ran-

dom-effects model, available case analysis, calculating risk differ-

ence, or by using empirical correction factors for zero-event trials.

Intra-abdominal collections requiring drainage


groups regarding intra-abdominal collections requiring drainage

using the fixed-effect model (OR 1.86, 95% CI 0.56 to 6.18),

random-effects model, available case analysis, or by calculating the

risk difference.

Superficial infections


groups regarding superficial infections using the fixed-effect model

(OR 1.39, 95% CI 0.56 to 3.44), random-effects model, available

case analysis, or by calculating the risk difference.

Deep infections


groups regarding deep infections using the fixed-effect model (OR

0.43, 95% CI 0.09 to 1.98), random-effects model, available case

analysis, calculating the risk difference, or by using empirical cor-

rection factors for zero-event trials.

Conversion to open cholecystectomy


groups regarding conversion to open cholecystectomy (OR 0.84,

95% CI 0.53 to 1.34). There was no change in the results by

adopting the random-effects model, available case analysis, or by

calculating the risk difference. The conversion rate was 20.3% in

the early group and 23.6% in the delayed group (Table 2).

The results of the meta-analysis are summarized in Table 3.

The heterogeneity was explored by the chi-squared test and I2

(Higgins 2002). There was no heterogeneity among the trials as

denoted by the chi-squared values and I2 in Table 4.



Mortality

There was no mortality in any of the trials.

Subgroup and sensitivity analysis

A sensitivity analysis including only trials with high methodolog-

ical quality (ie, low risk of bias) did not change the results of any

outcome apart from the fixed-effect model analysis of bile duct

leaks, which now became insignificant.

A subgroup analysis of trials which included only patients with less

than four days of onset of symptoms and those which also included

patients with more than four days of onset of symptoms in the

early group was performed. There was no statistically significant

difference between the early group and delayed group in any of the

outcome measures in spite of the change in duration of symptoms

(Table 5).

A subgroup analysis of trials in which the experience of the sur-

geons was a minimum of 25 to 50 laparoscopic cholecystectomies

was performed. There was no statistically significant difference be-

tween the early group and delayed group in any of the outcome

measures in spite of the moderate prior surgical experience of the

surgeons (Table 5).

Zero-event trials

We also performed a sensitivity analysis with and without empir-

ical continuity correction factors as suggested by Sweeting et al

(Sweeting 2004) for ’zero-event trials’. There was no statistically

significant difference in any of the outcomes (Table 3).

We also determined the risk difference to take into account the

’zero-event trials’. There was no statistically significant difference

in any of the outcomes (Table 3).

Funnel plots

Funnel plots did not reveal any bias for any of the outcomes mea-

sured. However, there were too few trials to perform the Egger’s

test for exploration of bias (Figure 1; Figure 2; Figure 3; Figure 4;

Figure 5; Figure 6).

Figure 1. Funnel plot - Bile duct injury



Figure 2. Funnel plot - Bile leak requiring ERCP



Figure 3. Funnel plot - Intra-abdominal collections requiring drainage



Figure 4. Funnel Plot - Superficial Infection



Figure 5. Funnel Plot - Deep Infection



Figure 6. Funnel plot - Conversions

Other outcome measures

We also recorded other outcome measures, which were not

amenable to meta-analysis because of the heterogenous ways of

reporting and also because only the delayed group was exposed to

the risk.

Non-resolving cholecystitis or recurrent cholecystitis

17.5% of the people belonging to the delayed group had either

non-resolution of symptoms or recurrence of symptoms before

their planned operation and had to undergo emergency laparo-

scopic cholecystectomy (Table 6). The proportion with conver-

sion to open cholecystectomy is 45% in this group (Table 2).

Other gallstone-related morbidity

Two patients in the delayed group developed cholangitis during

the waiting time. There were no reports of pancreatitis during the

waiting time.

Operating time and hospital stay

In all trials but one (Johansson 2003), the operating times were

longer for early compared with the delayed group (Table 7). How-

ever, the total hospital stay was about four days shorter for the

early compared with the delayed group in all the trials (Table 7).

In the trials of high methodological quality, this was 4.5 days on

average.

D I S C U S S I O N

In this systematic review we have found that there are no signif-

icant differences in the complication rate or the conversion rate

whether the laparoscopic cholecystectomy is performed during

acute cholecystitis or performed 6 to 12 weeks after the symp-

toms settle. However, early laparoscopic cholecystectomy has the

advantage of decreased hospital stay and these patients do not run

the risk of non-solved symptoms or risk of emergency operation.

The latter leads to a high proportion of patients undergoing open

cholecystectomy.

Before the advent of laparoscopic cholecystectomy, early open

cholecystectomy was preferable over delayed open cholecystec-

tomy for acute cholecystitis (Papi 2004). However, about 20%



of surgeons in United Kingdom prefer to perform laparoscopic

cholecystectomy during the phase of acute cholecystitis (Senapati

2003). About 30% of patients in USA are operated upon during

the phase of acute cholecystitis (Livingston 2004). The main rea-

sons for performing a delayed laparoscopic cholecystectomy are

because of the fear of increased morbidity rates (Cuschieri 1991;

Wilson 1991; Kum 1996) and conversion rates (Cheema 2003;

Livingston 2004).

Bile duct injury is one of the most feared complications during la-

paroscopic cholecystectomy. Bile duct injury can sometimes even

be fatal because of sepsis (Sicklick 2005). The corrective surgery

for bile duct injury also carries mortality and morbidity (Schmidt

2005; Sicklick 2005). The quality of life of these patients after

corrective surgery can be poor even after three years of surgery

(Moore 2004). Cholecystitis has been considered as a risk factor

for bile duct injury (Nuzzo 2005; Richardson 1996). However, we

found that the bile duct injury rate was lower in the early group

(0.5%) than in the delayed group (1.4%). However, this differ-

ence is not statistically significant and the numbers are too small

to detect any pattern. Although no bile duct injury in the delayed

group occurred in the cross-over group (no information available

from one study - Davila 1999), one possible reason for this con-

tradictory evidence between the observational studies and the ran-

domised studies is that the patients with repeated episodes of acute

cholecystitis (because of following a policy of delayed laparoscopic

cholecystectomy) may be classified under ’cholecystitis’ in the ob-

servational studies, while such cases would not be included under

the early group, if a strict ’intention-to-treat’ analysis was applied.

Bile leak is a complication in about 1% of laparoscopic cholecys-

tectomies (Buanes 1996; Barkun 1997). Common bile duct in-

juries can be a cause for bile leak (Buanes 1996). However, the

majority of these are due to cystic stump leaks (Barkun 1997; De

Palma 2002; Kaffes 2005). Obstruction to the bile duct is found

in nearly one third of the patients (Barkun 1997; De Palma 2002).

The majority of the bile leaks (not due to major bile duct injury) are

managed successfully by endoscopic retrograde cholangiopancre-

atography and endoscopic sphincterotomy with or without stent

(De Palma 2002; Kaffes 2005). However, endoscopic retrograde

cholangiopancreatography is not without risks and can have com-

plications such as mortality, pancreatitis, haemorrhage, and perfo-

ration (Christensen 2004). However, recently, contrast enhanced

MRCP cholangiography is being considered for the diagnosis of

the site of the leaks (Aduna 2005). However, after diagnosis, many

of these patients would require endoscopic intervention depend-

ing upon the nature of the leak. Hence, bile leak is a significant and

important complication. In this review, we found an increase in

the risk of bile leak in early laparoscopic cholecystectomy (3.2%)

compared to delayed laparoscopic cholecystectomy (0%). How-

ever, this was not statistically significant difference in the random-

effects model, which had to be adopted because of the presence of

statistical heterogeneity. The majority of the bile leaks occurred in

the early group in one trial (Johansson 2003).

Laparoscopic cholecystectomy during acute cholecystitis has been

found to have a higher conversion rate than elective cholecystec-

tomy. However, none of the trials included showed a statistically

significant difference in the conversion rates. In fact, the over-

all conversion rate was higher in the delayed intervention group

(23.6%) as compared with the early intervention group (20.3%).

This difference is not statistically significant.

While there are reports of increased conversion rate if the surgery is

delayed for more than 48 to 96 hours after the onset of symptoms

(Eldar 1997; Madan 2002; Liguori 2003; Peng 2005), other stud-

ies do not confirm this (Knight 2004). In our review, we found

two trials, which included only patients with less than four days of

onset of symptoms. Three trials included patients with less than

seven days of onset of symptoms. A subgroup analysis showed no

significant difference in the conversion rate or complication rate

in the early group (whether less than four days of onset of symp-

toms or less than seven days of onset of symptoms) compared with

delayed laparoscopic cholecystectomy, thereby proving the safety

of laparoscopic cholecystectomy up to seven days after onset of

symptoms. This provides adequate time for investigating the pa-

tient and dealing with common bile duct stones (depending upon

the individual surgeon’s strategy), before performing operation in

the next available operating list. Again, the reason for the con-

tradictory results between observational studies and randomised

trials may be due to not adopting the ’intention-to-treat’ analysis.

One would expect the infection proportion to be higher in the

early group than the delayed group because of the presence of in-

flammation. However, we found no statistically significant differ-

ence in the superficial infection rate (5% versus 3.7%) or deep

infection rate (1% versus 2.3%) between the early and delayed

group. Neither was there any statistically significant difference in

the rate of abdominal collections requiring percutaneous drainage

between the two operations (2.7% versus 1.4%).

One of the other issues is the management of common bile duct

stones. Pre-operative endoscopic sphincterotomy is one of the op-

tions available for the management of common bile duct stones

(Lo 1998). This may cause delay in surgery. However, where ex-

pertise is available, laparoscopic exploration of the common bile

duct can be performed successfully in the majority of the patients

(Snow 1999; Thompson 2002; Rojas-Ortega 2003; Hemli 2004).

Per-operative endoscopic sphincterotomy (Cox 1995; Enochsson

2004; Saccomani 2005) and post-operative endoscopic sphinc-

terotomy (Rhodes 1998; Nathanson 2005; Saccomani 2005) are

the other options available for the management of common bile

duct stones. Of the five trials included in this review, two trials

(Lai 1998; Kolla 2004) did not include patients with common

bile duct stones; in two trials (Davila 1999; Johansson 2003) the

stones were dealt with in the same operation, and in one trial (Lo

1998) pre-operative endoscopic sphincterotomy was performed in



the presence of common bile duct stones. This is summarized in

Table 1. One patient in each group in one of the trials (Johansson

2003) was converted to open cholecystectomy with open common

bile duct exploration due to large common bile duct stone (per-

sonal communication). Two patients from the early group in the

same trial underwent post-operative ERCP for removal of com-

mon bile duct stones (personal communication). Thus manage-

ment of common bile duct stones remains an issue in early laparo-


Another main issue is the experience of the surgeon (Johansson

2003). The surgeries were performed by surgeons who had a min-

imum experience of 25 laparoscopic cholecystectomies in one of

the trials (Johansson 2003) and in another trial (Lai 1998), the

surgeries had a minimum experience of 50 laparoscopic cholecys-

tectomies. The surgical experience in the different trials is sum-

marized in Table 1. The subgroup analysis of these trials did not

reveal significant difference in the outcomes between early and

delayed cholecystectomy. The techniques had to be modified and

gallbladder decompression had to be performed more often in the

early group than in the delayed group (Lai 1998; Lo 1998; Kolla

2004).

Operating time was less in early than in delayed group in one trial

(Johansson 2003). In the rest of the trials, early cholecystectomy

took an average of 10 minutes to 30 minutes longer than delayed

cholecystectomy (Lai 1998; Lo 1998; Davila 1999; Kolla 2004).

However, this increase in operating time and hence the costs are

more than compensated for by the duration of hospital stay, which

was 1.1 to 6 days longer (on an average) in the delayed group than

in the early group (Lai 1998; Lo 1998; Davila 1999; Johansson

2003; Kolla 2004).

Another important issue is gallstone-related morbidity during the

waiting period. The most important one is the non-resolution of

the current episode of cholecystitis or recurrence of cholecystitis.

Forty patients (17.5%) in the delayed group underwent emergency

surgery during the waiting period. Laparoscopic cholecystectomy

performed in such patients carries a higher conversion rate (45%

conversion rate) than those who undergo surgery in the acute

cholecystitis or those who are symptom-free during the interval

period (Table 2). Although, there were not many gallstone-related

morbidity events in the trials included in the meta-analysis, the

surgeries in the delayed group were actually performed within 12

weeks in all the trials. However, the actual reality may be different

and patients may have to wait for much longer than 12 weeks (

Glasgow 2000; Lawrentschuk 2003) and develop complications of

gallstones including pancreatitis, cholangitis, choledocholithiasis,

and recurrent attacks of cholecystitis while waiting for surgery

(Rutledge 2000; Lawrentschuk 2003; Vetrhus 2003).

While the trials reviewed here have performed delayed surgery

between 6 weeks and 12 weeks after the acute episode, another

strategy reported is of performing surgery after a short course of

antibiotics (Chandler 2000; Dimov 2005). This may provide time

to deal with common bile duct stones, where facilities are limited.

Because of the existing practice of performing delayed laparoscopic

cholecystectomy, it is possible that many patients are treated with

antibiotics and investigated by the primary care physician before

being electively referred to the surgeon for laparoscopic cholecys-

tectomy. However, by following a policy of urgent referral of these

patients to the surgeon (and urgent investigations to confirm the

diagnosis, as opposed to elective referral and elective investiga-

tions), it is quite possible that some patients having only biliary

colic and no associated inflammation are identified. Studies have

shown that laparoscopic cholecystectomy done for biliary colic has

a lower conversion rate and morbidity rate than that performed

after an attack of cholecystitis (Glasgow 2000; Peng 2005). Thus,

such patients may indirectly benefit if surgeons follow a policy of

early laparoscopic cholecystectomy.

A U T H O R S ’ C O N C L U S I O N SImplications for practice

1. Early laparoscopic cholecystectomy during acute

cholecystitis appears to be safe and shortens the total hospital

stay. However, the confidence intervals are wide for many of the

outcomes measured and hence significant benefits (lower

conversion and bile duct injury rates) and harms (higher risk of

bile leak requiring ERCP and abdominal collections requiring

percutaneous drainage) may be overlooked.

2. Common bile duct stone is an important issue and the

management of acute cholecystitis may vary in the presence of

common bile duct stones, depending upon the preference of the

surgeon.

3. Early laparoscopic cholecystectomy should only be

performed by surgeons with adequate laparoscopic experience

and prior experience of operating during the acute cholecystitis.

Establishment of units specializing in this type of surgery may be

necessary to accomplish this.

Implications for research1. Further randomised clinical trials are needed to compare

the early versus delayed laparoscopic cholecystectomy.

2. Further randomised clinical trials are needed to compare

the laparoscopic cholecystectomy performed within four days of

onset of symptoms of acute cholecystitis and that performed

between four and seven days of onset of symptoms.

3. Further randomised clinical trials are needed to compare

the laparoscopic cholecystectomy performed immediately and

that performed after a short course of antibiotics.

4. More trials on surgical interventions for acute cholecystitis

need to adapt blinded assessments of outcome measures.



5. Trials need to be conducted and reported according to the

CONSORT Statement (www.consort-statement.org).

A C K N O W L E D G E M E N T S

Martyn Parker, first author of more than 15 Cochrane reviews,

who taught me how to write papers and who created my interest

in writing Cochrane reviews.

Dimitrinka Nikolova, Cochrane Hepato-Biliary Review Group

Co-ordinator, who provided guidance and made corrections.

Christian Gluud, Cochrane Hepato-Biliary Group, who provided

guidance.

Sarah Louise Klingenberg, Cochrane Hepato-Biliary Group, who

provided help with searching the databases.

Yan Gong, Cochrane Hepato-Biliary Group, who provided statis-

tical advice.

Abe Fingerhut, Cochrane Hepato-Biliary Group Editor, who pro-

vided advice.

Pepe Mullerat, Registrar Northampton General Hospital, who

helped with a Spanish translation.

Stoke Mandeville Hospital library, which obtained the full text

articles for many of the references cited in this review.

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Johansson 2003 {published and unpublished data}

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Salman 2005 {published data only}

Salman B, Yuksel O, Irkorucu O, Akyurek N, Tezcaner

T, Dogan I, et al.Urgent laparoscopic cholecystectomy

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C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Davila 1999

Methods Randomised clinical trial

Generation of the allocation sequence: unclear.

Allocation concealment: unclear.

Follow-up: unclear.

Intention-to-treat analysis: unclear.

Sample size calculation: no.

Participants Country: Spain

Number randomised: 63.

Mean age: 56 years.

Females: not available.

Patients with acute cholecystitis.

Interventions Participants were randomly assigned to two groups.

Group 1: early laparoscopic cholecystectomy (n = 36).

Group 2: delayed laparoscopic cholecystectomy (n = 27).

Timing:

Early LC (less than 4 days of onset of symptoms).

Delayed LC (2 months after acute episode settles).

Peroperative cholangiogram: not mentioned.

Outcomes The main outcome measures were the complications and conversion in each group

The list of outcomes measured were bile duct injury, bile leak, infection, conversion, operating time, and

hospital stay

Notes Attempted to contact the author - no reply received.

Risk of bias

Item Authors’ judgement Description

Allocation concealment? Unclear B - Unclear



Johansson 2003


Generation of the allocation sequence: adequate. Computer generated randomisation list

Allocation concealment: adequate. Done by a third party after stratification for age and sex

Follow-up: adequate.

Intention-to-treat analysis: yes.


Participants Country: Sweden


Mean age: 57 years.

Females: 87 (60%).


Exclusion criteria:

1. Symptoms more than 1 week.

2. Older than 90 years.

3. Bilirubin more than 3.5 mg/dl.




Timing:


Delayed LC (6 to 8 weeks after symptoms settle).

Peroperative cholangiogram: yes.


The list of outcomes measured were recurrent cholecystitis, bile duct injury, bile leak, superficial Infection,

deep infection, conversion, operating time, hospital stay, and quality of life

Notes Information on allocation concealment and the way in which CBD stones were dealt with were obtained

on 16/8/2005 and 7/9/2005

Risk of bias


Allocation concealment? Yes A - Adequate

Kolla 2004


Generation of the allocation sequence: adequate. Computer generated randomization list

Allocation concealment: adequate. Held by a third party.


Intention-to-treat analysis: adequate.




Kolla 2004 (Continued)

Participants Country: India


Mean age: 40 years.

Females: 32 (80%).


Exclusion criteria:

1. Symptoms more than 4 days.

2. Previous upper abdominal surgery.

3. Unfit for laparoscopic surgery.

4. CBD stones.




Timing:

Early LC (less than 24 hours of admission and less than 4 days of onset of symptoms)

Delayed LC (6 to 12 weeks after index admission).

Peroperative cholangiogram: no.


The list of outcomes measured were bile duct injury, bile leak, infection, conversion, operating time,

hospital stay, and pain

Notes Further information on follow-up was obtained on 27/9/2005.

Risk of bias



Lai 1998


Generation of the allocation sequence: adequate. Computer generated

Allocation concealment: adequate. Kept by a third party.

Follow-up: clear.


Sample size calculation: yes.

Participants Country: Hong Kong


Mean age: 56 years.

Females: 66 (63.5%).


Exclusion criteria:





Lai 1998 (Continued)

3. Unfit for laparoscopic surgery.

4. CBD stones.

5. Acute cholangitis (co-existing).

6. Acute pancreatitis (co-existing).




Timing:


Delayed LC (6 to 8 weeks after initial attack settles).



The list of outcomes measured were bile duct injury, bile leak, infection, conversion, operating time, and

hospital stay

Notes

Risk of bias



Lo 1998


Generation of the allocation sequence: adequate. Random number table

Allocation concealment: adequate. Sealed opaque envelopes.



Sample size calculation: yes.

Participants Country: Hong Kong


Mean age: 58 years.

Females: 39 (38.4%).


Exclusion criteria:


2. More than 3 days of admission.


4. Unfit for surgery.

5. Uncertainty about diagnosis.

6. Peritonitis.

7. Pregnancy.



Lo 1998 (Continued)




Timing:

Early LC (less than 3 days of admission and less than 7 days of onset of symptoms)

Delayed LC (8 to 12 weeks after initial attack settles).



The list of outcomes measured were recurrent cholecystitis, cholangitis, bile duct injury, bile leak, infection,

conversion, operating time, hospital stay, and pain

Notes Further information on generation of random sequence was obtained on 20/8/2005, 29/11/2005, and 4/

12/2005

Risk of bias



LC = laparoscopic cholecystectomy

CBD = common bile duct

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Chandler 2000 Early treatment patients underwent surgery as soon as operating schedule allowed. Delayed treatment patients

underwent operation after resolution of symptoms or within five days if symptoms failed to resolve. According to

the definitions used by us, both these groups fall in the early group

Dimov 2005 Early treatment patients underwent surgery up to 72 hours of onset of symptoms. Delayed treatment patients

underwent operation after five to seven days of medical treatment. Some of these patients may belong to the early

group according to the definitions used by us

Salman 2005 Compares early or delayed laparoscopic cholecystectomy in biliary colic



D A T A A N D A N A L Y S E S

Comparison 1. Early versus delayed LC (number of people randomised)

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Bile duct injury 5 451 Odds Ratio (M-H, Fixed, 95% CI) 0.63 [0.15, 2.70]

2 Bile leak requiring ERCP 5 451 Odds Ratio (M-H, Fixed, 95% CI) 5.78 [1.00, 33.29]

3 Intra-abdominal collections

requiring percutaneous

drainage

5 451 Odds Ratio (M-H, Fixed, 95% CI) 1.86 [0.56, 6.18]

4 Superficial infection 5 451 Odds Ratio (M-H, Fixed, 95% CI) 1.39 [0.56, 3.44]

5 Deep infection 5 451 Odds Ratio (M-H, Fixed, 95% CI) 0.43 [0.09, 1.98]

6 Conversion to open

cholecystectomy


Comparison 2. Early versus delayed LC (number of people operated)


studies

No. of


1 Bile duct Injury 5 438 Odds Ratio (M-H, Fixed, 95% CI) 0.61 [0.14, 2.62]




drainage





cholecystectomy


Comparison 3. Early versus delayed LC - risk difference


studies

No. of


1 Bile duct injury 5 451 Risk Difference (M-H, Fixed, 95% CI) -0.01 [-0.03, 0.02]

2 Bile leak requiring ERCP 5 451 Risk Difference (M-H, Fixed, 95% CI) 0.03 [0.00, 0.06]



drainage

5 451 Risk Difference (M-H, Fixed, 95% CI) 0.02 [-0.01, 0.05]

4 Superficial infection 5 451 Risk Difference (M-H, Fixed, 95% CI) 0.01 [-0.02, 0.05]

5 Deep infection 5 451 Risk Difference (M-H, Fixed, 95% CI) -0.01 [-0.04, 0.01]




cholecystectomy

5 451 Risk Difference (M-H, Fixed, 95% CI) -0.03 [-0.10, 0.05]

Comparison 4. Early versus delayed LC (high-quality trials)


studies

No. of






drainage





cholecystectomy


Comparison 5. Early (< 4 days of onset of symptoms) versus delayed LC


studies

No. of






drainage



5 Deep infection 2 103 Odds Ratio (M-H, Fixed, 95% CI) Not estimable


cholecystectomy


Comparison 6. Early (including studies with > 4 days but < 7days of onset of symptoms) versus delayed LC


studies

No. of






drainage







cholecystectomy


Comparison 7. Early versus delayed LC (surgical experience: 25 to 50 laparoscopic cholecystectomies)


studies

No. of






drainage


4 Superficial Infection 2 249 Odds Ratio (M-H, Fixed, 95% CI) 1.47 [0.40, 5.35]



cholecystectomy


Analysis 1.1. Comparison 1 Early versus delayed LC (number of people randomised), Outcome 1 Bile duct

injury.

Review: Early versus delayed laparoscopic cholecystectomy for acute cholecystitis

Comparison: 1 Early versus delayed LC (number of people randomised)

Outcome: 1 Bile duct injury

Study or subgroup Early LC Delayed LC Odds Ratio Odds Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Davila 1999 0/27 1/36 0.43 [ 0.02, 10.98 ]

Johansson 2003 0/74 1/71 0.32 [ 0.01, 7.87 ]

Kolla 2004 1/20 0/20 3.15 [ 0.12, 82.16 ]

Lai 1998 0/53 0/51 0.0 [ 0.0, 0.0 ]

Lo 1998 0/49 1/50 0.33 [ 0.01, 8.38 ]

Total (95% CI) 223 228 0.63 [ 0.15, 2.70 ]

Total events: 1 (Early LC), 3 (Delayed LC)

Heterogeneity: Chi2 = 1.32, df = 3 (P = 0.72); I2 =0.0%

Test for overall effect: Z = 0.62 (P = 0.53)

0.01 0.1 1 10 100

Favours early LC Favours delayed LC



Analysis 1.2. Comparison 1 Early versus delayed LC (number of people randomised), Outcome 2 Bile leak

requiring ERCP.



Outcome: 2 Bile leak requiring ERCP



Davila 1999 0/27 0/36 0.0 [ 0.0, 0.0 ]

Johansson 2003 5/74 0/71 11.32 [ 0.61, 208.53 ]

Kolla 2004 1/20 0/20 3.15 [ 0.12, 82.16 ]

Lai 1998 1/53 0/51 2.94 [ 0.12, 73.92 ]

Lo 1998 0/49 0/50 0.0 [ 0.0, 0.0 ]

Total (95% CI) 223 228 5.78 [ 1.00, 33.29 ]




0.001 0.01 0.1 1 10 100 1000




Analysis 1.3. Comparison 1 Early versus delayed LC (number of people randomised), Outcome 3 Intra-

abdominal collections requiring percutaneous drainage.



Outcome: 3 Intra-abdominal collections requiring percutaneous drainage



Davila 1999 2/27 2/36 1.36 [ 0.18, 10.32 ]

Johansson 2003 2/74 0/71 4.93 [ 0.23, 104.53 ]

Kolla 2004 0/20 0/20 0.0 [ 0.0, 0.0 ]

Lai 1998 2/53 0/51 5.00 [ 0.23, 106.73 ]

Lo 1998 0/49 1/50 0.33 [ 0.01, 8.38 ]

Total (95% CI) 223 228 1.86 [ 0.56, 6.18 ]




0.001 0.01 0.1 1 10 100 1000




Analysis 1.4. Comparison 1 Early versus delayed LC (number of people randomised), Outcome 4

Superficial infection.



Outcome: 4 Superficial infection

Study or subgroup Early LC Delayed LC Odds Ratio Weight Odds Ratio


Davila 1999 1/27 0/36 5.1 % 4.13 [ 0.16, 105.45 ]

Johansson 2003 5/74 3/71 35.6 % 1.64 [ 0.38, 7.14 ]

Kolla 2004 1/20 2/20 23.7 % 0.47 [ 0.04, 5.69 ]

Lai 1998 1/53 1/51 12.5 % 0.96 [ 0.06, 15.79 ]

Lo 1998 3/49 2/50 23.2 % 1.57 [ 0.25, 9.80 ]

Total (95% CI) 223 228 100.0 % 1.39 [ 0.56, 3.44 ]




0.001 0.01 0.1 1 10 100 1000




Analysis 1.5. Comparison 1 Early versus delayed LC (number of people randomised), Outcome 5 Deep

infection.



Outcome: 5 Deep infection



Davila 1999 0/27 0/36 0.0 [ 0.0, 0.0 ]

Johansson 2003 2/74 3/71 0.63 [ 0.10, 3.88 ]

Kolla 2004 0/20 0/20 0.0 [ 0.0, 0.0 ]

Lai 1998 0/53 0/51 0.0 [ 0.0, 0.0 ]

Lo 1998 0/49 2/50 0.20 [ 0.01, 4.19 ]

Total (95% CI) 223 228 0.43 [ 0.09, 1.98 ]




0.001 0.01 0.1 1 10 100 1000




Analysis 1.6. Comparison 1 Early versus delayed LC (number of people randomised), Outcome 6

Conversion to open cholecystectomy.



Outcome: 6 Conversion to open cholecystectomy



Davila 1999 1/27 6/36 12.5 % 0.19 [ 0.02, 1.70 ]

Johansson 2003 23/74 20/71 35.5 % 1.15 [ 0.56, 2.35 ]

Kolla 2004 5/20 5/20 9.5 % 1.00 [ 0.24, 4.18 ]

Lai 1998 11/53 11/51 22.4 % 0.95 [ 0.37, 2.44 ]

Lo 1998 5/49 9/50 20.2 % 0.52 [ 0.16, 1.67 ]

Total (95% CI) 223 228 100.0 % 0.84 [ 0.53, 1.34 ]




0.01 0.1 1 10 100




Analysis 2.1. Comparison 2 Early versus delayed LC (number of people operated), Outcome 1 Bile duct

Injury.


Comparison: 2 Early versus delayed LC (number of people operated)

Outcome: 1 Bile duct Injury



Davila 1999 0/27 1/36 0.43 [ 0.02, 10.98 ]

Johansson 2003 0/74 1/69 0.31 [ 0.01, 7.65 ]

Kolla 2004 1/20 0/20 3.15 [ 0.12, 82.16 ]

Lai 1998 0/53 0/46 0.0 [ 0.0, 0.0 ]

Lo 1998 0/48 1/45 0.31 [ 0.01, 7.70 ]

Total (95% CI) 222 216 0.61 [ 0.14, 2.62 ]




0.01 0.1 1 10 100




Analysis 2.2. Comparison 2 Early versus delayed LC (number of people operated), Outcome 2 Bile leak

requiring ERCP.






Davila 1999 0/27 0/36 0.0 [ 0.0, 0.0 ]

Johansson 2003 5/74 0/69 11.00 [ 0.60, 202.75 ]

Kolla 2004 1/20 0/20 3.15 [ 0.12, 82.16 ]

Lai 1998 1/53 0/46 2.66 [ 0.11, 66.83 ]

Lo 1998 0/48 0/45 0.0 [ 0.0, 0.0 ]

Total (95% CI) 222 216 5.55 [ 0.96, 31.94 ]




0.001 0.01 0.1 1 10 100 1000




Analysis 2.3. Comparison 2 Early versus delayed LC (number of people operated), Outcome 3 Intra-







Davila 1999 2/27 2/36 34.6 % 1.36 [ 0.18, 10.32 ]

Johansson 2003 2/74 0/69 10.9 % 4.79 [ 0.23, 101.63 ]

Kolla 2004 1/20 0/20 10.1 % 3.15 [ 0.12, 82.16 ]

Lai 1998 2/53 0/46 11.1 % 4.51 [ 0.21, 96.49 ]

Lo 1998 0/48 1/45 33.3 % 0.31 [ 0.01, 7.70 ]

Total (95% CI) 222 216 100.0 % 1.91 [ 0.62, 5.88 ]




0.001 0.01 0.1 1 10 100 1000

Favours Early LC Favours Delayed LC



Analysis 2.4. Comparison 2 Early versus delayed LC (number of people operated), Outcome 4 Superficial

infection.






Davila 1999 1/27 0/36 5.0 % 4.13 [ 0.16, 105.45 ]

Johansson 2003 5/74 3/69 35.4 % 1.59 [ 0.37, 6.94 ]

Kolla 2004 1/20 2/20 23.2 % 0.47 [ 0.04, 5.69 ]

Lai 1998 1/53 1/46 12.8 % 0.87 [ 0.05, 14.24 ]

Lo 1998 3/48 2/45 23.6 % 1.43 [ 0.23, 9.00 ]

Total (95% CI) 222 216 100.0 % 1.33 [ 0.54, 3.29 ]




0.001 0.01 0.1 1 10 100 1000




Analysis 2.5. Comparison 2 Early versus delayed LC (number of people operated), Outcome 5 Deep

infection.






Davila 1999 0/27 0/36 0.0 [ 0.0, 0.0 ]

Johansson 2003 2/74 3/69 0.61 [ 0.10, 3.77 ]

Kolla 2004 0/20 0/20 0.0 [ 0.0, 0.0 ]

Lai 1998 0/53 0/46 0.0 [ 0.0, 0.0 ]

Lo 1998 0/48 2/45 0.18 [ 0.01, 3.84 ]

Total (95% CI) 222 216 0.41 [ 0.09, 1.88 ]




0.01 0.1 1 10 100




Analysis 2.6. Comparison 2 Early versus delayed LC (number of people operated), Outcome 6 Conversion

to open cholecystectomy.






Davila 1999 1/27 6/36 12.2 % 0.19 [ 0.02, 1.70 ]

Johansson 2003 23/74 20/69 35.1 % 1.10 [ 0.54, 2.26 ]

Kolla 2004 5/20 5/20 9.2 % 1.00 [ 0.24, 4.18 ]

Lai 1998 11/53 11/46 23.0 % 0.83 [ 0.32, 2.15 ]

Lo 1998 5/48 9/45 20.5 % 0.47 [ 0.14, 1.51 ]

Total (95% CI) 222 216 100.0 % 0.79 [ 0.50, 1.25 ]




0.01 0.1 1 10 100




Analysis 3.1. Comparison 3 Early versus delayed LC - risk difference, Outcome 1 Bile duct injury.


Comparison: 3 Early versus delayed LC - risk difference


Study or subgroup Early LC Delayed LCRisk

Difference WeightRisk

Difference


Davila 1999 0/27 1/36 13.7 % -0.03 [ -0.11, 0.05 ]

Johansson 2003 0/74 1/71 32.2 % -0.01 [ -0.05, 0.02 ]

Kolla 2004 1/20 0/20 8.9 % 0.05 [ -0.08, 0.18 ]

Lai 1998 0/53 0/51 23.1 % 0.0 [ -0.04, 0.04 ]

Lo 1998 0/49 1/50 22.0 % -0.02 [ -0.07, 0.03 ]

Total (95% CI) 223 228 100.0 % -0.01 [ -0.03, 0.02 ]




-1 -0.5 0 0.5 1




Analysis 3.2. Comparison 3 Early versus delayed LC - risk difference, Outcome 2 Bile leak requiring ERCP.






Difference


Davila 1999 0/27 0/36 13.7 % 0.0 [ -0.06, 0.06 ]

Johansson 2003 5/74 0/71 32.2 % 0.07 [ 0.01, 0.13 ]

Kolla 2004 1/20 0/20 8.9 % 0.05 [ -0.08, 0.18 ]

Lai 1998 1/53 0/51 23.1 % 0.02 [ -0.03, 0.07 ]

Lo 1998 0/49 0/50 22.0 % 0.0 [ -0.04, 0.04 ]

Total (95% CI) 223 228 100.0 % 0.03 [ 0.00, 0.06 ]


Heterogeneity: Chi2 = 5.01, df = 4 (P = 0.29); I2 =20%


-0.5 -0.25 0 0.25 0.5




Analysis 3.3. Comparison 3 Early versus delayed LC - risk difference, Outcome 3 Intra-abdominal

collections requiring percutaneous drainage.






Difference


Davila 1999 2/27 2/36 13.7 % 0.02 [ -0.11, 0.14 ]

Johansson 2003 2/74 0/71 32.2 % 0.03 [ -0.02, 0.07 ]

Kolla 2004 1/20 0/20 8.9 % 0.05 [ -0.08, 0.18 ]

Lai 1998 2/53 0/51 23.1 % 0.04 [ -0.02, 0.10 ]

Lo 1998 0/49 1/50 22.0 % -0.02 [ -0.07, 0.03 ]

Total (95% CI) 223 228 100.0 % 0.02 [ -0.01, 0.05 ]




-0.5 -0.25 0 0.25 0.5




Analysis 3.4. Comparison 3 Early versus delayed LC - risk difference, Outcome 4 Superficial infection.






Difference


Davila 1999 1/27 0/36 13.7 % 0.04 [ -0.05, 0.13 ]

Johansson 2003 5/74 3/71 32.2 % 0.03 [ -0.05, 0.10 ]

Kolla 2004 1/20 2/20 8.9 % -0.05 [ -0.21, 0.11 ]

Lai 1998 1/53 1/51 23.1 % 0.00 [ -0.05, 0.05 ]

Lo 1998 3/49 2/50 22.0 % 0.02 [ -0.07, 0.11 ]

Total (95% CI) 223 228 100.0 % 0.01 [ -0.02, 0.05 ]




-0.5 -0.25 0 0.25 0.5




Analysis 3.5. Comparison 3 Early versus delayed LC - risk difference, Outcome 5 Deep infection.






Difference


Davila 1999 0/27 0/36 13.7 % 0.0 [ -0.06, 0.06 ]

Johansson 2003 2/74 3/71 32.2 % -0.02 [ -0.07, 0.04 ]

Kolla 2004 0/20 0/20 8.9 % 0.0 [ -0.09, 0.09 ]

Lai 1998 0/53 0/51 23.1 % 0.0 [ -0.04, 0.04 ]

Lo 1998 0/49 2/50 22.0 % -0.04 [ -0.11, 0.03 ]

Total (95% CI) 223 228 100.0 % -0.01 [ -0.04, 0.01 ]




-0.5 -0.25 0 0.25 0.5




Analysis 3.6. Comparison 3 Early versus delayed LC - risk difference, Outcome 6 Conversion to open

cholecystectomy.






Difference


Davila 1999 1/27 6/36 13.7 % -0.13 [ -0.27, 0.01 ]

Johansson 2003 23/74 20/71 32.2 % 0.03 [ -0.12, 0.18 ]

Kolla 2004 5/20 5/20 8.9 % 0.0 [ -0.27, 0.27 ]

Lai 1998 11/53 11/51 23.1 % -0.01 [ -0.17, 0.15 ]

Lo 1998 5/49 9/50 22.0 % -0.08 [ -0.21, 0.06 ]

Total (95% CI) 223 228 100.0 % -0.03 [ -0.10, 0.05 ]




-0.5 -0.25 0 0.25 0.5




Analysis 4.1. Comparison 4 Early versus delayed LC (high-quality trials), Outcome 1 Bile duct injury.


Comparison: 4 Early versus delayed LC (high-quality trials)




Johansson 2003 0/74 1/71 0.32 [ 0.01, 7.87 ]

Kolla 2004 1/20 0/20 3.15 [ 0.12, 82.16 ]

Lai 1998 0/53 0/51 0.0 [ 0.0, 0.0 ]

Lo 1998 0/49 1/50 0.33 [ 0.01, 8.38 ]

Total (95% CI) 196 192 0.70 [ 0.14, 3.63 ]




0.01 0.1 1 10 100


Analysis 4.2. Comparison 4 Early versus delayed LC (high-quality trials), Outcome 2 Bile leak requiring

ERCP.






Johansson 2003 5/74 0/71 11.32 [ 0.61, 208.53 ]

Kolla 2004 1/20 0/20 3.15 [ 0.12, 82.16 ]

Lai 1998 1/53 0/51 2.94 [ 0.12, 73.92 ]

Lo 1998 0/49 0/50 0.0 [ 0.0, 0.0 ]

Total (95% CI) 196 192 5.78 [ 1.00, 33.29 ]




0.001 0.01 0.1 1 10 100 1000




Analysis 4.3. Comparison 4 Early versus delayed LC (high-quality trials), Outcome 3 Intra-abdominal

collections requiring percutaneous drainage.






Johansson 2003 2/74 0/71 16.9 % 4.93 [ 0.23, 104.53 ]

Kolla 2004 1/20 0/20 15.9 % 3.15 [ 0.12, 82.16 ]

Lai 1998 2/53 0/51 16.7 % 5.00 [ 0.23, 106.73 ]

Lo 1998 0/49 1/50 50.5 % 0.33 [ 0.01, 8.38 ]

Total (95% CI) 196 192 100.0 % 2.34 [ 0.60, 9.19 ]




0.001 0.01 0.1 1 10 100 1000




Analysis 4.4. Comparison 4 Early versus delayed LC (high-quality trials), Outcome 4 Superficial infection.






Johansson 2003 5/74 3/71 37.5 % 1.64 [ 0.38, 7.14 ]

Kolla 2004 1/20 2/20 25.0 % 0.47 [ 0.04, 5.69 ]

Lai 1998 1/53 1/51 13.1 % 0.96 [ 0.06, 15.79 ]

Lo 1998 3/49 2/50 24.4 % 1.57 [ 0.25, 9.80 ]

Total (95% CI) 196 192 100.0 % 1.24 [ 0.48, 3.23 ]




0.01 0.1 1 10 100


Analysis 4.5. Comparison 4 Early versus delayed LC (high-quality trials), Outcome 5 Deep infection.






Johansson 2003 2/74 3/71 0.63 [ 0.10, 3.88 ]

Kolla 2004 0/20 0/20 0.0 [ 0.0, 0.0 ]

Lai 1998 0/53 0/51 0.0 [ 0.0, 0.0 ]

Lo 1998 0/49 2/50 0.20 [ 0.01, 4.19 ]

Total (95% CI) 196 192 0.43 [ 0.09, 1.98 ]




0.01 0.1 1 10 100




Analysis 4.6. Comparison 4 Early versus delayed LC (high-quality trials), Outcome 6 Conversion to open

cholecystectomy.






Johansson 2003 23/74 20/71 40.5 % 1.15 [ 0.56, 2.35 ]

Kolla 2004 5/20 5/20 10.8 % 1.00 [ 0.24, 4.18 ]

Lai 1998 11/53 11/51 25.6 % 0.95 [ 0.37, 2.44 ]

Lo 1998 5/49 9/50 23.1 % 0.52 [ 0.16, 1.67 ]

Total (95% CI) 196 192 100.0 % 0.94 [ 0.58, 1.51 ]




0.1 0.2 0.5 1 2 5 10


Analysis 5.1. Comparison 5 Early (< 4 days of onset of symptoms) versus delayed LC, Outcome 1 Bile duct

injury.


Comparison: 5 Early (< 4 days of onset of symptoms) versus delayed LC




Davila 1999 0/27 1/36 73.2 % 0.43 [ 0.02, 10.98 ]

Kolla 2004 1/20 0/20 26.8 % 3.15 [ 0.12, 82.16 ]

Total (95% CI) 47 56 100.0 % 1.16 [ 0.15, 8.79 ]




0.01 0.1 1 10 100




Analysis 5.2. Comparison 5 Early (< 4 days of onset of symptoms) versus delayed LC, Outcome 2 Bile leak

requiring ERCP.






Davila 1999 0/27 0/36 0.0 [ 0.0, 0.0 ]

Kolla 2004 1/20 0/20 3.15 [ 0.12, 82.16 ]

Total (95% CI) 47 56 3.15 [ 0.12, 82.16 ]




0.01 0.1 1 10 100


Analysis 5.3. Comparison 5 Early (< 4 days of onset of symptoms) versus delayed LC, Outcome 3 Intra-







Davila 1999 2/27 2/36 77.4 % 1.36 [ 0.18, 10.32 ]

Kolla 2004 1/20 0/20 22.6 % 3.15 [ 0.12, 82.16 ]

Total (95% CI) 47 56 100.0 % 1.77 [ 0.33, 9.53 ]




0.01 0.1 1 10 100




Analysis 5.4. Comparison 5 Early (< 4 days of onset of symptoms) versus delayed LC, Outcome 4 Superficial

infection.






Davila 1999 1/27 0/36 17.7 % 4.13 [ 0.16, 105.45 ]

Kolla 2004 1/20 2/20 82.3 % 0.47 [ 0.04, 5.69 ]

Total (95% CI) 47 56 100.0 % 1.12 [ 0.19, 6.60 ]




0.001 0.01 0.1 1 10 100 1000


Analysis 5.5. Comparison 5 Early (< 4 days of onset of symptoms) versus delayed LC, Outcome 5 Deep

infection.






Davila 1999 0/27 0/36 0.0 [ 0.0, 0.0 ]

Kolla 2004 0/20 0/20 0.0 [ 0.0, 0.0 ]

Total (95% CI) 47 56 0.0 [ 0.0, 0.0 ]


Heterogeneity: Chi2 = 0.0, df = 0 (P<0.00001); I2 =0.0%

Test for overall effect: Z = 0.0 (P < 0.00001)

0.1 0.2 0.5 1 2 5 10




Analysis 5.6. Comparison 5 Early (< 4 days of onset of symptoms) versus delayed LC, Outcome 6

Conversion to open cholecystectomy.






Davila 1999 1/27 6/36 56.9 % 0.19 [ 0.02, 1.70 ]

Kolla 2004 5/20 5/20 43.1 % 1.00 [ 0.24, 4.18 ]

Total (95% CI) 47 56 100.0 % 0.54 [ 0.18, 1.66 ]




0.01 0.1 1 10 100


Analysis 6.1. Comparison 6 Early (including studies with > 4 days but < 7days of onset of symptoms) versus

delayed LC, Outcome 1 Bile duct injury.


Comparison: 6 Early (including studies with > 4 days but < 7days of onset of symptoms) versus delayed LC




Johansson 2003 0/74 1/71 0.32 [ 0.01, 7.87 ]

Lai 1998 0/53 0/51 0.0 [ 0.0, 0.0 ]

Lo 1998 0/49 1/50 0.33 [ 0.01, 8.38 ]

Total (95% CI) 176 172 0.32 [ 0.03, 3.16 ]




0.01 0.1 1 10 100





delayed LC, Outcome 2 Bile leak requiring ERCP.






Johansson 2003 5/74 0/71 11.32 [ 0.61, 208.53 ]

Lai 1998 1/53 0/51 2.94 [ 0.12, 73.92 ]

Lo 1998 0/49 0/50 0.0 [ 0.0, 0.0 ]

Total (95% CI) 176 172 7.03 [ 0.86, 57.69 ]




0.001 0.01 0.1 1 10 100 1000



delayed LC, Outcome 3 Intra-abdominal collections requiring percutaneous drainage.






Johansson 2003 2/74 0/71 20.1 % 4.93 [ 0.23, 104.53 ]

Lai 1998 2/53 0/51 19.8 % 5.00 [ 0.23, 106.73 ]

Lo 1998 0/49 1/50 60.0 % 0.33 [ 0.01, 8.38 ]

Total (95% CI) 176 172 100.0 % 2.18 [ 0.48, 9.90 ]




0.001 0.01 0.1 1 10 100 1000





delayed LC, Outcome 4 Superficial infection.






Johansson 2003 5/74 3/71 50.0 % 1.64 [ 0.38, 7.14 ]

Lai 1998 1/53 1/51 17.5 % 0.96 [ 0.06, 15.79 ]

Lo 1998 3/49 2/50 32.5 % 1.57 [ 0.25, 9.80 ]

Total (95% CI) 176 172 100.0 % 1.50 [ 0.52, 4.31 ]




0.01 0.1 1 10 100



delayed LC, Outcome 5 Deep infection.






Johansson 2003 2/74 0/71 4.93 [ 0.23, 104.53 ]

Lai 1998 0/53 0/51 0.0 [ 0.0, 0.0 ]

Lo 1998 0/49 2/50 0.20 [ 0.01, 4.19 ]

Total (95% CI) 176 172 0.99 [ 0.20, 5.00 ]




0.001 0.01 0.1 1 10 100 1000





delayed LC, Outcome 6 Conversion to open cholecystectomy.






Johansson 2003 23/74 20/71 45.5 % 1.15 [ 0.56, 2.35 ]

Lai 1998 11/53 11/51 28.7 % 0.95 [ 0.37, 2.44 ]

Lo 1998 5/49 9/50 25.8 % 0.52 [ 0.16, 1.67 ]

Total (95% CI) 176 172 100.0 % 0.93 [ 0.56, 1.54 ]




0.1 0.2 0.5 1 2 5 10


Analysis 7.1. Comparison 7 Early versus delayed LC (surgical experience: 25 to 50 laparoscopic

cholecystectomies), Outcome 1 Bile duct injury.


Comparison: 7 Early versus delayed LC (surgical experience: 25 to 50 laparoscopic cholecystectomies)




Johansson 2003 0/74 1/71 0.32 [ 0.01, 7.87 ]

Lai 1998 0/53 0/51 0.0 [ 0.0, 0.0 ]

Total (95% CI) 127 122 0.32 [ 0.01, 7.87 ]




0.01 0.1 1 10 100





cholecystectomies), Outcome 2 Bile leak requiring ERCP.






Johansson 2003 5/74 0/71 48.8 % 11.32 [ 0.61, 208.53 ]

Lai 1998 1/53 0/51 51.2 % 2.94 [ 0.12, 73.92 ]

Total (95% CI) 127 122 100.0 % 7.03 [ 0.86, 57.69 ]




0.001 0.01 0.1 1 10 100 1000



cholecystectomies), Outcome 3 Intra-abdominal collections requiring percutaneous drainage.






Johansson 2003 2/74 0/71 50.4 % 4.93 [ 0.23, 104.53 ]

Lai 1998 2/53 0/51 49.6 % 5.00 [ 0.23, 106.73 ]

Total (95% CI) 127 122 100.0 % 4.97 [ 0.57, 43.14 ]




0.001 0.01 0.1 1 10 100 1000





cholecystectomies), Outcome 4 Superficial Infection.



Outcome: 4 Superficial Infection



Johansson 2003 5/74 3/71 74.1 % 1.64 [ 0.38, 7.14 ]

Lai 1998 1/53 1/51 25.9 % 0.96 [ 0.06, 15.79 ]

Total (95% CI) 127 122 100.0 % 1.47 [ 0.40, 5.35 ]




0.01 0.1 1 10 100



cholecystectomies), Outcome 5 Deep infection.






Johansson 2003 2/74 3/71 0.63 [ 0.10, 3.88 ]

Lai 1998 0/53 0/51 0.0 [ 0.0, 0.0 ]

Total (95% CI) 127 122 0.63 [ 0.10, 3.88 ]




0.1 0.2 0.5 1 2 5 10





cholecystectomies), Outcome 6 Conversion to open cholecystectomy.






Johansson 2003 23/74 20/71 61.3 % 1.15 [ 0.56, 2.35 ]

Lai 1998 11/53 11/51 38.7 % 0.95 [ 0.37, 2.44 ]

Total (95% CI) 127 122 100.0 % 1.07 [ 0.61, 1.90 ]




0.2 0.5 1 2 5


A D D I T I O N A L T A B L E S

Table 1. Common bile duct stones

Study Surgeon’s expe-

rience

Early group Delayed group Treatment Per-operative

cholangiogram

Notes

Davila 1999 Not given. 0 2 ’Resolved at the

same operation’ -

No further details

given.

Not mentioned.

Johansson 2003 Minimum 25 la-

paro-

scopic cholecys-

tectomies.

5 3 Laparoscopic

common bile duct

exploration.

Post-op ERCP.

Yes. One patient in

each group had

to be converted

to open common

bile duct explo-

ration because of

large common bile

duct stones

Kolla 2004 Surgical consul-

tant.

0 0 Not applicable. No. Co-existing

common bile duct

stones were exclu-

sion criteria.



Table 1. Common bile duct stones (Continued)

Lai 1998 Minimum 50 la-

paro-

scopic cholecys-

tectomies.

0 0 Not applicable. No. Co-existing

common bile duct

stones were exclu-

sion criteria.

Lo 1998 More

than 300 laparo-

scopic cholecys-

tectomies.

0 0 Preoperative selec-

tive ERCP.

No.

ERCP = endoscopic retrograde cholangio-pancreatography

Table 2. Conversion and bile duct injury rates (Based on people who underwent surgery)

Study Conversion-ELC Conversion -DLC Conversion-

crossover

Bile duct injury-

ELC

Bile duct injury-

DLC

Davila 1999 1/27 (3.7%) 6/36 (16.7%) 4/5 (80%) 0/27 (0%) 1/36 (2.8%)

Johansson 2003 23/74 (31.1%) 20/69 (29%) 10/18 (55.5%) 0/74 (0%) 1/69 (1.4%)

Kolla 2004 5/20 (25%) 5/20 (25%) Not applicable. 1/20 (5%) 0/20 (0%)

Lai 1998 11/53 (20.8%) 11/46 (23.9%) 2/8 (25%) 0/53 (0%) 0/46 (0%)

Lo 1998 5/48 (10.4%) 9/45 (20%) 2/9 (22.2%) 0/48 (0%) 1/45 (2.2%)

All studies 45/222 (20.3%) 51/216 (23.6%) 18/40 (45%) 1/222 (0.5%) 3/216 (1.4%)

ELC = early laparoscopic cholecystectomy

DLC = delayed laparoscopic cholecystectomy

Table 3. Odds ratio and risk difference (95% Confidence intervals)

Outcome Fixed,

ITT

Random,

ITT

Fixed/

available

case

Random/

available

case

Good

quality,

fixed

“Zero”,

Kt+Kc=1 (

Sweeting

2004)

“Zero”,

Kt+Kc=0.

1

(Sweeting

2004)

“Zero”,

Kt+Kc=0.

01

(Sweeting

2004)

Risk

difference

Bile duct

injury

0.63 [0.15,

2.70]

0.61 [0.12,

3.07]

0.61 [0.14,

2.62]

0.59 [0.12,

2.98]

0.70 [0.14,

3.63]

1.47 [0.32,

6.70]

1.12 [0.09,

13.50]

1.02 [0.07,

15.91]

-0.01 [-0.

03, 0.02]

Bile leak

requiring

ERCP

5.78 [1.00,

33.29]

5.03 [0.83,

30.48]

5.55 [0.96,

31.94]

4.82 [0.80,

29.21]

5.78 [1.00,

33.29]

1.91 [0.57,

6.40]

17.3 [0.76,

391.37]

171.2 [0.

01,

0.03 [0.00,

0.06]



Table 3. Odds ratio and risk difference (95% Confidence intervals) (Continued)

2494435.

29]

Intra-

abdominal

collections

requiring

drainage

1.86 [0.56,

6.18]

1.91 [0.55,

6.63]

1.91 [0.62,

5.88]

1.85 [0.53,

6.41]

2.34 [0.60,

9.19]

Not appli-

cable

Not appli-

cable

Not appli-

cable

0.02 [-0.

01, 0.05]

Superficial

infections

1.39 [0.56,

3.44]

1.38 [0.54,

3.52]

1.33 [0.54,

3.29]

1.32 [0.52,

3.37]

1.24 [0.48,

3.23]

Not appli-

cable

Not appli-

cable

Not appli-

cable

0.01 [-0.

02, 0.05]

Deep

infections

0.43 [0.09,

1.98]

0.46 [0.10,

2.22]

0.41 [0.09,

1.88]

0.44 [0.09,

2.12]

0.43 [0.09,

1.98]

0.78 [0.24,

2.62]

0.43 [0.09,

2.08]

0.39 [0.08,

2.02]

-0.01 [-0.

04, 0.01]

Conver-

sions

0.84 [0.53,

1.34]

0.87 [0.55,

1.4]

0.79 [0.5,

1.25]

0.82 [0.51,

1.31]

0.94 [0.58,

1.51]

Not appli-

cable

Not appli-

cable

Not appli-

cable

-0.03 [-0.

10, 0.05]

ITT = intention-to-treat analysis


Table 4. Heterogeneity

Outcome Chi-square test Higgin’s I square

Bile duct injury 0.72 0%

Bile leak requiring ERCP 0.78 0%

Intra-abdominal collections requiring

drainage

0.58 0%

Superficial infections 0.86 0%

Deep infections 0.52 0%

Conversions 0.51 0%




Table 5. Subgroup analysis (Odds ratio - 95% Confidence intervals)

Outcome All studies ELC less than 4 days ELC (excluding column 3) Surgical experience 25 to

50 laparoscopic cholecys-

tectomy

Bile duct injury 0.63 [0.15, 2.70] 1.16 [0.15, 8.79] 0.32 [0.03, 3.16] 0.32 [0.01, 7.87]

Bile leak requiring ERCP 5.78 [1.00, 33.29] 3.15 [0.12, 82.16] 7.03 [0.86, 57.69] 7.03 [0.86, 57.69]

Intra-abdominal collec-

tions requiring drainage

1.86 [0.56, 6.18] 1.77 [0.33, 9.53] 2.18 [0.48, 9.90] 4.97 [0.57, 43.14]

Superficial Infections 1.39 [0.56, 3.44] 1.12 [0.19, 6.60] 1.50 [0.52, 4.31] 1.47 [0.40, 5.35]

Deep Infections 0.43 [0.09, 1.98] Not estimable 0.99 [0.20, 5.00] 0.63 [0.10, 3.88]

Conversions 0.84 [0.53, 1.34] 0.54 [0.18, 1.66] 0.93 [0.56, 1.54] 1.07 [0.61, 1.90]

ELC = early laparoscopic cholecystectomy

Table 6. Non-resolving or recurrent cholecystitis

Study Delayed laparoscopic

cholecystectomy

Emergency surgery in de-

layed group

Emergency surgery in de-

layed group (%)

Con-

version to open cholecys-

tecomy in the emergency

surgery in delayed group

Davila 1999 36 5 13.9% 4

Johansson 2003 71 18 25% 10

Kolla 2004 20 0 0% 0

Lai 1998 51 8 15.7% 2

Lo 1998 50 9 18% 2

Total 228 40 17.5% 18

Table 7. Operating time and hospital stay

Study Early-operating time Delay-operating time Early -hospital stay Delay-hospital stay

Minutes (Median) Minutes (Median) Days (Median) Days (Median)

Davila 1999 71 50 1.6 2.7



Table 7. Operating time and hospital stay (Continued)

Johansson 2003 98 100 5 8

Kolla 2004 104 (Mean) 93 (Mean) 4.1 (Mean) 10.1 (Mean)

Lai 1998 122.8 (Mean) 106.6 (Mean) 7.6 (Mean) 11.6 (Mean)

Lo 1998 135 105 6 11

A P P E N D I C E S

Appendix 1. Search Strategies

Database Period Search strategy used

The Cochrane Hepato-Biliary Group Con-

trolled Trials Register

November 2005 #1 laparoscop* or celioscop* or coelioscop* or ab-

dominoscop* or peritoneoscop*

#2 cholecystecto* or colecystecto*

#3 cholecystitis or colecystitis or colecistitis*

#4 #1 AND (#2 OR #3)

The Cochrane Central Register of Con-

trolled Trials in The Cochrane Library

(CENTRAL)

Issue 4, 2005 #1 laparoscop* or celioscop* or coelioscop* or ab-

dominoscop* or peritoneoscop*

#2 cholecystecto* or colecystecto*

#3 cholecystitis or colecystitis or colecistitis*

#4 CHOLECYSTECTOMY, LAPAROSCOPIC

(MeSH) - Explode

#5 CHOLECYSTITIS, ACUTE (MeSH) - Ex-

plode

#6 #1 AND (#2 OR #3 OR #4 OR #5)

MEDLINE (Pubmed) January 1987 to November 2005 #1 (randomized controlled trial [pt] OR controlled

clinical trial [pt] OR randomized controlled trials

[mh] OR random allocation [mh] OR double-blind

method [mh] OR single-blind method [mh] OR

clinical trial [pt] OR clinical trials [mh] OR (“clini-

cal trial” [tw]) OR ((singl* [tw] OR doubl* [tw] OR

trebl* [tw] OR tripl* [tw]) AND (mask* [tw] OR

blind* [tw])) OR (placebos [mh] OR placebo* [tw]

OR random* [tw] OR research design [mh:noexp])

NOT (animals [mh] NOT human [mh])

#2 ((laparoscop* OR celioscop* OR coelioscop*



(Continued)

OR abdominoscop* OR peritoneoscop*) AND

(cholecystecto* OR colecystecto*)) OR (cholecysti-

tis OR colecystitis OR colecistitis*) OR (CHOLE-

CYSTECTOMY LAPAROSCOPIC (MeSH) OR

CHOLECYSTITIS ACUTE (MeSH))

#3 #1 and #2

EMBASE (Dialog Datastar) January 1987 to November 2005 1.RANDOMIZED-CONTROLLED-TRIAL#.

DE.

2.RANDOMIZATION#.W..DE.

3.CONTROLLED-STUDY#.DE.

4.MULTICENTER-STUDY#.DE.

5.PHASE-3-CLINICAL-TRIAL#.DE.

6.PHASE-4-CLINICAL-TRIAL#.DE.

7.DOUBLE-BLIND-PROCEDURE#.DE.

8.SINGLE-BLIND-PROCEDURE#.DE.

9.1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8

10.RANDOM$ OR CROSSOVER$ OR CROSS-

OVER OR CROSS ADJ OVER OR FACTO-

RIAL$ OR PLACEBO$ OR VOLUNTEER$

11.(SINGLE OR DOUBLE OR TREBLE OR

TRIPLE) NEAR (BLIND OR MASK)

12.9 OR 10 OR 11

13.12 AND HUMAN=YES

14.laparoscop$ OR celioscop$ OR coelioscop$ OR

abdominoscop$ OR peritoneoscop$

15.cholecystect$ OR colecystect$

16.cholecystitis OR colecystitis OR colecistitis

17.CHOLECYSTECTOMY#.W..DE. AND LA-

PAROSCOPIC-SURGERY#.DE.

18.ACUTE-CHOLECYSTITIS#.DE.

19.14 AND 15

20.16 OR 17 OR 18 OR 19

21.13 AND 20

Science Citation Index Expanded ((http://

portal.isiknowledge.com/portal.cgi?

DestApp=WOS&Func=Frame)

January 1945 to December 2005 #1 TS=(laparoscop* or celioscop* or coelioscop* or

abdominoscop* or

peritoneoscop*)

#2 TS=(cholecystecto* or colecystecto*)

#3 TS=(cholecystitis or colecystitis or colecistitis*)

#4 #1 AND (#2 OR #3)

#5 TS=(random* OR blind* OR placebo* OR

meta-analysis)

#6 #4 AND #5



F E E D B A C K

Early versus delayed laparoscopic cholecystectomy

Summary

Date of Submission: 13-Feb-2007

Name: Groot Koerkamp

Email Address: [email protected]

Personal Description: Occupation resident general surgery, epidemiologist.

Feedback: The authors conclude that early laparoscopic cholecystectomy appears safe because no significant difference was found in

complication and conversion rate.

This is not a valid conclusion because the data is insufficiently powered to find such differences: the confidence intervals are very wide

and include over 6-fold differences in negative outcomes. If a 6-fold difference (lower border confidence interval of 0.15) is not unlikely

given the available evidence, you cannot conclude that you know that both strategies are equal: you don’t know! Absence of evidence

is not evidence of absence.

Submitter agrees with default conflict of interest statement:

I certify that I have no affiliations with or involvement in any organization or entity with a financial interest in the subject matter of

my feedback.

Reply

We thank Dr Groot Koerkamp for his comments.

The main reasons that delayed laparoscopic cholecystectomy has been preferred over early laparoscopic cholecystectomy is the fear of

increased bile duct injury risk and conversion to open cholecystectomy (although conversion is not considered a complication) during

early laparoscopic cholecystectomy. All the five trials included in our review reported the outcome ’bile duct injury’. The meta-analysis

showed an odds ratio of 0.63 (95% CI 0.15 to 2.70). Accordingly, there is no statistically significant difference. You are right that the

confidence interval is wide, ie, we cannot exclude that with the emergence of more data we could, one day, get evidence favouring one

strategy over the other.

In the Conclusions section, we have acknowledged the fact that the confidence intervals are wide and the benefits of early laparoscopic

cholecystectomy may have been overlooked indicating that the finding may be due to ’lack of evidence of effect’. However, with the

current evidence available, it appears that early laparoscopic cholecystectomy is at least as safe as delayed laparoscopic cholecystectomy.

We could not have made this conclusion if the bile duct injury rate was higher in early than delayed laparoscopic cholecystectomy

(whether statistically significant or not). At the same time, we could not have concluded that early laparoscopic cholecystectomy is safer

than delayed laparoscopic cholecystectomy as there is no statistical significance in the outcome. It may well be that early laparoscopic

cholecystectomy is better than delayed laparoscopic cholecystectomy with regards to reduced bile duct injury rate. However, until

further trials are available, it is not possible to come to this conclusion. In the interim, it is reasonable to conclude that early laparoscopic

cholecystectomy seems as safe as delayed laparoscopic cholecystectomy based on meta-analysis of five randomised clinical trials. If

expertise is available, there are other advantages in early laparoscopic cholecystectomy: decreased hospital stay and avoiding the exposure

of patients to the risks of gallstones during the waiting period.

We fully concert that absence of evidence is not evidence of absence of a difference between the two strategies. We may wish for more

data - but until they appear, we have to treat patients as continuously and evidence-based as possible.

Contributors

Kurinchi Gurusamy, primary author

14 February, 2007

London, UK



Early versus delayed laparoscopic cholecystectomy

Summary

Date of Submission: 26-Jul-2007

Name: Stefan Sauerland

Email Address: [email protected]

Personal Description: Occupation surgical researcher and meta-analyst

Feedback: This Cochrane review is a well-written and very informative piece of work. However, I have noticed one obvious mistake in

the tables, which requires correction. In table 8, the length of hospital stay for the delayed group of the Kolla trial is stated to be 6.1

days. In truth, the correct figure is 10.1 days. Only the standard deviation was 6.1 days. Therefore, the author’s summarizing statement

that “hospital stay was about three days shorter in the early group” seems too sceptical. In fact, three of the four fully published trials

(Lai, Lo, and Kolla) have shown larger reductions in hospital stay (4, 5, and 6 days, respectively).

Submitter agrees with default conflict of interest statement:

I certify that I have no affiliations with or involvement in any organization or entity with a financial interest in the subject matter of

my feedback.

Reply

Thank you for your comments. This has now been corrected.

Contributors

Kurinchi Gurusamy, primary author

28 July, 2007

London, UK

W H A T ’ S N E W

Last assessed as up-to-date: 9 August 2006.

Date Event Description

20 October 2008 Amended Converted to new review format.

H I S T O R Y

Protocol first published: Issue 3, 2005

Review first published: Issue 4, 2006



C O N T R I B U T I O N S O F A U T H O R S

K Gurusamy wrote the protocol, and is the lead author of the protocol and the review. He extracted data including the methodological

quality of the trials, performed the meta-analyses, and drafted the review.

K Samraj independently extracted data including the methodological quality of the trials and other data mentioned in the text.

D E C L A R A T I O N S O F I N T E R E S T

No potential conflict of interest.

I N D E X T E R M SMedical Subject Headings (MeSH)

Cholecystectomy, Laparoscopic [∗adverse effects]; Cholecystitis, Acute [∗surgery]; Randomized Controlled Trials as Topic; Time Factors

MeSH check words

Adult; Humans



Documents

1. Early Versus Delayed Laparoscopic Cholecystectomy for Acute